Clinical trial NCT05328297
Conditions: Bipolar Disorder
Sponsor: Janssen Pharmaceutica N.V., Belgium
Start date: 2022-06-03; Completion date: 2024-05-17
Enrollment: 116 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of JNJ-55308942 compared to placebo on symptoms of depression in participants with bipolar disorder (BD) in a major depressive episode (MDE) at Week 6.

Detailed description:

Arms: arm 1: Participants will receive a JNJ-55308942 capsule once daily for 6 weeks. arm 2: Participants will receive a matching placebo capsule once daily for 6 weeks.
Interventions: intervention 1: JNJ-55308942 intervention 2: Placebo
Intervention descriptions: intervention 1: JNJ-55308942 capsules will be administered orally. intervention 2: Matching placebo capsules will be administered orally.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 18 August 2023
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Randomized, Stratified, Double-blind, Placebo-Controlled Study to Investigate the
Efficacy, Safety and Tolerability of JNJ-55308942 in Bipolar Depression.
Short Title
A study to explore the efficacy ofJNJ-55308942
in the treatment of bipolar depression
Protocol 55308942BIP2001; Phase 2a
Amendment 5
JNJ-55308942
*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; Janssen Biopharma Inc.; 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).
IND: 152573
EudraCT NUMBER: 2021-004790-31
Status: 
Approved
Date: 
18 August 2023
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: EDMS-RIM-515350, 6.0
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.
NCT05328297


JNJ-55308942 
Clinical Protocol 55308942BIP2001 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 18 August 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 5 
18 August 2023
Amendment 4 
25 January2023
Amendment 3 
27 July 2022
Amendment 2 
4 July 2022
Amendment 1 
01-February-2022
Original Protocol 
02-September-2021
Amendment 5 (18 August 2023)
Overall Rationale for the Amendment: Antipsychotics approved for BD, however not effective for treating
the current major depressive episode, whether taken alone or in combination with a mood stabilizer may be
permitted. AiCure®services for medication compliance and meal intake are discontinued and replaced with
Q1.6 for medication reminders.  Vendor names are removed from the body of the protocol.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis;
Overall Design; 4.1
Overall Design; 4.2
Study Population;
and throughout
protocol
Modified text to include participantss taking an
antipsychotic alone or taking an antipsychotic and
a mood stabilizer. Participants taking an
antipsychotic and mood stabilizer may be
considered for eligibility upon investigator and
sponsor assessment.
Updated concomitant medications
to include antipsychotics approved
for BD that are not effective for the
participant’s current major
depressive episode, whether taken
alone or in combination with a
mood stabilizer.
1.1 Synopsis:
Secondary
Endpoints
Modified text to include participants with BD
taking an antipsychotic alone or taking a
combination of an antipsychotic and a mood
stabilizer.
Efficacy evaluation of JNJ-
55308942 compared to placebo to
include antipsychotics.
1.1 Synopsis
Overall Design; 4.1
Overall Design;
4.2 Blinding; Study
Phase/Periods,
Intervention Groups
Participants will enter the treatment period where
they will be randomly assigned to daily dose
administration with 
mg JNJ-55308942 or
placebo for 6 weeks, Day 1 up to and including the
last treatment visit, Day 43 +/- 1 day.
Clarification to ensure the study
drug is taken up to and including
the last treatment visit.
Throughout the
protocol,including
Schedule of
Activities and
footnotes.
Vendor names (AiCure®and Q1.6) removed and
replaced with Digital Health Asssessment app for
the medication compliance and reminders.
Footnotes (s) and (z) removed.
Applying best practice not to
include vendor details in the
protocol.
6.4.1 Medication
Adherence and
Reminder System;
8. Study Specific
Materials; 8.1.3
Double-blind
treatment phase
(Visit 2 to Visit 6);
8.6 Digital Health
Assessment;
Schedule of
Activities
AiCure® application removed throughout the
protocol.
AiCure services discontinued.
Meal intake is collected in the
eCRF.
The Digital Biomarker for US sites
discontinued.
C


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1.1 Synopsis 
Clinical Laboratory 
Tests; 9.4.3; Safety
Analyses; Clinical
Laboratory Tests
Removed summary of markedly abnormal results. 
Summarizing clinical labs using the
reference ranges is sufficient.
5.1 Inclusion 
Criteria 
Inclusion Criterion 5 modified to include 
participants taking an antipsychotic alone or taking 
a combination of an antipsychotic and a mood 
stabilizer. 
Participants taking a mood stabilizer and an 
antipsychotic may be considered for eligibility 
upon investigator and sponsor assessment.
Updated critiera to include
antipsychotics approved for BD
that are not effective for the
patient’s current major depressive
episode, whether taken alone or in
combination with a mood stabilizer.
5.2 Exclusion 
Criteria; Other 
Exclusions 
Added clinically stable as a status for participants 
successfully treated for HIV infection to be 
allowed in the study.
Clinically stable is acceptable for
eligibility.
5.2 Exclusion 
Criteria; Other 
Exclusions 
Added the status of clinically stable, removed the 
specifics of HCV and HCV RNA for infection 
treatment or recovery, added sponsor approval for 
eligibility if the participant is positive for hepatitis 
B surface antigen.
Added the possibility of a confirmatory PCR test if
the test results are ambiguous.
Clinically stable is acceptable for
eligibility.  Confirmatory PCR test
will support ambiguous results for
eligibility.
8. Study 
Assessments and 
Procedures 
The PCRS, MADRS (SIGMA), CGI-S and 
participant self-rating baseline assessment is to be 
performed predose.
Explicitly stating the order of
assessments for the study visits.
8. Study 
Assessments and 
Procedures; 
Schedule of 
Activities
Vital signs and 12-lead ECG, as well as C-SSRS 
and YMRS will be done pre-randomization on Day 
1, and will be done predose on Day 8, 15, 29 and 
43. 
Clarifying the procedures and
assessments to be done pre-
randomization at the baseline visit
versus pre-dose for treatment visits.
8. Study 
Assessments and 
Procedures; Study- 
Specific Materials
Added the Mood Stabilizer and Antipsychotic 
Eligibility Assessment form  
Form added as a part of the
investigator and sponsor
assessment for Inclusion Criteria 5
6.7 Concomitant 
Therapy; 10.6 
Appendix 6: 
Disallowed 
Concomitant 
Therapies 
For concomitant medication, added the permitted 
antipsychotics lurasidone, cariprazine, quetiapine, 
lumateperone, and olanzapine for the treatment of 
bipolar disorder. 
Updated to ‘Yes’ for episodic use (PRN) and ‘Yes’ 
for Continuous Use.
Updated concomitant medications
to include antipsychotics approved
for BD that are not effective for the
patient’s current major depressive
episode, whether taken alone or in
combination with a mood stabilizer.
10.6 Appendix 6: 
Disallowed 
Concomitant
Therapies
For concomitant medication, added fluticasone. 
No interaction effect for fluticasone
treatment.
Schedule of 
Activities 
Footnote (ac) added to clarify only a non-
confirmatory serology result for Hepatitis B, C
and/or HIV may require a confirmatory test to be
completed.
Clarify procedure for non-
confirmatory serology result.


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Status: Approved, Date: 18 August 2023
Footnote (ad) added for the completion of the 
Mood Stabilizer and Antipsychotic Eligibility 
Assessment form. 
Added ‘X’ for Day 43 RNA. 
Added +/- 1 day window for telephone visits 
Clinical judgement of the
investigator and sponsor to
document the eligibility outcome
for each patient with a combination
of an antipsychotic and a mood
stabilizer regimen for trial
participation.
Day 43 missing.
Window allowance applies to both
in clinic and telephone visits.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes 
were made.
Minor errors were noted.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 8
1. 
PROTOCOL SUMMARY..................................................................................................................... 9
1.1. 
Synopsis........................................................................................................................................... 9
1.2. 
Schema.......................................................................................................................................... 22
1.3. 
Schedule of Activities (SoA)........................................................................................................... 23
2. 
INTRODUCTION................................................................................................................................ 26
2.1. 
Study Rationale.............................................................................................................................. 26
2.2. 
Background.................................................................................................................................... 27
2.3. 
Benefit-Risk Assessment............................................................................................................... 33
2.3.1. 
Risks for Study Participation....................................................................................................... 33
2.3.2. 
Benefit-Risk Assessment for Study Participation ....................................................................... 34
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 34
4. 
STUDY DESIGN ................................................................................................................................ 37
4.1. 
Overall Design................................................................................................................................ 37
4.2. 
Scientific Rationale for Study Design............................................................................................. 41
4.2.1. 
Participant Input Into Design ...................................................................................................... 46
4.2.2. 
Study-Specific Ethical Design Considerations ........................................................................... 47
4.3. 
Justification for Dose...................................................................................................................... 47
4.4. 
End of Study Definition................................................................................................................... 48
5. 
STUDY POPULATION ...................................................................................................................... 48
5.1. 
Inclusion Criteria............................................................................................................................ 49
5.2. 
Exclusion Criteria........................................................................................................................... 52
5.3. 
Lifestyle Considerations................................................................................................................. 55
5.3.1. 
Meals and Dietary Restrictions................................................................................................... 55
5.3.2. 
Caffeine and Alcohol................................................................................................................... 55
5.4. 
Screen Failures.............................................................................................................................. 56
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 56
6.1. 
Study Intervention(s) Administered................................................................................................ 56
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 57
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 58
6.4. 
Study Intervention Compliance...................................................................................................... 59
6.4.1. 
Medication Adherence and Reminder System ........................................................................... 59
6.5. 
Continued Access to Study Intervention After the End of the Study ............................................. 60
6.6. 
Treatment of Overdose .................................................................................................................. 60
6.7. 
Concomitant Therapy..................................................................................................................... 61
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 62
7.1. 
Safety Data Review........................................................................................................................ 62
7.2. 
Discontinuation of Study Intervention ............................................................................................ 62
7.3. 
Protocol stopping criteria................................................................................................................ 63
7.4. 
Participant Discontinuation/Withdrawal From the Study................................................................ 63
7.4.1. 
Withdrawal From the Use of Research Samples ....................................................................... 64
7.5. 
Lost to Follow-up............................................................................................................................ 64
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 65
8.1. 
Study Procedures........................................................................................................................... 67


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8.1.1. 
Screening (Visit 1) ...................................................................................................................... 67
8.1.2. 
Baseline Visit (Visit 2; Study Day 1) ........................................................................................... 69
8.1.3. 
Double-blind Treatment Phase (Visit 2 to Visit 6)....................................................................... 69
8.1.4. 
Follow-up or Early Withdrawal Visit (Visit 7)............................................................................... 70
8.2. 
Screening Instruments ................................................................................................................... 70
8.2.1. 
MINI International Neuropsychiatric Interview with Borderline Personality Disorder
module ........................................................................................................................................ 70
8.2.2. 
P2RX7 GoF and LoF SNP Analysis ........................................................................................... 70
8.2.3. 
Antidepressant Treatment History Form-Short Form (ATHF-SF)............................................... 70
8.2.4. 
17-Item Hamilton Depression Rating Scale (HDRS17) ............................................................... 70
8.3. 
Efficacy Assessments .................................................................................................................... 71
8.3.1. 
Montgomery-Åsberg Depression Rating Scale (MADRS).......................................................... 71
8.4. 
Secondary Assessments................................................................................................................ 71
8.4.1. 
Clinical Global Impression—Severity scale (CGI-S) .................................................................. 71
8.5. 
Self-Rating Instruments.................................................................................................................. 71
8.5.1. 
Snaith-Hamilton Pleasure Scale (SHAPS) ................................................................................. 71
8.5.2. 
PROMIS—Ability to Participate in Social Roles and Activities................................................... 72
8.5.3. 
Patient Health Questionnaire-9 (PHQ-9).................................................................................... 72
8.5.4. 
Generalized Anxiety Disorder-7 (GAD-7)................................................................................... 72
8.6. 
Safety Assessments....................................................................................................................... 72
8.6.1. 
Physical Examinations................................................................................................................ 73
8.6.2. 
Vital Signs................................................................................................................................... 73
8.6.3. 
Electrocardiograms..................................................................................................................... 73
8.6.4. 
Clinical Safety Laboratory Assessments .................................................................................... 73
8.6.5. 
Pregnancy Testing...................................................................................................................... 74
8.6.6. 
Suicidal Ideation and Behavior Risk Monitoring ......................................................................... 74
8.6.6.1. 
Young Mania Rating Scale (YMRS)........................................................................................ 74
8.6.6.2. 
Columbia Suicide Severity Rating Scale (C-SSRS)................................................................ 74
8.6.6.3. 
Follow-up of Well-Being and Depression ................................................................................ 75
8.7. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 75
8.7.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 75
8.7.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 76
8.7.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 76
8.7.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 76
8.7.5. 
Pregnancy................................................................................................................................... 77
8.8. 
Pharmacokinetics........................................................................................................................... 77
8.8.1. 
Evaluations ................................................................................................................................. 78
8.8.2. 
Analytical Procedures................................................................................................................. 78
8.8.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 78
8.9. 
Genetics and Pharmacogenomics................................................................................................. 79
8.10. 
Biomarkers..................................................................................................................................... 79
8.11. 
Health Economics .......................................................................................................................... 80
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 80
9.1. 
Statistical Hypotheses.................................................................................................................... 80
9.2. 
Sample Size Determination ........................................................................................................... 80
9.3. 
Populations for Analysis Sets ........................................................................................................ 80
9.4. 
Statistical Analyses ........................................................................................................................ 81
9.4.1. 
Primary Endpoint(s).................................................................................................................... 81
9.4.2. 
Secondary Endpoint(s)............................................................................................................... 82
9.4.3. 
Safety Analyses.......................................................................................................................... 82
9.4.4. 
Other Analyses ........................................................................................................................... 84
9.5. 
Interim Analysis.............................................................................................................................. 85
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 86
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 86


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10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 89
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 91
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 91
10.3.2. 
Financial Disclosure.................................................................................................................... 94
10.3.3. 
Informed Consent Process ......................................................................................................... 94
10.3.4. 
Data Protection ........................................................................................................................... 95
10.3.5. 
Long-Term Retention of Samples for Additional Future Research ............................................ 96
10.3.6. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 96
10.3.7. 
Data Quality Assurance.............................................................................................................. 97
10.3.8. 
Case Report Form Completion................................................................................................... 98
10.3.9. 
Source Documents ..................................................................................................................... 98
10.3.10. Monitoring ................................................................................................................................... 99
10.3.11. On-Site Audits........................................................................................................................... 100
10.3.12. Record Retention...................................................................................................................... 100
10.3.13. Study and Site Start and Closure ............................................................................................. 101
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting............................................................................................................................... 102
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 102
10.4.2. 
Attribution Definitions................................................................................................................ 103
10.4.3. 
Severity Criteria........................................................................................................................ 103
10.4.4. 
Special Reporting Situations .................................................................................................... 103
10.4.5. 
Procedures ............................................................................................................................... 104
10.4.6. 
Product Quality Complaint Handling......................................................................................... 105
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 106
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ....................................................................... 107
10.6. 
Appendix 6: Disallowed Concomitant Therapies ......................................................................... 110
10.7. 
Appendix 7: Study Conduct During the COVID-19 Pandemic..................................................... 112
10.7.1. 
Guidance on Study Conduct During the COVID-19 Pandemic................................................ 112
10.7.2. 
Guidance Specific to this Protocol Related to the COVID-19 Pandemic ................................. 112
10.7.3. 
Study Conduct Related to COVID-19 Vaccine Deployment for NonCOVID-19 Clinical
Trials. ........................................................................................................................................ 114
10.8. 
Appendix 8: Protocol Amendment History................................................................................... 116
11. REFERENCES................................................................................................................................. 123
INVESTIGATOR AGREEMENT............................................................................................................... 125


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LIST OF IN-TEXT FIGURES
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 22


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1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Randomized, Stratified, Double-blind, Placebo-Controlled Study to Investigate the Efficacy, Safety and
Tolerability of JNJ-55308942 in Bipolar Depression.
A study to explore the efficacy of JNJ-55308942 in the treatment of bipolar depression.
Bipolar disorders (BD) are chronic, serious mood disorders that affect 45 million people worldwide. In a
publication by the National Institute of Mental Health (NIMH) in 2017, approximately 2.8% of adults in
the United States had BD the past year (NIMH Statistics 2017). Characterized by episodes of mania and
depression, it is often the depressive episodes that are most severe, common, and long-lasting. (Note, BD
type I and II are distinguished by mania in type I and hypomania in type II).
Unfortunately, depressive episodes in BD are difficult to treat, with currently approved options limited to
antipsychotics (e.g., lurasidone, cariprazine, lumateperone and quetiapine) or the olanzapine/fluoxetine
combination treatment. Of note, only one medication—quetiapine—is US Food and Drug Administration
(FDA) approved for bipolar II depression. It is estimated that patients with BD live 9 to 20 years less than
those without BD (Crump 2013, Chesney 2014). The extent to which this is a consequence of the disease,
the treatment, comorbidities, or all these factors combined, remains unclear. Nonetheless, there is a
desperate need for novel, safe treatments for this population.
JNJ-55308942 is a potent, selective, and brain penetrant antagonist of the adenosine triphosphate (ATP)
gated P2X7 receptor that is involved in the release of the proinflammatory cytokine, interleukin-1β (IL-1β)
(Solle 2001). Within the brain, IL-1β is thought to contribute to a neuroinflammatory  diathesis that is
involved in the pathophysiology of neuropsychiatric and neurodegenerative disorders (Bhattacharya 2018;
Chrovian 2014; Lord 2014; Sperlagh 2014). Therefore, JNJ-55308942 has potential for clinical application
in mood disorders, including BD.
Given this potential mechanism, it can further be hypothesized that participants with a Gain of Function
(GoF) single nucleotide polymorphism (SNP) mutation in the P2X7 receptor may be more likely to respond
to treatment. Conversely, those participants with a Loss of Function (LoF) SNP mutation in the P2X7
receptor would be less likely to respond to treatment. Therefore, patient enrichment based on SNP profile
may be a promising strategy for participant selection.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of depressionin 
participants with BD in a major depressive episode 
(MDE) at Week 6.
Change in Montgomery-Åsberg Depression Rating
Scale (MADRS) total score from baseline at Week
6.
Secondary Objectives of Special Interest
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of anhedonia 
Change in Snaith-Hamilton Pleasure Scale
(SHAPS) total score from baseline at Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of depression in 
participants with BD who are heterozygous or
Change in MADRS total score from baseline at
Week 6.


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Objectives 
Endpoints
homozygous for the 
 P2RX7 GoF SNP
(genetic subgroup analysis)
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of depression in 
participants with BD type I or BD type II
(diagnosis subgroup analysis)
Change in MADRS total score from baseline at
Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of depression in 
subgroups of patients with specific biomarker
profiles (biomarker subgroup analysis).
Change in MADRS total score from baseline at
Week 6.
Secondary
To evaluate the overall safety and tolerability of 
treatment with JNJ-55308942 as compared to 
placebo in participants with symptomatic BD over 
a treatment period of 6 weeks. 
Vital signs (pulse/heart rate [HR], systolic blood
pressure [SBP], diastolic blood pressure [DBP],
respiratory 
rate), 
clinical 
labs 
(chemistry,
hematology, urinalysis), Adverse Events, ECG,
Young Mania Rating Scale (YMRS) score,
Columbia Suicide Severity Rating Scale (C-SSRS)
score.
To evaluate the effect of JNJ-55308942 compared
to placebo on disease severity and improvement on
the Clinical Global Impression-Severity scale
(CGI-S)
CGI-S 
To 
evaluate 
pharmacokinetics 
(PK) 
of
JNJ-55308942 in participants with BD.
Plasma concentrations of JNJ-55308942.
To assess the effect of JNJ-55308942 on reduction
of symptoms associated with depression compared
to placebo as measured by self-rated outcomes.
PROMIS –Ability to Participate in Social Roles
and Activities, Patient Health Questionnaire-9
(PHQ-9), Generalized Anxiety Disorder 7 (GAD-
7) score.
To evaluate the impact of treatment with
JNJ-55308942 compared with placebo on response
(≥50% improvement in MADRS total score from
baseline) and remission (MADRS total score ≤12)
rates at Week 6.
Response (≥50% improvement in MADRS total
score from baseline) and remission (MADRS total
score ≤12) rates at Week 6.
To evaluate the efficacy of JNJ-55308942
compared to placebo on symptoms of depression in
a subgroup of patients with messenger ribonucleic
acid (mRNA) transcript levels at baseline that
exceed the median level for both P2RX7 and IL-1β.
Change in MADRS total score from baseline at
Week 6.
To evaluate the efficacy of JNJ-55308942
compared to placebo on symptoms of depression
in subgroups of participants with BD not taking
any mood stabilizer or antipsychotic, taking a
Change in MADRS total score from baseline at
Week 6.
CCI
CCI


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Objectives 
Endpoints
mood stabilizer alone, taking an antipsychotic
alone, and taking a combination of a mood
stabilizer and an antipsychotic (concomitant
medication subgroup analysis).
Exploratory
To explore the pharmacokinetic/pharmacodynamic 
(PK/PD) relationship between plasma exposure of 
JNJ-55308942, and efficacy and safety parameters
in patients with BD.
Exposure-response 
between 
exposure 
and
MADRS and selected safety events, as appropriate.
To explore the effect of JNJ-55308942 on PD- 
related biomarkers. 
Including, but not limited to, blood biomarkers
related to immune, inflammatory, hormonal,
metabolic, hypothalamic-pituitary-adrenal (HPA)
axis, P2X7 receptor and monocyte activity.
To explore the effect of pharmacogenomic
variations on the PK, efficacy, and safety of
JNJ-55308942.
Influence of genetic polymorphisms (e.g., 
1) on plasma exposure, as well as on efficacy
and safety measures.
To explore the effect of JNJ-55308942 compared
to placebo on the well-being of participants.
Self-Assessment of Well-Being (SAWB) outcome.
Hypothesis
The primary hypothesis that will be tested in this study is that JNJ-55308942, compared to placebo, results
in a significant improvement in the reduction of the symptoms of depression in participants with BD in a
MDE as assessed by change in MADRS total score from baseline at Week 6.
OVERALL DESIGN
This is a double-blind, randomized, stratified, placebo-controlled, parallel group, multicenter study. A total
of approximately 164 participants will be enrolled in this study to obtain approximately 132 completers.
The target study population includes participants of any gender, between 18 and 64 years of age inclusive,
with a Diagnostic and Statistical Manual of Mental Disorders – 5th  edition (DSM-5) diagnosis of BD
(types I or II) without current psychotic features as confirmed by the Mini International Neuropsychiatric
Interview (MINI) with Borderline Personality Disorder module. BD patients should be experiencing an
MDE that does not require either hospitalization or antidepressant medication.
Each potential participant must satisfy one of the three criteria listed below in order meet eligibility for the
study population.
 
Participants who are currently unmedicated and have not received any mood stabilizers or
antipsychotics for four weeks before screening.
 
Participants who are on a stable monotherapy regimen of one of the following mood stabilizers
(lithium, valproate forms [e.g., divalproex sodium], or lamotrigine) or one of the following
antipsychotics (lurasidone, cariprazine, quetiapine, lumateperone, or olanzapine) for four weeks
before screening.
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 
Participants who are on a stable adjunctive regimen of one of the following antipsychotics
(lurasidone, quetiapine, lumateperone, or olanzapine) and one of the following mood stabilizers
(lithium, or valproate forms [e.g., divalproex sodium]) may be considered for eligibility based on
the approved therapies in each market with  an eligibility assessment conducted between the
investigator and sponsor. Assessment of the stable adjunctive regimen of an antipsychotic and a
mood stabilizer will be conducted by the investigator and sponsor’s clinical judgement and
documented for each participant.  This regimen must be in place 4 weeks before screening.
The participant must be symptomatic as assessed using the 17-item Hamilton Depression Rating Scale
(HDRS17). Symptom intensity over the past week will be evaluated. Participants who are enrolled in the
study will continue on their current medication regimen, if applicable, throughout the study. No dose
changes are permitted from screening through the end of the study (until after the follow-up visit). No
concurrent use of antidepressants will be allowed (until after the follow-up visit).
For each participant, 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 post-treatment follow-up phase ofup to 2 weeks (Figure 1). Participants
will enter the treatment period where they will be randomly assigned to daily dose administration with
mg JNJ-55308942 or placebo for 6 weeks, Day 1 up to and including the last treatment visit, Day 43 +/-
1 day.  The study drug should be taken by the participant at every clinic visit during the treatment period.
Between approximately 1 to 2 weeks after administration of the last dose, participants will return to the
study site for a follow-up visit. The total study duration for each participant will be up to 12 weeks. There
will be 7 scheduled visits to the study site during the study, including screening, and follow-up visit.
For study visits, a window of±1 day will be allowed.
No study-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.
Eligibility Screening Examination (for all study participants)
After giving written consent for screening, participants will be screened between 28 days and 1 day prior
to the double-blind treatment phase to ascertain their eligibility for the study according to the inclusion and
exclusion criteria. Although the screening period allows for up to 4 weeks, shorter screening periods are
encouraged when possible. The assessments scheduled during the screening visit may be divided over
multiple days, according to operational and/or site/country-specific needs.
To ensure that a participant is part of the target study population, specific assessments are prioritized during
the screening period. These assessments must be administered on the first day of screening, and only if the
participant qualifies will the remainder of the assessments be performed/scheduled. These assessments will
be performed by a certified rater at the site. The priority screening procedures are as follows:
1. 
The MINI with Borderline Personality Disorder module.
a. 
The participant must meet criteria for a diagnosis of either BD type I or II.
b. The participant must not currently meet criteria for psychosis or psychotic disorder, borderline
personality disorder, antisocial personality disorder, eating disorder, or suicide behavior disorder.
c. 
The participant must not have ≥4 episodes of mood disturbances (e.g., mania, hypomania, or
depression) within the past 12 months.
2. 
The Structured Interview Guide for the HDRS17 (Structured Interview Guide for the HDRS17 [SIGH-
D]).
a. 
The participant must be in a current MDE with a total score >20 and with a score >2 on the
depressed mood item [question #1].
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b. SIGH-D is based on the HDRS17 and will be used in this study to perform the HDRS17 at screening
and at pre-randomization on Day 1, to confirm the participant continues to meet eligibility criteria.
3. 
The ATHF-SF: current and past antidepressant and antipsychotic treatments.
a. 
The participant must not have taken any disallowed medications (per appendix 6) during the 4
weeks prior to the screening visit. Disallowed medications include antidepressants.
b. Nonresponse to >4 treatments in the current episode is exclusionary. Of note, participants who
have been nonresponsive or inadequately responsive to electroconvulsive therapy (ECT) or
ketamine in the current episode will be excluded. Participants who received transcranial magnetic
stimulation (TMS), any transcranial electrical stimulation, including transcranial direct current
stimulation (tDCS), vagal nerve stimulation (VNS), and/or deep brain stimulation (DBS) within
6 weeks prior to randomization (assessed with the ATHF-SF at screening) will be excluded.
Newly initiated psychotherapy (defined as psychotherapy that was started within 4 weeks of the
screening visit and assessed with the ATHF-SF at screening) is also exclusionary.
If applicable, the Mood Stabilizer and Antipsychotic Eligibility Assessment form will be completed for
participants who are on a stable adjunctive regimen of an antipsychotic and a mood stabilizer for 4 weeks
before screening.
Once potential participants have met eligibility requirements for the MINI, SIGH-D, and ATHF-SF and the
Mood Stabilizer and Antipsychotic Eligibility Assessment form (if applicable), the remaining screening
procedures may be completed (see Sections 5.1 and 5.2 for details).
Participants will be screened to ascertain their eligibility for the study based on the presence of the GoF
P2RX7 mutation (for inclusion, must be 
 or 
 at 
nucleotide 
; 
) and the
absence of the LoF P2RX7 mutations (must be 
 or 
at rs
/nucleotide 
; 
 and
must be
at rs
/nucleotide
;
). In other words, participants will be excluded if they
have the presence of two copies of the LoF C allele at rs
 (i.e., exclude those with 
at nucleotide
), and/or one or more copies of the LoF  allele at rs
(i.e., exclude those with 
 or 
nucleotide 
). This assessment will include the collection of a blood sample. In case participants need
to be rescreened, this assessment does not need to be performed again.
Screening will also include assessment of study inclusion and exclusion criteria, medical history,
demographics, physical examination, psychiatric and safety evaluations, and standard laboratory tests. The
remaining assessments may be divided over multiple days, according to operational and/or site/country-
specific needs and may take place before or after the P2RX7 genotyping results and other laboratory results
become available.
Of note, although the SIGH-D will be used for study entry criteria, the MADRS will be used as the primary
endpoint. The Structured Interview Guide for the MADRS (SIGMA) is based on the MADRS and will be
used in this study to perform the MADRS. In order to protect against potential score inflation of the baseline
MADRS score, the inclusion criteria are based on the SIGH-D instead of the primary efficacy endpoint
(MADRS). Note, the first MADRS score will be obtained at randomization (pre-dose) in order to provide
the baseline score prior to treatment.
Double-blind Treatment Phase
The duration of the double-blind treatment phase is 6 weeks. Participants will visit the study center for a
baseline visit on Day 1 and receive the first dose of study intervention following randomization at the clinic.
On Day 1, after confirming the depressive state of the participant using the SIGH-D (HDRS17 total score
≥20 and with a score ≥2 on the depressed mood item [question #1]), and completing all assessments as
outlined in the schedule of activities (SoA), he/she will be randomly assigned to receive either treatment
with
 mg JNJ-55308942 or placebo once-daily in a 1:1 ratio for a 6-week treatment period. The SIGH-D
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(screening and pre-randomization on Day 1) will ideally be completed by the same qualified rater for a
given participant.
There will be 4 randomization stratification factors: BD type (I or II), country, P2RX7 GoF SNP genotype
(homozygous or heterozygous), as well as concomitant medicationuse (no mood stabilizer or antipsychotic,
a mood stabilizer alone, an antipsychotic alone, or a combination of a mood stabilizer and an antipsychotic).
Investigators and participants will remain blinded to response criterion and study intervention treatment
assignment for each participant.
During the double-blind treatment phase, the SIGMA (MADRS) and CGI-S will be completed by the same
qualified rater for a given participant. Exceptions should be discussed with and approved by the sponsor.
The sponsor can request a rater change based on quality concerns. The severity of depressive symptoms
will be assessed using the SIGMA (MADRS) at randomization (pre-dose) in order to provide the baseline
score prior to treatment and at subsequent visits to the study site.
Study intervention will be taken at home in the morning
mg JNJ-55308942 or placebo) at approximately
the same time (± 4 hours) each day, 30 minutes after the start of breakfast (maximum of 2 hours after the
start of breakfast). There is an exception on Day 1 where participants will receive the study intervention at
the study site after all baseline assessments have been completed.
On study visits 3, 4, 5, and 6, study intervention will be administered at the study site after the clinical lab
and PK samples have been collected and at approximately the same time (± 4 hours). Study intervention
will be dispensed at visits 2, 4, and 5 during this double-blind treatment period.  When the participant
returns to the site for visit 3, 4, 5 and 6, the participant will be administered the study intervention from the
bottle dispensed from the previous visit.
Of note, on study site visits 3, 4, 5, and 6, participants will be instructed to eat breakfast at home and come
to the site within 1 hour or less after completion of the meal. Inability to comply with these instructions
would not constitute a protocol violation, but the participants are encouraged to comply with these
instructions as closely as possible.
The well-being of the participant will be frequently tracked using an Digital Health Assessment app  to
monitor parameters such as, but not limited to, the pattern of sleep, energy level, and concentration level
via the SAWB Questionnaire. Additionally, the Digital Health Assessment app will alert the investigator
when a participant has indicated that their depression is ‘much worse’ or ‘very much worse’ when
answering weekly questions on depression.
The SHAPS will be administered once at baseline (pre-dose) and once at the end of the double-blind
treatment phase (after the final dose). Participants will complete the PROMIS  - Ability to Participate in
Social Roles and Activities and the PHQ-9 at baseline and once weekly, and the GAD-7 every two weeks.
As per SoA, the self-rating instruments will be administered at clinic visits or at home. For self-rating
instruments completed at home on paper, participants should complete these scales before the next clinic
visit and participants will receive notifications from the Digital Health Assessment app on their mobile
phones as reminders to complete these paper instruments.
Key safety assessments will include the monitoring of adverse events, physical examinations, vital signs
(e.g., blood pressure, pulse/heart rate, body  temperature), electrocardiogram (ECG), clinical laboratory
tests, emergence of mania (YMRS), and suicidal ideation (C-SSRS).
In addition, blood samples for PK, biomarker assessment, hormones (males only), and pharmacogenomics
(general SNPs and RNA) will be collected as per the SoA and use of concomitant medication will be
recorded.
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Status: Approved, Date: 18 August 2023
Follow-up Examination
Between 7 to 14 days after the last study visit, participants will return to the study site for a safety follow-
up visit. The procedures to be completed during the follow-up visit are listed in the SoA.
NUMBER OF PARTICIPANTS
Approximately 164 participants will be enrolled in this study.
INTERVENTION GROUPS AND DURATION
Study intervention will be taken at home in the morning (
mg JNJ-55308942 or placebo) at approximately
the same time (± 4 hours) each day 30 minutes after the start of breakfast (maximum of 2 hours after the
start ofbreakfast). There is an exception on Day 1 where participants will receive the study intervention at
the study site after all baseline assessments have been completed. On study visits 3, 4, 5 and 6, study
intervention will be taken at the study site after the clinical lab and PK samples have been collected and at
approximately the same time (± 4 hours). Study intervention will be dispensed at visits 2, 4 and 5 during
this double-blind treatment period. When the participant returns to the site for visit 3, 4, 5 and 6, the
participant will be administered the study intervention from the bottle dispensed from the previous visit.
The capsules must be swallowed whole and not chewed, divided, dissolved, or crushed.
The first dose of study intervention will be taken in the fed condition on Day 1 of the double-blind treatment
phase when the participant is at the study site.
On days when participants visit the study site, they should not take the study intervention at home before
arriving at the site. The participants will bring the study intervention with them at each study visit and will
take study intervention—from the bottle dispensed at the previous study visit—at the site in the fed
condition after completion of predose study assessments and blood collections. Dosing at the study site will
be witnessed by the study staff.
Description of Interventions
Group/Arm Name 
Active study intervention group  
Placebo group
Intervention name: 
JNJ-55308942 
Placebo for JNJ-55308942
Dosage formulation 
Capsule 
Capsule
Unit dose
strength(s)/
Dosage levels:
mg 
Not applicable
Dosage Level(s) and
Frequency
mg, 1 capsule once-daily  
1 capsule once-daily
Route of 
Administration 
☒Oral
☐IV infusion
☐IV injection
☐Intramuscular
☐Other
☒Oral
☐IV infusion
☐IV injection
☐Intramuscular
☐Other
Dosing instructions 
One capsule daily, preferably at the same
time, recommended to take each dose of
study intervention in the morning with a
glass of water 30 minutes after the start of
breakfast (max. 2 hours).
One capsule daily, preferably at the same
time, recommended to take each dose of
study intervention in the morning with a
glass of water 30 minutes after the start of
breakfast (max. 2 hours).
Use 
☒Experimental
☐Background intvn.
☐Challenge agent
☐Experimental
☒Placebo comparator
☐Active comparator
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☐Diagnostic 
☐Other 
☐Sham comparator
☐Rescue medication
☐Background intvn.
☐Challenge agent
☐Diagnostic
☐Other
Investigational 
Medicinal Product
(IMP)
☒Yes 
☐No 
☒Yes 
☐No
Non-Investigational 
Medicinal Product
(NIMP)
☐Yes 
☒No 
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Status: Approved, Date: 18 August 2023
ELIGIBILITYINSTRUMENTS
 
MINI International Neuropsychiatric Interview (MINI) with Borderline Personality Disorder module
 
The Antidepressant Treatment History Form-Short Form (ATHF-SF)
 
17-Item Hamilton  Depression Rating Scale (HDRS17) –administered via the Structured Interview
Guide for the HDRS17 (SIGH-D)
 
Determination of the allele variant for P2RX7 for 1 GoF P2RX7 SNP and 2 LoF P2RX7 SNPs.
 
If applicable, the Mood Stabilizer and Antipsychotic Eligibility Assessment form
EFFICACYEVALUATIONS
 
Montgomery-Åsberg Depression Rating Scale (MADRS) –administered via the Structured Interview
Guide for the MADRS (SIGMA)
OTHER CLINICIAN ADMINISTERED EVALUATIONS
 
Clinical Global Impression - Severity scale (CGI-S)
SELF-RATING INSTRUMENTS
 
Snaith-Hamilton Pleasure Scale (SHAPS)
 
PROMIS –Ability to Participate in Social Roles and Activities
 
Patient Health Questionnaire (PHQ-9)
 
Generalized Anxiety Disorder 7 (GAD-7)
 
Self-Assessment of Well-Being (SAWB)
PHARMACOKINETIC EVALUATIONS
Venous blood samples will be collected for PK evaluation as indicated in SoA. Samples will be used to
evaluate the plasma concentrations of JNJ-55308942 and metabolites (if required). In addition, some
samples may be used to measure plasma concentrations of concomitant medications used by the participant.
Participant confidentiality will be maintained.
BIOMARKER EVALUATIONS
Venous blood samples for the assessment of whole blood, serum, and plasma PD-related biomarkers
potentially including, but not limited to, immune, inflammatory, hormonal, metabolic, and HPA axis
activity will be collected as indicated in the SoA during the double-blind treatment phase. Samples may
also be used to study markers of P2RX7 and monocyte activation. Blood samples will be collected as
indicated in the SoA for gene expression analysis.
All PD-related biomarker data obtained during this study may be included in ongoing cross-study analyses
to investigate the relationship between depression severity, phenotypes, and biomarkers, or to help explain
interindividual variability in clinical outcomes or safety. Biomarker assays 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.
GENETIC AND PHARMACOGENOMIC EVALUATIONS
A blood sample will be collected during the screening period to assess whether the participant:


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1. 
is carrier of the
 GoF P2RX7 mutation (must be 
 or 
at 
nucleotide 
for inclusion).
2. 
is not a carrier of the 
or 
LoF P2RX7 mutations (must be 
 or 
 at
rs
/nucleotide 
; and must be 
 at rs
/nucleotide 
 In other words,
participants will be excluded if they have the presence of two copies of the LoF C allele at rs
(i.e., exclude those with
at nucleotide
), and/or has one or more copies of the LoF  allele at
rs
 (i.e., exclude those with
or 
nucleotide
An additional optional pharmacogenomic blood sample will be collected from enrolled participants on
Day 1 to identify genetic factors that may influence the PK, PD, efficacy, safety and/or tolerability of
JNJ-55308942 and to identify genetic factors associated with BD. If collection on Day 1 is not feasible, it
can be collected on any other visit during the double-blind treatment phase.
SAFETYEVALUATIONS
Adverse events (AEs) will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant’s legally acceptable representative) from obtaining the screening informed consent
through the day of last dose plus 30 days. There are no AEs of special interest.
The following safety assessments will be performed: physical examination, body weight, vital signs
(including oral, tympanic or temporal temperature, blood pressure, pulse/heart rate and respiratory rate),
12-lead electrocardiogram (ECG), urine drug testing, alcohol breath test, pregnancy testing (female
participants only), hormones, and clinical labs (hematology, chemistry panel and urinalysis) as per SoA. In
addition, serology and hemoglobin A1c (HbA1c) assessments will be performed at screening only.
Emergence of mania will be assessed using the YMRS at each visit.
Emergence of suicidal ideation will be assessed using the C-SSRS at screening and during each visit. The
Digital Health Assessment app will alert the investigator when a participant has indicated that the
depression is ‘much worse’ or ‘very much worse’ when answering weekly questions on depression.
STATISTICAL METHODS
Sample Size
The estimated sample size of 164 participants (82 participants per group) was determined based on the
assumption of an effect size of at least 0.45 for the MADRS total score (difference in mean change from
baseline at Week 6 between the JNJ-55308942 and placebo groups of 3.9 units with a standard deviation
of 8.6). This is considered to be a clinically relevant difference in a population with BD types I or II. The
standard deviation of 8.6 in the change in MADRS total score from baseline is a reasonable assumption
based on data in a published phase 3 study of quetiapine in BD type I and type II depression
(Calabrese 2005). Power is set at 90%, with a 1-sided alpha of 0.10 and a 6-week drop-out rate of 20%. The
estimated number of completers to be included in the primary analysis is 132.
Efficacy Analyses
The full analysis set (FAS) will include all randomized participants who receive at least 1 dose of study
intervention and have both the baseline and at least 1 post-baseline MADRS measurement. Efficacy
analyses will be based on the FAS.
The estimand for the primary efficacy analysis is defined with the following 5 attributes:
 
Population: participants with BD types I or II in an MDE.
 
Endpoint: change from baseline in the MADRS total score at Week 6.
 
Treatment: JNJ-55308942
 mg once-daily versus placebo.
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 
Population-level summary: the difference in mean change from baseline in MADRS total score at
Week 6 between JNJ-55308942
 mg once-daily and placebo.
 
Intercurrent events (ICE) and corresponding strategy: The ICE to be considered is discontinuation of
study intervention. The ICE will be addressed with a hypothetical strategy, targeting the effect ofthe
initially randomized treatment that would have been observed had all participants remained on their
treatment throughout the double-blind treatment phase.
The primary efficacy analysis will be performed utilizing the hypothetical estimand defined above. The
change from baseline in MADRS total score will be compared between the JNJ-55308942
mg once-daily
group and the placebo group at Week 6 in a mixed-effects model using repeated measures (MMRM), with
time, treatment (placebo or JNJ-55308942), BD type (I or II), country, concomitant medication status (no
mood stabilizer or antipsychotic, a mood stabilizer alone, an antipsychotic alone, or a combination of a
mood stabilizer and an antipsychotic), P2RX7 GoF SNP genotype (homozygous or heterozygous) and time-
by-treatment interaction as factors, with baseline MADRS total score as a continuous covariate. Data after
treatment discontinuation is considered as missing. An unstructured variance-covariance matrix will be
used. In case of convergence problems, alternative variance-covariance structures will be attempted in the
following order, with the first structure that converges being used in the analysis: heterogeneous Toeplitz,
standard Toeplitz, and first order autoregressive. Kenward-Roger approximation will be used to estimate
the denominator degrees of freedom. Sandwich estimator will be used to address the potential
misspecification of the covariance matrix when a structured covariance matrix is used due to the
convergence problem with the unstructured covariance matrix. The comparison of JNJ-55308942 
mg
once-daily versus placebo will be performed using appropriate contrast.
To support the primary efficacy analysis, two sensitivity analyses will be performed:
 
MMRM analysis with copy-reference multiple imputation where missing outcomes due to treatment
discontinuation in the JNJ-55308942 
mg once-daily group is assumed to be similar to those in the
placebo group.
 
Tipping point analysis that imputes missing outcomes over a range of possible scenarios for the
treatment effect and finds a ‘tipping point’ where the treatment effect in participants with missing data
overturns the significant treatment effect. This analysis will be performed if the results from the
primary analysis show a significantly greater improvement in the MADRS total score at Week 6 in the
JNJ-55308942
 mg once-daily group compared to the placebo group.
Response and remission rates with respect to MADRS will be summarized by treatment group and by
scheduled timepoint.
For the Secondary Objectives of Special Interest, change from baseline in SHAPS total score at Week 6
will be compared between JNJ-55308942
mg once-daily and placebo in an ANCOVA model. The model
will include intervention (placebo or JNJ-55308942), BD type (I or II), country, concomitant medication
status (no mood stabilizer or antipsychotic, a mood stabilizer alone, an antipsychotic alone, or a
combination of a mood stabilizer and an antipsychotic), P2RX7 GoF SNP  genotype (homozygous or
heterozygous) as factors, and baseline SHAPS total score as a covariate. Comparison between JNJ-
55308942 
 mg once-daily and placebo will be performed using appropriate contrasts. Change from
baseline in MADRS total score at Week 6 will be assessed with confidence intervals in subgroups for BD
type (I or II), P2RX7 GoF SNP  genotype (heterozygous or homozygous), and patients with specific
biomarker profiles (yes or no) using a similar MMRM as the one used for the primary endpoint analysis.
For other Secondary Objectives, similar MMRM analyses will be conducted for changes in T-score of
PROMIS –Ability to Participant in Social Roles and Activities, the PHQ-9 total score, and the GAD-7 total
score. Subgroup analyses by mRNA transcript (P2RX7 and IL-1β) level status at baseline (yes or no) and
use of concomitant medication (no mood stabilizer or antipsychotic, a mood stabilizer alone, an
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antipsychotic alone, or a combination of a mood stabilizer and an antipsychotic) will also be assessed with
confidence intervals using a similar MMRM.
For the CGI-S efficacy endpoint, a frequency distribution of severity scores will be provided by treatment
group from Week 1 to Week 6. In addition, frequency of shifting scale at Week 6 from baseline will be
provided.
Descriptive statistics will be provided for the SAWB assessments.
Safety Analyses
Statistical analysis of the safety data will be done by the sponsor or under the authority of the sponsor.
Specific details will be provided in the statistical analysis plan (SAP).
All safety analyses will be performed based on the safety analysis set, which will include all randomized
participants who receive at least 1 dose of study intervention. Safety summaries will be provided by
treatment, unless specified otherwise.
Adverse Events
The verbatim terms used in the case report form (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 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 post-
treatment cross-tabulations (with classes for below, within, and above normal ranges).
Electrocardiogram (ECG)
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).
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 (males), >470 (females), >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. Also, descriptive statistics of QTc will be provided by gender.


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Vital Signs
Descriptive statistics of body temperature, pulse/heart rate, supine blood pressure, and respiratory rate
values and changes from baseline will be summarized at each scheduled time point. The percentage of
participants with values outside clinically relevant 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.
Young Mania Rating Scale (YMRS)
Exploratory analyses will be performed for changes from baseline in YMRS total score and for changes
from baseline in individual YMRS items by treatment group for all participants receiving at least 1 dose of
study intervention. Details will be provided in the SAP.
Columbia Suicide Severity Rating Scale (C-SSRS)
Results from the C-SSRS will be tabulated by treatment group for all participants receiving at least 1 dose
of study intervention.
Interim analysis
No interim analysis is planned.
It may be recommended that an unblinded data review needs to be performed by an independent reviewer
(e.g., data review committee) if deemed critical by the Janssen clinical team. Committee membership
responsibilities, authorities, and procedures will be documented in a charter.


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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
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1.3. 
Schedule of Activities (SoA)


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2. 
INTRODUCTION
Bipolar disorders (BD) are chronic, serious mood disorders that affect 45 million people
worldwide. In a publication by the National Institute of Mental Health  (NIMH) in 2017,
approximately 2.8% of adults in the United States had BD the past year (NIMH Statistics 2017).
Characterized by episodes of mania and depression, it is often the depressive episodes that are
most severe, common, and long-lasting. (Note, BD type I and II are distinguished by mania in type
I and hypomania in type II).
Unfortunately, depressive episodes in BD are difficult to treat, with currently approved options
limited to antipsychotics (e.g., lurasidone, cariprazine, lumateperone, and quetiapine) or the
olanzapine/fluoxetine combination treatment. Of note, only one medication—quetiapine—is US
Food and Drug Administration (FDA) approved for bipolar II depression.
It is estimated that patients with BD live 9 to 20 years less than those without BD (Crump 2013,
Chesney 2014). The extent to which this is a consequence of the disease, the treatment,
comorbidities, or all these factors combined, remains unclear. Nonetheless, there is a desperate
need for novel, safe treatments for this population.
JNJ-55308942 is a potent, selective, and brain penetrant antagonist of the adenosine triphosphate
(ATP) gated P2X7 receptor that is involved in the release of the proinflammatory cytokine,
interleukin-1β (IL-1β) (Solle 2001). Within  the brain, IL-1β is thought to contribute to a
neuroinflammatory diathesis that is involved in the pathophysiology of neuropsychiatric and
neurodegenerative disorders (Bhattacharya 2018; Chrovian 2014; Lord 2014; Sperlagh 2014).
Therefore, JNJ-55308942 has potential for clinical application in mood disorders, including BD.
Given this potential mechanism, it can further be hypothesized that participants with a Gain of
Function (GoF) single-nucleotide polymorphism (SNP) in the P2RX7gene may be more likely to
respond to treatment. Conversely, those patients with Loss of Function (LoF) SNPs in the P2RX7
gene would be unlikely to respond to treatment.
For the most comprehensive nonclinical and clinical information regarding JNJ-55308942, refer
to the latest version of the Investigator’s Brochure (IB) for JNJ-55308942.
The term “study intervention” throughout the protocol, refers to study drug as defined in
Section 6.1, Study Interventions Administered.
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.
2.1. 
Study Rationale
JNJ-55308942 is a selective, brain penetrant P2RX7 receptor antagonist. Nonclinical and clinical
literature suggest that P2RX7 receptor antagonism may have clinical utility in the treatment of BD.
In this study, we will investigate the effect of JNJ-55308942 in outpatients with BD Types I or II
who are in a current major depressive episode (MDE). This study is being performed to collect


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initial efficacy and safety signals in this patient population, which will guide the further
development of JNJ-55308942.
2.2. 
Background
Nonclinical Studies
Pharmacologic Profile
A calcium flux assay showed JNJ-55308942 to be a potent antagonist at the human, rat, mouse,
dog, and monkey P2X7 receptor orthologues. In human blood and monocytes, the compound
attenuated IL-1β release with potencies (pIC50) of 7.7±0.2 and 7.2±0.1, respectively.
Ex vivo P2X7 receptor occupancy (RO) studies of JNJ-55308942 after oral 10 mg/kg dose
administration in rats indicated that maximal levels of brain P2X7 receptor occupancy occurred at
minutes (94%±4%) and that high occupancy levels (>80%) were maintained up to  hours after
compound administration. The concentration of JNJ-55308942 producing 50% (EC50) and 90%
(EC90) of maximal effect in rats are
ng/mL, and 
 ng/mL, respectively.
Clear functional inhibition of central P2X7 receptors was demonstrated in an in vivo brain
microdialysis assay in freely moving rats. Orally administered JNJ-55308942, significantly
suppressed brain IL-1β release resulting from challenge with the P2X7 receptor agonist
benzoyl-ATP (BzATP).
JNJ-55308942 dampened microglial activation in a mouse model of lipopolysaccharide
(LPS)-induced neuroinflammation. In a model of chronic mild stress in rats, anhedonic-like
behavior (i.e., reduction in sucrose intake) observed in stressed animals was reversed by
JNJ-55308942. JNJ-55308942 was also efficacious in a mouse model of neuroinflammation
associated depressive behaviors. The active doses in both models would result in high (>80%)
occupancy of P2X7 receptors in the brain.
JNJ-55308942 is highly selective for the P2X7 receptor: no relevant binding at a broad panel of
ion channels, enzymes, and receptors (at 10 µM) and no activity was seen when against tested
kinases (at 1 µM). In addition, no activity was seen at other human P2X receptor subtypes when
tested at concentrations of up to 100 µM.
Safety Pharmacology
The cardiovascular safety of JNJ-55308942 was extensively tested in several in-vitro and in-vivo
models. In human Ether-à-go-go-Related Gene (hERG)-transfected human embryonic kidney
cells 293 (HEK293) cells, expressing hERG potassium channels, the IC50 for potassium current
inhibition was 
µM, indicating a very low risk for electrocardiogram (ECG) effects or
arrhythmogenic events. This was confirmed in perfused rabbit ventricular wedge preparations, an
anesthetized guinea pig model, and in anesthetized and conscious dog studies, in which no ECG
abnormalities were identified up to the highest concentrations/doses tested. Cardiovascular effects
observed in these models were hemodynamic in nature. In the anesthetized guinea pig, increases
in mean arterial blood pressure were seen at plasma concentrations >
µg/mL and in the freely
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moving telemetered dog, systolic blood pressure increased, and heart rate decreased transiently at
doses of
mg/kg (mean C6.5h  =
µg/mL) and higher. Mild hemodynamic changes were also
seen in anesthetized dogs at plasma exposures >
µg/mL. In rats, single oral dosing up to
mg/kg did not affect respiratory parameters, however, in combination with isoflurane
anesthesia 2-4 hours the maximal tolerated dose was 
mg/kg (plasma exposures [Cplasma] =
μg/mL at 2 hours and 
µg/mL at 4 hours).
A neurobehavioral safety assessment in rats showed a transient effect on defecation frequency and
body temperature at plasma exposures of
 µg/mL. At plasma exposures >
µg/mL, more
pronounced adverse effects on motor-affective, sensory motor, and autonomic responses were
identified and at the highest dose tested of 500 mg/kg (Cplasma =
µg/mL), 1 rat was euthanized
because of clonic convulsions. In all other animals, all observations were reversible.
Toxicology
In single oral dose experiments in dogs, doses up to
mg/kg were tested and no mortality was
observed. In rat studies, doses as high as 
mg/kg were given, but mortality occurred at
≥
mg/kg. In the Irwin’s test, 1 rat dosed with
mg/kg was euthanized after showing clonic
convulsions. In mice, doses ≥
mg/kg were associated with mortality.
The toxicity profile after chronic, oral administration of JNJ-55308942 was further assessed in
repeated dose (RD) GLP toxicity studies with a maximum treatment duration of 9 months in dogs
and 6 months in rats.
In the dog studies, organ changes were mostly seen at the 
 These changes were mainly
histological in nature. Microscopic examination showed 
and 
 in all dose groups, indicating the 
 The
 sometimes resulted in increased
 At dose
levels considered non-adverse, these 
 changes were sometimes accompanied by minimal to
mild and reversible increases in 
 and 
]). Furthermore, 
) inclusions were observed in the 
of several
treated animals. The ultrastructural characteristics of these inclusions strongly suggest that they
are composed of 
. It can be assumed that the
, the 
 appearance, and the 
 are all part of the same adaptive process. Dose levels where the
 changes were
limited to the above description, were considered non adverse.
At higher dose levels, these adaptive, non-adverse 
 findings evolved to changes that were
considered adverse because they were associated with more pronounced increases in
 and/or resulted on adverse effects on
 and
.
In the 1-month dog study doses >
mg/kg/day led to severe toxicity with 
 evidence of 
 and 
 and 
 In the 9-month dog
study, the no observed adverse effect level (NOAEL) was
mg/kg/day. At the NOAEL, the mean
Cmax and AUC0-24h  values for males were 
µg/mL and
µg.h/mL
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In rats, the main organs of toxicity were the 
 in females and the 
in males.
At the 
 of female rats dosed for 6 months at
mg/kg/day, 
 and hyperplasia of the
 were found. These findings
showed an ongoing recovery after 3 months (presence of
in the region affected
by the
, representing
from a previous
 No
 changes were
seen in male rats, probably because of the difference in high dose between female and male rats
mg/kg/day in females and
mg/kg/day in males). It is possible that these changes represent
a localized effect of the test item and dosing procedure (i.e., deposition of the test item in the
stomach by gavage). The NOAEL for the adverse 
changes in female rats was
mg/kg/day (AUC0-24h  = 
µg.h/mL; ie. 
fold the AUC at the anticipated clinically
efficacious exposure).
 toxicity was seen in the Sprague-Dawley male rat during the 1-, 3- and 6-month toxicity
studies (lowest observed effect level [LOEL] of 
 mg/kg/day), but not in the 1-, 3-, or 9-month
toxicity studies in dogs (while exposures were higher than the LOEL in rats). In short: 1-month
dosing ≥
mg/kg/day resulted in a dose-related increased incidence of 
 with
secondary findings of lower numbers of
 and 
 morphology in
the 
. This bilateral finding showed full recovery after 1 month. The no observed
effect level (NOEL) for the finding in the 1-month study was 
mg/kg/day. In the follow-up
3- and 6-month studies, 
 changes comprised 
, and marked to severe 
.
Concurrently, there were secondary changes at the 
 of affected animals. As in the
1-month study, the NOEL for 
changes was 
mg/kg/day; the LOEL in the 6-month
study was
mg/kg/day. Following the 3-month recovery period, there was no reversibility of the
findings in the
 and 
 in males. There were no effects on 
(
 and
 in males or on female 
Pharmacokinetic andMetabolism Profile
Following a single intravenous (IV) administration, plasma clearance in mice, rats, dogs, and
monkeys was 
 relative to hepatic blood flow (
% to %), with a 
 volume of
distribution. Elimination and clearance were approximately
fold reduced in dogs compared to
mice, rats, and monkeys.
Following single oral dosing, 
absorption was observed in rats, dogs, and monkeys (time to
reach the maximum plasma concentration [Tmax]
hours). The absolute bioavailability was
(
% to
%).
After 6 months dosing in the rat GLP study, exposure (maximum plasma concentration [Cmax] and
area under the concentration time curve from 0 to 24 hours [AUC0-24h]) generally increased close
to dose proportionally from
to
mg/kg in males, and less than dose proportionally from 
to
 mg/kg in females. No relevant change in exposure was seen after repeated dosing at all dose
levels in males, whereas in females, exposure increased at all dose levels after repeated
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administration. After 9 months of dosing in the dog GLP study, exposure generally increased dose
proportionally from 
to
mg/kg and more than dose proportionally from  to 
 mg/kg. No
clear sex differences were observed.
In a 14-day mouse study, exposure (Cmax and AUC0-24h) increased in a generally dose proportional
manner from 
 to 
 mg/kg/day following a single dose and after repeat dosing for 14 days in
males. Females were only dosed at 
mg/kg/day. On Day 14, exposure was slightly higher in
females than in males at that dose.
In vitro plasma protein binding was 
 in all species (unbound fraction: 
% in mouse, 
% in
monkey,
% in dog, 
% in human, and 
% in rat).
In vivo tissue distribution in rat after single oral administration of  mg/kg showed differential
distribution, with tissue to plasma ratios ranging from 
 (brain) to 
 (liver). Quantitative
whole-body  autoradiography (QWBA) in rat confirmed wide distribution of radioactivity
throughout the body -hour postdose, which was mostly eliminated within
-hour postdose.
There was no specific affinity to melanin.
The main metabolic pathway in human hepatocytes was the ring opening of the pyridine with
formation of the carboxylic acid (major metabolite) and the primary alcohol. Acyl glucuronide
isomers were also observed. Formation of a glutathione conjugate was also observed, as well as
multiple additional minor metabolites.
All human in vitro metabolites were observed in rat and/or dog hepatocytes or in vivo in rat with
the exception of 2 minor in vitro metabolites.
In rats and dogs, JNJ-55308942 clearance was mainly mediated by metabolism.
In human hepatocytes in vitro, the oxidative metabolism of JNJ-55308942 was mediated mainly
by cytochrome P450 (CYP)3A4; 
-P1-1 was also involved, the relative contribution of
 vs
is unclear.
In vitro, moderate inhibition of CYP
 was seen (IC50 =
µM in human liver microsomes)
with no inhibition of other isoforms (IC50 values >100 µM). No time-dependent inhibition of
CYP
 (IC50 >10 µM) was observed. In human liver microsomes, JNJ-55308942 was not an
inducer of CYP
 or CYP
activity but was an inducer of CYP
 and CYP
 messenger
ribonucleic acid (mRNA) at concentrations of ≥10 µM in human hepatocytes in vitro.
JNJ-55308942 is not a substrate of
, and 
.
JNJ-55308942 shows limited inhibitory potential towards 
 (
µM< IC50 
 µM),
 (
µM< IC50 <
 µM), 
(IC50 = 
 µM), 
 (
 µM <IC50
<
µM), 
 (IC50 >
µM), 
 (IC50 = 
µM), 
 (
µM< IC50 <
µM), 
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(IC50 = 
 µM), 
 (IC50 >
 µM). Based on this, no transporter mediated interaction
is expected at a dose of
mg once-daily.
Clinical Studies
To date, JNJ-55308942 has been tested in 3 Phase 1 clinical studies: 55308942EDI1001 (part 1
[SAD]: n=62; part 2 [MAD]: n=36), 55308942EDI1002 (part 1: n=9; part 2: n=3), and
55308942EDI1003 (n=14).
Study 55308942EDI1001 consisted of 2 parts: a single ascending dose (SAD) and food effect part
(Part 1), followed by a multiple ascending dose (MAD) part (Part 2) in healthy male and female
participants.
Study 55308942EDI1002 was an open-label positron emission tomography (PET) study in healthy
male participants to investigate P2X7 receptor occupancy (RO) by JNJ-55308942 using
[18F]-JNJ-64413739. Part 1 investigated the occupancy of P2X7 receptors in the human brain and
gut at Tmax  after a single dose of JNJ-55308942 solution using [18F]-JNJ-64413739. Part 2
investigated receptor occupancy of JNJ-55308942 over time by measuring the brain P2X7 receptor
occupancy at both Tmax  and at 24 hours after a single dose of JNJ-55308942 solution using
[18F]-JNJ-64413739.
Study 55308942EDI1003 was an open-label drug interaction study in healthy male and female
participants to evaluate the effects of multiple doses of JNJ-55308942 on CYP3A4, CYP2D6, and
CYP2C19 activity.
Human Pharmacokinetics and Product Metabolism
Following single oral doses of JNJ-55308942 solution in study 55308942EDI1001
 to
 mg)
under fasted conditions, the Tmax was within
 to
 hours and the half-life (T1/2) ranged from
 to
 hours across doses.
Mean exposure parameters (Cmax, AUC0-24h, AUC from time zero to the time of the last quantifiable
concentration [AUClast], and AUC from time zero to infinite time [AUC∞]) increased generally in
a dose proportional manner.
Aftera single dose administration of
 mg JNJ-55308942 in the presence of food, Cmax and AUC∞
were decreased by 28% and 18%, respectively, compared to when dosed in the fasted state.
After once-daily dosing with  to 
 mg JNJ-55308942 for 10 consecutive days in healthy male
and female participants, the mean T1/2 values after steady-state administration were similar to the
mean T1/2 values after a single dose, suggesting no time-dependent mechanisms are involved in
the metabolism of JNJ-55308942. The average Day 10 to Day 1 accumulation ratio ranged between
1.98 and 2.51 after once-daily dosing. Mean T1/2 values at steady-state were similar among the
different doses.
At 
 mg once-daily for 10 days, JNJ-55308942 was the major circulating entity in plasma. Major
metabolites M9 and M5 (hydrolysis of 5-fluropyrimidine- triazole bond and subsequent
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glucuronidation) were estimated as 5.9% and 4.2% of unchanged drug and were deemed as the
most important metabolites, but none of the metabolites reached 10% of JNJ-55308942
concentrations.
A drug-drug interaction study (55308942EDI1003) showed that JNJ-55308942, at steady-state
after once-daily administration of
 mg dose (solution), is a weak inducer of CYP
and a
moderate inhibitor of CYP
. There was no clinically significant inhibition observed for
CYP
.
Efficacy/Safety Studies
JNJ-55308942 was generally safe and well tolerated. Overall, there were no safety concerns
observed in healthy adult participants after the repeated dosing of JNJ-55308942 either alone or in
combination with a drug cocktail consisting of 
There were no deaths, SAEs, or treatment emergent adverse events (TEAEs) leading to
discontinuation during any of the studies.
There were no consistent treatment-related effects in clinical laboratory parameters (hematology,
biochemistry, coagulation, and urinalysis), vital signs, or ECG measurements and no treatment-
related, clinically significant abnormalities were observed during physical examination in any of
the clinical studies.
55308942EDI1001 (part 1: 
 to 
 mg; part 2: to 
 mg): In the 70 participants dosed with
JNJ-55308942, the most common TEAEs for all doses of JNJ-55308942 in all parts of the study
were: headache (n=20); viral respiratory tract infection (n=4); and cough, abdominal pain, and skin
irritation (n=3 each). Most TEAEs were mild in severity. The following TEAEs of moderate
severity were reported during the study: headache (n=2), fibromyalgia (n=1), paresthesia (n=1),
dry eye (n=1), and viral upper respiratory tract infection (n=1).
55308942EDI1002 ( to
mg): In the 12 participants dosed with JNJ-55308942 and/or the tracer
[18F]-JNJ-64413739, the most commonly reported (≥20% of participants) TEAEs under system
organ class (SOC) were general disorders and administration site conditions (3 participants,
33.3%) infections and infestations (3 participants, 33.3%) and psychiatric disorders (2 participants,
22.2%) in Part 1 and nervous system disorders (reported term: headache) in Part 2.
55308942EDI1003 (
 mg): The overall incidence of TEAEs was higher in participants when the
drug cocktail (midazolam, dextromethorphan, and omeprazole) was administered alone (8 [57.1%]
of 14 participants) compared to when JNJ-55308942
 mg (solution)was administered once-daily
on Days 3 to 11 (5 [35.7%] of 14 participants) and on Day 13 (1 [7.1%] of 14 participants). Only
1 [7.1%] of 14 participants had TEAEs when taking the drug cocktail in combination with
JNJ-55308942 80 mg on Day 12.
The most frequently reported TEAEs by SOC were seen in nervous system disorders SOC
(6 [42.9%] of 14 participants who received drug cocktail alone, 3 [21.4%] of 14 participants who
received JNJ-55308942
 mg alone [on Days 3-11], and 1 [7.1%] of 14 participants who received
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JNJ-55308942
 mg and drug cocktail; none was reported on Days 13 or 14 when JNJ-55308942
was administered alone following the combined dosing).
The small number of TEAEs that were considered possibly related to JNJ-55308942 
mg
included dizziness (n=2), hyperacusis (n=1), photosensitivity reaction (n=1), and headache (n=1).
Pharmacodynamics
In the SAD part of Study 55308942EDI1001, the release of IL-1β was measured from ex vivo
LPS-primed/BzATP-stimulated peripheral blood cells and showed a dose responsive inhibition of
the ex vivo LPS stimulated release of IL-1β. The estimated IC50 and IC90 (JNJ-55308942 plasma
exposures) were
 ng/mL and 
ng/mL, respectively.
In the MAD part at steady-state, at the Day 10 predose (trough) timepoint, based on group means,
no inhibition was seen up to  mg, approximately half maximal inhibition was seen at 
 mg, near
maximal inhibition was evident at 
mg, and maximal inhibition was seen at 
mg.
In study 55308942EDI1002, the PD evaluation of P2X7 RO in human brain showed that P2X7
RO in general increased with increasing JNJ-55308942 doses. At the lower dose range, the
increase in RO with dose appeared more pronounced, i.e., 7.44% (after  mg JNJ-55308942) to
59.58% (after
 mg JNJ-55308942). Receptor occupancy appeared to reach a plateau at the higher
doses (
 mg and
 mg JNJ-55308942).
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of JNJ-55308942 may
be found in the IB.
2.3.1. 
Risks for Study Participation
Potential Risks of Clinical
Significance
Summary of Data/
Rationale for Risk  
Mitigation Strategy
Emerging safety and tolerability
profile in human participants
JNJ-55308942 has not been dosed 
in humans for >10 days and 
patients with bipolar depression 
have not previously been exposed 
to JNJ-55308942. 
Participants in this study will have
to attend scheduled visits to the
study site, where the safety and
tolerability of the study intervention
will be evaluated along with
efficacy evaluations.
Patients will be regularly evaluated
for symptom changes.
Risks Due to Study Intervention(s) [JNJ-55308942]
Testicular toxicity (males only) 
 toxicity was seen in the
1-, 3-, and 6-month toxicity studies
in Sprague Dawley rats with
JNJ-55308942.
No 
toxicity was observed
in similar studies in dogs with up to
9 months of dosing.
Male participants in this study will
have regular
measurements at defined
timepoints.
The dose of 
mg once-daily has a
predicted >12-fold safety margin.
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Drug-Drug Interactions 
JNJ-55308942 is a weak inducer of 
CYP
 and a moderate inhibitor 
of CYP
 
JNJ-55308942 is mainly 
metabolized by CYP
.
The use of concomitant medications
that are metabolized solely by
CYP
 should preferably be
avoided, or participants should be
carefully monitored.
Co-administration with moderate or
strong inhibitors/inducers of
CYP
should be avoided.
A list of disallowed concomitant
therapies is provided in
Section 10.6
2.3.2. 
Benefit-Risk Assessment for Study Participation
JNJ-55308942 is in the early stages of clinical development. Patients with BD typically require
lifelong treatment. Therefore, benefits of study participation in a 6-week trial may be limited (even
though participants may experience short-term symptom relief). If the results from this study
support the continued development of JNJ-55308942 for the treatment of bipolar
depression/disorder, study participation may enhance future treatment options. Although study
participation is associated with specified risks (see 2.3.1 above), the sponsor aims to minimize
such risk both by protocol design (schedule and nature of assessments) and by thorough evaluation
of the nonclinical safety of JNJ-55308942 at high dose levels.
Prior 
studies 
in 
humans 
have 
established 
a 
firm 
understanding 
of 
the
pharmacokinetic/pharmacodynamic (PK/PD) relationship of JNJ-55308942 and established
reproducible PD activity at safe and tolerable dose levels, including the 
mg/day dose level
selected for this study. Thus, participants will be exposed to a dose level that is characterized by
PD activity with a benign risk profile.
Taking into account the measures taken to minimize risk to participants ofthis study, the potential
risks identified in association with JNJ-55308942 are justified by the potential benefits that may
be afforded to participants with BD.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in participants with BD in an MDE 
at Week 6.
Change in Montgomery-Åsberg Depression
Rating Scale (MADRS) total score from
baseline at Week 6.
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Objectives 
Endpoints
Secondary Objectives of Special Interest
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
anhedonia
Change in Snaith-Hamilton Pleasure Scale
(SHAPS) total score from baseline at Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in participants with BD. Who are
heterozygous 
or 
homozygous 
for 
the
 P2RX7 GoF SNP  (genetic
subgroup analysis)
Change in MADRS total score from baseline
at Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in participants with BD type I or
BD type II (diagnosis subgroup analysis)
Change in MADRS total score from baseline
at Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in subgroups of patients with
specific 
biomarker 
profiles 
(biomarker
subgroup analysis).
Change in MADRS total score from baseline
at Week 6.
Secondary
To evaluate the overall safety and tolerability
of treatment with JNJ-55308942 as compared
to placebo in participants with symptomatic
BD over a treatment period of 6 weeks.
Vital signs (pulse/heart rate, systolic blood
pressure [SBP], diastolic blood pressure
[DBP], 
respiratory 
rate), 
clinical 
labs
(chemistry, hematology, urinalysis), adverse
events (AEs), ECG, Young Mania Rating
Scale (YMRS) score, Columbia Suicide
Severity Rating Scale (C-SSRS) score.
To evaluate the effect of JNJ-55308942
compared to placebo on disease severity and
improvement 
on 
the 
Clinical 
Global
Impression-Severity Scale (CGI-S)
CGI-S
To evaluate the pharmacokinetics (PK) of
JNJ-55308942 in participants with BD.
Plasma concentrations of JNJ-55308942.
To assess the effect of JNJ-55308942 on
reduction of symptoms associated with
PROMIS – Ability to Participate in Social
Roles 
and 
Activities, 
Patient 
Health
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Objectives 
Endpoints
depression compared to placebo as measured 
by self-rated outcomes. 
Questionnaire (PHQ-9), Generalized Anxiety
Disorder 7 (GAD-7) score.
To evaluate the impact of treatment with 
JNJ-55308942 compared with placebo on 
response (≥50% improvement in MADRS 
total score from baseline) and remission
(MADRS total score ≤12) rates at Week 6.
Response (≥50% improvement in MADRS
total score from baseline) and remission
(MADRS total score ≤12) rates at Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in a subgroup of patients with
messenger ribonucleic acid (mRNA) transcript
levels at baseline that exceed the median level
for both P2RX7 and IL-1β.
Change in MADRS total score from baseline
at Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in subgroups of participants with
BD not taking any mood stabilizer or
antipsychotic, taking a mood stabilizer alone,
taking an antipsychotic alone, and taking a
combination of a mood stabilizer and an
antipsychotic 
(concomitant 
medication
subgroup analysis).
Change in MADRS total score from baseline
at Week 6.
Exploratory
To explore the PK  / PD  (pharmcodynamic)
relationship between plasma exposure of
JNJ-55308942, and efficacy and safety
parameters in patients with BD.
Exposure-response between exposure and
MADRS and selected safety events, as
appropriate.
To explore the effect of JNJ-55308942 on
PD-related biomarkers.
Including, but not limited to, blood biomarkers
related to immune, inflammatory, hormonal,
metabolic, 
hypothalamic-pituitary-adrenal
(HPA) axis, P2X7 receptor and monocyte
activity.
To explore the effect of pharmacogenomic
variations on the PK, efficacy, and safety of
JNJ-55308942.
Influence of genetic polymorphisms (e.g.,
-1) on plasma exposure, as well as on
efficacy and safety measures.
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Objectives 
Endpoints
To explore the effect of JNJ-55308942 
compared to placebo on the well-being of 
participants.
Self-Assessment of Well-Being (SAWB)
outcome.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis that will be tested in this study is that JNJ-55308942, compared to placebo,
results in a significant improvement in the reduction of the symptoms of depression in participants
with BD in an MDE as assessed by change in MADRS total score from baseline at Week 6.
Further details on the statistical consideration can be found under Section 9.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a double-blind, randomized, stratified, placebo-controlled, parallel group, multicenter
study. A total of approximately 164 participants will be enrolled in this study to obtain
approximately 132 completers.
The target study population includes participants of any gender, between 18 and 64 years of age
inclusive, with a Diagnostic and Statistical Manual of Mental Disorders –5th  edition (DSM-5)
diagnosis of BD (types I or II) without current psychotic features as confirmed by the Mini
International Neuropsychiatric Interview (MINI) with Borderline Personality Disorder module.
BD participants should be experiencing an MDE that does not require either hospitalization or
antidepressant medication.
Each potential participant must satisfy one of the three criteria listed below in order meet eligibility
for the study population.
 Participants who are currently unmedicated and have not received any mood stabilizers or
antipsychotics for four weeks before screening.
 Participants who are on a stable monotherapy regimen of one of the following mood
stabilizers (lithium, valproate forms [e.g., divalproex sodium], or lamotrigine) or one of the
following antipsychotics (lurasidone, cariprazine, quetiapine, lumateperone, or olanzapine)
for four weeks before screening.
 Participants who are on a stable adjunctive regimen of one of the following antipsychotics
(lurasidone, quetiapine, lumateperone, or olanzapine) and one of the following mood
stabilizers (lithium, or valproate forms [e.g., divalproex sodium]) may be considered for
eligibility based on the approved therapies in each market with an eligibility assessment
conducted between the investigator and sponsor. Assessment of the stable adjunctive
regimen of an antipsychotic and a mood stabilizer will be conducted by the investigator


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and sponsor’s clinical judgement and documented for each participant.  This regimen must
be in place 4 weeks before screening.
The participant must be symptomatic as assessed using the 17-item Hamilton Depression Rating
Scale (HDRS17). Symptom intensity over the past week will be evaluated. Participants who are
enrolled in the study will continue on their current medication regimen, if applicable, throughout
the study. No dose changes are permitted from screening through the end of the study (until after
the follow-up visit). No concurrent use of antidepressants will be allowed (until after the follow-
up visit).
For each participant, 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 post-treatment follow-up phase of up to 2 weeks
(Figure 1). Participants will enter the treatment period where they will be randomly assigned to
daily dose administration with 
mg JNJ-55308942 or placebo for 6 weeks, Day 1 up to and
including the last treatment visit, Day 43 +/- 1 day.  The study drug should be taken by the
participant at every clinic visit during the treatment period. Between approximately 1 to 2 weeks
after administration of the last dose, participants will return to the study site for a follow-up visit.
The total study duration for each participant will be up to 12 weeks. There will be 7 scheduled
visits to the study site during the study, including screening, and follow-up visit
For study site visits, a window of±1 day will be allowed.
No study-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.
Eligibility Screening Examination (for all study participants)
After giving written consent for screening, participants will be screened between 28 days and 1 day
prior to the double-blind treatment phase to ascertain their eligibility for the study according to the
inclusion and exclusion criteria. Although the screening period allows for up to 4 weeks, shorter
screening periods are encouraged, when possible. The assessments scheduled during the screening
visit may be divided over multiple days, according to operational and/or site/country-specific
needs.
To ensure that a participant is part of the target study population, specific assessments are
prioritized during the screening period. These assessments must be administered on the first day
of screening, and only if the participant qualifies will the remainder of the assessments be
performed/scheduled. These assessments will be performed by a certified rater at the site. The
priority screening procedures are as follows:
1. The MINI with Borderline Personality Disorder module.
a. The participant must meet criteria for a diagnosis of either BD type I or II.
b. The participant must not currently meet criteria for psychosis or psychotic disorder,
borderline personality disorder, antisocial personality disorder, eating disorder, or suicide
behavior disorder.
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c. The participant must not have ≥4 episodes of mood disturbances (e.g., mania, hypomania,
or depression) within the past 12 months.
2. The Structured Interview Guide for the HDRS17 (Structured Interview Guide for the HDRS17
[SIGH-D]).
a. The participant must be in a current MDE with a total score >20 and with a score >2 on
the depressed mood item [question #1].
b. SIGH-D is based on the HDRS17 and will be used in this study to perform the HDRS17 at
screening and at pre-randomization on Day 1, to confirm the participant continues to meet
eligibility criteria.
3. The ATHF-SF: current and past antidepressant treatments.
a. The participant must not have taken any disallowed medications (per appendix 6) during
the 4 weeks prior to the screening period. Disallowed medications include
antidepressants. Nonresponse to >4 treatments in the current episode is exclusionary. Of
note, participants who have been nonresponsive or inadequately responsive to
electroconvulsive therapy (ECT) or ketamine in the current episode will be excluded.
Participants who received transcranial magnetic stimulation (TMS), any transcranial
electrical stimulation, including transcranial direct current stimulation (tDCS), vagal
nerve stimulation (VNS), and/or deep brain stimulation (DBS) within 6 weeks prior to
randomization (assessed with the ATHF-SF at screening) will be excluded. Newly
initiated psychotherapy (defined as psychotherapy that was started within 4 weeks of the
screening visit and assessed with the ATHF-SF at screening) is also exclusionary.
If applicable, the Mood Stabilizer and Antipsychotic Eligibility Assessment form will be
completed for participants who are on a stable adjunctive regimen of an antipsychotic and a mood
stabilizer for 4 weeks before screening.
Once potential participants have met eligibilityrequirements for the MINI, SIGH-D and ATHF-SF
and the Mood Stabilizer and Antipsychotic Eligibility Assessment form (if applicable), the
remaining screening procedures may be completed (see Sections 5.1 and 5.2 for details).
Participants will be screened to ascertain their eligibility for the study based on the presence of the
GoF P2RX7 mutation (for inclusion, must be 
 or 
at 
nucleotide 
;
) and the absence of the LoF P2RX7 mutations (must be 
 or 
 at
rs
/nucleotide 
 
 and must be 
 at rs
/nucleotide 
;
). In other words, participants will be excluded if they have the presence of two copies
of the LoF C allele at rs
 (i.e., exclude those with 
 at nucleotide 
), and/or one or
more copies of the LoF
 allele at rs
 (i.e., exclude those with
 or
 nucleotide
).
This assessment will include the collection of a blood sample. In case participant needs to be
rescreened, this is the only assessment that does not need to be performed again.
Screening will also include assessment of study inclusion and exclusion criteria, medical history,
demographics, physical examination, psychiatric and safety evaluations, and standard laboratory
tests. The remaining assessments may be divided over multiple days, according to operational
and/or site/country-specific needs and may take place before or after the P2RX7 genotyping results
and other laboratory results become available.
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Of note, although the SIGH-D will be used for study entry criteria, the MADRS will be used as
the primary endpoint. The Structured Interview Guide for the MADRS (SIGMA) is based on the
MADRS and will be used in this study to perform the MADRS. In order to protect against potential
score inflation of the baseline MADRS score, the inclusion criteria are based on the SIGH-D
instead of the primary efficacy endpoint (MADRS). Note, the first MADRS score will be obtained
at randomization (pre-dose) in order to provide the baseline score prior to treatment.
Double-blind Treatment Phase
The duration of the double-blind treatment phase is 6 weeks. Participants will visit the study center
for a baseline visit on Day 1 and receive the first dose of study intervention following
randomization at the clinic.
On Day 1, after confirming the depressive state of the participant using the SIGH-D (HDRS17 total
score ≥20 and with a score ≥2 on the depressed mood item [question #1]), and completing all
assessments as outlined in the Schedule of Assessments (SoA), he/she will be randomly assigned
to receive either treatment with
mg JNJ-55308942 or placebo once-daily in a 1:1 ratio for a 6-
week treatment period. The SIGH-D (screening and pre-randomization on Day 1) will ideally be
completed by the same qualified rater for a given participant.
There will be 4 randomization stratification factors: BD type (I or II), country, P2RX7 GoF SNP
genotype (homozygous or heterozygous), as well as concomitant medication status (no mood
stabilizer or antipsychotic, a mood stabilizer alone, an antipsychotic alone, or a combination of a
mood stabilizer and an antipsychotic). Investigators and participants will remain blinded to
response criterion and study intervention treatment assignment for each participant.
During the double-blind treatment phase, the SIGMA (MADRS) and CGI-S will be completed by
the same qualified rater for a given participant. Exceptions should be discussed with and approved
by the sponsor. The sponsor can request a rater change based on quality concerns. The severity of
depressive symptoms will be assessed using the SIGMA (MADRS) at randomization (pre-dose)
in order to provide the baseline score prior to treatment and at subsequent visits to the study site.
Study intervention will be taken at home in the morning (
mg JNJ-55308942 or placebo) at
approximately the same time (± 4 hours) each day, 30 minutes after the start of breakfast
(maximum of 2 hours after the start of breakfast). There is an exception on Day 1 where
participants will receive the study intervention at the study site after all baseline assessments have
been completed.
On study visits 3, 4, 5 and 6, study intervention will be administered at the study site after the
clinical lab and PK samples have been collected and at approximately the same time (± 4 hours).
Study intervention will be dispensed at visits 2, 4, and 5 during this double-blind treatment period.
Of note, on study site visits 3, 4, 5 and 6, participants will be instructed to eat breakfast at home
and come to the site within 1 hour or less after completion of the meal. Inability to comply with
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these instructions would not constitute a protocol violation, but the participants are encouraged to
comply with these instructions as closely as possible.
The well being of the participant will be frequently tracked using a Digital Health Assessment app
to monitor parameters such as, but not limited to, the pattern of sleep, energy level, and
concentration level via the SAWB Questionnaire. Additionally, the Ditigal Health Assessment app
will alert the investigator when a participant has indicated that their depression is ‘much worse’ or
‘very much worse’ when answering weekly questions on depression.
The SHAPS will be administered once at baseline (pre-dose) and once at the end of the double-
blind treatment phase (after the final dose). Participants will complete the PROMIS –Ability to
Participate in Social Roles and Activities and the PHQ-9 at baseline and once weekly, and the
GAD-7 every two weeks. As per SoA, the self-rating instruments will be administered at clinic
visits or at home. For self-rating instruments completed at home on paper, participants should
complete these scales before the next clinic visit and participants will receive notifications from
the Digital Health Assessment app on their mobile phones as reminders to complete these paper
instruments.
Key safety assessments will include the monitoring of adverse events, physical examinations, vital
signs (e.g., blood pressure, pulse/heart rate, body temperature), electrocardiogram (ECG), clinical
laboratory tests, emerging of mania (YMRS), and suicidal ideation (C-SSRS).
In addition, blood samples for PK, biomarker assessment, hormones (males only), and
pharmacogenomics (general SNPs and ribonucleic acid [RNA]) will be collected as per the SoA
and use of concomitant medication will be recorded.
Follow-up Examination
Between 7 to 14 days after the last study visit, participants will return to the study site for a safety
follow-up visit. The procedures to be completed during the follow-up visit are listed in the SoA.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
Blinding, Study Phase/Periods, Intervention Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints that may occur in the absence of active study intervention.
Randomization will be used to minimize 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 statistical comparisons across intervention  groups. Blinded
intervention will be used to reduce potential bias during data collection and evaluation of clinical
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For each participant, the study will consist of 3 phases:
1. a screening phase of up to 4 weeks
2. a double-blind treatment phase of6 weeks. Participants will enter the treatment period where
they will be randomly assigned to daily dose administration with 
mg JNJ-55308942 or
placebo for 6 weeks, Day 1 up to and including the last treatment visit, Day 43 +/- 1 day.  The
study drug should be taken by the participant at every clinic visit during the treatment period.
This is considered an acceptable duration of treatment in a study with an antidepressant
medication and is supported by available nonclinical data.
3. a post-treatment follow-up phase of up to 2 weeks
The total study duration for each participant will be up to 12 weeks. There will be 7 scheduled
visits to the study site during the study, including the screening and follow-up visits.
Study population
The target study population includes participants of any gender, between 18 and 64 years of age
inclusive, with a DSM-5 diagnosis of BD (type I or II) without current psychotic features as
confirmed by the MINI with Borderline Personality Disorder module. BD participants should be
experiencing an MDE that does not require hospitalization or antidepressant medication.
Each potential participant must satisfy one of the three criteria listed below in order meet eligibility
for the study population.
 Participants who are currently unmedicated and have not received any mood stabilizers or
antipsychotics for four weeks before screening.
 Participants who are on a stable monotherapy regimen of one of the following mood
stabilizers (lithium, valproate forms [e.g., divalproex sodium], or lamotrigine) or one of the
following antipsychotics (lurasidone, cariprazine, quetiapine, lumateperone, or olanzapine)
for four weeks before screening.
 Participants who are on a stable adjunctive regimen of one of the following antipsychotics
(lurasidone, quetiapine, lumateperone, or olanzapine) and one of the following mood
stabilizers (lithium, or valproate forms [e.g., divalproex sodium] may be considered for
eligibility based on the approved therapies in each market with an eligibility assessment
conducted between the investigator and sponsor. Assessment of the stable adjunctive
regimen of an antipsychotic and a mood stabilizer will be conducted by the investigator
and sponsor’s clinical judgement and documented for each participant. This regimen must
be in place 4 weeks before screening.
No concurrent use of antidepressants will be allowed. This is to avoid a possible switch to a
hypomanic or manic episode due to treatment with antidepressants, to decrease the risk of drug-
drug interactions from polypharmacy, to decrease treatment heterogeneity in the sample, and to
maximize the chance to identify possible signals from JNJ-55308942. Despite stable use of mood
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stabilizers in some patients, eligible participants must be symptomatic, as assessed using the
HDRS17.
Past and current history of antidepressant drug treatment and response to treatment (per the
structured ATHF-SF) should be used retrospectively to determine antidepressant therapies used in
this current episode. A failed trial of electroconvulsive therapy (ECT) or ketamine will be
considered exclusionary. Participants who received transcranial magnetic stimulation (TMS), any
transcranial electrical stimulation, including transcranial direct current stimulation (tDCS), vagal
nerve stimulation (VNS), and/or deep brain stimulation (DBS) within 6 weeks prior to
randomization (assessed with the ATHF-SF at screening) will be excluded. Newly initiated
psychotherapy (defined as psychotherapy that was started within 4 weeks of the screening visit
and assessed with the ATHF-SF at screening) is also exclusionary.
Men, women of non-childbearing potential (WONCBP), and women of childbearing potential
(WOCBP) will be recruited to participate in this study. The inclusion of WOCBP is enabled by
embryofetal development studies in rats and rabbits. Pregnancy and pregnancy  risks will be
evaluated at each visit for WOCBP. Refer to the latest version of the IB for JNJ-55308942.
Placebo as the control
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints that may occur in the absence of active study intervention. Participants will be randomly
assigned to receive placebo or 
 mg JNJ-55308942 once-daily for 6 consecutive weeks during
the double-blind treatment period.
Similar to participants randomized to receive JNJ-55309842, participants with BD randomized to
receive placebo must continue on their current medication regimen, that was present at least 4
weeks before screening. As needed, medications for anxiety and insomnia will be allowed, per
protocol guidelines.
At each in-person study visit, a placebo-control reminder script (PCRS) (Cohen 2021) will be
completed prior to completing the primary outcome measure, the MADRS. The PCRS was
designed to educate clinical trial participants about commonly cited factors that impact placebo
responses and the importance to attending to these factors when reporting on symptoms and
potential side effects. The entire procedure takes about 3 minutes.
Genetic and Pharmacogenomic and Biomarker Collection
A blood sample will be collected during screening to allow for the analysis of 3 SNPs in the P2RX7
gene to determine participant eligibility for the study. These polymorphisms have been shown to
alter P2X7 receptor function in vitro and be associated with altered IL-1β release from peripheral
blood mononuclear cells (Stokes 2010, Gu 2001, Wiley 2003). It is hypothesized that P2X7
receptor inhibition would be most effective in participants with increased P2X7 receptor
functionality. Participants are eligible if they carry the GoF P2RX7mutation (must be 
 or 
at
nucleotide
;
). Participants will be excluded if two copies of the LoF
allele are present at rs
 (i.e., exclude those with 
 at nucleotide 
), and/or one or
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more copies of the LoF  allele is present at rs
 (i.e., exclude those with 
 or 
nucleotide 
). It is expected that participants that lack functional P2X7 receptors would not
respond to a P2X7 receptor antagonist such as JNJ-55308942, and therefore would not be
anticipated to derive potential benefit and also may not provide safety and tolerability data that
results from on-target pharmacology.
An additional optional blood sample will be collected on Day 1 from enrolled participants for
pharmacogenomic research. If collection on Day 1 is not feasible, it can be collected on any other
visit during the double-blind treatment phase. It is recognized that genetic variation can be an
important contributory factor to interindividual differences in intervention 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 an intervention. The goal
of the pharmacogenomic component is to collect Deoxyribonucleic acid (DNA) to allow the
identification of genetic factors that may influence the PK, PD, efficacy, safety, or tolerability of
JNJ-55308942 and to identify genetic factors associated with BD.
Blood samples for measuring biomarkers will be collected to evaluate the mechanism of action
and/or target engagement (PD effect) of JNJ-55308942, help to explain inter-individual variability
in clinical outcomes, or to identify population subgroups that respond differently to an intervention
and/or for exploratory analyses. The goal of the biomarker analyses is to evaluate the PD of JNJ-
55308942 and aid in evaluating the intervention-clinical response relationship.
DNA, RNA, and biomarker samples may be used to help address emerging issues and to enable
the development of safer, more effective, and ultimately individualized therapies. Biomarker data
obtained from this study may also be included in an ongoing cross-study analysis to investigate
the relationship between depression severity and phenotypes and biomarkers.
Clinical Assessments
Assessment of Depression
17-Item Hamilton Depression Rating Scale (HDRS17)
The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms
in participants diagnosed with depression with a total score range of 0 to 52, with higher scores
indicating greater severity of depressive symptoms. It is the most widely used symptom severity
measure for depression. The HDRS17 will be performedat screening and Day 1 pre-randomization,
by an appropriately trained staff member, using the SIGH-D.
Montgomery–Åsberg Depression Rating Scale (MADRS)
The 10-item clinician-administered MADRS was designed to be used in persons with major
depressive disorder (MDD) to measure the overall severity of depressive symptoms with a total
score range of 0 to 60, with higher scores indicating greater severity of depressive symptoms. The
MADRS scale has been selected as the primary efficacy measure for this study because it is
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validated, reliable, and acceptable to regulatory health authorities as a primary scale to determine
efficacy for depression. The MADRS will be administered during the double-blind treatment phase
using the SIGMA.
The primary efficacy endpoint is the change from the baseline (Day 1) MADRS total score at the
end of the 6-week treatment period.
Clinical Global Impression – Severity (CGI-S)
The CGI-S is included to rate the severity of the participant’s illness at the time of assessment,
relative to the clinician’s experience with participants who have the same diagnosis and
improvement with treatment (Guy 1976). The CGI-S evaluates the severity of illness on a scale
from 1 to 7.
Patient Health Questionnaire (PHQ-9)
The 9-item PHQ-9 scale scores each of the 9 symptom domains of the DSM-5 MDD criteria, and
it has been used both as a screening tool and a measure of response to treatment for depression
(Kroenke 2001). Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than
half the days, and 3=nearly every day). The participant’s item responses are summed to provide a
total score (range 0 to 27), with higher scores indicating greater severity of depressive symptoms.
The recall period is 2 weeks.
Self-Assessment of Well-Being (SAWB)
During the double-blind treatment phase, participants will answer a 1- or 2-item self-report scale
designed to provide the participant’s subjective experience with relation to their depression while
taking the treatment. This is an internal Janssen questionnaire, and the questions will be asked to
the participant weekly by the Digital Health Assessment app. The Digital Health Assessment app
will send an alert to the investigator when the participant replies that her/his depression is ‘much
worse’ or ‘very much worse’.
Assessment of Social Isolation
PROMIS - Ability to Participate in Social Roles and Activities
The PROMIS - Ability to Participate in Social Roles and Activities item bank assesses the
perceived ability to perform one’s usual social roles and activities. The item bank does not use a
time frame (e.g., over the past seven days) when assessing ability to participate in social roles and
activities. The Short Form 4a includes 4 items that represent this concept. Each question has 5
response options ranging in value from 1 to 5. The total raw score for the short form is calculated
by summing the values of the response to each question, so for the 4-item form, the lowest possible
raw score is 4; the highest possible raw score is 20. Raw scores can also be converted to a T score
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Assessment of Anxiety
Generalized Anxiety Disorder-7 (GAD-7)
The GAD-7 is a self-reported questionnaire for screening for and measuring the severity of GAD.
The GAD-7 has 7 items, which measure the severity of various signs of GAD according to reported
response categories with assigned points. Assessment is indicated by the total score (0 to 21),
which is calculated by adding together the scores for all 7 items. For each item, as well as for the
total score, a higher score represents a more severe condition.
Assessment of Anhedonia
Snaith-Hamilton Pleasure Scale (SHAPS)
An instrument developed for the assessment of hedonic capacity is the 14-item, self-report, Snaith–
Hamilton Pleasure Scale (Snaith et al., 1995). The SHAPS was developed to minimize cultural,
gender, and age biases in the evaluation of hedonic capacity. It not only measures hedonic tone,
but also its absence, i.e. anhedonia. Anhedonia can be a core symptom of depression. Four major
domains are covered in the scale, namely interest/pastimes, social interaction, sensory experience,
and food/drink.
Assessment of Disease Progression at Home
Self-Assessment of Well-Being (SAWB)
The SAWB questionnaire is a multiple-item self-report questionnaire designed to provide
additional information regarding the participant’s subjective experience while taking study
intervention. This is an internal Janssen questionnaire, and the questions will be asked to the
participant daily by the Digital Health Assessment app during the double-blind treatment phase.
Several items of interest can be covered: such as, but not limited to, the pattern of sleep, energy
level, and concentration level.
Safety Assessments
Standard safety assessments including physical examination, body weight, vital signs (including
oral, tympanic or temporal body temperature, pulse/heart rate, and respiratory rate), 12-lead ECG,
urine drug testing, alcohol breath test, pregnancy testing (female participants only), and clinical
labs (hematology, chemistry panel, hormones [male participants only], and urinalysis) will be
performed as per SoA. In addition, serology and hemoglobin A1C (HbA1C) assessments will be
performed at screening only.
Additionally, emergence of suicidal ideation will be assessed using the C-SSRS at screening and
during each visit.
4.2.1. 
Participant Input Into Design
To gather the insights of patients suffering from BD, a live Patient Advisory Committee was
organized with clinical and operations study team members in attendance. The patient advocates
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disease (e.g., medication, impact on family life or professional life). Study participants were also
asked for their opinion on several design aspects of this clinical study (e.g., placebo, the use of
apps). All information was collected and evaluated, and, if relevant, implemented in the protocol
(e.g., kept number of assessments to a minimum; added a follow-up visit based on patient feedback
about needing continuity of care) or in operational aspects (e.g., development of
recruitment/retention and site engagement strategy, use bright colors for pamphlets or posters).
4.2.2. 
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 BD participants 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. The results
of the investigation of JNJ-55308942 may help future patients.
The primary ethical concern is the use of placebo (in addition to the ongoing treatment with a
mood stabilizer, if applicable) during the double-blind treatment phase of 6 weeks, while
symptoms of at least moderate depression are present. The rationale for this placebo treatment and
the impact on the study population has been described in Section 4.2, ‘Placebo as the control’.
Although placebo treatment may not harm most of the participants, participants who deteriorate in
a clinically significant manner during the double-blind treatment phase will be withdrawn from
the study (see Section 7.3) and will be referred to treatment according to local standards. The status
of depressive symptoms will be assessed and documented weekly or every 2 weeks. Furthermore,
the well-being of the participant will be tracked using an Digital Health Assessment app  to monitor
parameters such as, but not limited to, the pattern of sleep, energy level, and concentration level
via the SAWB. The Digital Health Assessment app will alert the investigator when a participant
has indicated that their depression is ‘much worse’ or ‘very much worse’ when answering weekly
questions on depression.
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. For each participant, the maximum amount of blood drawn from each
participant in this study will not exceed 450 mL.
4.3. 
Justification for Dose
The PK/PD models developed based on concentration and PD responses (% inhibition of IL-1β
release or % receptor occupancy) were used for dose selection simulations. The
mg once-daily
dose proposed for this study is expected to provide maximal target engagement based on the results
of the receptor occupancy study (55308942EDI1002) where a plateau in receptor occupancy was
reached after participants received doses of 
 and 
mg JNJ-55308942 (ranging from 54% to
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80% receptor occupancy after a single dose). In addition, the proposed
 mg dose is predicted to
provide near maximal inhibition of P2X7-mediated peripheral release of IL-1β.
The proposed dose for this proof-of-concept study is 
 mg once-daily. The steady-state exposure
margin (based on area under the curve [AUC]) between the exposures calculated for humans
receiving a daily dose of
mg JNJ-55308942 and the exposures in rats at the no observed effect
level (NOEL) for 
toxicity is 12-fold, which is above the 10-fold safety margin outlined
in the FDA guidance (FDA Guidance 2018; ICH Guidance 2021). Additionally, comparing the
exposures at 
mg daily with the rat exposure at the lowest observed effect level (LOEL) for
toxicity, there is a 16-fold difference. Based on these data, the once-daily dose of 
mg
JNJ-55308942 demonstrates a 12-fold safety margin  to 
toxicity NOEL in rats and
supports inclusion of men in the study. Further, the results from the Phase 1 clinical program have
shown JNJ-55308942 to be safe and well-tolerated at repeated doses of up to 
 mg daily for 10
days, with no severe or serious adverse events observed. This further supports the use of the
proposed 
mg daily dose of JNJ-55308942. Additionally, the proposed duration of treatment of
6 weeks for this study is supported by data from the nonclinical toxicology studies.
JNJ-55308942 showed delayed Tmax and decreased exposures (Cmax by
% and AUC by 
%) in
the presence of a high-fat diet. So, to reduce the overall PK variability to facilitate establishing
PK/PD relationship, a regular diet of standard breakfast will be administered first and then
JNJ-55308942 should be administered 30 minutes to 2 hours after breakfast.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last visit (Visit 7) for the last participant in the study. The
final data from the study site will be sent to the sponsor 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 treatment phase.
Participants who prematurely discontinue study intervention for any reason before completion of
the double-blind treatment phase will not be considered to have completed the study. Any
participant who withdraws after receiving the study intervention will have an early withdrawal
evaluation as described in Section 8.1.4.
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.
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5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
Criterion modified per Amendment 2
1.1. 
Any gender, 18 to 64 years of age, inclusive.
Participants should be at least 18 years of age or older as per the legal age of consent in
the jurisdiction in which the study is taking place.
Type of Participant and Disease Characteristic
2. 
Presence of one or two copies of the GoF A allele at 
 (must be 
or 
at
nucleotide
 
) in the P2RX7gene.
3. 
Criterion modified per Amendment 4
3.1. 
Have a primary DSM-5 diagnosis of BD (Type I or II) without current psychotic features,
as confirmed by the MINI.
4. 
Must be experiencing an MDE (current episode must be of ≥4 weeks but <24 months in
duration), meeting the following criteria at screening and baseline (Day 1,
pre-randomization):
 
Have a HDRS17 total score ≥20 and with a score ≥2 on the depression question
(question #1).
5. 
Criterion modified per Amendment 5
5.1A
Must meet one of the following criteria regarding current medication regimen.
 Currently unmedicated and has not received any mood stabilizers or antipsychotics
for four weeks before screening.
OR
 Currently on a stable monotherapy regimen of one of the following mood stabilizers
(lithium, valproate forms [e.g., divalproex sodium], or lamotrigine) or one of the
following antipsychotics (lurasidone, cariprazine, quetiapine, lumateperone, or
olanzapine) for four weeks before screening.
OR
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 Currently  on a stable adjunctive regimen of one of the following antipsychotics
(lurasidone, quetiapine, lumateperone, or olanzapine) and one of the following mood
stabilizers (lithium, or valproate forms [e.g., divalproex sodium])
5.1B
 Participants on adjunctive regimens as described above may be considered for
eligibility based on the approved therapies in each market with an eligibility
assessment conducted between the investigator and sponsor. Assessment of the stable
adjunctive regimen of an antipsychotic and a mood stabilizer will be conducted by the
investigator and sponsor’s clinical judgement and documented for each participant.
This regimen must be in place 4 weeks before screening. Participants on a stable
adjunctive regimen of an antipsychotic and a mood stabilizer who do not qualify per
the assessment will not be eligible for the study.
6. 
Medically stable on the basis of physical examination, medical history, and vital signs
performed at screening. Any abnormalities must be consistent with the underlying illness
in the study population. This determination must be recorded in the participant's source
documents and initialed by the investigator.
7. 
Medically stable on the basis of clinical laboratory tests performed at screening. If the
results of the serum chemistry panel, hematology, or urinalysis are outside the normal
reference ranges, the participant may be included only if the investigator judges the
abnormalities or deviations from normal to be not clinically significant or to be
appropriate and reasonable for the population under study. This determination must be
recorded in the participant's source documents and initialed by the investigator.
Weight
8. 
Have a Body Mass Index (BMI) between 18.0 and 35.0 kg/m2 inclusive (BMI =
weight/height2).
Sex and Contraceptive/Barrier Requirements (also see section 10.5)
9. 
A woman of childbearing potential (WOCBP) must have a negative highly sensitive
serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) at screening and a
negative urine pregnancy test before the first dose of study intervention.
10. 
A woman using oral contraceptives must use an additional contraceptive method (see
Inclusion Criterion 11).
11. 
Criterion modified per Amendment 2
11.1. 
Before randomization, a woman must be either:


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 Not of childbearing potential defined as:
o Postmenopausal (amenorrhea for at least 12 months without an alternative
medical cause. A serum follicle stimulating hormone (FSH) level at
screening >40 IU/L in women not using hormonal contraception or hormonal
replacement therapy may be used for confirmation, however in the absence
of 12 months of amenorrhea, a single FSH measurement is insufficient), or
o Permanently sterilized (including hysterectomy, bilateral
salpingectomy,bilateral oophorectomy and bilateral tubal occlusion/ligation),
or
o Otherwise, be incapable of pregnancy.
 Of childbearing potential and practicing a highly effective method of birth
control consistent with local regulations regarding the use of birth control
methods for participants in clinical studies (i.e., one that results in a less than 1%
per year failure rate when used consistently and correctly). This may include:
o Established and ongoing use of oral hormonal methods of contraception in
combination with barrier methods.
o Established and ongoing use of patch, injected or implanted hormonal
methods of contraception.
o Placement of an intrauterine device (IUD) or intrauterine hormone-releasing
system (IUS).
Accepted barrier methods as indicated above include:
 condom with spermicidal foam/gel/film/cream/suppository
 occlusive cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository.
Note that a barrier method on its own is not sufficient.
o Male partner sterilization (the vasectomized partner should be the sole
partner for that participant).
o 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 1 month after receiving the last dose of study
intervention.
o 
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.
12. 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for at least 1 month after receiving the last dose of
study intervention.


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13. 
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 (i.e., a condom with
spermicidal foam/gel/film/cream/suppository) for the duration of the study plus
3 months after receiving the last dose of study intervention, and all men must not donate
sperm during the study and for 3 months after receiving the last dose of study
intervention. 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.
Informed Consent
14. 
Must sign an ICF (or their legally acceptable representative must sign) indicating that he
or she understands the purpose of, and procedures required for, the study and is willing
to participate in the study.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
Medical Conditions
1. 
Presence of two copies of the LoF
 allele at rs
 (i.e., exclude those with
 at
nucleotide
), and/or has one or more copies of the LoF
allele at rs
 (i.e.,
exclude those with
 or
 nucleotide
 in the P2RX7gene.
2. 
Criterion modified per Amendment 4:
2.1. 
Based on the MINI (with Borderline Personality Disorder module) and clinical
discretion, has a current DSM-5 diagnosis of:
 borderline personality disorder
 antisocial personality disorder
 eating disorder
 suicide behavior disorder
 ≥4 episodes of mood disturbances (e.g., mania, hypomania, or depression)
within the past 12 months
 any psychotic disorder
3. 
Currently meets the DSM-5 criteria for Manic Episode (ME) on the MINI.
4. 
A YMRS of >12.
5. 
Received transcranial magnetic stimulation (TMS), any transcranial electrical
stimulation, including transcranial direct current stimulation (tDCS), vagal nerve
stimulation (VNS) and/or deep brain stimulation (DBS) within 6 weeks prior to
randomization (assessed with the ATHF-SF at screening).
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6. 
Criterion modified per Amendment 4:
6.1 
Nonresponse or inadequate response to ECT (assessed with the ATHF-SF at
screening) or ketamine in the current episode.
7. 
Nonresponse to >4 treatments in the current episode (assessed with the ATHF-SF at
screening).
8. 
History of alcohol misuse according to DSM-5 criteria within 6 months before
screening.
9. 
History of substance misuse disorder (aside from mild cannabis misuse disorder),
according to the DSM-5 criteria, within 6 months before screening, or has a positive
urine drug screen for opioids (including methadone), cocaine, barbiturates or
amphetamine/methamphetamine at screening. In the case of a positive drug screen for
prohibited substances, a one-time repeat urine drug screen may be performed at the
discretion of the investigator, provided the participant is willing to abstain from all
prohibited substances during the study.
10. 
History of moderate to severe cannabis misuse according to DSM-5 criteria within
6 months before screening.
11. 
Has a current or recent (within the past 3 months) history of clinically significant
suicidal ideation (corresponding to a score of ≥3 for ideation on the C-SSRS) or any
suicidal behavior within the last 6 months, as validated on the C-SSRS at screening.
Participants with a prior suicide attempt, 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.
12. 
Participant is currently in need of hospitalization.
13. 
History of malignancy within 5 years before screening (exceptions are squamous and
basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy
that in the opinion of the investigator is considered cured with minimal risk of
recurrence).
14. 
Known allergies, hypersensitivity, or intolerance to JNJ-55308942, placebo, or its
excipients.
15. 
Had major surgery (e.g., involving a major body cavity or significant blood loss)
within 12 weeks before screening, or will not have fully recovered from surgery, or
has surgery planned during the time the participant is expected to participate in the
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Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate.
16. 
Evidence of clinically severe or active disease, or a clinical finding that is unstable or
that, in the opinion of the investigator, would be negatively affected by the study
intervention or that would affect the study intervention.
Prior/Concomitant Therapy
17. 
Taken any disallowed therapies (as noted in Section 6.7, Concomitant Therapy) within
the past 4 weeks (5 weeks for fluoxetine) prior to screening.
18. 
Criterion modified per Amendment 4:
18.1. 
Newly initiated psychotherapy (defined as psychotherapy that was started within
4 weeks of the screening visit and assessed with the ATHF-SF at screening).
Prior/Concurrent Clinical Study Experience
19. 
Received an investigational intervention (including investigational vaccines) or used an
invasive investigational medical device within 60 days or 5 half-lives, whichever is
longer, before the planned first dose of study intervention.
20. 
Is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this
study or within 1 month after the last dose of study intervention.
21. 
Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the participant (e.g., compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
Other Exclusions
22. 
Employee of the investigator or study site, with direct involvement in the proposed
study or other studies under the direction of that investigator or study site, as well as
family members of the employees or the investigator.
23. 
Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV)
at Screening, or other clinically active liver disease (in SoA). If participants are
clinically stable, or have been successfully treated for infection, or have spontaneously
recovered from infection, they may be allowed in the study with sponsor approval.
Confirmatory PCR testing may be required in the case of ambiguous serology results.
24. 
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, or are clinically stable, they will be allowed in the study.


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NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study intervention is given
such that the participant no longer meets all eligibility criteria, then the participant should be
excluded from participation in the study. Exceptional and limited retesting of abnormal screening
values that lead to exclusion are allowed only once using an unscheduled visit during the screening
period (to reassess eligibility). The required source documentation to support meeting the
enrollment criteria is noted in Section 10.3, (Appendix 3: Regulatory, Ethical, and Study Oversight
Considerations).
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the study to be eligible for participation:
1. 
Refer to Section 6.7, Concomitant Therapy for details regarding prohibited and
restricted therapy.
2. 
Agree to follow all requirements that must be met during the study as noted in the
inclusion and exclusion criteria (e.g., contraceptive requirements).
3. 
Avoid donating blood for at least 90 days after completion (i.e., final follow-up visit)
of the study.
4. 
Avoid strenuous exercise/activity for 24 hours prior to Visits 2, 4, 5, 6, and 7.
5.3.1. 
Meals and Dietary Restrictions
1. 
May not consume any food or beverages containing grapefruit, grapefruit juice, Seville
oranges (including any orange marmalade), or quinine (e.g., tonic water) from 72 hours
before first dose of study intervention to the end of study visit.
5.3.2. 
Caffeine and Alcohol
1. 
Must avoid excessive use of caffeine (e.g., no more than approximately 500 mg/day, as
contained in 5 cups of tea or coffee or 8 cans of cola), during the entire study (from
screening to end of study)
2. 
The use of limited amounts of alcohol (up to 2 standard drink consumptions daily) will be
allowed, but not within 24 hours before any study visit. A standard drink is defined as: a
350 mL/12 oz glass of 5% alcohol-by-volume (ABV) beer (1.7 units), a
150 mL/5 oz glass of 12% ABV wine (2 units), or a 45 mL/1.5 oz glass of a 40% ABV
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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.
For the “Screening” period, rescreening will be permitted when the time between the first
screening visit and the baseline visit has passed. Individuals who do not meet the criteria for
participation in this study (screen failure) may be rescreened once. In the event of a rescreen the
blood sample for the GoF and LoF P2RX7 SNPs should not be redrawn. If participants were found
ineligible for the SNP analysis outcome (5.2 Exclusion Criteria: exclusion criteria 1) they cannot
be rescreened.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention(s) Administered
Description of Interventions
All participants will take 1 capsule once-daily in the morning (JNJ-55308942 or matching placebo)
from Day 1 up to and including the last treatment visit, Day 43 ± 1 day (at home and when at the
study site unless otherwise specified in the protocol) in a fed condition (30 minutes after the start
of breakfast [maximum of 2 hours after the start of breakfast]) with some water. The first dose of
study intervention will be taken in the fed condition on Day 1 of the double-blind treatment phase
when the participant is at the study site after all baseline assessments have been completed. On
study visits 3, 4, 5 and 6, study intervention will be taken at the study site after the clinical lab and
PK samples have been collected and at approximately the same time (± 4 hours).
The capsules must be swallowed whole and not chewed, divided, dissolved, or crushed.
On days when participants visit the study site, they will take the dose of the study intervention at
the study site. Specifically, they should eat a meal before coming to the site. They will bring all
study intervention, including the study intervention for that day, to the study site in the bottles
dispensed at the previous visit. They will take the study medication at the study site, after
completion of the predose study assessments and blood collections. Dosing at the study site will
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Group/Arm Name 
Active study intervention group  
Placebo group
Intervention Name 
JNJ-55308942 
Placebo for JNJ-55308942
Type 
Drug 
Placebo
Dose Formulation 
Capsule 
Capsule
Unit Dose Strength(s) 
 mg 
Not applicable
Dosage Level(s) 
 mg, 1 capsule once-daily  
1 capsule once-daily
Route of Administration 
Oral 
Oral
Use 
Experimental 
Experimental
Investigational Medicinal Product 
(IMP)
Yes 
Yes
Non-Investigational Medicinal 
Product/Auxiliary Medicinal
Product (NIMP/AxMP)
No 
No
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor
Packaging and Labeling 
(Labels will contain information to 
meet the applicable regulatory 
requirements) 
Study intervention (JNJ-55308942) 
will be provided in bottles. Each 
bottle package will be identified by 
a unique kit number. 
Study intervention (placebo) will
be provided in bottles. Each bottle
package will be identified by a
unique kit number.
Child resistant 
Child resistant
Delivery Instructions 
One capsule daily, preferably at the 
same time point, recommended to 
take each dose of study intervention 
in the morning with a glass of water 
One capsule daily, preferably at
the same time point,
recommended to take each dose
of study intervention in the
morning with a glass of water
Food/Fasting Requirement 
30 minutes after the start of 
breakfast (max. 2 hours) 
30 minutes after the start of
breakfast (max. 2 hours)
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.
JNJ-55308942 and placebo 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 at the study site will be stored in  a secure area with restricted access.
Capsules must be stored at controlled room temperatures as indicated on the product specific
C
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labeling. All study intervention must be stored at controlled temperatures ranging from 59 °F to
86 °F (15 °C to 30 °C).
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.
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, must be documented on the
intervention  accountability form. Participants must be instructed to return all original bottles,
whether empty or containing study intervention.
Study intervention must be handled in strict accordance with the protocol and the bottle label.
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.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 groups (JNJ-55308942 or placebo) based on a computer-generated randomization
schedule prepared before the study by or under the supervision of the sponsor. The randomization
will be balanced by using randomly permuted blocks and will be stratified by 4 factors: BD type
(I or II), country, P2RX7 GoF SNP genotype (homozygous or heterozygous), as well as
concomitant medication status (no mood stabilizer or antipsychotic, a mood stabilizer alone, an
antipsychotic alone, or a combination of a mood stabilizer and an antipsychotic). 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. Sites will be given
instructions and training on the number of study intervention kits expected to be assigned by IWRS
per patient visit. The requestor must use his or her own user identification and personal


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identification number when contacting the IWRS and will then give the relevant participant details
to uniquely identify the participant.
Blinding
Blinded treatment will be used to reduce potential bias during data collection and evaluation of
clinical endpoints.
The investigator will not be provided with randomization codes. The codes will be maintained
within the 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 (e.g., 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. Also, the site staff should
not discuss insights on unblinding of randomization with the participants.
Under normal circumstances, the blind should not be broken until all participants have completed
the study and the database is finalized/locked. 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 electronic case report form (eCRF), 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 study intervention assignment unblinded should continue to return
for scheduled follow-up evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed/locked.
6.4. 
Study Intervention Compliance
Study intervention will be taken at home by the participant, unless otherwise indicated below. The
first dose will be taken by the participant on Day 1 of the study at the site.
6.4.1. 
Medication Adherence and Reminder System
The administration of study medication will be witnessed by the investigator or a properly trained
designee. The date and time of study administration during clinic visits will be recorded in the
eCRF. Daily study medication reminder(s) will be provided by the Digital Health Asessment app


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on the participant’s smartphone, or on a smartphone provided to the participant for use in the study
if they are unable to use their own.
The investigator or designated study personnel will maintain a log of all study intervention
dispensed and returned. Study intervention  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. 
Continued Access to Study Intervention After the End of the Study
Investigators may recontact the participant to obtain long-term follow-up information regarding
the participant's safety or survival status as noted in the ICF (refer to Informed Consent in
Section 10.3, Appendix 3: Regulatory, Ethical, and Study Oversight Considerations).
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.
It is recommended participants continue taking their mood stabilizer or antipsychotic, if they were
using them during the study, until such time as changes are recommended by their treating
physician. If the participant has persistent symptoms of depression at the completion of the study
and has no access to a primary physician or psychiatrist, the investigator should ensure appropriate
medical care for the participant after completion of the study.
6.6. 
Treatment of Overdose
For this study, any dose of JNJ-55308942 greater than 
mg within a 24-hour time period will
be considered an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Evaluate the participant to determine, in consultation with the Medical Monitor, whether study
intervention should be interrupted.
 
Closely monitor the participant for AE/serious adverse event (SAE) and laboratory
abnormalities until JNJ-55308942 can no longer be detected systemically (at least 8 days).
 
Obtain a plasma sample for PK analysis within 8 days from the date of the last dose of study
intervention if requested by the Medical Monitor (determined on a case-by-case basis).
 
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.
CCI


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6.7. 
Concomitant Therapy
All prestudy therapies administered up to 4 weeks before the intial screening visit must be recorded
at screening.
Any administration of concomitant therapy throughout the study, from signing of the screening
informed consent to final follow-up visit, must be recorded in the eCRF.
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, or other specific categories of interest) different from the study
intervention must be recorded in the eCRF. Recorded information will include a description of the
type of therapy, duration of use, dosing regimen, route of administration, and indication.
One of the following regimens will be followed for the concomitant medication status:
 Participants who are currently unmedicated and have not received any mood stabilizers or
antipsychotics for four weeks before screening.
 Participants who are on a stable monotherapy regimen of one of the following mood
stabilizers (lithium, valproate forms [e.g., divalproex sodium], or lamotrigine) or one of the
following antipsychotics (lurasidone, cariprazine, quetiapine, lumateperone, or olanzapine)
for four weeks before screening.
 Participants who are on a stable adjunctive regimen of one of the following antipsychotics
(lurasidone, quetiapine, lumateperone, or olanzapine) and one of the following mood
stabilizers (lithium, or valproate forms [e.g., divalproex sodium]) may be considered for
eligibility based on the approved therapies in each market with an eligibility assessment
conducted between the investigator and sponsor. Assessment of the stable adjunctive
regimen of an antipsychotic and a mood stabilizer will be conducted by the investigator
and sponsor’s clinical judgementand documented for each participants.  This regimen must
be in place 4 weeks before screening.
Participants will continue to take their current medication regimen, if applicable, throughout the
study at an adequate and tolerated dose. No dose changes are permitted from screening through
the end of the study (until after the follow-up visit). Modification of an effective pre-existing
therapy should not be made for the explicit purpose of entering a participant into the study. Newly
initiated psychotherapy (defined as psychotherapy that was started within 4 weeks of the screening
visit) is prohibited. Regular ongoing psychotherapy that was initiated prior to 4 weeks before the
screening visit will be permitted.
JNJ-55308942 is a weak inducer of CYP
, and a moderate inhibitor of CYP
. It is preferred
that the use of co-medications that are metabolized solely by CYP
is avoided, or participants
should be carefully monitored.
CCI
CCI
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JNJ-55308942 is mainly metabolized by CYP
 Therefore, co-administration with moderate
or strong inhibitors/inducers of CYP
 should be avoided.
See section 10.6, (Appendix 6: Disallowed Concomitant Therapies) for an important list of
prohibited concomitant medications from 4 weeks prior to the screening visit until 7 days after last
dose of study intervention. Of special note, treatment with antidepressants is not allowed in the
study.
Following any administration of any disallowed concomitant medication during the study, the
sponsor and investigator will evaluate whether a participant should be discontinued or remain in
the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
See Section 10.6 for more information on disallowed concomitant therapies.
7. 
DISCONTINUATION  OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
If a participant discontinues study medication or withdraws from the study before the end of the
double-blind treatment phase, the early withdrawal assessments should be obtained.
7.1. 
Safety Data Review
Continuous or periodic blinded safety reviews will be done by the study responsible physician
(SRP). An unblinded review of the data (on the individual participant level) will be conducted
if there are safety concerns from this blinded review as a result ofsevere, serious, or unexpected
AEsthatareatleastpossiblyrelated to thestudyinterventionorifthe frequencyofdiscontinuations
due to TEAEs exceeds 10% ofthe participants.
7.2. 
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:
 
Serious violation of protocol procedures after discussion with and agreement of the medical
monitor
 
The participant withdraws consent to receive study intervention
 
The investigator or sponsor believes that for safety reasons or tolerability reasons (e.g., an
SAE at least possibly related to the study intervention) it is in the best interest of the participant
to discontinue study intervention
 
The participant becomes pregnant
 
Non-adherence to take the study medication. Non-adherence will be decided on a case-by-
case basis depending on the number of missed capsules and the interval between missed doses.
 
Aspartate aminotransferase (AST) and/or ALT exceeds 5x the upper limit of normal (ULN)
(confirmed by repeat testing)
CCI
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 
AST and/or ALT exceeds 3x the ULN and total bilirubin exceeds 1.5x ULN (confirmed by
repeat testing)
If a participant discontinues study intervention for any reason before the end of the double-blind
treatment phase, then the early withdrawal assessments should be obtained, and scheduled
assessments of study intervention should be continued.
7.3. 
Protocol stopping criteria
BD is a serious mental condition with significant morbidity and mortality. In this study,
participants with at least moderate depression (HDRS17 total score ≥20 and with a score ≥2 on the
depression question [question #1]) will be included.
For this reason, stopping criteria have been established in this study which will ensure participants
who experience any harmful worsening of their symptoms are withdrawn from the study to permit
transfer onto alternative active treatment and referral to a psychiatrist when required. Participants
will be seen weekly or every 2 weeks and will be monitored with the Digital Health Assessment
app for worsening symptoms daily. Therefore, any deterioration is anticipated to be detected
quickly.
Blinded medical monitoring by the sponsor will occur on a continuous basis including AEs,
laboratory and ECG data. Any concerning safety data will be reviewed with the Safety Management
Team (SMT). Issues may be escalated to an internal Janssen Medical Safety Council (MSC). The study
will be stopped at any time if significant safety  concerns are related to JNJ-55308942 as per
the Safety Council’s decision.
The principal investigator (PI) may decide to stop study participation at any  time when he/she
estimates there is an acute risk for participants in study.
7.4. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
If the participant experiences clinically significant worsening of major depression that
requires any new intervention based on clinician judgment or participant preference.
 
A participant who shows signals of clinically meaningful acute suicidal ideation at any time
during the study should be withdrawn from the study and referred for appropriate
medical/psychiatric care.
Also, a participant will be automatically withdrawn from the study for any of the following
reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Discontinuation of the study treatment for any reason, including those outlined in Section 7.2,
(Discontinuation of Study Intervention)
 
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Additional participants may be enrolled if a relatively large number of participants discontinue or
are withdrawn from the study before the end of the double-blind treatment phase and the number
of participants completing the study will be below 132.
These additional participants will receive a new participant ID number and will be assigned to a
new randomization code in the IWRS.
Study intervention assigned to the withdrawn participant may not be assigned to another
participant.
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent, 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 as local regulations permit.
7.4.1. 
Withdrawal From the Use of Research Samples
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, Appendix 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.
7.5. 
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, e.g., 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 the participant 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, and 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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emails, 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, e.g., 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, safety, PK, PD, and biomarker
measurements applicable to this study.
Information regarding collection, handling, shipment, and labeling of biological samples
(including safety labs) will be provided in a separate lab manual.
Any changes to the lab manual will not result in a protocol amendment.
It is preferred that the self-rating scales and other clinical assessments (except blood collection, if
applicable) are done in the fed condition. Participants will be asked to eat a meal before their
in-person study site visits, ideally within 1 hour of the study visit. During the site visits it is
recommended that:
On Visit 2, Day 1:
 
A HDRS17 (SIGH-D) has to be administered pre-randomization to verify eligibility of the
participant.
 
A PCRS, MADRS (SIGMA), CGI-S and participant self-rating baseline assessment has to be
performed predose.
 
All baseline blood collections should be completed predose.
On Visit 3, 4, 5, and 6(Weeks 1, 2, 4, and 6respectively):
 
Blood sampling will be performed predose.
 
A PK sample will be taken predose and 1.5 (± 0.5 hour) and 4 hours (range between 2 to
4 hours) postdose. Note: note that the blood is ideally drawn at 4 hours postdose. However,
the ranges allow the PK measurement to be obtained while still maintaining flexibility (e.g.,
if the site cannot accommodate the participant for 4 hours, if the participant must go to work,
etc.). If the participant is unable to complete a PK draw, electing to withdrawal participation
in the study, the PK draw can be missed to avoid an early withdrawal due to blood collection
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All study visits:
The primary outcome MADRS (SIGMA) should be admistered as early in the study visit as
possible to reduce confounding effects of the subsequent study assessments on mood. The PCRS
must be administered before the MADRS.
The order of assessments for study visits on Day 8, 15, 29 and 43 is PCRS followed by the
MADRS followed by the CGI-S.
Vital signs and 12-lead ECG, as well as C-SSRS and YMRS will be done pre-randomization on
Day 1, and will be done predose on Day 8, 15, 29 and 43.
It is recommended that the order of multiple assessments within 1 protocol time point are the same
throughout the study. Additional blood collections for PK and PD assessments need to be kept as
close to the specified time as possible. Actual dates and times of assessments will be recorded in
the source documentation and eCRF.
Additional blood sampling or urine pregnancy tests may be performed, as determined necessary
by the investigator or required by local regulation. The time points for individual measures may
be changed (with or without affecting the overall frequency of these investigations) prior to and
during the study based on newly obtained data to allow for optimal fit to the actual safety or PK/PD
profile of the study intervention. This modification may result in a change in the overall frequency
of the individual measures (e.g., safety measures, blood samplings) provided the defined maximal
total blood volume collected per participant is not be exceeded. Such modifications, where
performed only to allow optimal fit to the actual safety or PK/PD profile of the study intervention,
will not be an (substantial) amendment to the protocol.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples. For each participant, the maximum amount of blood drawn from each participant in this
study will not exceed 450 mL.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form. If blood samples are collected via an indwelling cannula, an appropriate amount
(1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock will be
removed from the cannula and discarded before each blood sample is taken. After blood sample
collection, the cannula will be flushed and charged with a volume equal to the dead space volume
of the lock. If a mandarin (obturator) is used, blood loss due to discard is not expected.
Refer to the SoA for the timing and frequency of all sample collections. During screening, the
blood sample for the SNP analysis can  be collected along with the other screening clinical
laboratory samples.
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


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must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
IB for JNJ-55308942
 
Sample ICF
 
Paper forms for MINI
 
Paper documents for the completion of YMRS, C-SSRS, CGI-S, SIGH-D and SIGMA
 
Paper documents and instrument completion guidelines for self-rating instruments for the
completion of SHAPS, PROMIS - Ability to Participate in Social Roles and Activities, PHQ-9
and GAD-7
 
PCRS
 
IWRS manual
 
Electronic data capture (eDC) manual
 
Pharmacy manual/study site investigational product manual or equivalent document e.g.,
Investigational Product Preparation Instructions
 
Laboratory manual, tubes, and labels
 
Manuals for investigator and participant for the Digital Health Assessment app to complete
the follow-up on self-assessment of treatment experience. The Digital Health Assessment app
will be downloaded on the participant’s own smartphone, or a smartphone with the app
installed will be provided to the participant for use in the study. The Digital Health Assessment
app will ask the pre-programmed study-related questions after opening/unlocking the
smartphone by the participant. A privacy statement will be provided by the Digital Health
Assessment provider. The Digital Health Assessemnt app will report non-adherence of the
participant to the investigator.
 
Mood Stabilizer and Antipsychotic Eligibility Assessment Form
8.1. 
Study Procedures
8.1.1. 
Screening (Visit 1)
Participants will report to the study site for the eligibility screening assessment within 28 to 1 day
prior to Day 1 (Baseline). Although the screening period allows for up to 4 weeks, shorter
screening periods are encouraged, when possible. The procedures scheduled during the screening
visit may be divided over multiple days, according to operational and/or site/country-specific
needs. Before any study specific procedures are conducted and following an explanation of the
purpose and risks of the study, participants will sign a screening ICF. The collection of AEs and
concomitant medications will start after the screening ICF has been signed through the day of last
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To ensure that a participant is part of the target study population, specific assessments are
prioritized during the screening period. These assessments must be administered on the first day
of screening, and only if the participant qualifies will the remainder of the assessments be
performed/scheduled. The priority screening procedures are as follows:
1) The MINI with Borderline Personality Disorder module.
a) The participant must meet criteria for a diagnosis of either Bipolar Depression type I or II.
b) The participant must not currently meet criteria for psychosis or psychotic disorder,
borderline personality disorder, antisocial personality disorder, eating disorder, or suicide
behavior disorder.
c) The participant must not have ≥4 episodes of mood disturbances (e.g., mania, hypomania,
depression, or hypomania) within the past 12 months.
2) The Structured Interview Guide for the HDRS17 (Structured Interview Guide for the HDRS17
[SIGH-D]).
a) The participant must be in a current MDE with a total score >20 and with a score >2 on the
depressed mood item [question #1].
3) The ATHF-SF.
a) The participant must not have taken any disallowed medications (per appendix 6) during
the 4 weeks prior to the initial screening visit. Disallowed medications include
antidepressents.
If applicable, the Mood Stabilizer and Antipsychotic Eligibility Assessment form  will be
completed for participants who are on a stable regimen of an antipsychotic and a mood stabilizer
for four weeks before screening.
Once potential participants have met eligilibity requirements for the MINI, SIGH-D, and
ATHF-SF, and the Mood Stabilizer and Antipsychotic Eligibility Assessment form (if applicable)
the remaining screening procedures may be completed (see Sections 5.1 and 5.2 for details).
Participants will be screened (collection of a blood sample) to ascertain their eligibility for the
study, based on the presence of GoF P2RX7 mutation and the absence of the LoF P2RX7
mutations. Further screening will include the full assessment of study inclusion and exclusion
criteria, medical history, demographics, physical examination, psychiatric and safety evaluations,
and standard laboratory tests. The remaining assessments may be divided over multiple days,
according to operational and/or site/country-specific needs and may take place before or after the
P2RX7 genotyping results and other laboratory results become available.
After all inclusion and exclusion criteria have been met and confirmed, the participant will be
invited to return to the study center for Day 1 of the double-blind treatment study period.


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It is recommended that during screening (Visit 1), the Digital Health Assessment app  will be
downloaded but, if this is not feasible, it is allowed to be performed at Visit 2 instead. Site staff
will check to see if the participant’s phone is compatible with the app. If the participant has a phone
that is not compatible with the app, a compatible phone may be provided for use in the study. In
the Digital Health Assessment app, the date of Visit 2 (i.e., Baseline; Study Day 1) should be
entered in the dashboard. It is important that the latter is done to ensure that the participant starts
receiving the questions from Study Day 1 onwards.
After all inclusion and exclusion criteria have been met and confirmed, the participant will be
invited to return to the study center for Day 1 of the double-blind treatment study period.
8.1.2. 
Baseline Visit (Visit 2; Study Day 1)
The study participant will be asked to come to the study site in fed condition (i.e., to eat a meal
before coming to the study site). During the study visit, all assessments will be completed per the
SoA. For the “Study Assessments and Procedures” see Section 8.
If the participant is still eligible based on the inclusion and exclusion criteria, the participant will
be randomized and supplied with study intervention. The first dose of study intervention will be
taken in the fed condition on Day 1 when the participant is at the study site. All baseline study
assessments must be completed before taking the study intervention.
8.1.3. 
Double-blind Treatment Phase (Visit 2 to Visit 6)
The double-blind treatment phase will start on the day of first study intervention administration -
the baseline visit (i.e., Visit 2; Study Day 1).
From Day 2 onwards, the participant will take the study intervention at home in the fed condition.
During this phase, the participant will visit the study site weekly or every 2 weeks. At each study
visit, the participant should come to the study site in the fed condition and will take his/her dose
at the study site after predose blood collections. Study intervention administration should be
witnessed by the study staff. At each study visit, participants should bring their study medication
with them and return used and partly used bottles.
During the study visits, all assessments will be completed per the SoA. For the “Study Assessments
and Procedures” see Section 8.
Between visits, the Digital Health Assessment app will ask the participant about their current
depressive state and they will receive questions about their well-being (SAWB). Additionally, they
will also need to complete self-rating instruments on paper (see SoA and Section 8.5 for an
overview of the self-rating instruments). For self-rating instruments completed at home on paper,
participants will receive notifications from the Digital Health Assessment app on their mobile
phones as reminders to complete these paper instruments.


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8.1.4. 
Follow-up or Early Withdrawal Visit (Visit 7)
All participants will have to complete Visit 7 (final follow-up visit or early withdrawal visit).
Participants who prematurely withdraw from the study are encouraged to complete Visit 7. During
Visit 7, all assessments will be completed per the SoA.
8.2. 
Screening Instruments
8.2.1. 
MINI International Neuropsychiatric Interview with Borderline
Personality Disorder module
The MINI (Sheehan 1998) to assess DSM-5 depressive features in manic and hypomanic episodes
is a short structured diagnostic interview which can be administered by clinicians including
research nurses and research assistants. The MINI will be completed with a Borderline Personality
Disorder module. An appropriately trained staff member at the investigational site will perform
the MINI interview once during the screening phase.
8.2.2. 
P2RX7 GoF and LoF SNP Analysis
Pharmacogenomic blood samples will be collected to assess whether the participant is a carrier of
the allele variants for a GoF P2RX7 SNP (≥1 copy of the  allele for 
[
needed for inclusion) and 2 LoF P2RX7 SNPs (2 copies of the
 allele for
 [rs
]
and/or ≥1 copy of the 
allele for 
 [rs
] needed for exclusion). In other words,
participants will be excluded if they have the presence of two copies of the LoF  allele at
rs
 (exclude those with 
 at nucleotide 
), and/or has one or more copies of the LoF
 allele at rs
 (exclude those with
 or 
nucleotide
).
This assessment will include the collection of a blood sample that can be collected along with the
other screening clinical laboratory tests. In case participants need to be rescreened, this is the only
assessment that does not need to be performed again.
8.2.3. 
Antidepressant Treatment History Form-Short Form (ATHF-SF)
The 
ATHF-SF  
consists 
of 
scoring 
instructions 
and 
ratings 
for 
most
antidepressants / augmentation / and ECT trials. The ATHF-SF documents the administration of
common depressantsants, as well as brain/nerve stimulation interventions (ECT, TMS, and VNS),
and provides explicit criteria to assess the adequacy of these interventions with established
efficacy.
8.2.4. 
17-Item Hamilton Depression Rating Scale (HDRS17)
The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms
in participants diagnosed with depression (Hamilton 1960) with a total score range of 0 to 52, with
higher scores indicating greater severity of depressive symptoms. It is the most widely used
symptom severity measure for depression. The HDRS17 will be administered at screening and at
baseline, by an appropriately trained staff member, using the SIGH-D.
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8.3. 
Efficacy Assessments
8.3.1. 
Montgomery-Åsberg Depression Rating Scale (MADRS)
The MADRS is a clinician-rated scale designed to measure depression severity and detects changes
due to antidepressant treatment (Montgomery 1979). The scale consists of 10 items, each of which
is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms),
for a total possible score of 60. Higher scores represent a more severe condition. The MADRS
evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration,
lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. The test
exhibits high inter-rater reliability. The MADRS will be administered by an appropriately trained
staff member, using the SIGMA.
8.4. 
Secondary Assessments
8.4.1. 
Clinical Global Impression—Severity scale (CGI-S)
The CGI-S provides an overall clinician-determined summary measure of the severity of the
participant’s illness that takes into account all available information, including knowledge of the
participant’s history, psychosocial circumstances, symptoms, behavior, and the impact of the
symptoms on the participant’s ability to function (Guy 1976). The CGI-S evaluates the severity of
psychopathology on a scale of 0 to 7. Considering total clinical experience, a participantis assessed
on severity of mental illness at the time of rating according to: 0=not assessed; 1=normal (not at
all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill;
7=among the most extremely ill patients. The CGI-S permits a global evaluation of the
participant’s condition at a given time.
8.5. 
Self-Rating Instruments
 
The patient reported outcome (PRO) instrument will be provided in the local language in
accordance with local guidelines.
 
The PRO instrument must be available for regulators and for IRB/ERC submissions, therefore
the PRO instrument or screen shots need to be attached to the protocol or provided in a
companion manual with the instruments that will be submitted with the protocol.
 
Non completion of the PRO instrument will not be considered a protocol deviation ifthe scale
has not been approved by the IRB/ERC.
 
The PRO and AE data will not be reconciled with one another.
8.5.1. 
Snaith-Hamilton Pleasure Scale (SHAPS)
An instrument developed for the assessment of hedonic capacity is the 14-item, self-report,
Snaith-Hamilton Pleasure Scale (Snaith et al., 1995). The SHAPS was developed to minimize
cultural, gender, and age biases in the evaluation of hedonic capacity. It not only measures hedonic
tone, but also its absence, i.e. anhedonia. Anhedonia can be a core symptom of depression. Four
major domains are covered in the scale, namely interest/pastimes, social interaction, sensory
experience, and food/drink.


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8.5.2. 
PROMIS—Ability to Participate in Social Roles and Activities
The PROMIS—Ability to Participate in Social Roles and Activities item bank assesses the
perceived ability to perform one’s usual social roles and activities. The item bank does not use a
time frame (e.g., over the past 7 days) when assessing ability to participate in social roles and
activities. The Short Form 4a includes 4 items that represent this concept. Each question has 5
response options ranging in value from 1 to 5. The total raw score for the short form is calculated
by summing the values of the response to each question, so for the 4-item form, the lowest possible
raw score is 4; the highest possible raw score is 20.
8.5.3. 
Patient Health Questionnaire-9 (PHQ-9)
The 9-item PHQ-9 scale scores each of the 9 symptom domains of the DSM-5 MDD criteria, and
it has been used both as a screening tool and a measure of response to treatment for depression
(Kroenke 2001). Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than
half the days, and 3=nearly every day). The participant’s item responses are summed to provide a
total score (range 0 to 27), with higher scores indicating greater severity of depressive symptoms.
The recall period is 2 weeks.
8.5.4. 
Generalized Anxiety Disorder-7 (GAD-7)
The GAD-7 is a self-reported questionnaire for screening for and measuring the severity of GAD.
The GAD-7 has 7 items, which measure the severity of various signs of GAD according to reported
response categories with assigned points. Assessment is indicated by the total score (0 to 21),
which is calculated by adding together the scores for all 7 items. For each item, as well as for the
total score, a higher score represents a more severe condition.
8.6. 
Safety Assessments
Adverse events will be reported and followed by the investigator as specified in Section 7, Adverse
Events, Serious Adverse Events, and Other Safety Reporting, and Appendix 4: Adverse Events,
Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
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. After
completion of the study, a safety follow-up visit may be scheduled if deemed necessary by the
study responsible safety physician or the investigator (e.g., for the collection af additional blood
or urine samples).
The study will include the following evaluations of safety and tolerability according to the time
points provided in the SoA.


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8.6.1. 
Physical Examinations
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.
8.6.2. 
Vital Signs
Body temperature (oral, tympanic, or temporal), pulse/heart rate, respiratory rate, blood pressure
will be assessed.
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 have to be preceded by at least 5 minutes of rest
in a quiet setting without distractions (e.g., television, cell phones).
8.6.3. 
Electrocardiograms
Twelve-lead ECGs, intended for safety monitoring, will be recorded in supine position (following
5 minutes of rest) so that the different ECG intervals (pulse/heart rate [BPM], PR [msec], QRS
duration [msec], QT interval, and QTc [msec])can be measured at multiple timepoints at screening
and during the study as indicated in the SoA.
During the collection of ECGs, it is recommended that participants stay in a quiet setting without
distractions (e.g., television, cell phones). It is recommended that participants rest in a supine
position for at least 5 minutes before ECG collection and refrain from talking or moving their arms
or legs. If blood sampling or vital sign measurement is scheduled for the same time point as ECG
recording, it is recommended the procedures be performed in the following order: ECG(s), vital
signs, blood draw.
At each timepoint at which triplicate ECGs are required, 3 individual ECG tracings will be
obtained as closely as possible in succession. The full set of triplicates will be completed in less
than 8 minutes.
Clinically relevant abnormalities occurring during the study should be recorded in the AE Section
of the eCRF.
8.6.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry, hematology, hormone levels (if applicable), and pregnancy
testing (if applicable) and urine samples for urinalysis and pregnancy testing (if applicable) will
be collected as noted in Appendix 2: Clinical Laboratory Tests. The investigator must review the
laboratory results, document this review, and record any clinically relevant changes occurring
during the study in the AE section of the electronic case report form (eCRF). In addition, serology


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and HbA1C assessments will be performed at screening only. The laboratory reports must be filed
with the source documents.
A urine drug screen (UDS) and an alcohol breath test will be performed at the timepoints indicated
in the SoA.
8.6.5. 
Pregnancy Testing
For WOCBP, a negative screening serum pregnancy test must be obtained at screening. Urine
pregnancy testing will be performed before the first dose of study intervention on Day 1 and at all
subsequent visits to the study site.
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.
8.6.6. 
Suicidal Ideation and Behavior Risk Monitoring
8.6.6.1. 
Young Mania Rating Scale (YMRS)
The YMRS is one of the most frequently utilized rating scales to assess manic symptoms
(Young 1978). The scale has 11 items and is based on the patient’s subjective report ofhis or her
clinical condition over the previous 48 hours. Additional information is based upon clinical
observations made during the clinical interview. The items are selected based upon published
descriptions of the core symptoms of mania. There are 4 items (irritability, speech, thought content,
and disruptive/aggressive behavior) that are graded on a 0 to 8 scale, while the remaining 7 items
are graded on a 0 to 4 scale. These 4 items are given twice the weight of the others to compensate
for poor cooperation from severely ill patients. There are well described anchor points for each
grade of severity. The YMRS total score, with range of 0 to 60, is the sum of each of the 11
individual scores, with higher total YMRS scores reflecting greater symptom severity.
The scale is generally performed by a qualified clinician or other qualified trained rater with
expertise with manic patients and takes 15 to 30 minutes to complete.
8.6.6.2. 
Columbia Suicide Severity Rating Scale (C-SSRS)
An interview to assess the risk of suicidal ideation and behavior will be conducted at regular
timepoints during the study from screening through the follow-up visit, as indicated in the SoA.
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was
developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters
Study to assess severity and track suicidal events through any treatment. The C-SSRS is a clinical
interview providing a summary of both ideation and behavior that can be administered during any
evaluation or risk assessment to identify the occurrence and intensity of suicidal thoughts and
suicidal behaviors. It can also be used during treatment to monitor for clinical worsening.
If a suicide-related thought or behavior is identified at any time during the study, a thorough
evaluation will be performed by a study physician, and appropriate medical care will be provided.


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8.6.6.3. 
Follow-up of Well-Being and Depression
The SAWB questionnaire is a multiple-item self-report questionnaire designed to provide
additional information regarding the participant’s subjective experience while taking study
intervention. This is an internal Janssen questionnaire, and the questions will be asked to the
participant daily by the Digital Health Assessment app during the double-blind treatment phase.
Several items of interest can be covered: such as, but not limited to, the pattern of sleep, energy
level, and concentration level. The Digital Health Assessment app will also alert the investigator
when a participant has indicated that their depression is ‘much worse’ or ‘very much worse’ when
answering weekly questions on depression.
8.7. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and product quality complaints (PQCs), 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.
AEs 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 and for 30 days after
the last dose of study intervention.
AEs of special interest (AESI) have not yet been defined in this study. If observations of AEs
during the study require inclusion of AESI, a protocol amendment will be issued.
Further details on AEs, SAEs, and PQCs can be found in Appendix 4: Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.7.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated screening ICF through the day of last dose plus 30 days, which may include
contact for follow-up of safety.
Serious Adverse Events
All SAEs, as well as PQCs, 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.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety


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information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the CRF, which must be completed and reviewed by a physician
from the study site andtransmitted to the sponsor within 24 hours. The initial and follow-up reports
of an SAE should be transmitted electronically or by facsimile (fax). Telephone reporting should
be the exception and the reporter should be asked to complete the appropriate form(s) first.
8.7.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
8.7.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety  Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
8.7.4. 
Regulatory Reporting Requirements for Serious Adverse Events and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). 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.
An anticipated event is an AE that commonly occurs in the study population independent of
exposure to the intervention under investigation. For the purposes of this study, the following
SAEs will be considered anticipated events:
 
Depression
 
Mania
 
Suicidal ideation/thinking/behavior
 
Suicide attempt


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 
Bipolar disorder (bipolar I/bipolar II)
 
Depression suicidal
 
Overdose
 
Intentional self-injury
 
Anxiety
 
Panic attacks
 
Substance abuse
 
Alcohol abuse
 
Intoxication
 
Aggression
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the intervention group than in the
control group and the sponsor concludes there is a reasonable possibility that the study intervention
under investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events
according to the requirements of the countries in which the studies are conducted.
8.7.5. 
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 (e.g.,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must be promptly withdrawn from the study and discontinue further
study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.8. 
Pharmacokinetics
Venous blood samples will be collected for PK evaluation as indicated in SoA. Samples will be
used to evaluate the plasma concentrations of JNJ-55308942 and metabolites (if required). In
addition, some samples may be used to measure plasma concentrations of concomitant medications
used by the participant. Participant confidentiality will be maintained.


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8.8.1. 
Evaluations
Venous blood samples of approximately  2 mL will be collected for measurement of plasma
concentrations of JNJ-55308942 as per SoA. The exact dates and times of blood sampling must be
recorded in the eCRF.
8.8.2. 
Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of JNJ-55308942 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 samples may be analyzed to document the presence of circulating
metabolites using a qualified research method. In addition, plasma PK samples may be stored for
future analysis of other co-administered treatments and the metabolite profile.
8.8.3. 
Pharmacokinetic Parameters and Evaluations
Pharmacokinetic and statistical analyses will be done by the sponsor or under the authority of the
sponsor. A general description of the methods to be used to analyze the PK data is outlined below.
Specific details will be provided in the PK Analysis Plan. Data will be listed for all participants
with available JNJ-55308942 plasma concentrations by intervention. Participants will be excluded
from the PK analysis if their data do not allow for accurate assessment of the PK (e.g.,
non-adherence to study intervention administration; missing PK draws; or early discontinuation
from the study). All concentrations below the lowest quantifiable (BLQ) concentration or missing
data will be labeled as such in the concentration data presentation. Concentrations below the BLQ
concentration will be treated as zero in the summary statistics. All participants and samples
excluded from the analysis will be clearly documented in the study report.
For all participants, based on the individual plasma concentration-time data, using the binned
nominal sampling times, the following JNJ-55308942 concentrations will be summarized at Visits
2, 3, 4, 5, and 6.
Cpre-dose: observed plasma concentration measured before study intervention intake.
C1.5h: observed plasma concentration at approximately 1.5 hours after study intervention intake
(sampling window of +/- 0.5 hours).
C4h: 
observed plasma concentration at approximately 4 hours after study intervention  intake
(sampling window will be 2 to 4 hours post-dose, to allow flexibility, but with the preferred time
point being 4 hours postdose).
Other PK parameters may be calculated as needed to characterize the PK of JNJ-55308942.
Population PK analysis of plasma concentration-time data of JNJ-55308942 may be performed if
deemed useful using nonlinear mixed-effects modeling. If performed, details may be given in a


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population PK analysis plan and the results of the population PK analysis will be presented in a
separate report.
Pharmacokinetic/Pharmacodynamic Evaluations
The exposure-response between JNJ-55308942 and MADRS may be explored. The exposure-
response between exposure and adverse events may also be explored. When applicable, details of
this PK/PD analysis may be given in a separate analysis plan and the results will be presented in a
separate report.
8.9. 
Genetics and Pharmacogenomics
A blood sample will be collected during screening to assess whether the participant:
 
is carrier of the
GoF P2RX7 mutation (must be
 or
 at
nucleotide
for inclusion).
 
is not a carrier of the 
or 
 LoF P2RX7 mutations (must be
 or 
 at
rs
/nucleotide 
; and must be 
 at rs
/nucleotide 
). In other words,
participants will be excluded if they have the presence of two copies of the LoF  allele at
rs
 (exclude those with 
 at nucleotide 
), and/or has one or more copies of the
LoF
 allele at rs
 (exclude those with
or
nucleotide
).
A second pharmacogenomic optional blood sample will be collected from enrolled participants on
Day 1 to identify genetic factors that may influence the PK, PD, efficacy, safety, and/or tolerability
of JNJ-55308942 and to identify genetic factors associated with BD. If collection on Day 1 is not
feasible, it can be collected on any other visit during the double-blind treatment phase.
8.10. Biomarkers
Venous blood samples for the assessment of whole blood, serum, and plasma PD related
biomarkers will be collected as indicated in the SoA during the double-blind treatment phase.
Biomarker measurements may include cytokine levels, such as TNF-α, IL-1β, IL-6, IL-10 and
inflammatory markers, such as IL-6 receptor, CRP, and other exploratory markers. Samples may
also be used to study markers of P2X7 and monocyte activation via IL-1β release, shed P2X7
receptor and TREM2 ectodomains, and RNA expression of P2RX7, IL-1β, and other genes related
to immune and HPA axis activity. Treatment effects will be analyzed in patients with specific
biomarker profiles using statistical modeling.
Biomarker blood samples that may be collected for the research assays measuring functional
inhibition of P2X7 receptor in whole blood (TruCulture) may be collected at certain sites in the
US, Canada, Spain, and Poland, and those collected for peripheral blood mononuclear cells
(PBMCs) inflammatory profiles is taken in the US. The list of countries for these 2 biomarker
assays may be updated if countries are added or removed throughout the study. This change will
not be considered a protocol deviation.
All biomarker data obtained during this study may be included in ongoing cross-study analyses to
investigate the relationship between depression severity, phenotypes, and biomarkers, or to help
explain interindividual variability in clinical outcomes or safety. Biomarker assays may be added
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or deleted based on scientific information or technical innovations under the condition that the
total volume of blood collected will not be increased.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical response rates. Biomarker analyses may be deferred or not performed, if during or at the
end of the study, it becomes clear that the analyses 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 or shows poor clinical efficacy,
completion of biomarker assessments may not be performed.
8.11. 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not
evaluated in this study.
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 statistical analysis plan (SAP).
9.1. 
Statistical Hypotheses
JNJ-55308942, compared to placebo, results in a significant improvement in the severity of the
symptoms of depression in participants with BD in an MDE, as evaluated by change in MADRS
total score from baseline at Week 6.
Hypotheses will be tested at 1-sided alpha 0.10. Multiplicity adjustment will not be carried out.
9.2. 
Sample Size Determination
The estimated sample size of 164 participants (82 participants per group) was determined based
on the assumption of an effect size of at least 0.45 for the MADRS total score (difference in mean
change from baseline at Week 6 between the JNJ-55308942 and placebo groups of 3.9 units with
a standard deviation of 8.6). This is considered to be a clinically relevant difference in a population
with BD types I or II. The standard deviation of 8.6 in the change in MADRS total score from
baseline is a reasonable assumption based on data in a published phase 3 study of quetiapine in
BD type I and type II depression (Calabrese 2005). Power is set at 90%, with a 1-sided alpha of
0.10 and a 6-week drop-out rate of 20%. The estimated number of completers to be included in
the primary analysis is 132.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants who signed the ICF at screening


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Randomized 
All participants who were randomized in the study
Safety  
All randomized participants who received at least 1 dose of study intervention
Full analysis set 
(FAS) 
All randomized participants who received at least 1 dose of study intervention and have both
the baseline and at least 1 post-baseline MADRS measurement
9.4. 
Statistical Analyses
The SAP will be finalized prior to database lock and it will include a more technical and detailed
description of the statistical analyses described in this section. This section is a summary of the
planned statistical analyses of the most important endpoints, including primary and secondary
objectives of special interest.
9.4.1. 
Primary Endpoint(s)
Efficacy analyses will be based on the full analysis set.
The estimand for the primary efficacy analysis is defined with the following 5 attributes:
 
Population: participants with BD types I or II and in an MDE.
 
Endpoint: change from baseline in the MADRS total score at Week 6.
 
Treatment: JNJ-55308942
 mg once-daily versus placebo.
 
Population-level summary: the difference in mean change from baseline in MADRS total
score at Week 6 between JNJ-55308942
 mg once-daily and placebo.
 
Intervention events (ICE) and corresponding strategy: The ICE to be considered is
discontinuation of study intervention. The ICE will be addressed with a hypothetical strategy,
targeting 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 primary efficacy analysis will be performed utilizing the hypothetical estimand defined above.
The change from baseline in MADRS total score will be compared between the JNJ-55308942
mg once-daily group and the placebo group at Week 6 in a mixed-effects model using repeated
measures (MMRM), with time, treatment (placebo or JNJ-55308942), BD type (I or II), country,
concomitant medication status (no mood stabilizer or antipsychotic, a mood stabilizer alone, an
antipsychotic alone, a combination of a mood stabilizer and an antipsychotic), P2RX7 GoF SNP
genotype (homozygous or heterozygous) and time-by-treatment interaction as factors, with
baseline MADRS total score as a continuous covariate. Data after treatment discontinuation will
be considered as missing. An unstructured variance-covariance matrix will be used. In case of
convergence problems, alternative variance-covariance structures will be attempted in the
following order, with the first structure that converges being used in the analysis: heterogeneous
Toeplitz, standard Toeplitz, and first order autoregressive. Kenward-Roger approximation will be
used to estimate the denominator degrees of freedom. Sandwich estimator will be used to address
the potential misspecification of the covariance matrix when a structured covariance matrix is used
due to the convergence problem with the unstructured covariance matrix. The comparison of
JNJ-55308942 versus placebo will be performed using the appropriate contrast.
To support the primary efficacy analysis, 2 sensitivity analyses will be performed:
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 
MMRM analysis with copy-reference multiple imputation where missing outcomes due to
treatment discontinuation in the JNJ-55308942 
 mg once-daily group are assumed to be
similar to those in the placebo group.
 
Tipping point analysis that imputes missing outcomes over a range of possible scenarios for
the treatment effect and finds a ‘tipping point’ where the treatment effect in participants with
missing data overturns the significant treatment effect. This analysis will be performed if the
results from the primary analysis show a significantly greater improvement in the MADRS
total score at Week 6 in the JNJ-55308942
 mg once-daily group compared to the placebo
group.
Response and remission rates with respect to MADRS will be summarized by treatment group and
by scheduled timepoint.
9.4.2. 
Secondary Endpoint(s)
For the secondary objectives of special interest, changes from baseline in SHAPS total score at
Week 6 will be compared between JNJ-55308942
 mg once-daily and placebo in an ANCOVA
model. The model will include intervention (placebo or JNJ-55308942), BD type (I or II), country,
concomitant medication status (no mood stabilizer or antipsychotic, a mood stabilizer alone, an
antipsychotic alone, a combination of a mood stabilizer and an antipsychotic), P2RX7 GoF SNP
genotype (homozygous or heterozygous) as factors, and baseline SHAPS total score as a covariate.
Comparison between JNJ-55308942 
 mg once-daily and placebo will be performed using
appropriate contrasts. Change from baseline in MADRS total score will be assessed with
confidence intervals in subgroups for BD type (I or II), P2RX7 GoF SNP genotype (heterozygous
or homozygous), and patients with specific biomarker profiles (yes or no) using a similar MMRM
as the one used for the primary endpoint analysis.
For the other secondary objectives, similar MMRM analyses will be conducted for changes in the
T-score of PROMIS –Ability to Participant in Social Roles and Activities, the PHQ-9 total score,
and the GAD-7 total score. Subgroup analyses by mRNA transcript (P2RX7 and IL-1β) level status
at baseline (yes or no) and use of concomitant medication (no mood stabilizer or antipsychotic, a
mood stabilizer alone, an antipsychotic alone, a combination of a mood stabilizer and an
antipsychotic) will also be conducted for the change from baseline in MADRS total score using a
similar MMRM.
For the CGI-S efficacy endpoint, a frequency distribution of severity scores will be provided by
treatment group from Week 1 to Week 6. In addition, frequency of shifting scale at Week 6 from
baseline will be provided.
Descriptive statistics will be provided for the SAWB assessments.
9.4.3. 
Safety Analyses
All safety analyses will be performed on the Safety population.
Statistical analysis of the safety data will be done by the sponsor or under the authority of the
sponsor. Specific details will be provided in the SAP.
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Safety summaries will be provided by treatment, unless specified otherwise.
AEs will be coded using the current version of Medical Dictionary for Regulatory Activities
(MedDRA) and tabulated by system organ class, by severity and relationship to study intervention
and will be presented by intervention. SAEs will be summarized separately.
The safety analysis will include the incidence of AEs, actual data and changes in blood pressure,
pulse/heart rate, oral, tympanic, or temporal body temperature, laboratory safety data, 12-lead
ECG, and physical examination data from Day 1 predose to all postdose assessments.
Results from the C-SSRS will be tabulated by treatment group for all participants receiving at least
1 dose of study intervention.
Exploratory analyses for changes in YMRS total score, as well as for individual YMRS items,
from baseline will be performed. Details will be provided in the SAP.
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 AEs 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 study  intervention group. In addition, comparisons between  study
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 studyintervention due to an AE, or who experience a severe
or a serious AE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges  will be used in
the summary of laboratory data. Descriptive statistics will be calculated for each laboratory analyte
at baseline (Day 1 predose) and at each scheduled time point. Changes from baseline results will
be presented in pre- versus post-treatment cross-tabulations (with classes for below, within, and
above normal ranges).
Electrocardiogram
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 pulse/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).


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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 (males), >470
(females), >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. Also, descriptive statistics of
QTc will be provided by gender.
Vital Signs
Descriptive statistics of body temperature, pulse/heart rate, supine blood pressure 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 Examinations
Abnormalities observed during the physical examination will be summarized and listed by
treatment group at each scheduled time point.
9.4.4. 
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics, including arithmetic mean, standard deviation (SD), coefficient of variation,
geometric mean, median, minimum, and maximum will be calculated for the JNJ-55308942
plasma concentrations at each sampling time. For other demographic covariates, as specified in
the PK analysis plan, descriptive statistics will also be calculated.
Mean and/or median plasma JNJ-55308942 concentration-time profiles will be plotted. Individual
plasma concentration-time profiles may also be plotted.
Population PK analysis of plasma concentration-time data of JNJ-55308942 may be performed if
deemed useful using nonlinear mixed-effects modeling. Details will be given in a population PK
analysis plan and the results of the population PK analysis will be presented in a separate report.
Biomarkers Analyses
Biomarker data will be tabulated for each time point and summary statistics will be calculated.
Post-treatment changes in each assay will be assessed.
The remaining exploratory biomarkers will be tabulated by intervention and summary statistics
will be calculated. Post-treatment changes in exploratory biomarkers will be summarized by
intervention group. Associations between baseline biomarker levels and clinical endpoints may be
explored. Also, exploratory analyses on P2RX7 and IL-1β mRNA signatures may be performed.
Planned biomarker analyses may not be performed if emerging study data show no likelihood of
providing useful scientific information. Results may be presented in a separate biomarkers report.
Pharmacokinetic/Pharmacodynamic Analysis
The exposure-response between JNJ-55308942 and MADRS may be explored. The exposure-
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applicable, details of this PK/PD analysis may be given in a separate analysis plan and the results
will be presented in a separate report.
Genetic and Pharmacogenomic Analyses
DNA samples will be analyzed to assess whether the participant is a carrier of allele variants for
P2RX7 in order to determine eligibility for the study, and to identify genetic factors that may
influence the PK, PD, safety, and/or tolerability of JNJ-55308942. As part of the exploratory
analysis, mutations of the 
 enzyme (
[rs
 and 
[rs
]) will
be measured and may be compared to PK data. Additional analyses may be conducted if it is
hypothesized that this may help resolve issues with the clinical data.
DNA samples will be used for research related to JNJ-55308942 and/or BD. They may also be
used to develop tests/assays related to JNJ-55308942 and/or BD. Pharmacogenomic research may
consist of the analysis of 1 or more candidate genes or the analysis of genetic markers throughout
the genome (as appropriate) in relation to JNJ-55308942 and/or BD clinical endpoints.
Results will be presented in a separate report.
9.5. 
Interim Analysis
No interim analysis is foreseen.
It may be recommended that a data review needs to be performed by an independent reviewer (e.g.,
safety review committee), if deemed critical by the Janssen clinical team. Committee membership
responsibilities, authorities, and procedures will be documented in a charter.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. 
Appendix 1: Abbreviations
ABV  
alcohol-by-volume
AE  
adverse event
ALP  
alkaline phosphatase
ALT 
alanine aminotransferase
AST 
aspartate aminotransferase
ATHF-SF  
antidepressant treatment history form-short form
ATP  
adenosine triphosphate
AUC  
area under the curve
BCRP  
breast cancer resistance protein
BD  
bipolar disorder
BMI 
body mass index
BUN 
blood urea nitrogen
BzATP  
benzoyl-ATP
CGI 
Clinical Global Impression
CGI-S  
Clinical Global Impression-Severity scale
CNS 
central nervous system
CPK 
creatine phosphokinase
Cplasma 
plasma concentration
CRF  
case report form(s) (paper or electronic as appropriate for this study)
C-SSRS  
Columbia Suicide Severity Rating Scale
CYP  
cytochrome P450
DBP  
diastolic blood pressure
DBS  
deep brain stimulation
DNA  
deoxyribonucleic acid
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
DTP  
direct-to-patient
ECT 
electroconvulsive therapy
ECG  
Electrocardiogram
eCRF  
electronic data capture system
eDC  
electronic data capture
EW  
early withdrawal
FDA  
US Food and Drug Administration
FSH  
follicle stimulating hormone
GAD-7 
Generalized Anxiety Disorder 7
GCP 
Good Clinical Practice
GGT 
gamma-glutamyl transferase
GLP  
Good Laboratory Practice
GoF  
Gain of Function
GST 
glutathione S-transferase
HbA1c 
hemoglobin A1c
HBsAg 
hepatitis B surface antigen
HCV 
hepatitis C virus
HDRS17 
17-item Hamilton Depression Rating Scale
HEK293 
human embryonic kidney cells
hERG  
human Ether-à-go-go-Related Gene
HIV 
human immunodeficiency virus
HPA  
hypothalamic-pituitary-adrenal
HRT 
hormonal replacement therapy
IB 
investigator’s brochure
ICF  
informed consent form
ICH  
International Conference on Harmonization
ICMJE  
International Committee of Medical Journal Editors
IEC  
Independent Ethics Committee
IL 
Interleukin


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IMP 
Investigational Medicinal Product
IRB  
Institutional Review Board
ITT 
intent-to-treat
IUD 
intrauterine device
IUS 
intrauterine hormone-releasing system
IV 
Intravenous
IWRS  
interactive web response system
LC-MS/MS  
liquid chromatography/mass spectrometry/mass spectrometry
LDH  
lactic acid dehydrogenase
LDL  
low density lipoprotein
LH  
luteinizing hormone
LOEL  
lowest observed effect level
LoF  
loss of function
LPS  
Lipopolysaccharide
LTM  
local trial manager
MAD  
multiple ascending dose
MADRS  
Montgomery-Åsberg Depression Rating Scale
MATE  
multidrug and toxin extrusion
MCH  
mean corpuscular hemoglobin
MCV  
mean corpuscular volume
MDD  
major depressive disorder
MDE  
major depressive episode
MDR1 
multidrug resistance protein 1
ME 
manic episode
MedDRA  
Medical Dictionary for Regulatory Activities
MINI 
Mini International Neuropsychiatric Interview
MMRM  
mixed-effects model for repeated measures
mRNA  
messenger ribonucleic acid
NIMH 
National Institute of Mental Health
NIMP 
Non-Investigational Medicinal Product
NOAEL  
no observed adverse effect level
NOEL  
no observed effect level
OAT 
organic anion transporter
OATP  
organic anion transporter polypeptide
OCT 
organic cation transporter
PBMC  
peripheral blood mononuclear cells
PCRS  
placebo-control reminder script
PD  
pharmacodynamic(s)
PET 
positron emission tomography
PHQ-9 
Patient Health Questionnaire-9
PK 
pharmacokinetic(s)
PQC  
Product Quality Complaint
PRO  
patient reported outcome
QTc 
corrected QT
QTcB  
QT corrected according to Bazett's formula
QTcF  
QT corrected according to Fridericia's formula
QWBA  
quantitative whole-body autoradiography
RBC  
red blood cell
RD  
repeated dose
RNA  
ribonucleic acid
RO  
receptor occupancy
SAE  
serious adverse event
SAD  
single ascending dose
SAP  
statistical analysis plan
SAWB  
Self-Assessment of Well-Being questionnaire
SBP  
systolic blood pressure
SD 
standard deviation
SHAPS  
Snaith-Hamilton Pleasure Scale


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SIGH-D  
Structured Interview Guide for the HDRS17
SIGMA 
Structured Interview Guide for the MADRS
SNP 
single-nucleotide polymorphism
SoA 
Schedule of Activities
SRP  
study responsible physician
SUSAR  
suspected unexpected serious adverse reaction
TEAE  
treatment emergent adverse event
Tbili 
total bilirubin
tDCS  
transcranial direct current stimulation
TMS  
transcranial magnetic stimulation
UDS  
urine drug screen
VNS  
vagal nerve stimulation
WBC  
white blood cell
WHO  
World Health Organization
WMH  
World Mental Health
WOCBP  
women of childbearing potential
WONCBP  
women of non-childbearing potential
YMRS  
Young Mania Rating Scale
β-hCG  
β-human chorionic gonadotropin
Definitions of Terms
Cmax  
maximum plasma concentration
EC50 
The concentration of JNJ-55308942 producing 50% of maximal effect
EC90 
The concentration of JNJ-55308942 producing 90% of maximal effect
ED50 
median effective dose
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.
IC50 
50% inhibitory concentration
pIC50 
-log of 50% inhibitory concentration
pKi 
the negative logarithm of the molar concentration of an antagonist that would
produce a 2-fold shift in the concentration response curve for an agonist
Tmax  
time to reach the maximum plasma concentration
T1/2 
time required for a quantity to reduce to half of its initial value.


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10.2. 
Appendix 2: Clinical Laboratory Tests
The following tests will be performed according to the Schedule of Activities by the central
laboratory.
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology  
Platelet count
Red blood cell count
Hemoglobin
Hematocrit
RBC Indices: 
MCV  
MCH  
% Reticulocytes 
White Blood Cell
(WBC) count with
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical
Chemistry
Sodium  
Potassium  
Chloride 
Bicarbonate 
Blood urea nitrogen (BUN) 
Creatinine 
Glucose 
Aspartate aminotransferase 
(AST)/Serum glutamic-oxaloacetic 
Alanine aminotransferase (ALT)/Serum 
glutamic-oxaloacetic 
Gamma-glutamyltransferase (GGT) 
Total bilirubin (Tbili) and Direct
bilirubin
Alkaline phosphatase
Creatine phosphokinase (CPK)
Lactic acid dehydrogenase (LDH)
Uric acid
Calcium
Phosphate
Albumin
Total protein
Cholesterol
Triglycerides
Magnesium
Routine
Urinalysis
Dipstick  
Specific gravity  
pH  
Glucose 
Protein  
Blood 
Ketones 
Bilirubin  
Urobilinogen
Nitrite
Leukocyte esterase
Sediment (if dipstick result is
abnormal)
Red blood cells
White blood cells
Epithelial cells
Crystals
Casts
Bacteria
If dipstick result is abnormal, flow cytometry or microscopy will be used to
measure sediment.
Hormones 
Women only:
Follicle Stimulating Hormone (FSH) (at screening)
Males only:
Inhibin B
Luteinizing hormone (LH)
Prolactin
Total Testosterone (low sensitivity = LC/MS-MS)
Total Testosterone (high sensitivity = ELISA)
Free Testosterone


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Sex Hormone Binding Globulin (SHBG)
Other
Screening
Tests
 
Serum β-hCG pregnancy test performed at Screening (WOCBP only). At
all other time points, if the urine pregnancy test is positive, a serum β-
hCG test will be performed. Investigators may perform additional serum
or urine pregnancy testing at their discretion as clinically needed.
 
Serology (human immunodeficiency virus [HIV] antibody, hepatitis B
surface antigen [HBsAg], and hepatitis C virus [HCV] antibody)
 
HbA1c at screening
 
Urine drug screen (UDS) (opiates [including methadone], cocaine,
barbiturates, cannabinoids, and amphetamine/methamphetamine). At
screening: aurine sample will be analysed by the central lab. At all other
visits: a dipstick test will be used and only in case of a positive result will
the urine sample be analysed by the central lab for confirmation of the
positive result.
 
Alcohol breath test


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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
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 Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) Document may be prepared. The PCC Document will be communicated to
the Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC Document
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
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.
In situations where a departure from the protocol is unavoidable during the study, 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


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agree on an appropriate course ofaction. 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:
 
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, ICFs, 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 (e.g., Form FDA 1572), if applicable
 
Documentation of investigator qualifications (e.g., 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 (e.g., 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


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 
Local laboratory documentation demonstrating competence and test reliability
(e.g., 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 ICFs (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
 
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 ICFs 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 AEs that are serious, unlisted/unexpected, and associated with the study
intervention


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 
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).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.2.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators 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 study and
for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial
disclosure.
10.3.3. 
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.


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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. 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. The physician may also recontact the participant
for the purpose of obtaining consent to collect information about his or her survival status.
The participant will be given sufficient time to read the ICF(s)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.
A participant who is rescreened is not required to sign another ICF if the rescreening occurs within
35 days from the previous ICF signature date.
Where local regulations require, a separate ICF may be used for the required DNA and RNA
components of the study.
10.3.4. 
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.


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Exploratory DNA, PD, 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.
10.3.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand JNJ-55308942, to understand
differential intervention responders, and to develop tests/assays related to JNJ-55308942 and/or
any indication for which this compound is developed. 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 7.4.1, Withdrawal From the Use of Research Samples).
10.3.6. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding JNJ-55308942 or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including pharmacogenomic or exploratory biomarker
research data, generated as a result of this study, are considered confidential and remain the sole
property of the sponsor. The investigator agrees to maintain this information in confidence and use
this information only to accomplish this study and will not use it for other purposes without the
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of JNJ-55308942, 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 e.g.,
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


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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
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 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.
10.3.7. 
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.


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Guidelines for CRF completion will be provided and reviewed with study site personnel before
the start of the study.
The sponsor may review the 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 uploading the data into the study database, they will be verified for
accuracy and consistency with the data sources.
10.3.8. 
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 the CRF. All CRF entries, corrections,
and alterations must be made by the investigator or authorized study site personnel. The
investigator must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
the 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 (e.g., clinician-administered scales or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after
the initial entry into the CRF, this can be done in either of the following ways:
 
Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.9. 
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 AEs and follow-up of AEs; 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
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The author of an entry in the source documents should be identifiable. Given that patient-reported
outcomes (PROs) are reports of a patient's health condition that come directly from the patient,
without interpretation by a clinician or anyone else, the responses to PRO measures entered by
study participants into source records cannot be overridden by site staff or investigators.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The following data will be recorded directly into the CRF and will be considered source data:
 
Race
 
Blood pressure and pulse/heart rate
 
Height and weight
 
Details of physical examination
 
Investigator-completed scales and assessments
 
PROs
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 
Referral letter from treating physician
 
Complete history of medical notes at the site
 
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (e.g., electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. These data are electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system, but information collected through eSource may not be limited to that found in the
CRF.
10.3.10. 
Monitoring
The sponsor will use a combination of monitoring techniques; central, remote, or on-site
monitoring to monitor this study.
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 data entered into the CRF with the source documents (e.g.,


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hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature and
location of all source documents will be identified to ensure that all sources of original data
required to complete the CRF are known to the sponsor and study site personnel and are accessible
for verification by the sponsor study site contact. If electronic records are maintained at the study
site, the method of verification must be discussed with the study site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the
relevant study site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.3.11. 
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 regulatorybody, 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.
10.3.12. 
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


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in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of anystudy 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.
10.3.13. 
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/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 
Inadequate recruitment of participants by the investigator
 
Discontinuation of further study intervention development


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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per International Council 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 AEs starting with the signing of the ICF (refer to All Adverse Events
under Section  8.7.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An  SAE 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 should usually be considered serious.


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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (e.g., death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For JNJ-55308942, the expectedness of an AE will be determined by
whether or not it is listed in the IB.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort, and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional studythat may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention


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 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product [e.g., product name confusion, product label confusion,
intercepted prescribing or dispensing errors])
 
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 an SAE should be recorded on the SAE page of the CRF.
10.4.5. 
Procedures
All Adverse Events
All AEs, 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
AE to study therapy. All measures required for AE 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
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from 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


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 
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)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
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 an
SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form and
safety report form of the CRF, which must be completed and reviewed by a physician from the
study site and transmitted in a secure manner to the sponsor within 24 hours. The initial and follow-
up reports of an SAE should be transmitted in a secure manner electronically or by facsimile (fax).
Telephone reporting should be the exception and the reporter should be asked to complete the
appropriate form(s) first.
10.4.6. 
Product Quality Complaint Handling
Definition
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, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential
quality issue during manufacturing, packaging, release testing, stability monitoring, dose
preparation, storage or distribution of the product or the drug delivery system.
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.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.


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10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study 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 and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.7.5, Pregnancy and
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: 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.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or 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.
If reproductive status is questionable, additional evaluation should be considered.
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.


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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)
 Intrauterine hormone-releasing system (IUS)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(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.


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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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10.6. Appendix 6: Disallowed Concomitant Therapies
The pharmacotherapies listed below are permitted (Y) or excluded (N) due to potential impact on
efficacy evaluation and/or participant safety, or because they are indicated for exclusionary
conditions.
Except where specifically noted in the protocol, the prohibited therapies listed in this table are
prohibited from 4 weeks prior to the initial screening visit until 7 days after the last dose of study
medication.
The table below is intended for GENERAL GUIDANCE and is not exhaustive. Please contact the
study team to discuss any questions or concerns regarding any specific concomitant therapies for
a participant.
Of note, if any concomitant medication that is not listed below has the potential to be a strong or
moderate CYP
inhibitor or inducer, please check with the study team.
Drug Class 
Episodic 
Use (PRN) 
Continuous 
Use
Comments
ADHD Medications 
N 
N 
See also “Psychostimulants” row.
Amantadine 
N 
N
Anorexiants (e.g., 
phenteramine)
N 
N
Antibiotics: 
Macrolides
N 
N
Antibiotics: Nafcillin  N 
N
Antibiotics: 
Quinolones
N 
N
Anticonvulsants 
N 
N 
Lithium, valproic acid, and
lamotrigine products are permitted, per
protocol guidelines, for the indication
of bipolar disorder. Gabapentin and
pregabalin are allowed if not
prescribed for use as an
anticonvulsant.
Antidepressants 
N 
N
Antifungals 
N 
N 
Topical terbinafine is allowed.
Antipsychotics 
Y 
Y- if on a 
stable dose 
for 4 weeks
prior to
screening
lurasidone, cariprazine, quetiapine,
lumateperone, olanzapine are allowed.
Antivirals: non- 
nucleoside reverse
transcriptase inhibitor
(NNRTIs)
N 
N
CCI


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Antivirals: Protease 
Inhibitors
N 
N
Aprepitant 
N 
N
Avasimibe 
N 
N
Benzodiazepines (at 
doses equal to or less 
than the equivalent of 
2 mg/day of 
lorazepam) 
Y –
maximum of
3
consecutive
days PRN
Y –if on a
stable dose
for 4 weeks
prior to
screening
The ONLY permitted benzodiazepines
are as follows: clonazepam,
lorazepam, oxazepam, temazepam.
All other benzodiazepines are
prohibited.
Bosentan  
N 
N
Calcium Channel 
Blockers
N 
N
Chloral hydrate 
N 
N
Caffeine 
Y 
N 
Caffeine supplements and pills are
prohibited. Certain caffeine-containing
drinks (soda, tea, and coffee) are
allowed, but cannot exceed
500 mg/day.
Conivaptan  
N 
N
Corticosteroids 
N 
N 
Fluticasone permitted.
Cough/Cold/Allergy 
Preparations 
Y 
Y 
Dextromethorphan- and
diphenhydramine-containing products
are not allowed.
Crizotinib  
N 
N
Hypnotics (Non- 
Benzodiazepine)
Y 
Y
Fluticasone 
Y 
Y
Imatinib 
N 
N
Methyldopa 
N 
N
Opioids 
N 
N
St. John’s wort 
N 
N
Proton Pump 
Inhibitors (PPI) 
Y 
Y 
PPI levels may be increased.
Maximum doses of PPI medications
are not recommended.
Psychostimulants 
(e.g., amphetamine,
methylphenidate,
modafinil,
armodafinil)
N 
N
Scopolamine 
N 
N


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10.7. 
Appendix 7: Study Conduct During the COVID-19 Pandemic
10.7.1. 
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 unavailable, isolated or reassigned to critical tasks.
The sponsor is providing options for study related participant management 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 travel to the study site is considered to be
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes
necessary to discontinue participation in the study, the procedures outlined in the protocol for
discontinuing study intervention will be followed.
If, as a result of the COVID-19 pandemic , scheduled visits cannot be conducted in person at the
study site, they will be performed to the extent possible remotely/virtually or delayed until such
time that on-site visits can be resumed. At each contact, participants will be interviewed to collect
safety data. Key efficacy endpoint assessments should be performed if required and as feasible.
Participants will also be questioned regarding general health status to fulfill any physical
examination requirement.
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 via COVID-19 Appendix after consultation with the participant, investigator, and 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 will be communicated to the sites and to the health authorities according to local guidance.
If a participant tests positive for COVID-19 during the study, the investigator should contact the
sponsor’s responsible medical officer to discuss plans for administration of study intervention,
performing study assessments, 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.
10.7.2. 
Guidance Specific to this Protocol Related to the COVID-19 Pandemic
Scheduled Visits
In the event that a participant is unable to come to the site due to COVID-19-related restrictions
for a protocol-required visit, the visit should be conducted by phone. The date of the phone call
should be recorded as the visit date. If a visit is conducted by phone, at a minimum data should be
recorded for the following in the eCRF:


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 Adverse event (AE)
 Serious AE
 Concomitant therapy
 Pregnancy test results (as applicable for women of childbearing potential)
o For participants in the double-blind treatment period, the urine pregnancy tests
provided to the site by the central lab for on-site visits may be shipped to the patient
for use at home under guidance from the site.
Additionally, all clinician reported measures may be administered by phone (at a minimum the
MADRS) if applicable to the scheduled visit
 
EFFICACYEVALUATIONS
o MADRS –administered via the Structured Interview Guide for the MADRS (SIGMA)
 
OTHER CLINICIAN ADMINISTERED EVALUATIONS
o CGI-S
Site personnel may not conduct any self-rating instruments over the telephone.
 
SELF-RATING INSTRUMENTS
o SHAPS
o PROMIS –Ability to Participate in Social Roles and Activities
o PHQ-9
o GAD-7
In the event that a participant cannot come to the site due to COVID-19-related restrictions for
laboratory safety tests, required tests may be conducted at a certified local laboratory. The use of
local laboratories must be done in accordance with local regulations.
If samples are analyzed by a local laboratory, results, including units and normal ranges, must be
recorded in the eCRF. The investigator must review all safety assessments to confirm the
participant can continue his/her study treatment. If the safety assessments cannot be performed
and reviewed by the investigator in a timely manner, the investigator may decide to interrupt or
permanently discontinue study intervention, if it is in the best interests of the participant.
If assessments are done at a time other than at a scheduled visit, an unscheduled visit should be
created in the eCRF to record the results.
Modifications to any assessment due to COVID-19-related restrictions (e.g., assessments done
over the phone instead of in-person) must be documented in the participant’s source documents.


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Missed visits and/or assessments
If a visit is missed entirely due to COVID-19-related restrictions (i.e., no site visit or phone visit
performed), it will be captured as a protocol deviation in the clinical trial management system with
the prefix “COVID-19-RELATED”.
Missed assessments or assessments done out of window due to COVID-19-related restrictions will
be captured in the clinical trial management system as protocol deviations with the prefix
“COVID-19-RELATED”.
Laboratory tests that are missed or delayed due to the COVID-19 pandemic will be identified in
the clinical trial management system as “COVID-19-RELATED”.
Premature discontinuations due to the COVID-19 pandemic will be documented in the eCRF with
the reason “COVID-19-RELATED”.
Investigational medical product (IMP)
Direct-to-patient (DTP) shipment of study intervention from the site may be considered with prior
approval from the sponsor. Site staff need to obtain permission from the participant and record this
in the participant source record for DTP shipments. DTP shipments must be done in accordance
with local regulations.
Used, partially used, and unused study treatment bottles, including empty study treatment bottles
must be returned to the site for treatment accountability.
Statistical Analysis
The sponsor will evaluate the totality of impact of COVID-19 on collection or missingness of key
study data, and additional data analyses will be outlined in the study statistical analysis plan(s).
10.7.3. 
Study Conduct Related to COVID-19 Vaccine Deployment for
NonCOVID-19 Clinical Trials.
 
Study participants can undergo a COVID-19 vaccination procedure in compliance with
applicable local governmental regulations.
 
No pharmacokinetic interactions between the study intervention and currently available
COVID-19 vaccines are expected. In addition, based on the mechanism of action of the study
intervention and COVID-19 vaccines, no relevant interaction is expected.
 
Any COVID-19 vaccine administered to a study participant is considered a concomitant
medication and should be reported in the eCRF.
 
For SAEs reported after COVID-19 vaccination, the investigator should provide narrative
details on the SAE form to allow adequate assessment of causality relationship between the
reported SAE and vaccination. This is particularly relevant in cases where the reported SAE
is an expected event with the study intervention and the COVID-19 vaccine. If the event is
serious and considered to be related to both the COVID-19 vaccine and the study intervention,


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it is a serious adverse reaction and expectedness must be assessed. SUSAR reporting will be
performed if the serious adverse reaction is unexpected as per applicable reference safety
document.
 
Study participants do not require unblinding of the study intervention to receive a COVID-19
vaccine.


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10.8. 
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 4 (25 January 2023)
Overall Rationale for the Amendment: To allow for operational efficiency the prescreening visit will be
removed from the study and the prescreening assessment, a blood sample for P2RX7 genotyping, will be
part of the screening phase.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis; 1.3. 
Schedule of 
Activities; 4.1. 
Overall Design; 4.2. 
Scientific Rationale 
for Study Design;
5.4. Screen Failures;
8.1. Study
Procedures
The prescreening visit is not a separate visit 
anymore. All assessments (a blood sample for
P2RX7 genotyping) will be performed during the
screening visit. Visit numbers are updated to reflect
this throughout the protocol.
To allow for operational efficiency.
1.1. Synopsis; 4.1.
Overall Design; 4.2.
Scientific Rationale
for Study Design;
5.4. Screen Failures;
8.1. Study
Procedures
It has been clarified that before the blood sample
collection for P2RX7 genotyping it is important to
evaluate if participants meet the criteria of the
target study population (bipolar disorder [BD] type
I or II in a major depressive episode [MDE]). This
will be done by using the International
Neuropsychiatric Interview (MINI) with
Borderline Personality Disorder module and the
antidepressant treatment history form-short form
(ATHF-SF).
To allow the sites to make a better
assessment of potential participants
for the study.
1.1. Synopsis; 4.1.
Overall Design; 4.2.
Scientific Rationale
for Study Design;
5.4. Screen Failures;
8.1. Study
Procedures
It has been clarified that the remainder of the
screening assessments can be performed at any
time in the screening period after the P2RX7
genotyping blood sample has been collected. No
changes have been made to the single nucleotide
polymorphism (SNP) genotyping test itself.
To allow flexibility to the sites and
the patients to plan the remainder of
the screening assessments.
1.1. Synopsis; 4.1.
Overall Design; 4.2.
Scientific Rationale
for Study Design
It has been clarified that a mood stabilizer is only
allowable when taken as a monotherapy.
Patients on more than one mood
stabilizer will not be allowed into
the study.
1.3. Schedule of
Activities;
It has been clarified that the Digital Health 
Assessment will only be performed in the US.
Clarification.
5.2. Exclusion
Criteria
Serology exclusion criteria were added. 
These were missing from the
protocol and added to ensure the
safety of the participant.
1.3. Schedule of
Activities; 8.Study
Assessments and
Procedures
The text has been updated to reflect the correct 
timing for pharmacokinetic (PK) sampling.
Correction.


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1.1. Synopsis; 8.1.1. 
Screening (Visit 1); 
8.8.1. Time Period 
and Frequency for
Collecting Adverse
Event and Serious
Adverse Event
Information
It has been clarified that the collection period for 
AEs is from the screening informed consent
through the day of last dose plus 30 days.
Clarification.
1.1. Synopsis; 8.2.3. 
Antidepressant 
Treatment History
Form-Short Form
(ATHF-SF)
The ATHF-SF has been added as a screening 
instrument.
It has been added for completeness.
8.7. Safety 
Assessments 
Language was added to clarify that an additional 
safety visit can be scheduled if this is deemed
necessary (e.g., for an additional safety blood
sample).
Clarification.
1.1. Synopis; 8.7.2. 
Vital Signs; 9.4.3. 
Safety Analysis 
In addition to oral and tympanic body temperature 
measurement, temporal body temperature 
measurement is allowed.
To allow sites to use devices to take
temporal temperature.
8.7.6.3. Follow-up 
of Well-Being and 
depression  
It has been clarified that the Q1.6 app is also used 
for safety follow-up more specifically for 
depression status. 
To clarify that the Q1.6 can be used
by the site/investigator to monitor
the safety, related to depression, of
the participant.
1.1. Synopsis; 9.3. 
Populations for 
Analysis Sets; 9.4.1. 
Primary Endpoint(s) 
The name of the primary efficacy analysis 
population is changed from modified Intent-to- 
Treat (mITT) to Full Analysis Set (FAS) and the 
reference to the inclusion/exclusion criteria in the 
Population attribute ofthe estimand for primary
efficacy endpoint is removed.
To clarify the efficacy analysis
population will include the
maximum possible set of
participants.
1.1. Synopsis; 3.
Objectives and
Endpoints; 9.4.2.
Secondary
Endpoint(s)
Subgroup analyses by messenger ribonucleic acid
(mRNA) transcript (P2RX7 and interleukin-1β
[IL-1β]) level status at baseline (yes or no) is
changed from a secondary objective of special
interest to a secondary objective.
P2RX7 and IL-1β mRNA transcript
levels are considered as exploratory
biomarkers.
1.1. Synopsis; 9.4.1.
Primary
Endpoint(s); 9.4.2.
Secondary
Endpoint(s)
Biomarker profile status (yes or no) and mRNA
transcript (P2RX7 and IL-1β) level status (yes or
no) are removed from the list of covariates to be
included in analyses of primary and secondary
endpoints.
Using these biomarkers as
covariates in the analysis is
considered exploratory. The effect
of these biomarkers on the efficacy
of JNJ-55308942 will be examined
in the corresponding subgroup
analyses.
1.1. Synopsis; 9.4.1.
Primary Endpoint(s)
Changed the sensitivity analyses for the primary
estimand to mixed-effects model using repeated
measures (MMRM) analysis with copy-reference
multiple imputation and tipping point analysis.
To use more sophisticated
sensitivity analysis approaches,
such as multiple imputation and
tipping point analysis, based on
regulatory feedback.
1.3. Schedule of
Activities; 10.2.
Appendix 1:
Clinical Laboratory
Tests
It was clarified that at screening a urine sample will
be analysed by the central lab for urine drug
screening. At all other visits a dipstick test will be
used and only in case of a positive result will the
sample be analysed by the central lab for
confirmation of the positive result.
To give better operational guidance
to the sites on how to manage the
urine drug screen.


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1.1. Synopsis; 4.1. 
Overall Design; 
8.1.1. Screening 
(Visit 1) 
Dysthemia was removed as an example of a mood 
disturbance that the participant must not have ≥4 of 
within the past 12 months. 
Dysthymia by definition is
depressed mood for 2 years. It does
not make clinical sense to ask if the
patient had an episode of dysthymia
that lasted less than a year.
6.6. Treatment of 
Overdose 
The text has been updated to reflect that any dose 
of JNJ-55308942 greater than
mg within a 
24-hour time period will be considered an
overdose.
This is a more relevant
representation of the time period.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes 
were made.
Minor errors were noted.
Amendment 3 (27 July 2022)
Overall Rationale for the Amendment: To change the definition of a treatment emergent AE on
regulatory request.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis; 9.4.3. 
Safety Analyses 
Changed: 
Any AE occurring at or after the initial
administration of study intervention through the
day of last dose plus 6 days is considered to be
treatment emergent.
Into
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.
On regulatory request.
Amendment 2 (4 July 2022)
Overall Rationale for the Amendment: To add clarifications on timing of self-rating assessments,
downloading of apps, prohibited concomitant therapy. To add recommendations on order of events and
when the second pharmacogenomics sample can be taken. To add Canada as a new country where
TruCulture sampling will be performed, provide flexibility on the country list where TruCulture assay or
determination of peripheral blood mononuclear cells (PBMCs) inflammatory profiles can be perfomed and
to remove Russia where we were provisioning phones to all participants.
The changes made to the clinical protocol 55308942BIP2001 as part of Protocol Amendment 2 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 10.8 Appendix 8: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis; 3. 
Objectives and 
Endpoints 
SHAPS was removed as secondary outcome. 
SHAPS is already analyzed as an
endpoint for secondary objectives
of special interest.
1.1 Synopsis; 4.1. 
Overall Design; 
The prescreening Phase has been extended from up 
to 3 weeks to up to 4 weeks and the total study 
duration was therefore updated to 15 weeks.
To allow the sites more time to
schedule the screening visit.
CC


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1.1 Synopsis; 4.1. 
Overall Design; 
8.1.4. Double-blind 
Treatment Phase 
(Visit 3 to Visit 7) 
The timing of the self-rating instruments 
assessments has been clarified and language was
added on the reminders from Q1.6 that will occur
when self-rating assessments are performed at
home.
This is a clarification.
1.1 Synopsis; 4.2. 
Scientific Rationale 
for Study Design; 
8.11. Genetics and 
Pharmacogenomics
If the second pharmacogenomics sample cannot be 
taken on Day 1, it is allowed to collect this sample 
during any other visit of the double-blind treatment
phase.
The collection of this sample is not
time sensitive.
1.1 Synopsis; 9.4. 
Statistical Analyses 
The statistical analysis section is updated. 
To better align with the Objectives
and Endpoints (Section 3).
1.1 Synopsis; 10.2. 
Appendix 2: 
Clinical Laboratory 
Tests
Added language to clarify that FSH is for women 
only and at screening only. All other hormones are
for males only.
This is a clarification.
1.3. Schedule of 
Activities 
Study medication will not be dispensed on Visit 7. 
This had been added to the
schedule of Activities (SoA) in
error and is therefore now removed.
1.3. Schedule of 
Activities 
“Paxgene tubes” has been replaced by “RNA 
samples”. 
To be consistent throughout the
protocol and avoid confusion.
1.3. Schedule of 
Activities; 8. Study 
Assessments and
Procedures
The recommendation on order of events has been 
clarified.
This is a clarification.
1.3. Schedule of 
Activities; 8.1.2.
Screening (Visit 2)
Added language to explain that downloading the
Q1.6 app can happen at Visit 3 if it is not feasible
to be done at Visit 2.
Operational flexibility to the sites.
1.3. Schedule of
Activities; 8.12
Biomarkers
Canada was added as a country where the
TruCulture sampling will be performed. We also
added language to allow updates to the country list
for the TruCulture assay and determination of
peripheral blood mononuclear cells (PBMCs)
inflammatory profiles without it being considered a
protocol deviation
Canada is a new country and it was
decided TruCulture sampling can
be performed there. In addition we
wanted to add flexibility on the
country list where TruCulture assay
or determination of peripheral
blood mononuclear cells (PBMCs)
inflammatory profiles can be
perfomed.
4.2. Scientific
Rationale for Study
Design
Added language to clarify the use of mood
stabilizers in both JNJ-55308942 and placebo
treatment groups.
To clarify that the approach for
mood stabilizers is the same for
both treatment groups
(JNJ-55308942 and placebo).
6.3. Measures to
Minimize Bias:
Randomization and
Blinding
Added language to clarify that sites will be given
instructions and training on the number of study
intervention kits expected to be assigned by IWRS
per patient visit.
This is a clarification.
6.4.1. Medication
Adherence and
Reminder System
Language on agreement for participants in Russia
has been removed.
Russia is no longer participating in
the study.
6.7. Concomitant
Therapy; 10.6.
Appendix 6:
Added language to clarify that “prohibited
concomitant medications from 4 weeks prior to
To be in line with inclusion criteria
17.


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Disallowed 
Concomitant 
Therapies
screening until 5 half-lives after last dose of study
intervention.”
8. Study 
Assessments and 
Procedures
ECG manual was removed. 
This ECG manual is not provided
and therefore removed from the list.
8.1.2. Screening 
(Visit 2) 
Added language to explain that the AiCure app will 
be downloaded to same phone as used for Q1.6 
App which can be done at screening or Visit 3
(baseline visit, Day 1).
This is a clarification and to allow
operational flexibility to the sites.
8.1.3. Baseline Visit 
(Visit 3; Study 
Day 1)
To allow consistency, for the order of assessments 
we refer to section 8 and the SoA. 
This is a clarification and to allow
operational flexibility to the sites.
8.8.4. 
Electrocardiogram  
Updated language: “If blood sampling or vital sign 
measurement is scheduled for the same time point
as ECG recording, it is recommended the
procedures be performed in the following order:
ECG(s), vital signs, blood draw.”
Operationally more feasible.
9.3. Populations for 
Analysis Sets; 9.4.1. 
Primary Endpoints 
Updated name of analysis population for primary 
endpoint from ITT (Intent-To-Treat) to mITT 
(Modified Intent-To-Treat) 
The analysis population defined for
primary endpoint is different from
the standard definition for ITT. It is
typically called mITT.
10.7. Appendix 7: 
Guidance on Study 
Conduct During the
COVID-19
The language in this appendix was updated. 
To be aligned with the most recent
updated internal template language.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes 
were made.
Minor errors were noted


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Amendment 1 (01 February 2022)
Overall Rationale for the Amendment:  To remove the Safety, Tolerability, and Efficacy Preview (STEP)
interview, PROMIS - social isolation and Patient and Global Impression of Severity for Depression
(PGI-S), to add clarification on the antidepressant treatment history-short form (ATHF-SF), to replace the
DARS with the SHAPS, to replace the SMDDS with the PHQ-9, and the use of the AiCure application, to
add the digital health assessment by the AiCure app, and to add the urine drug screen (UDS) to every visit.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis Objectives,
Overall Design; 1.3
Schedule of Activities; 3
Objectives and Endpoints;
4.1 Overall Design; 8.6
Self-Rating Instruments
The STEP interview was removed from the
protocol.
It was decided not to implement
this exit interview for this study.
1.1 Synopsis Objectives,
Overall Design; 1.3
Schedule of Activities; 3
Objectives and Endpoints;
4.1 Overall Design; 4.2
Scientific Rationale for
Study Design; 8. Study
Assessments and
Procedures; 8.6 Self-Rating
Instruments; 9.4.2
Secondary Endpoints
The PROMIS - social isolation and PGI-S are
removed from the protocol.
It was decided not to implement
these self-rating scales for this
study.
1.1 Synopsis Objectives, 
Overall Design; 1.3 
Schedule of Activities; 3 
Objectives and Endpoints;
4.1 Overall Design; 4.2
Scientific Rationale for
Study Design; 8. Study
Assessments and
Procedures; 8.6 Self-Rating
Instruments; 9.4.2
Secondary Endpoints
For the self-rating assessment: the DARS was
replaced by the SHAPS and the SMDDS was
replaced by the PHQ-9.
It was decided these self-ratings
assessments are considered
better suited for this study.
8.6 Self-Rating Instruments 
Added language to describe flexibility on the
incorporation/removal of the PROs in the
study.
To increase study feasibility.
5.2 Exclusion Criteria 
Exclusion criteria 5, 6 and 18 were further
clarified by adding that the ATHF-SF was
used at screening.
Exclusion criteria 5, 6 and 18
were further clarified by adding
that the ATHF-SF will be used
at screening to determine the
antidepressant treatment history.
5.2 Exclusion Criteria 
Vagal nerve stimulation (VNS) and deep brain
stimulation (DBS) were added to exclusion
criterion 5.
These two treatments were
added for completeness.
1.3 Schedule of Activities 
Meal intake status on the day of PK sampling,
prior to dosing, will be captured in the
AiCure® app. This is now also updated in the
SoA.
This is a clarification.
6.4 Study Intervention 
Compliance 
Language was added to further clarify the use
of the AiCure® application. Russia was added
This is a clarification.


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Section Number 
and Name
Description of Change 
Brief Rationale
as a country where all participants will receive
a provisioned device. It was clarified that the
application is compliant with all applicable
privacy and data security laws.
8.7 Digital Health 
Assessment; 8. Study 
Assessments and
Procedures
Digital health assessment (AiCure® ) was 
added to the protocol.
New assessment.
8.12 Biomarkers 
Language was added that the P2X7 monocyte 
activation status assay and PBMC 
inflammatory profile may only be performed 
in certain countries.
These two assays will not be
performed in all countries
participating in this study.
1.3 Schedule of Activities; 
8.11. Genetics and 
Pharmacogenomics
The general pharmacogenomics sample will 
be optional. 
It was decided to make this an
optional sample.
1.3 Schedule of Activities 
UDS was added to each in-person visit. 
UDS added to provide additional
protection of participant safety
and to minimize confounding
bias from drug use.
10.7 Appendix 7: Study 
Conduct During COVID-19 
COVID-19 guidance specific to this protocol 
was added. 
Language was added to further
clarify protocol specific actions
needed to be taken specific to
COVID-19.
9.4.1 Primary Endpoints 
Primary estimand definition was updated and 
sensitivity analyses were added. Language 
was added to further clarify intercurrent events 
and corresponding handling strategy.
To align with FDA guidance and
clarify the strategy for handling
intercurrent events.
7.4 Participant 
Discontinuation/Withdrawal 
From the Study  
Rephrase sentence to remove replacement. 
Since the additional participants not necessary
receive the same intervention as the early
withdrawal.
This is a clarification.
1.1 Synopsis Objectives, 
Overall Design; 1.3 
Schedule of activities; 4.1 
Overall Design; 4.2 
Scientific Rationale for
Study Design
The prescreening window has been reduced to 
up to 3 weeks. 
This represents a more realistic
timeline to perform the P2RX7
Gain of function (GoF) and Loss
of Function (LoF) SNP process.
2.2. Background 
It was clarified that in study 
55308942EDI1002 that 12 participants were
dosed with JNJ-55308942 and/or the tracer
[18F]-JNJ-64413739.
This is a clarification.
Throughout the protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted


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11. 
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Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
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is better. J Am Coll Cardiol. 1983;1:694.
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(2009). Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation.
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polymorphism leads to loss of function of the human P2X7 receptor. J Biol Chem. 2001;276(14):11135-42.
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on, and Welfare; 1976. International Council on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval
prolongation and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
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Pharmaceuticals. Guidance for Industry. (revision 3, May 2021).
Lord B, Aluisio L, Shoblock JR, Neff RA, Varlinskaya EI, Ceusters M, et al. Pharmacology of a novel central
nervous system-penetrant P2X7 antagonist JNJ-42253432. J. Pharmacol. Exp. Ther. 2014;351:628–641.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry.
1979;134:382-389.
NIMH (2017): Statistics for Bipolar Disorder. https://www.nimh.nih.gov/health/statistics/bipolar-disorder.shtml
Patrick DL, Burke LB, Powers JH, Scott JA, Rock EP, Dawisha S, et al. Patient-Reported Outcomes to Support
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568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor. J Biol Chem.
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Psychiatry. 1978;133:429-435.


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Status: Approved, Date: 18 August 2023
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): 
Institution: 
Janssen Research & Development
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 study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
PPD


Signature
User 
Date 
Reason
 
18-Aug-2023
15:46:43
(GMT)
Document Approval
PPD
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 07 June 2024
Janssen Research & Development
Statistical Analysis Plan
A Randomized, Stratified, Double-blind, Placebo-Controlled Study to Investigate the 
Efficacy, Safety and Tolerability of JNJ-55308942 in Bipolar Depression
Protocol 55308942BIP2001; Phase 2a
JNJ-55308942
Status:
Approved
Date:
07 June 2024
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.: EDMS-RIM-736880, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
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.
NCT05328297


JNJ-55308942
Statistical Analysis Plan 55308942BIP2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 07 June 2024
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints ................................................................................................................ 5
1.2.
Study Design.................................................................................................................................... 7
1.2.1.
Randomization and Blinding......................................................................................................... 9
2.
STATISTICAL HYPOTHESES.......................................................................................................... 10
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 10
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 11
5.
STATISTICAL ANALYSES............................................................................................................... 11
5.1.
General Considerations ................................................................................................................. 11
5.1.1.
Analysis Phases ......................................................................................................................... 11
5.1.2.
Visit Windows ............................................................................................................................. 11
5.1.3.
Imputation of Efficacy ................................................................................................................. 13
5.2.
Participant Dispositions.................................................................................................................. 13
5.3.
Primary Endpoint(s) Analysis......................................................................................................... 14
5.3.1.
Definition..................................................................................................................................... 14
5.3.2.
Estimand..................................................................................................................................... 14
5.3.2.1.
Analysis Methods .................................................................................................................... 15
5.3.2.1.1.
Primary Analysis .................................................................................................................. 15
5.3.2.1.2.
Sensitivity Analysis............................................................................................................... 15
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 17
5.4.1.
Secondary Endpoints of Special Interest.................................................................................... 17
5.4.1.1.
Snaith-Hamilton Pleasure Scale (SHAPS) .............................................................................. 17
5.4.1.1.1.
Definition .............................................................................................................................. 17
5.4.1.1.2.
Analysis Methods ................................................................................................................. 17
5.4.1.2.
MADRS Subgroup Analysis..................................................................................................... 18
5.4.1.2.1.
Definition of Subgroups of Special Interest.......................................................................... 18
5.4.1.2.2.
Analysis Methods ................................................................................................................. 18
5.4.2.
Other Secondary Endpoints ....................................................................................................... 18
5.4.2.1.
Clinical Global Impression – Severity (CGI-S) ........................................................................ 18
5.4.2.1.1.
Definition .............................................................................................................................. 18
5.4.2.1.2.
Analysis Methods ................................................................................................................. 19
5.4.2.2.
PROMIS – Ability to Participate in Social Roles and Activities ............................................... 19
5.4.2.2.1.
Definition .............................................................................................................................. 19
5.4.2.2.2.
Analysis Methods ................................................................................................................. 19
5.4.2.3.
Patient Health Questionnaire – 9 (PHQ-9).............................................................................. 20
5.4.2.3.1.
Definition .............................................................................................................................. 20
5.4.2.3.2.
Analysis Methods ................................................................................................................. 20
5.4.2.4.
Generalized Anxiety Disorder – 7 (GAD-7) ............................................................................. 20
5.4.2.4.1.
Definition .............................................................................................................................. 20
5.4.2.4.2.
Analysis Methods ................................................................................................................. 20
5.4.2.5.
Response Based on MADRS Total Score............................................................................... 21
5.4.2.5.1.
Definition .............................................................................................................................. 21
5.4.2.5.2.
Analysis Methods ................................................................................................................. 21
5.4.2.6.
Remission Based on MADRS Total Score.............................................................................. 21
5.4.2.6.1.
Definition .............................................................................................................................. 21
5.4.2.6.2.
Analysis Methods ................................................................................................................. 21
5.4.2.7.
Additional MADRS Subgroup Analysis.................................................................................... 22


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5.5.
Exploratory Endpoint(s) Analysis ................................................................................................... 22
5.5.1.
Self-Assessment of Well-Being (SAWB) .................................................................................... 22
5.5.1.1.
Definition.................................................................................................................................. 22
5.5.1.2.
Analysis Methods .................................................................................................................... 23
5.6.
Safety Analyses ............................................................................................................................. 23
5.6.1.
Extent of Exposure ..................................................................................................................... 23
5.6.1.1.
Intervention Compliance.......................................................................................................... 23
5.6.2.
Adverse Events........................................................................................................................... 23
5.6.3.
Additional Safety Assessments .................................................................................................. 24
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 24
5.6.3.2.
Vital Signs and Physical Examination Findings....................................................................... 25
5.6.3.3.
Electrocardiogram ................................................................................................................... 26
5.6.3.4.
Other Safety Parameters......................................................................................................... 27
5.6.3.4.1.
Young Mania Rating Scale (YMRS)..................................................................................... 27
5.6.3.4.2.
Columbia Suicide Severity Rating Scale (C-SSRS)............................................................. 27
5.7.
Other Analyses............................................................................................................................... 28
5.7.1.
Pharmacokinetics ....................................................................................................................... 28
5.8.
Interim Analyses............................................................................................................................. 29
6.
SUPPORTING DOCUMENTATION .................................................................................................. 30
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 30
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 31
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 32
6.4.
Appendix 4 Protocol Deviations and Quality Tolerance Limits (QTL)............................................ 33
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 34
6.6.
Appendix 6 Medical History ........................................................................................................... 35
6.7.
Appendix 7 Adverse Events of Special Interest............................................................................. 36
6.8.
Appendix 8 Medications of Special Interest................................................................................... 37
6.9.
Appendix 9 Conversion of Raw Score to T-Score for PROMIS - Ability to Participate in 
Social Roles and Activities............................................................................................................. 38
7.
REFERENCES................................................................................................................................... 39


JNJ-55308942
Statistical Analysis Plan 55308942BIP2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 07 June 2024
VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1.0
21 November 2023
Not Applicable
Initial release
2.0
07 June 2024
1. Section 5.1.2: The end of 
Week 6 visit window was 
updated to the day before the 
first Follow-up/Early 
Withdrawal visit for safety 
assessments.
2. Section 5.4.2: Summary 
statistics and frequency 
tables were added for 
individual items of patient-
reported outcomes, including 
PROMIS- Ability to 
Participate in Social Roles 
and Activities, PHQ-9, and 
GAD-7.
3. Section 5.4.2.7: MADRS 
subgroup analysis by country 
was added.
4. Section 6.2: The method for
handling the assessments that 
were not performed predose 
on Treatment Day 1 as per 
protocol in the analyses was 
added as a change to protocol 
planned analyses. 
5. Section 6.3: Specifications 
on the analysis sets to be 
used for summarizing 
demographics and baseline 
characteristics were added.
6. Throughout the SAP: Minor 
grammatical, formatting, or 
spelling changes were made.
1. To clarify the visit window 
start and end dates.
2. To evaluate the efficacy of 
JNJ-55308942 compared to 
placebo on the individual 
items of the patient-reported 
outcomes.
3. To evaluate the efficacy of 
JNJ-55308942 compared to 
placebo on symptoms of 
depression in different 
countries.
4. To utilize all collected data in 
analyses. A significant change 
in these assessments is not 
expected on the same day.
5. To clarify the analysis sets to 
be used for summarizing 
demographics and baseline 
characteristics.
6. Minor errors were noted.


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions, data handling conventions, algorithms, 
and statistical methods for the planned analyses for the clinical study report (CSR) of Study 
55308942BIP2001 (Protocol Amendment 5, 18 August 2023).
Population pharmacokinetics (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses, if 
conducted, will be specified in separate documents as appropriate.
With the exception of the biomarkers used to define subgroups in the analysis of the secondary 
endpoints of special interest, analyses of other biomarkers and pharmacogenomics data, if 
conducted, will be specified in separate documents as appropriate.
1.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in participants with bipolar 
disorders (BD) in a major depressive episode 
(MDE) at Week 6.
Change in Montgomery-Åsberg Depression 
Rating Scale (MADRS) total score from 
baseline at Week 6.
Secondary Objectives of Special Interest
To evaluate the efficacy of JNJ-55308942
compared to placebo on symptoms of 
anhedonia.
Change in Snaith-Hamilton Pleasure Scale
(SHAPS) total score from baseline at Week 6.
To evaluate the efficacy of JNJ-55308942
compared to placebo on symptoms of 
depression in participants with BD who are 
heterozygous or homozygous for the rs
 
P2RX7 Gain of Function (GoF) single-
nucleotide polymorphism (SNP) (genetic 
subgroup analysis)
Change in MADRS total score from baseline at 
Week 6.
To evaluate the efficacy of JNJ-55308942
compared to placebo on symptoms of 
depression in participants with BD type I or BD 
type II (diagnosis subgroup analysis)
Change in MADRS total score from baseline at 
Week 6.
To evaluate the efficacy of JNJ-55308942
compared to placebo on symptoms of 
depression in subgroups of patients with 
specific biomarker profiles (biomarker 
subgroup analysis).
Change in MADRS total score from baseline at 
Week 6.
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Objectives
Endpoints
Secondary
To evaluate the overall safety and tolerability 
of treatment with JNJ-55308942 as compared 
to placebo in participants with symptomatic BD 
over a treatment period of 6 weeks.
Vital signs (pulse/heart rate [HR], systolic 
blood pressure [SBP], diastolic blood pressure 
[DBP], respiratory rate), clinical labs 
(chemistry, hematology, urinalysis), Adverse 
Events, ECG, Young Mania Rating Scale 
(YMRS) score, Columbia Suicide Severity 
Rating Scale (C-SSRS) score.
To evaluate the effect of JNJ-55308942 
compared to placebo on disease severity and 
improvement on the Clinical Global 
Impression-Severity scale (CGI-S)
CGI-S
To evaluate the pharmacokinetics (PK) of JNJ-
55308942 in participants with BD.
Plasma concentrations of JNJ-55308942.
To assess the effect of JNJ-55308942 on 
reduction of symptoms associated with 
depression compared to placebo as measured 
by self-rated outcomes.
PROMIS – Ability to Participate in Social 
Roles and Activities, Patient Health
Questionnaire-9 (PHQ-9), Generalized Anxiety
Disorder 7 (GAD-7) score.
To evaluate the impact of treatment with JNJ-
55308942 compared with placebo on response 
(≥50% improvement in MADRS total score 
from baseline) and remission (MADRS total 
score ≤12) rates at Week 6.
Response (≥50% improvement in MADRS 
total score from baseline) and remission 
(MADRS total score ≤12) rates at Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in a subgroup of patients with 
messenger ribonucleic acid (mRNA) transcript 
levels at baseline that exceed the median level 
for both P2RX7 and IL-1β.
Change in MADRS total score from baseline at 
Week 6.
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in subgroups of participants with 
BD not taking any mood stabilizer or 
antipsychotic, taking a mood stabilizer alone, 
taking an antipsychotic alone, and taking a 
combination of a mood stabilizer and an 
antipsychotic (concomitant medication 
subgroup analysis).
Change in MADRS total score from baseline at
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Objectives
Endpoints
Exploratory
To explore the 
pharmacokinetic/pharmacodynamic (PK/PD) 
relationship between plasma exposure of JNJ-
55308942, and efficacy and safety parameters 
in patients with BD.
Exposure-response between exposure and 
MADRS and selected safety events, as 
appropriate.
To explore the effect of JNJ-55308942 on PD-
related biomarkers.
Including, but not limited to, blood biomarkers 
related to immune, inflammatory, hormonal, 
metabolic, hypothalamic-pituitary-adrenal 
(HPA) axis, P2X7 receptor and monocyte 
activity.
To explore the effect of pharmacogenomic 
variations on the PK, efficacy, and safety of 
JNJ-55308942.
Influence of genetic polymorphisms (e.g., 
-1) on plasma exposure, as well as on 
efficacy and safety measures.
To explore the effect of JNJ-55308942 
compared to placebo on the well-being of 
participants.
Self-Assessment of Well-Being (SAWB) 
outcome.
1.2.
Study Design
This is a double-blind, randomized, stratified, placebo-controlled, parallel-group, multicenter 
study to investigate the efficacy, safety, and tolerability of JNJ-55308942 in bipolar depression. 
Approximately 164 participants will be enrolled in this study to obtain approximately 132
completers.
The target study population includes participants of any gender, between 18 and 64 years of age 
inclusive, with a Diagnostic and Statistical Manual of Mental Disorders - 5th edition (DSM-5) 
diagnosis of BD (types I or II) without current psychotic features as confirmed by the Mini 
International Neuropsychiatric Interview (MINI) with Borderline Personality Disorder module. 
The participants should be experiencing an MDE that does not require either hospitalization or 
antidepressant medication. Each potential participant must satisfy one of the three criteria listed 
below to meet eligibility for the study population.

Participants who are currently unmedicated and have not received any mood stabilizers or 
antipsychotics for four weeks before screening.

Participants who are on a stable monotherapy regimen of one of the following mood stabilizers 
(lithium, valproate forms [e.g., divalproex sodium], or lamotrigine) or one of the following 
antipsychotics (lurasidone, cariprazine, quetiapine, lumateperone, or olanzapine) for four 
weeks before screening.
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
Participants who are on a stable adjunctive regimen of one of the following antipsychotics 
(lurasidone, quetiapine, lumateperone, or olanzapine) and one of the following mood 
stabilizers (lithium or valproate forms [e.g., divalproex sodium]) may be considered for 
eligibility based on the approved therapies in each market with an eligibility assessment 
conducted between the investigator and sponsor. Assessment of the stable adjunctive regimen 
of an antipsychotic and a mood stabilizer will be conducted by the investigator and sponsor’s 
clinical judgement and documented for each patient. This regimen must be in place 4 weeks 
before screening.
The patient must be symptomatic as assessed using the 17-item Hamilton Depression Rating Scale
(HDRS17). Symptom intensity over the past week will be evaluated.
In addition, the participants must carry the GoF P2RX7 mutation (for inclusion, must be 
 or 
 at rs
9/nucleotide 
; 
) and must not have the Loss of Function (LoF) 
P2RX7 mutations (must be 
 or 
 at rs
3/nucleotide 
; 
 and must be
 
at rs
/nucleotide 
 
).
Participants who are enrolled in the study will continue on their current medication regimen, if 
applicable, throughout the study. No dose changes are permitted from screening through the end 
of the study (until after the follow-up visit). No concurrent use of antidepressants will be allowed
until after the follow-up visit.
For each participant, 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 post-treatment follow-up phase of up to 2 weeks
(Figure 1). After giving written informed consent for screening, participants will be screened
between 28 days and 1 day before the double-blind treatment phase to ascertain their eligibility for 
the study according to the inclusion and exclusion criteria. Eligible participants will enter the 
double-blind treatment phase where they will be randomly assigned with a 1:1 ratio to once daily 
administration with 
mg JNJ-55308942 or placebo for 6 weeks, Day 1 up to and including the 
last treatment visit, Day 43 +/- 1 day. Between approximately 1 to 2 weeks after administration of 
the last dose, participants will return to the study site for a follow-up visit. The total study duration 
for each participant will be up to 12 weeks. There will be 7 scheduled visits to the study site during 
the study, including screening and follow-up visit.
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Figure 1:
Schematic Overview of the Study
1.2.1.
Randomization and Blinding
Procedures for Randomization 
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 groups (JNJ-55308942 or placebo) based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The randomization 
will be balanced by using randomly permuted blocks and will be stratified by 4 factors: BD type 
(I or II), country, P2RX7 GoF SNP mutation genotype (homozygous or heterozygous), as well as
concomitant medication status (no mood stabilizer or antipsychotic, a mood stabilizer alone, an 
antipsychotic alone, or a combination of a mood stabilizer and an antipsychotic). 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.
Blinding
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the 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 (e.g., 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, 
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or others as appropriate until the time of database lock and unblinding. Also, the site staff should 
not discuss insights on unblinding of randomization with the participants.
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized/locked. 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.
Participants who have had their study intervention assignment unblinded should continue to return 
for scheduled evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed/locked.
2.
STATISTICAL HYPOTHESES
The primary objective of this study is to evaluate the efficacy of JNJ-55308942 compared to 
placebo on symptoms of depression in participants with BD in an MDE. The null hypothesis that 
will be tested to address the primary objective of the study is that there is no difference between 
JNJ-55308942 (
mg once daily) and placebo in reducing the symptoms of depression in 
participants with BD in an MDE as assessed by change in MADRS total score from baseline to
Week 6.
3.
SAMPLE SIZE DETERMINATION
The estimated sample size of 164 participants (82 participants per group) was determined based
on the assumption of an effect size of at least 0.45 for the MADRS total score (difference in mean
change from baseline at Week 6 between the JNJ-55308942 and placebo groups of 3.9 units with
a standard deviation of 8.6). This is considered to be a clinically relevant difference in a population
with BD types I and II. The standard deviation of 8.6 in the change in MADRS total score from
baseline is a reasonable assumption based on data in a published phase 3 study of quetiapine in
BD type I and type II depression (Calabrese 2005). Power is set at 90%, with a 1-sided alpha of
0.10 and a 6-week drop-out rate of 20%. The estimated number of completers to be included in
the primary analysis is 132.
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4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Population
Description
Enrolled
All participants who signed the ICF at screening
Randomized
All participants who were randomized in the study
Full Analysis Set (FAS)
All randomized participants who received at least 1 dose of study 
intervention and have both the baseline and at least 1 post-
baseline MADRS measurement
Safety
All randomized participants who take at least 1 dose of study 
intervention
Pharmacokinetics (PK) 
Analysis Set
All participants who received at least 1 dose of JNJ-55308942 
and have at least 1 valid blood sample drawn for PK analysis
The randomized
analysis set will 
be used 
for 
summarizing the overall study 
completion/withdrawal information. Efficacy analyses will be based on the full analysis set unless 
otherwise specified. Safety analyses will be based on the safety analysis set and PK analyses will 
be based on the PK analysis set.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
Continuous variables will be summarized by descriptive statistics including the number of 
participants (N), mean, standard deviation (SD), median, and range (minimum; maximum) unless 
otherwise specified. Categorical variables will be summarized by frequency counts and 
percentages.
5.1.1.
Analysis Phases
Screening
The screening phase begins on the date the first informed consent is obtained and ends 1 day before 
the first dose of study intervention in the double-blind treatment phase. The screening phase end 
date is left missing for those participants who did not receive study intervention.
Double-Blind Analysis Phase
The analysis reference start date of the double-blind analysis phase is the date of the first dose of 
the double-blind study intervention. The analysis reference end date of the double-blind analysis
phase is the date of study disposition (last contact).
5.1.2.
Visit Windows
As participants 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 treatment 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 


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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 except for the endpoint. Listed below 
(Table 2) are the analysis visit windows and the target days for each visit defined in the protocol.
The baseline is defined as the last observation before the start of the first study intervention 
administration in the double-blind treatment phase. Assessments prior to Day 1 of the double-blind 
treatment phase that are not considered baseline assessments will be labeled as ‘Screening’.
Table 2:
Visit Windows
Parameter
Analysis 
Phase
Scheduled 
Visit Number
Time Interval
(Label on 
Output)
Time Interval
(Day)*
Target Time 
Point (Day)*
MADRS,
CGI-S
Double-Blind
2
Baseline
≤1
1
3
Week 1
[2,11]
8
4
Week 2
[12,21]
15
5
Week 4
[22,35]
29
6
Week 6
≥36
43
SHAPS
Double-Blind
2
Baseline
≤1
1
6
Week 6
≥2
43
PROMIS, PHQ-9
Double-Blind
2
Baseline
≤1
1
3
Week 1
[2,11]
8
4
Week 2
[12,18]
15
Week 3
[19,25]
22
5
Week 4
[26,32]
29
Week 5
[33,39]
36
6
Week 6
≥40
43
GAD-7
Double-Blind
2
Baseline
≤1
1
4
Week 2
[2,21]
15
5
Week 4
[22,35]
29
6
Week 6
≥36
43
Clinical 
Laboratory tests 
(Hematology, 
Serum, Urinalysis)
Screening
1
Screening
<1
<1
Double-Blind
2
Baseline
≤1
1
4
Week 2
[2,21]
15
5
Week 4
[22,35]
29
6
Week 6
[36, Day of FU/EW)
43
7
FU/EW
49 to 56
Vital signs, 
12-lead ECG,
C-SSRS, 
Urine Drug Screen
Screening
1
Screening
<1
<1
Double-Blind
2
Baseline
≤1
1
3
Week 1
[2,11]
8
4
Week 2
[12,21]
15
5
Week 4
[22,35]
29
6
Week 6
[36, Day of FU/EW)
43
7
FU/EW
49 to 56
Physical 
examination, 
Body weight
Screening
1
Screening
<1
<1
Double-Blind
2
Baseline
≤1
1
6
Week 6
[2, Day of FU/EW)
43
7
FU/EW
49 to 56
YMRS
Screening
1
Screening
<1
<1
Double-Blind
2
Baseline
≤1
1
3
Week 1
[2,11]
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Table 2:
Visit Windows
Parameter
Analysis 
Phase
Scheduled 
Visit Number
Time Interval
(Label on 
Output)
Time Interval
(Day)*
Target Time 
Point (Day)*
4
Week 2
[12,21]
15
5
Week 4
[22,35]
29
6
Week 6
≥36
43
*Relative to Study Day 1; FU/EW = Follow-up/Early Withdrawal
5.1.3.
Imputation of Efficacy
Imputation for missing data will include the following methods (Table 3).
Table 3:
Imputation of Missing Efficacy Data
Imputation
Text
Multiple Imputation (MI) 
method
1) Copy Reference
2) Delta Adjustment.
Non-Responder 
Participants with missing values will be imputed as non-responders. 
Non-Remitter 
Participants with missing values will be imputed as non-remitters. 
Imputation of total scores will apply only to the MADRS. Imputation of the MADRS total score 
will be performed only when 1 item score is missing. If 2 or more items are missing, the total score 
will be left missing. The total score will be imputed by calculating the sum of the scores of the 
non-missing items and multiplying it by the ratio of the maximum possible number of items (i.e., 
10) to the number of non-missing items (i.e., 9).
For all other efficacy scales where multiple items are summed to create a total score, if any item 
of the scale is missing on one visit, the total score for that scale at that visit will be left missing.
5.2.
Participant Dispositions
The number of participants in the following disposition categories will be summarized throughout 
the study by intervention group and overall:

Participants randomized

Participants who received study intervention

Participants who completed, discontinued study intervention and reasons for discontinuation

Participants who completed, terminated study prematurely and reasons for termination
Listings of participants will be provided for the following categories:

Participants who discontinued study intervention

Participants who terminated study prematurely (trial disposition page)

Participants who were unblinded during the study period

Participants who were randomized yet did not receive study intervention.
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5.3.
Primary Endpoint(s) Analysis
The primary endpoint analysis will be based on the full analysis set using the MADRS total 
scores collected during the double-blind treatment phase.
5.3.1.
Definition
The MADRS is a clinician-administered scale designed to measure depression severity and detects
changes due to antidepressant intervention (Montgomery 1979). The scale consists of 10 items,
each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence
of the symptoms).Higherscores represent a moreseverecondition.TheMADRSevaluates reported
sadness, apparent sadness, inner tension, reduced sleep, reduced appetite, concentration
difficulties, lassitude, inabilityto feel, pessimistic thoughts, and suicidal thoughts. The test exhibits
high inter-rater reliability. The recall period for the MADRS is 7 days.
The MADRS total score is the sum of scores from individual question items at a given time point
and ranges from 0 to 60. Higher scores represent a more severe condition. Imputation of the total 
score is presented in section 5.1.3.
Negative changes in the MADRS total score indicate improvement.
5.3.2.
Estimand
Primary Trial Objective: To evaluate the efficacy of JNJ-55308942 compared to placebo on 
symptoms of depression in participants with BD in an MDE
Estimand Scientific Question of Interest: What is the effect of assigning BD patients in an MDE 
to JNJ-55308942 vs. placebo in reducing the symptoms of depression after 6 weeks of treatment 
if no participant discontinued the treatment?
The estimand for the primary efficacy analysis is defined by the following 5 components:
Study Intervention: JNJ-55308942 
 mg once daily versus placebo
Population: participants with BD types I and II and in an MDE
Variable: change from baseline in the MADRS total score to Week 6
Population-level Summary: the difference in mean change from baseline in MADRS total score 
to Week 6 between JNJ-55308942
 mg once daily and placebo
Intercurrent events and their corresponding strategies:
Intercurrent Events
Strategy for Addressing Intercurrent Events and 
Its Description
Discontinuation of study intervention
Hypothetical strategy: as if no participant 
discontinued the study intervention. After study 
intervention discontinuation, similar efficacy is 
assumed for participants who discontinued as those 
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Intercurrent Events
Strategy for Addressing Intercurrent Events and 
Its Description
participants from the same intervention group who 
did not discontinue the study intervention.
Change or discontinuation of 
background therapy (mood stabilizer 
and/or antipsychotic)
Hypothetical strategy: same as above. Change or 
discontinuation of background therapy will result in 
discontinuation of study intervention.
5.3.2.1.
Analysis Methods
5.3.2.1.1.
Primary Analysis
The primary efficacy analysis will be performed utilizing the hypothetical estimand defined above.
The change from baseline in MADRS total score will be compared between the JNJ-55308942 
mg once daily group and the placebo group at Week 6 in a mixed-effects model for repeated 
measures (MMRM), with time, intervention (placebo or JNJ-55308942), BD type (I or II), country, 
P2RX7 GoF SNP mutation genotype (homozygous or heterozygous), concomitant medication 
status (no mood stabilizer or antipsychotic, a mood stabilizer alone, an antipsychotic alone, or a 
combination of a mood stabilizer and an antipsychotic), and time-by-intervention interaction as 
factors, with baseline MADRS total score as a continuous covariate. Data after treatment 
discontinuation will be considered missing. The within-subject covariance between visits will be 
estimated via an unstructured variance-covariance matrix. In case of convergence problems, 
alternative variance-covariance structures will be attempted in the following order, with the first 
structure that converges being used in the analysis: heterogeneous Toeplitz, standard Toeplitz, and 
first order autoregressive. Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom. Sandwich estimator will be used to address the potential misspecification of 
the covariance matrix when a structured covariance matrix is used due to the convergence problem
with the unstructured covariance matrix.
The comparison of JNJ-55308942 versus placebo will be performed using the appropriate contrasts
directly from the MMRM analysis. A 2-sided 80% confidence interval (CI) for the difference in 
least squares means will be presented over time. A 1-sided p-value will be calculated at Week 6.
Least square means of change from baseline (+/- SE) will be presented graphically over time.
Descriptive statistics of the actual values and the change from baseline to each postbaseline time 
point will be presented for MADRS total score by intervention group.
5.3.2.1.2.
Sensitivity Analysis
The primary analysis based on MMRM is valid and produces unbiased estimates of the treatment 
effect if missing data are missing at random (MAR), meaning that the probability of a value being 
missing, conditional on the observed data in the statistical model, is random and not dependent on 
the unknown value of missing data point. The MAR assumption cannot be verified vs. missing not 
at random (MNAR) using observed data. Therefore, a sensitivity analysis using copy-reference 
multiple imputation will be conducted under the MNAR assumption to evaluate the robustness of 
efficacy results and the effect of the missing data. In addition, a tipping-point analysis will be 
conducted if the primary analysis results show a significantly greater improvement in the MADRS 
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total score at Week 6 in JNJ-55308942 compared to placebo (i.e., 1-sided p-value ≤ 0.1 in favor 
of JNJ-55308942).
The copy reference multiple imputation approach does not assume a sustained benefit of 
experimental intervention for the efficacy data that is either not used or missing after the 
intercurrent event and uses an imputation method that is based on the control group distribution 
and the estimated correlations between time points in the control group. MAR is assumed for 
intermediate missing data (i.e., missing data between non-missing observations). MNAR is 
assumed for monotone missing (i.e., missing data after the participant experienced an intercurrent 
event) in participants in the experimental intervention group, where efficacy scores are assumed 
as if the participant had always been in the control group. MAR is assumed for missing data in the 
control group.
This method will employ the following 3 steps:
Step 1 – Multiple imputation
If there are participants with a 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 Chain Monte Carlo (MCMC) method, which assumes a multivariate normal distribution 
over all variables included in the imputation model. This imputation will be done by intervention 
group. The variables to be used in the imputation are treatment, corresponding baseline values, 
and values observed at all double-blind visits (Weeks 1, 2, 4, 6). 50 imputations will be performed 
to create 50 datasets that now have monotone missing (i.e., missing data after the participant 
experienced an intercurrent event) data pattern.
The efficacy data that is either not used or missing after the intercurrent event at a given time point 
will be imputed using the imputation model of the control group, i.e., conditional on the data 
observed or imputed at previous time points relative to the mean of the model for the control group.
Step 2 – Analysis
The same MMRM analysis as described for the primary efficacy analysis will be performed for 
each of the adjusted fully imputed datasets.
Step 3 – Pooling
Rubin’s methodology (Rubin 1987) will be applied to the MMRM results from the 50 imputed 
datasets to produce final inferences.
An additional sensitivity analysis using the delta adjustment multiple imputation (tipping-point) 
approach will be conducted if the results from the primary analysis show a significantly greater 
improvement in the MADRS total score at Week 6 in JNJ-55308942 compared to placebo (i.e., 1-
sided p-value ≤ 0.1 in favor of JNJ-55308942). This approach imputes missing data over a range 
of possible scenarios for the treatment effect and finds a “tipping point” where the treatment effect 
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employ the same 3 steps as in the copy-reference multiple imputation sensitivity analysis except 
during the first step monotone missing data will first be imputed by MAR-based MI, and the 
imputed values in the experimental intervention group will be adjusted using a range of delta 
values to generate adjusted fully imputed datasets. The adjusted fully imputed datasets will be 
analyzed and combined using the same methods as Steps 2 and 3 of the copy-reference multiple 
imputation approach. The delta will be set in a range from 0 to ∆∗in increments of 1 as adding 
positive values results in higher (worse) scores. ∆∗represents the adjustments leading to the 
“tipping point”. It is the smallest delta adjustment value at which conclusions change from 
favorable (i.e., statistically significant, 1-sided p-value ≤ 0.1 in favor of JNJ-55308942) to 
unfavorable. Between-group comparisons to placebo at Week 6 (e.g., 1-sided p-values, point 
estimates for intervention difference) will be displayed graphically for each considered delta, up 
to the “tipping point” adjustment. Clinical judgement will be applied to evaluate the plausibility 
of the assumptions underlying this “tipping point”.
5.4.
Secondary Endpoint(s) Analysis
All secondary endpoints analysis will be based on the full analysis set. 
5.4.1.
Secondary Endpoints of Special Interest
5.4.1.1.
Snaith-Hamilton Pleasure Scale (SHAPS)
5.4.1.1.1.
Definition
The SHAPS is a reliable, valid, and unidimensional instrument to assess hedonic capacity in adults 
with Major Depressive Disorder in the last few days. It is a 14-item, self-report tool with a 
completion time below 5 minutes.  Each of the items has a set of 4 response categories: 
1=Definitely Agree/Strongly Agree, 2=Agree, 3=Disagree, and 4=Strongly Disagree.  The SHAPS 
total score is the sum of the 14 item scores, ranging from 14 to 56. A higher SHAPS total score 
indicates higher levels of current anhedonia (Nakonezny 2010).
Negative changes in the SHAPS total score indicate improvement.
5.4.1.1.2.
Analysis Methods
Descriptive statistics of the actual values at Baseline, Week 6, and the change from baseline to 
Week 6 will be presented for SHAPS total score by intervention group.
An analysis of covariance (ANCOVA) model will be used to test the difference of change from 
baseline at Week 6 in SHAPS total score between JNJ-55308942
 mg once daily and placebo. 
The model will include intervention (placebo or JNJ-55308942), BD type (I or II), country, P2RX7 
GoF SNP mutation genotype (homozygous or heterozygous), and concomitant medication status 
(no mood stabilizer or antipsychotic, a mood stabilizer alone, an antipsychotic alone, or a 
combination of a mood stabilizer and an antipsychotic) as factors, and baseline SHAPS total score
as a covariate. Comparison between JNJ-55308942
 mg once daily and placebo will be 
performed using appropriate contrast. Difference of least square means and 2-sided 80% CI will 
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be presented. Least square means of change from baseline (+/- SE) to Week 6 will be presented 
graphically.
Frequency distributions of the SHAPS individual items will be provided at each assessment time 
point.
5.4.1.2.
MADRS Subgroup Analysis
5.4.1.2.1.
Definition of Subgroups of Special Interest
MADRS subgroup analysis will be conducted according to the definition below. 
Subgroup
Variant
Definition
P2RX7 GoF SNP mutation genotype
1
Heterozygous / Homozygous
BD type
1
I / II
Biomarker profile
1
Yes / No
5.4.1.2.2.
Analysis Methods
Changes in MADRS total score at Week 6 from baseline, will be assessed in subgroups for BD 
type (I or II), P2RX7 GoF SNP mutation genotype (heterozygous vs. homozygous), and patients 
with specific biomarker profiles (yes or no). Participants will be divided into subgroups based on 
the definition in Section 5.4.1.2.1 to evaluate efficacy within these subgroups (i.e., evaluating 
change from baseline to the end of Week 6 in the MADRS total score in participants within each 
subgroup).
Descriptive statistics of the actual values and change from baseline at each postbaseline time point
in the MADRS total score will be presented by intervention group for these subgroups. The change 
from baseline in the MADRS total score will be analyzed using the same MMRM described in 
Section 5.3.2.1.1 for each subgroup. Comparison between JNJ-55308942 
mg once daily and 
placebo will be performed using the appropriate contrasts. Difference of least square means and 
2-sided 80% CI will be presented over time. Least square means of change from baseline (+/- SE) 
will be presented graphically over time.
A forest plot summarizing the differences of least square means and 2-sided 80% CI between JNJ-
55308942 
 mg once daily and placebo at Week 6 in the subgroups will be presented.
5.4.2.
Other Secondary Endpoints
5.4.2.1.
Clinical Global Impression – Severity (CGI-S)
5.4.2.1.1.
Definition
The CGI-S provides an overall clinician-determined summary measure of the severity of the 
participant's illness that takes into account all available information, including knowledge of the 
participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the participant’s ability to function (Guy 1991). The CGI-S evaluates the severity of 
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psychopathology on a scale of 1 to 7. Considering total clinical experience with the depression 
population, a participant is assessed on severity of illness at the time of rating according to 0=not 
assessed; 1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 
6=severely ill; 7=among the most extremely ill patients.
A score of 0 indicates that the participant was not assessed and will be treated as missing. The 
score from 1 to 7 will be summarized as recorded.
Negative changes in CGI-S score indicate improvement.
5.4.2.1.2.
Analysis Methods
Descriptive statistics of the actual values and the change from baseline will be presented by 
intervention group for observed case data.
Frequency distribution of the CGI-S scores at each scheduled time point will be provided over 
time by intervention group. The frequencies of CGI-S scores will be plotted over time by 
intervention group. In addition, frequency of shifting scale at Week 6 from baseline will be 
provided.
5.4.2.2.
PROMIS – Ability to Participate in Social Roles and Activities
5.4.2.2.1.
Definition
The PROMIS - Ability to Participate in Social Roles and Activities item bank assesses the 
perceived ability to perform one’s usual social roles and activities. The item bank does not use a 
time frame (e.g., over the past seven days) when assessing the ability to participate in social roles 
and activities. The Short Form 4a includes 4 items that represent this concept. Each question has 
5 response options ranging in value from 1 to 5 with higher scores indicating better social function. 
The total raw score for the short form is calculated by summing the values of the response to each 
question, so for the 4-item form, the lowest possible raw score is 4; the highest possible raw score 
is 20. The total raw score can also be converted to a T score with a mean of 50 and a standard 
deviation of 10 (Appendix 6.9).
5.4.2.2.2.
Analysis Methods
Descriptive statistics of the actual values and the change from baseline at each post-baseline time 
point will be presented for PROMIS - Ability to Participate in Social Roles and Activities total T-
score, total raw score, and individual items by intervention group and visit.  
The change from baseline in the PROMIS - Ability to Participate in Social Roles and Activities 
total T-score will be analyzed using a similar MMRM as described in Section 5.3.2.1.1, with the 
covariate “baseline MADRS total score” changed to “baseline PROMIS - Ability to Participate in 
Social Roles and Activities total T-score”. Comparison between JNJ-55308942 
mg once daily
and placebo will be performed using the appropriate contrasts. Difference in least square means 
and 2-sided 80% CI will be presented over time. Least square means of change from baseline (+/-
SE) for PROMIS T-score will be presented graphically over time.
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Frequency distributions of the individual items of the PROMIS - Ability to Participate in Social 
Roles and Activities will be provided at each assessment time point.
5.4.2.3.
Patient Health Questionnaire – 9 (PHQ-9)
5.4.2.3.1.
Definition
The PHQ-9 scale scores each of the 9 symptom domains of the DSM-5 major depressive disorder 
criteria and it has been used both as a screening tool and a measure of response to intervention for 
depression. Each item is rated on a 4-point scale (0=Not at all, 1=Several Days, 2=More than half 
the days, and 3=Nearly every day). The participant’s item responses are summed to provide a total 
score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. 
The recall period is 2 weeks.
Negative changes in the PHQ-9 total score indicate improvement.
5.4.2.3.2.
Analysis Methods
Descriptive statistics of the actual values and the change from baseline to each post-baseline time 
point will be presented for the PHQ-9 total score and individual items by intervention group.
The analysis for changes from baseline in PHQ-9 total score at each week will be carried out
using a similar MMRM as described in Section 5.3.2.1.1 for the primary efficacy endpoint, with 
the covariate “baseline total MADRS score” changed to “baseline PHQ-9 total score”. Comparison 
between JNJ-55308942 
mg once daily and placebo will be performed using the appropriate 
contrasts. Least square means of change from baseline (+/- SE) for the PHQ-9 total score will be 
presented graphically over time.
Frequency distributions of the PHQ-9 individual items will be provided at each assessment time 
point.
5.4.2.4.
Generalized Anxiety Disorder – 7 (GAD-7)
5.4.2.4.1.
Definition
The GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants 
respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 
2=over half the days, and 3=nearly every day. The total score is the sum of item responses, ranging 
from 0 to 21. Higher scores indicate more anxiety.
Negative changes in the GAD-7 total score indicate improvement.
5.4.2.4.2.
Analysis Methods
Descriptive statistics of the actual values and the change from baseline at weeks 2, 4, and 6 will 
be presented for the GAD-7 total score and individual items by intervention group for observed 
case data.
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The analyses for changes from baseline in GAD-7 total score at weeks 2, 4, and 6 will be carried
out using a similar MMRM as described in Section 5.3.2.1.1 for the primary efficacy endpoint, 
with the covariate “baseline total MADRS score” changed to “baseline GAD-7 total score”.
Comparison between JNJ-55308942 
mg once daily and placebo will be performed using the 
appropriate contrasts. Least square means of change from baseline (+/- SE) for the GAD-7 total 
score will be presented graphically over time.
Frequency distributions of the GAD-7 individual items will be provided at each assessment time 
point.
5.4.2.5.
Response Based on MADRS Total Score
5.4.2.5.1.
Definition
A participant is defined as a responder at a given time point if the percent improvement from 
baseline in MADRS is ≥50% at that time point (i.e., percent change ≤-50%). Participants who do 
not meet such a criterion will be considered as non-responders. Imputation of missing response 
status is presented in Section 5.1.3.
5.4.2.5.2.
Analysis Methods
The number and percentage of participants who achieve a response will be summarized at each 
time point during the double-blind treatment phase by intervention group. The analysis will be 
performed on observed as well as imputed data (participants with missing values will be imputed 
as non-responders).
A Chi-square test will be used to test the difference between JNJ-55308942
 mg once daily and 
placebo for response rate at each time point. A 2-sided 80% CI for the intervention difference will 
be calculated based on the Wald statistic. The point estimate and 2-sided 80% CI will be provided 
for the relative risk of response.
Response rate will be plotted over time by intervention group.
The cumulative response rate, defined as the percentage of participants experiencing at least a 
given value of percent reduction from baseline to Week 6 in the MADRS total score, will be 
presented graphically for observed data.
5.4.2.6.
Remission Based on MADRS Total Score
5.4.2.6.1.
Definition
A participant is defined as a remitter at a given time point if the MADRS total score is ≤12 at that 
time point. Participants who do not meet such a criterion will be considered as non-remitters.
Imputation of missing remission status is presented in Section 5.1.3.
5.4.2.6.2.
Analysis Methods
The number and percentage of participants who achieve remission will be summarized at each 
time point during the double-blind treatment phase by intervention group. The analysis will be 
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performed on observed as well as imputed data (participants with missing values will be imputed 
as non-remitters).
A Chi-square test will be used to test the difference between JNJ-55308942 
mg once daily and 
placebo for remission rate at each time point. A 2-sided 80% CI for the intervention difference will 
be calculated based on the Wald statistic. The point estimate and 2-sided 80% CI will be provided 
for the relative risk of remission.
The remission rate will be plotted over time by intervention group.
5.4.2.7.
Additional MADRS Subgroup Analysis
Changes in MADRS total score to Week 6 from baseline, will be assessed in subgroups for 
concomitant medication status (no mood stabilizer or antipsychotic, a mood stabilizer alone, an 
antipsychotic alone, or a combination of a mood stabilizer and an antipsychotic) and country. 
Descriptive statistics of the actual values and change from baseline at each postbaseline time point 
in the MADRS total score will be presented by intervention group for the subgroups. Mean changes 
from baseline (+/- SE) will be presented graphically over time. A forest plot summarizing the 
differences of mean changes and 2-sided 80% CI between JNJ-55308942
 mg once daily and 
placebo at Week 6 in the subgroups will be presented. The change from baseline in the MADRS 
total score will be analyzed using the same MMRM described in Section 5.3.2.1.1 for each 
subgroup when feasible.
5.5.
Exploratory Endpoint(s) Analysis
5.5.1.
Self-Assessment of Well-Being (SAWB)
5.5.1.1.
Definition
The SAWB questionnaire is a multiple-item self-report questionnaire designed to provide 
additional information regarding the participant’s subjective experience while taking study 
intervention. This is an internal Janssen questionnaire, and the questions will be asked to the 
participant daily by the Q1.6 app during the double-blind treatment phase. The SAWB 
questionnaire has a total of 11 questions. The first 8 questions monitor the participant’s manic
symptoms, pattern of sleep, energy level, social activities, and concentration level. Each question 
is answered with a visual analog scale (VAS) between 0 and 100. Question 9 asks the participant’s 
subjective experience of overall depression level since study start with 3 possible answers: a) 
improved, b) not changed, or c) worsened. If the participant answers “improved”, Question 10 will 
be asked to assess how much depression has improved (slightly improved, much improved, or very 
much improved). If the participant answers “worsened” to Question 9, Question 11 will be asked 
to assess how much depression has worsened (slightly worse, much worse, or very much worse). 
The 8 VAS questions will be rotated with 2 questions being asked on a single day. The remaining 
questions will be asked weekly. The Q1.6 app will send an alert to the investigator when the 
participant has indicated that her/his depression is “much worse” or “very much worse”.
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5.5.1.2.
Analysis Methods
Analysis of the SAWB data will be based on the safety analysis set.
Actual values will be averaged by study week for each of the 8 VAS items. Descriptive statistics 
of the weekly average of each of the 8 VAS items will be presented by intervention group over 
time. Mean (+/- SE) of the weekly average of each of the 8 VAS items will be presented graphically 
over time.  
A frequency distribution at each time point by intervention group will be provided for Questions 
9 to 11. The number and percentage of participants with a reply that her/his depression is ‘much 
worse’ or ‘very much worse’ will be summarized by intervention group. A listing of participants 
with a reply that her/his depression is ‘much worse’ or ‘very much worse’ will be provided.
5.6.
Safety Analyses
All safety analyses will be based on the safety analysis set based on actual intervention received, 
unless otherwise specified.
5.6.1.
Extent of Exposure
Duration of study intervention and total number of capsules taken will be summarized by 
intervention group using descriptive statistics.
Study intervention duration is defined as (date of last dose of study intervention – date of first dose 
of study intervention) +1.
Total number of capsules taken will be calculated based on drug accountability data.
In case a medication packet is not returned by a participant or the drug accountability data is 
missing, the actual number of capsules taken may be inferred based on Digital Healthy Assessment 
app data if available.
5.6.1.1.
Intervention Compliance
Compliance will be summarized descriptively for each intervention.
The percent compliance will be categorized and the number and percentage of participants in each 
category will be summarized by intervention group.
Compliance will be calculated as follows:
Compliance (%) = (actual number of capsules taken/total number of capsules supposed to be taken) 
x100.
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events (AEs) will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or 
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is considered to be treatment-emergent. If the event occurs on the day of the initial administration 
of study intervention, and either event time or time of administration is 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 intervention based on the partial onset date or resolution date. 
All reported treatment-emergent adverse events (TEAEs) will be included in the analysis. For each 
AE, the number and percentage of participants who experience at least 1 occurrence of the given 
event will be summarized by intervention group.
Summary tables will be provided for:

Overall summary of TEAEs, including any TEAEs, serious TEAEs, TEAEs leading to 
discontinuation of study intervention, related TEAEs, and TEAEs by worst severity

TEAEs by system organ class and preferred term

Treatment-emergent serious adverse events (SAEs) by system organ class and preferred term

TEAEs leading to discontinuation of study intervention by system organ class and preferred 
term

TEAEs by system organ class, preferred term, and worst severity

TEAEs by system organ class, preferred term, and relationship to study intervention.
In addition to the summary tables, listings will be provided for participants who had:

AEs

SAEs

AEs leading to discontinuation of study intervention
A listing of participants who died will be provided.
5.6.3.
Additional Safety Assessments
5.6.3.1.
Clinical Laboratory Tests
Descriptive statistics of chemistry, hematology, and urinalysis (pH and specific gravity) laboratory 
tests and changes from baseline will be presented at each scheduled time point by intervention
group.
Abnormality criteria based on normal ranges will be applied to baseline and postbaseline values. 
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). A listing of participants with 
any laboratory results outside of the reference ranges will be provided.
A listing of participants meeting any of the following hepatic toxicity stopping criteria (confirmed 
by repeat testing) will be provided:

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
Alanine aminotransferase (ALT) exceeds 5x the ULN

AST exceeds 3x the ULN and total bilirubin exceeds 1.5x ULN

ALT exceeds 3x the ULN and total bilirubin exceeds 1.5x ULN
The number and percentage of participants with positive urine drug screen results will be presented 
over time by intervention group.
5.6.3.2.
Vital Signs and Physical Examination Findings
Vital sign parameters that will be analyzed are temperature (oral, tympanic, or temporal), 
respiration rate, pulse, blood pressure (systolic and diastolic), weight, and Body Mass Index 
(BMI). BMI will be calculated as weight (kg)/(height (m))2. The height measurement collected at
screening will be used in the calculation. Change from baseline will be summarized at each 
assessment time point by intervention group.
Vital sign parameters and changes from baseline will be summarized using descriptive statistics at 
each scheduled time point by intervention group.
Abnormality criteria (as defined in Table 4) will be applied to baseline and postbaseline values.
For baseline values, increase or decrease criteria are not applied.
Postbaseline values will be considered treatment-emergent if they meet both value and change 
criteria in Table 4.
For criteria that do not include an increase or decrease from baseline:

Treatment-emergent will be concluded if the postbaseline value is above the upper limit and 
the baseline value is below the upper limit (e.g., Normal or Low). The same applies to the 
postbaseline value being below the lower limit with the baseline value being above the lower 
limit (e.g., Normal or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as 
treatment-emergent.
Incidence of treatment-emergent clinically important abnormalities in vital signs during 
intervention will be summarized at each scheduled time point by intervention group. A listing of
participants with clinically important abnormalities in vital signs will be presented.
Table 4:
Clinically Important Abnormalities in Vital Signs
Vital Sign
Abnormal Category
Criteria
Pulse
Abnormally high
>100 bpm and with >15 bpm increase from baseline
Abnormally low
<50 bpm and with >15 bpm decrease from baseline
Systolic blood 
pressure
Abnormally high
>180 mm Hg and with >20 mm Hg increase from baseline
Abnormally low
<90 mm Hg and with >20 mm Hg decrease from baseline


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Vital Sign
Abnormal Category
Criteria
Diastolic blood 
pressure
Abnormally high
>105 mm Hg and with >15 mm Hg increase from baseline
Abnormally low
<50 mm Hg and with >15 mm Hg decrease from baseline
Temperature
Abnormally high
>37.5oC
Abnormally low
<35.5oC
Weight
Abnormally high
increase >7% from baseline
Abnormally low
decrease >7% from baseline
Respiratory rate
Abnormally high
>20 breaths per minute
In addition, a by-subject listing of the abnormal physical examination data will be presented.
5.6.3.3.
Electrocardiogram
The ECG parameters that will be analyzed are heart rate (HR), PR interval, QRS interval, QT 
interval, and corrected QT(QTc)intervalusing thefollowing correction methods: Bazett’sformula
(QTcB), andFridericia’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
If ECG measurements are repeated at a visit, they will be averaged. The averaged value will 
considered the ‘Visit’ ECG result.
Descriptive statistics of ECG parameters and change from baseline will be summarized at each 
scheduled time point by intervention group.
The number and percentage of participants with categorized QTc interval values will be 
summarized at each scheduled time point. The number and percentage of participants with 
categorized QTc interval increases from baseline to the maximum postbaseline value will be 
summarized. A shift table will be provided summarizing the shift from baseline to maximum QTc 
interval classification. Refer to Table 5 for summary categories.
Table 5:
Criteria for Abnormal QTc Values and Changes from Baseline
QTc value (msec)
Normal QTc
≤450 for male, ≤470 for female
>450 to ≤480 for male, >470 to ≤480 for female
>480 to ≤500
>500
QTc change from baseline (msec)
No concern
≤30
Concern
>30 to ≤60
Clear concern
>60
Abnormality criteria (Table 6) will be applied to baseline and postbaseline values. Postbaseline 
abnormalities will be compared with their corresponding baseline result:


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
Treatment-emergent will be concluded if the postbaseline value is above the upper limit and 
the baseline value is below the upper limit (e.g., Normal or Low). The same applies to the 
postbaseline value being below the lower limit with the baseline value being above the lower
limit (e.g., Normal or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as 
treatment-emergent.
The number and percentage of participants with treatment-emergent abnormal postbaseline values 
(relative to baseline) will be presented by intervention group over time:
Table 6:
Abnormal Limits for ECG Parameters
ECG Parameter
Abnormally low
Abnormally high
Heart Rate (bpm)
<50 bpm
>100 bpm
PR interval (msec)
<120 msec
>200 msec
QRS interval (msec)
<60 msec
>120 msec
QT interval (msec)
<200 msec
>500 msec
The interpretation of the ECGs as determined by a qualified physician (investigator or qualified 
designee) will be displayed by the number and percentage of participants meeting the normality 
criteria. The interpretation will be summarized over time.
A listing of clinically relevant ECG abnormalities will also be provided.
5.6.3.4.
Other Safety Parameters
5.6.3.4.1.
Young Mania Rating Scale (YMRS)
The YMRS is one of the most frequently utilized rating scales to assess manic symptoms (Young 
1978). The scale has 11 items and is based on the patient’s subjective report of his or her clinical 
condition over the previous 48 hours. Additional information is based on clinical observations 
made during the clinical interview. The items are selected based on published descriptions of the 
core symptoms of mania. There are 4 items (irritability, speech, thought content, and 
disruptive/aggressive behavior) that are graded on a 0 to 8 scale, while the remaining 7 items are 
graded on a 0 to 4 scale. These 4 items are given twice the weight of the others to compensate for 
poor cooperation from severely ill patients. There are well-described anchor points for each grade 
of severity. The YMRS total score, with a range of 0 to 60, is the sum of each of the 11 individual 
scores, with higher total YMRS scores reflecting greater symptom severity.
Descriptive statistics of the actual values and the change from baseline to each postbaseline time 
point will be presented for YMRS total score and individual items by intervention group. A listing 
of YMRS items throughout the study for individual participants at any time point will be provided.
5.6.3.4.2.
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 to assess severity and track suicidal events through any intervention (Posner 2007). It 
is a clinical interview providing a summary of both suicidal ideation and behavior that can be 


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administered during any evaluation or risk assessment to identify the level and type of suicidality 
present. The C-SSRS has been used frequently in clinical studies and is a validated, standard 
measure for suicidal ideation assessment. Using the C-SSRS, the outcomes will be categorized 
using the scoring for the 11 categories:
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
10
Suicide
Non-suicidal self-injurious behavior (11)
11
Non-suicidal self-injurious behavior
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0 = “no suicidal ideation 
or behavior that can be assessed on the basis of C-SSRS”). A participant with a score of 11 will be 
considered as not having suicidal ideation or behavior.
Shifts from baseline to the maximum postbaseline score pertaining to suicidal ideation or suicidal 
behavior (i.e., scores 1 to 10) will be summarized by intervention group.
The maximum score (of scores 1 to 10) assigned to each participant will be grouped into one of 
three broad categories: No suicidal ideation or behavior (0), Suicidal ideation (1-5), and Suicidal 
behavior (6-10). Shifts from baseline to the maximum postbaseline category will be summarized 
by intervention group.
Frequency distribution of the scores for the 11 categories will be provided at each time point by 
intervention group.
A listing of C-SSRS items throughout the study for participants with Suicidal Ideation or Behavior 
at any time point will be provided.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
PK analyses will be performed on the PK analysis set, defined as participants who have received 
at least 1 dose of JNJ-55308942 and have at least 1 valid blood sample drawn for PK analysis.


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Based on the individual plasma concentration-time data, using the binned nominal sampling times 
at Visits 2, 3, 4, 5, and 6, descriptive statistics (N, arithmetic mean, SD, coefficient of variation, 
geometric mean, median, range) will be used to summarize JNJ-553098942 plasma concentrations. 
All concentrations below the lowest quantifiable (BLQ) concentration will be treated as zero in 
the summary statistics. Mean and/or median (+/- SD) plasma concentration-time profiles of JNJ-
55308942 will be plotted.
5.8.
Interim Analyses
No interim analysis is planned.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
BMI
body mass index
BD
bipolar disorders
CGI-S
Clinical Global Impression – Severity
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition
ECG
electrocardiogram
GAD-7
Generalized Anxiety Disorder – 7 Items
GoF
Gain of Function
HDRS-17
Hamilton Depression Rating Scale – 17 Items
HR
heart rate
iARBM
Integrated Analytical Risk-Based Monitoring
IWRS
interactive web response system
LoF
Loss of Function
MADRS
Montgomery-Asberg Depression Rating Scale
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MDE
major depressive episode
MedDRA
Medical Dictionary for Regulatory Activities
MINI
MINI International Neuropsychiatric Interview
MMRM
mixed-effects model for repeated measures
MNAR
missing not at random
mRNA
messenger ribonucleic acid 
PD
pharmacodynamic(s)
PHQ-9
Patient Health Questionnaire – 9 Item
PK
pharmacokinetic(s)
PROMIS
Patient-Reported Outcomes Measurement Information System
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula
QTL
Quality Tolerance Limit
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAWB
Self-Assessment of Well-Being
SD
standard deviation
SHAPS
Snaith-Hamilton Pleasure Scale
SNP
single nucleotide polymorphism
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VAS
Visual Analog Scale
WHO-DD
World Health Organization Drug Dictionary
YMRS
Young Mania Rating Scale


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
Protocol Planned Analysis
Changes and Rationale
Analysis 
for 
the 
following 
secondary 
objective:
To evaluate the efficacy of JNJ-55308942 
compared to placebo on symptoms of 
depression in a subgroup of patients with 
messenger ribonucleic acid (mRNA) transcript 
levels at baseline that exceed the median level 
for both P2RX7 and IL-1β.
This analysis may be conducted in the future
when validated assays for mRNA transcript 
levels of P2RX7 and IL-1β become available.
If conducted, the analysis may be reported 
separately.
Analyses of the patient-reported outcomes 
including SHAPS, PROMIS – Ability to 
Participate in Social Roles and Activities, 
PHQ-9, and GAD-7; analysis of the safety 
scale YMRS.
Several participants had their Treatment Day 1 
assessment of these scales performed postdose 
instead of predose as per protocol. The 
assessments performed postdose on Treatment 
Day 1 will be included in the analyses as the 
baseline for these participants.


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized and listed by intervention 
group, and overall. In addition, the distribution of participants by country and site ID will be 
presented unless otherwise noted.
Table 7 presents a list of the demographic variables that will be summarized by intervention group 
and overall for the safety and the full analysis sets.
Table 7:
Demographic Variables
Continuous Variables
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median,
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Frequency distribution with the 
number and percentage of 
participants in each category.
Age (18-25 years, 26-50 years, 51-64 years)
Sex (male, female, undifferentiated)
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)
Country
aIf multiple race categories are indicated, the Race is recorded as ‘Multiple’
Additional summaries will be presented by the randomization stratification factors (BD type [I or 
II], country, P2RX7 GoF SNP mutation genotype [homozygous or heterozygous], as well as 
concomitant medication status [no mood stabilizer or antipsychotic, a mood stabilizer alone, an 
antipsychotic alone, or a combination of a mood stabilizer and an antipsychotic]) for the full 
analysis set.
Table 8 presents a list of the baseline disease characteristics variables that will be summarized by 
intervention group and overall for the safety and the full analysis set.
Table 8:
Baseline Disease Characteristics
Continuous Variables
Summary Type
Baseline HDRS-17 total score
Descriptive statistics (N, mean, 
standard deviation [SD], median,
and range [minimum and 
maximum]).
Baseline MADRS total score
Baseline CGI-S score
Categorical Variables
Frequency distribution with the 
number and percentage of 
participants in each category.
Number of prior nonresponse in the current episode (0, 1, 2, 3, 4)
BD Type (I or II)
Baseline CGI-S score (0, 1, 2, 3, 4, 5, 6, 7)
P2RX7 GoF SNP mutation genotype (homozygous or heterozygous)
Specific biomarker profile (Yes, No)
Concomitant medication status (no mood stabilizer or antipsychotic, a 
mood stabilizer alone, an antipsychotic alone, a combination of a mood 
stabilizer and an antipsychotic)


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6.4.
Appendix 4 Protocol Deviations and Quality Tolerance Limits (QTL)
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by the following categories.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other medically important protocol deviations identified during medical and statistical review
Quality Tolerance Limit parameters and thresholds are defined and will be monitored in this study. 
QTL parameters will be summarized. More details are described in the Integrated Analytical Risk-
Based Monitoring (iARBM) Plan (VTMF-17567624, 03 August 2022).


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6.5.
Appendix 5 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 the 
first dose (partial or complete) of study intervention. Concomitant medications are defined as any 
therapy used on or after the same day as the first dose of study intervention, including those that 
started before and continued on after the first dose of study intervention.
Summaries of concomitant medications will be presented by ATC term and intervention group. 
The proportion of participants who receive each concomitant medication will be summarized as 
well as the proportion of participants who receive at least 1 concomitant medication.
Prior medications will be summarized by ATC term and intervention group.


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6.6.
Appendix 6 Medical History
A listing of medical history abnormalities will be provided.


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6.7.
Appendix 7 Adverse Events of Special Interest
Not applicable


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6.8.
Appendix 8 Medications of Special Interest
Not applicable.


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6.9.
Appendix 9 Conversion of Raw Score to T-Score for PROMIS - Ability to 
Participate in Social Roles and Activities
CCI


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7.
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Rubin, D. (1987), Multiple Imputation for Nonresponse in Surveys, Wiley, New York, XXIX+258 pp.
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