Conditions: Depressive Disorder, Major
Keywords: Depressive disorder, major Sirukumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 193
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of sirukumab as adjunctive treatment to antidepressant therapy (monoaminergic antidepressant) where sirukumab (administered as a 50 milligram (mg) subcutaneous (SC) injection at Day 1, Day 28 and Day 56 during the 12- week double-blind treatment period) is compared to adjunctive placebo based on the change from baseline to 12-week endpoint in depressive symptoms as measured by the total score on the Hamilton Depression Rating Scale (HDRS), in participants diagnosed with Major Depressive Disorder (MDD) who have had a suboptimal response to the current standard oral antidepressant therapy and have a screening high sensitivity C-Reactive Protein (hsCRP) \>=0.300 milligram per deciliters (mg/dL) (International System of Units (SI) 3.00 mg/L). A cohort of subjects with hsCRP \<0.300 milligram per deciliter will also be enrolled to allow a better understanding of the relationship between CRP and clinical changes.

Detailed description:
A double-blind, placebo-controlled, multicenter study of sirukumab as adjunctive treatment to a monoaminergic antidepressant in adults with major depressive disorder. Participants will be randomly assigned to receive either placebo or sirukumab 50 milligram (mg) at a ratio of 1:1 at Day 1, 28 and 56. Participants will primarily be assessed for change from baseline in Hamilton Depression Rating Scale (HDRS17) score at Week 12. Safety will be monitored throughout the study.

Arms:
arm 1: Participants will receive sirukumab 50 mg as subcutaneous injection on Day 1, 28 and 56. arm 2: Participants will receive matching placebo on Day 1, 28 and 56.

Interventions: intervention 1: Sirukumab 50 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive sirukumab 50 mg as subcutaneous injection on Day 1, 28 and 56. intervention 2: Participants will receive matching placebo on Day 1, 28 and 56.

Protocol document:
Prot_000.pdf: 
1
Status: Approved,  Date: 22 January 2018
Janssen Research & Development *
Clinical Protocol
A Double-Blind, Placebo-Controlled, Multicenter Study of Sirukumab as Adjunctive 
Treatment to a MonoAminergic antidepressant in Adults with Major Depressive Disorder
Protocol CNTO136MDD2001; Phase 2a
Amendment INT-5
CNTO136  sirukumab
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.  
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:         2014-005206-37
Status:
Approved
Date:
22 January 2018
Prepared by:
Janssen Research & Development
EDMS number:
EDMS-ERI-99699138
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
2
Approved, Date: 22 January 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES [IF APPLICABLE] ................................................................. 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 11
TIME AND EVENTS SCHEDULE .............................................................................................................. 22
ABBREVIATIONS ...................................................................................................................................... 26
1.
INTRODUCTION................................................................................................................................ 28
1.1.
Background .................................................................................................................................... 30
1.1.1.
Nonclinical Studies ..................................................................................................................... 30
1.1.1.1.
Pharmacologic Profile.............................................................................................................. 30
1.1.1.2.
Toxicology................................................................................................................................ 31
1.1.2 Clinical Studies................................................................................................................................... 31
1.1.2.1
Human Pharmacokinetics and Immunogenicity ..................................................................... 34
1.1.2.2
Efficacy/Safety Studies............................................................................................................ 35
1.1.2.2.1
Efficacy................................................................................................................................. 35
1.1.2.2.2
Safety ................................................................................................................................... 36
1.2.
Overall Rationale for the Study...................................................................................................... 39
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 40
2.1.
Objectives ...................................................................................................................................... 40
2.2.
Hypothesis ..................................................................................................................................... 42
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 42
3.1.
Overview of Study Design.............................................................................................................. 42
3.2 
Study Design Rationale.................................................................................................................. 44
4.
SUBJECT POPULATION.................................................................................................................. 48
4.1.
Inclusion Criteria ............................................................................................................................ 48
4.2.
Exclusion Criteria ........................................................................................................................... 52
4.3.
Prohibitions and Restrictions ......................................................................................................... 56
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 57
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 59
7.
TREATMENT COMPLIANCE............................................................................................................ 59
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 59
9.
STUDY EVALUATIONS .................................................................................................................... 62
9.1.
Study Procedures........................................................................................................................... 62
9.1.1.
Overview..................................................................................................................................... 62
9.1.2.
Screening Phase ........................................................................................................................ 62
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 64
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 65
9.2.
Efficacy........................................................................................................................................... 65
9.2.1.
Evaluations ................................................................................................................................. 65
9.2.2.
Endpoints.................................................................................................................................... 67
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
3
Approved, Date: 22 January 2018
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 68
9.3.1.
Evaluations ................................................................................................................................. 68
9.3.2.
Pharmacokinetics ....................................................................................................................... 68
9.3.2.1.
Sample Collection and Handling ............................................................................................. 68
9.3.2.2.
Analytical Procedures.............................................................................................................. 68
9.3.3.
Immunogenicity Assessments (Antibodies to sirukumab).......................................................... 69
9.4.
Biomarkers ..................................................................................................................................... 69
9.5.
Pharmacogenomic (DNA) Evaluations .......................................................................................... 70
9.6.
Safety Evaluations ......................................................................................................................... 70
9.7.
Sample Collection and Handling.................................................................................................... 75
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 75
10.1.
Completion ..................................................................................................................................... 75
10.2.
Discontinuation of Study Treatment............................................................................................... 76
10.2.1.
Interruption of Study Agent Administration................................................................................. 79
10.3.
Withdrawal From the Study............................................................................................................ 80
11.
STATISTICAL METHODS................................................................................................................. 81
11.1.
Subject Information ........................................................................................................................ 81
11.2.
Sample Size Determination ........................................................................................................... 81
11.3.
Efficacy Analyses ........................................................................................................................... 82
11.4.
Pharmacokinetic Analyses............................................................................................................. 83
11.5.
Immunogenicity.............................................................................................................................. 84
11.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 84
11.7.
Biomarker Analyses ....................................................................................................................... 84
11.8.
Pharmacogenomic Analyses ......................................................................................................... 84
11.9.
Safety Analyses ............................................................................................................................. 84
11.10.
Interim Analysis.............................................................................................................................. 85
11.11.
Interim Analysis Committee ........................................................................................................... 86
11.12.
First Database Lock for the Primary Efficacy Analyses................................................................. 86
12.
ADVERSE EVENT REPORTING ...................................................................................................... 87
12.1.
Definitions ...................................................................................................................................... 87
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 87
12.1.2.
Attribution Definitions.................................................................................................................. 88
12.1.3.
Severity Criteria .......................................................................................................................... 89
12.2.
Special Reporting Situations.......................................................................................................... 89
12.3.
Procedures..................................................................................................................................... 89
12.3.1.
All Adverse Events...................................................................................................................... 89
12.3.2.
Serious Adverse Events ............................................................................................................. 90
12.3.3.
Pregnancy................................................................................................................................... 91
12.4.
Adverse Events of Special Interest................................................................................................ 91
12.5.
Contacting Sponsor Regarding Safety........................................................................................... 92
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 92
13.1.
Procedures..................................................................................................................................... 93
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 93
14.
STUDY DRUG INFORMATION......................................................................................................... 93
14.1.
Physical Description of Study Drug................................................................................................ 93
14.2.
Packaging ...................................................................................................................................... 93
14.3.
Labeling.......................................................................................................................................... 94
14.4.
Preparation, Handling, and Storage............................................................................................... 94
14.5.
Drug Accountability ........................................................................................................................ 94
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 95
16.
ETHICAL ASPECTS ......................................................................................................................... 95
16.1.
Study-Specific Design Considerations........................................................................................... 95
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
4
Approved, Date: 22 January 2018
16.1.1.
Investigator Responsibilities ....................................................................................................... 97
16.1.2.
Independent Ethics Committee or Institutional Review Board ................................................... 97
16.1.3.
Informed Consent ....................................................................................................................... 99
16.1.4.
Privacy of Personal Data .......................................................................................................... 100
16.1.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 100
16.1.6.
Country Selection ..................................................................................................................... 100
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 101
17.1.
Protocol Amendments.................................................................................................................. 101
17.2.
Regulatory Documentation .......................................................................................................... 101
17.2.1.
Required Prestudy Documentation........................................................................................... 101
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 102
17.4.
Source Documentation................................................................................................................. 102
17.5.
Case Report Form Completion .................................................................................................... 103
17.5.1.
Regulatory Approval/Notification .............................................................................................. 104
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 104
17.7.
Record Retention ......................................................................................................................... 104
17.8.
Monitoring .................................................................................................................................... 105
17.9.
Study Completion/Termination..................................................................................................... 105
17.9.1.
Study Completion ..................................................................................................................... 105
17.9.2.
Study Termination..................................................................................................................... 105
17.10.
On-Site Audits .............................................................................................................................. 106
17.11.
Use of Information and Publication.............................................................................................. 106
REFERENCES.......................................................................................................................................... 108
INVESTIGATOR AGREEMENT ............................................................................................................... 137
LAST PAGE.............................................................................................................................................. 137
LIST OF ATTACHMENTS
Attachment 1:
QuantiFERON®-TB Gold Testing ............................................................................ 110
Attachment 2:
Tuberculin Skin Testing............................................................................................ 112
Attachment 3:
Representative Example of the Clinical Global Impression Questionnaire-
Severity (CGI-S) questions that will be used in this study........................................ 113
Attachment 4:
Representative Example of the Massachusetts General Hospital –
Antidepressant Treatment Response Questionnaire questions that will be 
used in this study...................................................................................................... 114
Attachment 5:
Representative Example of the Columbia Suicide Severity Rating Scale –
Baseline questions that will be used in this study .................................................... 118
Attachment 6:
Representative Example of the Columbia Suicide Severity Rating Scale 
(Since Last Visit) questions that will be used in this study....................................... 120
Attachment 7:
Representative Example of the 17-Item Hamilton Depression Rating Scale 
(HDRS17) questions that will be used in this study................................................... 122
Attachment 8:
Representative Example of the Inventory of Depressive Symptomatology -
Clinician (IDS-C30) questions that will be used in this study ................................... 125
Attachment 9:
Representative Example of the Patient Health Questionnaire questions that 
will be used in this study........................................................................................... 128
Attachment 10:
Representative Example of the Snaith Hamilton Pleasure Scale questions 
that will be used in this study.................................................................................... 129
Attachment 11: 
Representative Example of the Functional Assessment of Chronic Illness 
Therapy-Fatigue questionnaire questions that will be used in this study................. 131
Attachment 12: 
Representative Example of the Childhood Trauma Questionnaire questions 
that will be used in this study.................................................................................... 134
Attachment 13:
Instructions for the Completion of the Patient-Reported Outcome (PRO) 
Case Report Forms .................................................................................................. 135
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
5
Approved, Date: 22 January 2018
LIST OF IN-TEXT TABLES AND FIGURES [IF APPLICABLE]
TABLES
Table 1:
Adverse Drug Reactions with Sirukumab (CNTO136) ............................................................. 37
Table 2:
Values for liver transaminase levels, absolute neutrophil count, and platelet count that 
require study agent interruption and/or permanent discontinuation of study agent 
administration............................................................................................................................ 80
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 44
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
6
Approved, Date: 22 January 2018
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
16 Feb 2015
Amendment INT-1
Amendment INT-2
Amendment INT-3
Amendment INT-4
Amendment INT-5
2 Apr 2015
13 May 2015
8 June 2015
3 Feb 2016
22 Jan 2018
Amendments below are listed beginning with the most recent amendment.
Amendment 5 (22 Jan 2018)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to have a first database lock 
when all subjects have completed the 12-week double-blind treatment phase for the primary efficacy analyses.
Applicable Section(s)
Description of Change(s)
Rationale: Section about analyses for primary efficacy added to the statistical methods
Synopsis 
Section about analyses for primary efficacy added to the statistical methods
Rationale: Randomization codes will be disclosed fully for sponsor staff for the primary efficacy analyses 
5. Treatment 
allocation and 
blinding
Specified that randomization codes will be disclosed fully for sponsor staff for the 
primary efficacy analyses
Rationale: Section added to describe the first database lock for the primary efficacy analyses
11. Statistical 
Methods
Section added to describe the first database lock for the primary efficacy analyses
Amendment INT-4 (3 Feb 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to include subjects who may be 
more reflective of the general population of subjects with Major Depressive Disorder (MDD) by updating the list of 
allowed antidepressants and concomitant therapies and comorbidities in subjects with MDD. Another reason is to 
add 50 subjects with hsCRP < 0.300 mg/dL (SI <3.00 mg/L).
Applicable Section(s)
Description of Change(s)
Rationale: To add mirtazapine, fluvoxamine, agomelatine, imipramine, nortriptyline and amitriptyline as 
allowed antidepressants
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
7
Approved, Date: 22 January 2018
Synopsis –Overview 
of Study Design; 
3.1 Overview of 
Study Design;
4.1 Inclusion Criteria;
8. Prestudy and 
Concomitant Therapy;
9.1.2 Screening Phase
Mirtazapine, fluvoxamine, agomelatine, imipramine, nortriptyline and amitriptyline 
added as allowed antidepressants.
Rationale: Due to time consuming nature of the screening assessments of the first screening visit, they may be 
divided over 2 days. 
Synopsis –Overview 
of Study Design;
T&E schedule; 
3.1 Overview of 
Study Design;
9.1.2 Screening Phase
Screening assessments of the first screening visit may be divided over 2 days. However, 
C-SSRS, IDS-C30 and HDRS17 must be performed on the same day.
Rationale: Allow improvement of up to and including 25% on the HDRS17 total score from the screening visit 
to the baseline visit to reflect the most commonly used criteria for minimal response.
Synopsis –Overview 
of Study Design; 
3.1 Overview of 
Study Design;
4.1 Inclusion Criteria;
9.1.3 Double-Blind 
Treatment Phase
Acceptable improvement on HDRS17 total score from the screening to baseline visit 
increased from  < 20% to ≤ 25%
Rationale: Study drug has no effect on blood pressure
T&E schedule; 
9.6 Safety 
Evaluations;
11.9 Safety Analyses
Orthostatic vital signs removed.
Rationale: To have criteria for interruption of study agent administration
10.2 Discontinuation 
of Study Treatment
Section with criteria for interruption of study agent administration added.
Rationale: Have a better reflection of the general population of subjects with Major Depressive Disorder
4.1 Inclusion Criteria
-
Comorbid Persistent Depressive Disorder and ADHD allowed; specified that 
Panic Disorder can be with or without agoraphobia.
-
Acceptable improvement on HDRS17 total score from the screening to baseline 
visit increased from  < 20% to ≤ 25%
-
Mirtazapine, 
fluvoxamine, 
agomelatine, 
imipramine, 
nortriptyline
and 
amitriptyline added to allowed antidepressants.
-
After completion of the hsCRP < 0.300 mg/dL cohort, retesting for CRP will be 
allowed, but only for subjects who have hsCRP ≥ 0.250 mg/dL (SI 2.50 mg/L) and 
< 0.300 mg/dL (SI 3.00 mg/L) at screening. Retesting for CRP is only allowed 
once.
4.2 Exclusion criteria
-
Comorbid Persistent Depressive Disorder and ADHD allowed; specified that 
Panic Disorder can be with or without agoraphobia.
-
Length of current major depressive episode increased to 60 months.
-
Supine systolic blood pressure increased to 150 mmHg.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
8
Approved, Date: 22 January 2018
-
One-time repeat urine drug screen allowed for positive drug screen for 
barbiturates or opioids.
8. Prestudy and 
Concomitant Therapy
-
Use of prophylactic use of low dose aspirin allowed.
-
Involuntarily commitment to psychiatric hospitalization limited to the current 
episode.
-
Benzodiazepines up to the equivalent of 2 mg of lorazepam per day allowed at 
intake if administered fixed daily dose for at least 2 weeks prior to screening.
-
Phenazepam up to 1.5 mg daily allowed.
-
Zoplicone and melatonin allowed as sleep medications.
-
Continuous fixed dose or PRN use of sleep medications is allowed. 
-
Trazodone allowed (not exceeding 150 mg/day) given as a sleep aid or for sexual 
dysfunction).
-
PRN use of specific NSAIDs allowed.
-
Requirement for stable frequency of psychotherapy decreased to last 3 months 
prior to screening.
-
Psychostimulants for ADHD are prohibited, but cognitive behavioral therapy is 
allowed.
Rationale: To achieve a better understanding of the relationship between CRP (and potentially other 
inflammatory biomarkers) and clinical response, by studying 50 additional subjects with hsCRP levels 
<0.300 mg/dL.
Synopsis – secondary 
objectives; 
2.1 Objectives;
Four secondary objectives added.
4.1 Inclusion criteria
Inclusion criterion #4 removed.
Synopsis – Statistical 
Methods;
3. Study Design and 
Rationale;
4.1 Inclusion Criteria;
5. Treatment 
Allocation and 
Blinding;
9.1.3 Double-Blind 
Treatment Phase;
9.2.2. Endpoints;
11.2 Sample Size 
Determination;
11.3 Efficacy Analyses
- Figure 1 adjusted
- Sample size determination adjusted.
- Analyses for additional secondary objectives added.
- Group of 50 subjects with screening hsCRP<0.300 mg/dL (SI 3.00 mg/L) added.
- 4th stratum with hsCRP level 0.000 to <0.300 mg/dL (SI 0.00 to <3.00 mg/L)
added.
Rationale: Administrative: correction MGH-ATRQ
Attachment 4
Updated version of MGH-ATRQ added, with minimal dose for fluoxetine corrected to 
20mg/d and agomelatine, nefazodone, tianeptine and reboxetine added.
Rationale: Administrative: ADR table adjusted
Section 1.1.2.2.2 
Safety
Column with frequency added, to be consistent with IB ED 10 addendum 2
Amendment INT-3 (8 June 2015)
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
9
Approved, Date: 22 January 2018
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is feedback from the Health 
Canada to add  risk of sepsis according to the Investigator’s Brochure.
Applicable Section(s)
Description of Change(s)
Rationale: Sepsis added as an adverse drug reaction.
1.1.2 Clinical Studies
1.1.2.2.2 Safety
Sepsis added in text and in Table 1. Adverse Drug Reactions with Sirukumab 
(CNTO136)  
Rationale: Administrative: correction text Attachment 3
Attachment 3
Global improvement section has been deleted as only the Clinical Global Impression 
Questionnaire-Severity (CGI-S) is used in this study.
Amendment INT-2 (13 May 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is feedback from the FDA to add 
an additional clinical laboratory assessment (to monitor neutrophils, platelets, and liver enzymes) at the Week 4 
visit, as hematologic effects and effects on liver enzymes occurred within the first 4 weeks of treatment in the Phase 
2 RA study (C1377T04), according to the Investigator’s Brochure.
Applicable Section(s)
Description of Change(s)
Rationale: To add an additional clinical laboratory assessment at the Week 4 visit.
Time & Events 
schedule
Clinical laboratory assessment added on W4 visit.  
Rationale: Administrative: Clarification of timing of MGH-ATRQ
Time & Events 
schedule
Clarified that MGH –ATRQ is to be done at the first screening visit.
Rationale: Clarify that the Structured Interview Guide for the Hamilton Depression Scale (SIGH-D) will be used 
for HDRS17 assessment.
Synopsis; 
9.2.1 Evaluations
Clarification and rationale added that Structured Interview Guide for the Hamilton 
Depression Scale (SIGH-D) will be used.
Rationale: Administrative: correction of typo 
Synopsis; 
9.2.1 Evaluations
Score for ‘nearly every day’ for PHQ-9 corrected from ‘4=Nearly every day’ to ‘3=Nearly 
every day’
Rationale: Administrative: correction discontinuation of treatment criteria 
10.2 Discontinuation 
of Study Treatment
QTc and QT criteria removed as no ECG’s are taken during the study
Rationale: Administrative: correction title attachment 3
Attachment 3
‘Severity’ added to title to reflect that it is the Clinical Global Impression Questionnaire-
Severity (CGI-S) that is used in this study.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
10
Approved, Date: 22 January 2018
Amendment INT-1 (2 Apr 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to update the physical 
description of study drug to be consistent with the IB version 9 addendum 1.
Applicable Section(s)
Description of Change(s)
Rationale: IB edition 9 addendum 1 contained updated description of the needle shield for the prefilled syringe 
(PFS)-Ultrasafe; the info in this protocol is updated so it is consistent.
14.1.
Physical 
Description of Study 
Drug
Specified that the needle shield on the PFS (assembled into UltraSafe needle guard) does 
contain a derivative of natural rubber latex, which may cause allergic reactions in 
individuals sensitive to latex.  
Rationale: Correct an inconsistency in the protocol related to the criterion about improvement of  ≥20% on HDRS17
total score from the screening to baseline visit.
4.1. Inclusion 
Criteria;      
4.2. Exclusion 
Criteria
Clarified that improvement on HDRS17 total score from screening to baseline should be 
less than 20% for a subject to be eligible.
Rationale: To decrease the burden on the subject, certain screening assessments will only be performed once the 
subject has been confirmed to be eligible for all other screening criteria. 
Synopsis – overview 
of study design; Time 
& Events schedule; 
3.1 Overview of study 
design; 3.2 Study 
design rationale; 4. 
Subject population; 
9.1.2. Screening 
phase
Split the screening in 2 visits: at the second visit only ²-ray and SAFER interview will be 
done, if subject has been confirmed eligible for all other screening criteria assessed at the 
first screening visit.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
11
Approved, Date: 22 January 2018
SYNOPSIS
A Double-Blind, Placebo-Controlled, Multicenter Study of Sirukumab as Adjunctive 
Treatment to a MonoAminergic antidepressant in Adults with Major Depressive Disorder
Sirukumab (also known as CNTO 136) is a human immunoglobulin G1κ (IgG1κ) monoclonal 
antibody (mAb) with a molecular weight of approximately 150,000 daltons.  Sirukumab binds to 
and neutralizes human IL-6 and subsequently attenuates IL-6 signaling and the biological effects 
of IL-6.  Sirukumab is being developed for the treatment of disorders of the immune system, 
including rheumatoid arthritis, and is being studied in neuropsychiatric conditions with an 
established immune component, such as depression.   
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to evaluate the efficacy of sirukumab as adjunctive 
treatment to antidepressant therapy (monoaminergic antidepressant) where sirukumab 
(administered as a 50mg subcutaneous (SC) injection at Day 1, Day 28 and Day 56 during the 
12- week double-blind treatment period) is compared to adjunctive placebo based on the change 
from baseline to 12-week endpoint in depressive symptoms as measured by the total score on the 
Hamilton Depression Rating Scale (HDRS17), in subjects diagnosed with Major Depressive 
Disorder (MDD) who have had a suboptimal response to the current standard oral antidepressant 
therapy and have a screening and baseline high sensitivity C-Reactive Protein (hsCRP) ≥0.300 
mg/dL (International System of Units (SI) 3.00 mg/L) (approximately 142 subjects).
Secondary Objectives

To evaluate the overall safety and tolerability of adjunctive sirukumab compared to 
adjunctive placebo in subjects with MDD.

To evaluate the impact of adjunctive sirukumab compared to adjunctive placebo on 
anhedonia as measured by the change from study baseline to 12-week endpoint on the Snaith 
Hamilton Pleasure Scale (SHAPS) in subjects with MDD and screening hsCRP ≥0.300 
mg/dL.

To evaluate the impact of treatment with adjunctive sirukumab compared to adjunctive 
placebo on global severity of symptoms of MDD, as measured by the change in the Clinical 
Global Impression - Severity (CGI-S) scale from study baseline to 12-week endpoint in 
subjects with MDD and screening hsCRP ≥0.300 mg/dL.

To evaluate the impact of treatment with adjunctive sirukumab compared to adjunctive 
placebo on remission and response rates at 12-week end point, defined as a HDRS17 total 
score ≤7 or a ≥ 50% improvement in HDRS17 total score from baseline, respectively in 
subjects with MDD and screening hsCRP ≥0.300 mg/dL.

To evaluate the impact of treatment with adjunctive sirukumab compared to adjunctive 
placebo on subject-reported severity of symptoms of MDD, as measured by the change in the 
Patient Health Questionnaire (PHQ-9) from study baseline to 1- week endpoint and to 
12-week endpoint in subjects with MDD and screening hsCRP ≥0.300 mg/dL.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
12
Approved, Date: 22 January 2018

To evaluate the impact of treatment with adjunctive sirukumab compared to adjunctive 
placebo on fatigue, as measured by the change from study baseline to 1-week, 4-week, 
8-week and 12-week endpoint in the Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT Fatigue) scale in subjects with MDD and screening hsCRP ≥0.300 mg/dL.

To evaluate the efficacy measured by change in the HDRS17 scores following adjunctive 
sirukumab compared to adjunctive placebo in the Treatment Resistant Depression (TRD)
versus non-TRD subjects. TRD is defined as having being treated with ≥ 2 trials of 
antidepressants of adequate dose and duration (according to the Massachusetts General 
Hospital Antidepressant Treatment History Questionnaire (MGH-ATRQ)) during the current 
episode.

To evaluate pharmacokinetics and immunogenicity of sirukumab in subjects with MDD.

To evaluate the impact of treatment with adjunctive sirukumab in subjects with screening 
hsCRP≥0.300 mg/dL as compared to in those with screening hsCRP<0.300 mg/dL based on 
changes from baseline to Week 12 in HDRS17 total score.

To assess the efficacy of sirukumab compared to placebo as adjunctive therapy to an 
antidepressant in subjects with MDD with screening hsCRP levels <0.300 mg/dL versus 
those with screening hsCRP levels ≥ 0.300 mg/dL in improving response of depressive 
symptoms, defined as the proportion of subjects having a ≥50% improvement in HDRS17
total score from baseline to the end of Week 12. 

To assess the efficacy of sirukumab compared to placebo as adjunctive therapy to an 
antidepressant in subjects with MDD with screening hsCRP levels <0.300 mg/dL versus 
those with screening hsCRP levels ≥ 0.300 mg/dL in achieving remission of depressive 
symptoms, defined as the proportion of subjects having a HDRS17 total score ≤7 at the end of 
Week 12.

To evaluate whether hsCRP levels correlate with clinical efficacy as measured by the change 
from baseline to Week 12 in HDRS17 total score.
Exploratory Objectives

To explore the efficacy of adjunctive sirukumab compared to adjunctive placebo, based on 
the change from baseline to 12-week endpoint in the Inventory of Depressive 
Symptomatology – Clinician Rated 30 Item Scale (IDS-C30) in subjects with MDD and 
screening hsCRP ≥0.300 mg/dL.

To explore immune-system related biomarkers (hsCRP, cytokines, chemokines), as well as 
other mood disorder related biomarkers (growth factors, hypothalamic–pituitary–adrenal 
(HPA) axis markers, metabolic markers) and to explore the potential correlation between 
these biomarkers and the clinical response, non-response or safety parameters of sirukumab.

To explore genetic and epigenetic variation that may be related to clinical response, non-
response, or safety parameters of sirukumab.

To explore
the effect of sirukumab on the pharmacokinetics of monoaminergic 
antidepressants.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
13
Approved, Date: 22 January 2018

To explore the relationship between the severity of childhood trauma as assessed through the 
Childhood Trauma Questionnaire and the change in HDRS17 scores following adjunctive 
sirukumab or placebo.
Hypothesis
The primary hypothesis of this study is that sirukumab will determine significant improvement in 
depressive symptoms from baseline compared  to placebo when administered as an adjunctive 
treatment to a monoaminergic antidepressant in the treatment of patients with MDD who have 
shown a suboptimal response to standard oral antidepressant therapy and have a screening and 
baseline hsCRP ≥ 0.300 mg/dL (SI 3.00 mg/L), demonstrated by improvement in depressive 
symptoms from baseline to 12-week endpoint in the Hamilton Depression Rating Scale 
(HDRS17) total score.
OVERVIEW OF STUDY DESIGN
This is a multicenter, double-blind, placebo-controlled study in male and female subjects, 21 to 
64 years of age inclusive, with MDD who have had a suboptimal response to standard oral 
antidepressant therapy; have failed no more than 3 antidepressant treatments in the current major 
depressive episode; approximately 192 subjects will be enrolled.
Determination of suboptimal response to the current standard oral antidepressant therapy will be 
made retrospectively using the structured MGH-ATRQ. Determination of the number of failed 
antidepressant treatments in the current episode will be made retrospectively using medical or 
pharmacy records and documented on the MGH-ATRQ. Serum concentration of hsCRP will be 
measured from a venous blood sample at screening.
The study will consist of 3 phases: a screening phase of up to 4 weeks, consisting of 2 visits, a 12 
week double-blind treatment phase, and a 14 week posttreatment follow-up phase. The total 
duration of subject participation will be approximately 26 weeks. 
Screening Phase:
Subjects with a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) 
diagnosis of MDD, confirmed by the MINI International Neuropsychiatric Inventory (MINI), 
who are currently being treated with a monoaminergic antidepressant and have failed no more 
than 3 antidepressants (of adequate dose and duration) in the current major depressive episode 
will be eligible for screening. Screening will include informed consent, evaluation for eligibility 
in the study, medical history, physical and psychiatric evaluations, venous blood sampling for 
hsCRP assay and standard labs. Determination of suboptimal response to the current standard 
oral antidepressant therapy will be made retrospectively using the structured MGH-ATRQ. 
Determination of failure of antidepressant treatments in the current episode will be made 
retrospectively using medical or pharmacy records and documented on the MGH-ATRQ.  
Subjects with partial improvement (<50%) according to the MGH-ATRQ and moderate to severe 
depression (HDRS17 total score ≥18 at screening, as measured by a remote independent rater) 
will be eligible for inclusion. Subjects must be currently receiving no more than 2 of the 
following antidepressants for at least 6 weeks duration at screening with at least one 
antidepressant being at an adequate therapeutic dose, as determined by the MGH-ATRQ:  
bupropion, 
fluoxetine, 
citalopram, 
escitalopram, 
sertraline, 
paroxetine, 
venlafaxine, 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
14
Approved, Date: 22 January 2018
desvenlafaxine, mirtazapine, fluvoxamine, agomelatine, imipramine, nortriptyline, amitriptyline, 
duloxetine, vilazodone, vortioxetine and levomilnacipram.  
The screening phase will consist of 2 visits; the procedures scheduled during the first screening 
visit may be divided over two days, according to operational and/or site/country-specific needs;
in case the first screening visit is conducted over two days, the following assessments must be 
performed on the same day: C-SSRS, IDS-C30 and HDRS17.
The second visit will only be performed once all in- and exclusion criteria have been confirmed, 
except for the SAFER interview and chest X-ray (if applicable). These will only be performed at 
the second screening visit. If some in and/or exclusion criteria still have to be confirmed at the 
time of this second screening visit, this will be discussed prior to this second screening visit with 
the JRD responsible safety physician on a case by case basis.
Double blind treatment phase:
Subjects who continue to meet inclusion and exclusion criteria at the baseline visit will be 
eligible for randomization.  At the baseline visit, subjects must have a HDRS17 total score ≥18, 
as measured by a remote independent rater, and must not demonstrate an improvement of >25 %
on their HDRS17 total score from the screening to baseline visit. Randomization will be 
stratified by country and screening hsCRP level: 0.00 to <0.300 mg/dL (SI 0.00 to <3.00 mg/L),
≥0.300 to <0.500 mg/dL (SI ≥3.00 to <5.00 mg/L), ≥0.500 to <0.800 mg/dL (SI ≥5.00 to <8.00 
mg/L), and ≥0.800 mg/dL (SI ≥8.00 mg/L). Subjects will receive either adjunctive placebo or 
adjunctive sirukumab in a 1:1 ratio. 
Refer to the Time and Events Schedule for a list of study evaluations that will be performed 
during the double-blind treatment phase.
Posttreatment Follow-Up:
Subjects will have two follow-up safety visits, 8 and 14 weeks after last SC injection, to assess 
clinical condition, monitor safety and adverse events and record concomitant medications. 
Subjects with unresolved adverse events at Week 22 will be continued to be monitored as 
clinically appropriate to ensure subjects’ safety.
SUBJECT POPULATION
In total, approximately 192 subjects will be enrolled in this study, with approximately 
96 subjects randomized per treatment group. The sample size may increase up to 228 if the 
interim analysis suggests the need to do so in order to ensure adequate statistical power to test 
the primary hypothesis.
The target study population is male and female subjects with MDD who have had a suboptimal 
response to standard oral antidepressant therapy; have failed no more than 3 antidepressant 
treatments in the current major depressive episode; approximately 142 subjects with screening 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
15
Approved, Date: 22 January 2018
hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) and approximately 50 subjects with screening 
hsCRP<0.300 mg/dL (SI 3.00 mg/L) will be enrolled.
Subjects will be enrolled after reading the subject information sheet and signing the informed 
consent form (ICF) indicating that they understand the purpose of the study and procedures 
required for the study and are willing to participate in the study and comply with the study 
procedures.
DOSAGE AND ADMINISTRATION
Subjects who meet the study criteria of a HDRS17 total score ≥ 18 at the baseline visit will be 
randomly assigned in a 1:1 ratio to receive adjunctive treatment with SC injection of placebo or 
sirukumab 50 mg, while continuing on their baseline oral monoaminergic antidepressant(s). The 
matching placebo injection will consist of an identical volume of placebo solution, administered 
SC at the same time points. All subjects will receive 3 injections in total, one injection each at 
Day 1, Day 28 and Day 56.
If an injection is missed, every effort should be made to have the missed injection administered 
within 4 days after the scheduled date for that injection.  In case it is not possible to administer 
the missed injection in time, site personnel should discuss the issue with the JRD responsible 
safety physician.
The study agent will be administered SC at the site by a health care professional.
EFFICACY EVALUATIONS/ENDPOINTS
Primary Efficacy Evaluation/Criteria
The primary efficacy endpoint for this study will be the improvement in depressive symptoms, as 
measured by the change in the HDRS17 total score from baseline to 12-week endpoint (see 
section Efficacy Analyses). The primary comparisons will be between the adjunctive sirukumab 
group and the adjunctive placebo group in subjects hsCRP ≥0.300 mg/dL at screening and 
baseline.
Hamilton Depression Rating Scale (HDRS17)
The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms 
in subjects diagnosed with depression (Hamilton M 1960) with a score range of 0 to 52. It is the 
most widely used symptom severity measure for depression. Each of the 17 items is rated by the 
clinician on either a 3- or a 5-point scale. The HDRS17 has an inter-rater reliability correlation of 
r = .90 and the internal consistency of the measure is reported to be high with a coefficient alpha 
of 0.88. Criterion-related validity for this measure is high (Knesevich J et al., 1977). The original 
HDRS17 scale lacks instructions for administration and clear anchor points for the assignment of 
severity ratings. For this reason, the structured interview guide version of the HDRS17 (the 
Structured Interview Guide for the Hamilton Depression Scale [SIGH-D]) will be used in the 
current study to facilitate and standardize gathering clinical information from the subject.
An example of the HDRS17 is provided in Attachment 7.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
16
Approved, Date: 22 January 2018
Secondary Efficacy Evaluations/Criteria
Secondary efficacy endpoints will include the change from baseline to 12-week endpoint 
between the adjunctive sirukumab group and the adjunctive placebo group in the SHAPS total 
score, CGI-S, PHQ-9 and FACIT as well as the distribution of remitters and responders in 
subjects with screening hsCRP ≥ 3.00 mg/L (the number and percentage of subjects in remission 
as measured by a HDRS17 total score ≤ 7 or responders defined as ≥ 50% improvement on the 
HDRS17 from baseline to 12 week endpoint). The same secondary efficacy endpoints will be 
compared between subjects with screening hsCRP ≥3.00 mg/L and subjects with hsCRP <3.00 
mg/L
Clinical Global Impression - Severity (CGI-S)
The CGI-S will provide an overall clinician-determined summary measure that takes into 
account all available information, including knowledge of the subject’s history, psychosocial 
circumstances, symptoms, behavior, and the impact of the symptoms on the subject’s ability to 
function (Guy 1976). The CGI evaluates the severity of psychopathology from 1 to 7.
An example of the CGI-S is provided in Attachment 3.
Patient Health Questionnaire (PHQ-9)
The PHQ-9 will be used as a subject-reported measure of depressive symptomatology 
(Spitzer 1999). The PHQ-9 is a 9-item scale, where each item is rated on a 4-point scale (0=Not 
at all, 1=Several Days, 2=More than half the days, and 3=Nearly every day), with a total score 
range of 0 to 27. The recall period is 2 weeks.
An example of the PHQ-9 is provided in Attachment 9.
Snaith–Hamilton Pleasure Scale (SHAPS)
Anhedonia, the inability to experience pleasure, is a major endophenotype of depression. The 
Snaith–Hamilton Pleasure Scale (SHAPS) is a self-reported, short, 14-item instrument to 
measure anhedonia, which has been shown to be valid and reliable in normal and clinical 
samples (Snaith et al, 1995).  Each of the 14 items has a set of four response categories:  
Definitely Agree (= 1), Agree (= 2), Disagree (= 3), and Definitely Disagree (= 4). A higher total 
score indicates higher levels of state anhedonia.
An example of the SHAPS is provided in Attachment 10.
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT Fatigue)
The FACIT-Fatigue is a questionnaire that assesses self-reported tiredness, weakness, and 
difficulty conducting usual activities due to fatigue. The total FACIT-Fatigue score ranges from 
0 to 52, with a higher score indicating less fatigue (Webster et al., 1999).
An example of the FACIT is provided in Attachment 11.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
17
Approved, Date: 22 January 2018
Exploratory Efficacy Evaluations/Criteria
Exploratory efficacy evaluations will include the change from baseline to 12-week endpoint in 
the IDS-C30 total score in subjects with MDD and screening hsCRP ≥0.300 mg/dL, evaluation 
of the association between change from baseline of the HDRS17, baseline and post-treatment 
biomarker measurements (including hsCRP), the effect of sirukumab on the pharmacokinetics of 
monoaminergic antidepressants, evaluation of the relationship between the severity of childhood 
trauma as assessed through the CTQ and the change in HDRS17 scores following adjunctive 
sirukumab or placebo and assessment of genes/genotypes.
Inventory of Depressive Symptomatology – Clinician Rated 30 (IDS-C30)
The clinician-rated IDS is a 30-item, depression-specific symptom severity rating scale (Rush et 
al., 1986). The IDS is designed to measure the specific signs and symptoms of depression, 
including melancholic, atypical and anxious features. Scores range from 0 to 84 with higher 
scores representing greater severity of depressive symptoms. The inter-rater reliability and 
internal consistency coefficients are high (Rush et al., 1996).  The IDS-C and the IDS-self report 
have reasonable construct validity, and a concurrent validity index above 0.90, correlating well 
with the HDRS17 and the Beck Depressive Inventory (Rush et al., 1996). 
An example of the IDS-C30 is provided in Attachment 8.
Childhood Trauma Questionnaire (CTQ)
The CTQ was developed as a screening tool for histories of abuse and neglect. The self-report 
includes a 28-item test that measures 5 types of maltreatment – emotional, physical, and sexual 
abuse, and emotional and physical neglect (Bernstein et al., 1998). A 5-point Likert scale is used 
for the responses which range from Never True to Very Often True.
An example of the CTQ is provided in Attachment 12.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
18
Approved, Date: 22 January 2018
PHARMACOKINETIC EVALUATIONS
Venous blood samples will be collected for determination of serum sirukumab concentrations at 
the time points specified in the Time and Event Schedule. Additionally, to assess the effect of 
sirukumab on the pharmacokinetics of monoaminergic antidepressants, blood samples will be 
collected for the determination of monoaminergic antidepressant concentrations before and after 
sirukumab treatment.
Serum sirukumab concentrations will be summarized by visit. Monoaminergic antidepressants
concentration data will be summarized. 
IMMUNOGENICITY EVALUATIONS
Antibodies generated in response to sirukumab have the potential to accelerate the clearance of 
the drug and hence affect efficacy and safety. To evaluate the immunogenicity of sirukumab in 
subjects with MDD, serum samples for the detection of antibodies to sirukumab will be collected 
according to the Time and Events Schedule. The incidence and titers of antibodies to sirukumab
will be summarized.
BIOMARKER EVALUATIONS 
During the study, blood and saliva will be collected at the time points indicated in the Time and 
Events schedule for the assessment of biomarkers related to the immune system activity, 
hypothalamus pituitary adrenal (HPA) axis activation, neurotrophic factors and metabolic factors 
to allow for exploratory immunophenotyping and for an exploratory pharmacodynamics 
evaluation.
PHARMACOGENOMIC (DNA) EVALUATIONS
Pharmacogenomic blood samples will be collected to allow for the identification of genetic 
and/or epigenetic factors that may influence the pharmacokinetics, pharmacodynamics, efficacy, 
safety, or tolerability of sirukumab in a sample of subjects with MDD.  
SAFETY EVALUATIONS
Safety will be monitored by the evaluation of adverse events, clinical laboratory test results, vital 
signs measurements, body weight, physical examination findings, allergic and injection site 
reactions to SC injections, early detection of active tuberculosis and hepatobiliary abnormalities. 
The Columbia Suicide Severity Rating Scale (C-SSRS) will be administered to monitor suicidal 
ideation and behavior.
STATISTICAL METHODS
Sample Size Determination
The expected sample size of 142 subjects for those with screening hsCRP≥0.300 mg/dL was
determined based on the assumption of an effect size of at least 0.5 for the HDRS17 (difference in 
mean change from baseline to Week 12 endpoint between the sirukumab and placebo groups of 4 
units with SD=8).  This is considered to be a clinically relevant difference in a population with 
suboptimal response to standard oral antidepressant therapy. Power is set at 90.0%, with a 
1-sided alpha of 0.125 and a 12-week drop-out rate of 25%. It was also assumed that 10% of the 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
19
Approved, Date: 22 January 2018
randomized subjects would be excluded from the primary efficacy analysis due to having 
hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) at screening but not baseline. The number of treatment 
resistant subjects will be monitored on an on-going basis to ensure enough sample size for a 
secondary efficacy analysis in the TRD population. If an insufficient number of TRD subjects is 
being enrolled in the study, the sponsor will encourage the sites to enroll more TRD subjects. 
Note that the study is not statistically powered for comparing effect sizes between treatment 
groups in the TRD population.     
Sample size determination for the additional stratum (screening hsCRP < 0.300 mg/dL 
(SI 3.00 mg/L):
Assuming a difference for the mean change from baseline to the week 12 primary endpoint of 4 
between the hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) stratum and the hsCRP < 0.300 mg/dL 
(SI 3.00 mg/L) stratum, and a SD of 8, a 1-sided alpha of 0.125, and a week 12 drop-out rate of 
25%, a sample size of 71 subjects in the active treatment group (142 total) in the 
hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) stratum and 25 subjects in the active treatment group (50 
total) in the hsCRP < 0.300 mg/dL (SI 3.00 mg/L) stratum would provide 75% power to detect a 
difference between the two strata.   
Interim Analysis
An interim analysis will be conducted to monitor safety data, assess futility, sample size re-
estimation, and hsCRP enrichment criteria.  The interim analysis is planned when 40-50% of the 
planned number of subjects who are eligible to be included in the primary efficacy analysis 
complete the week 12 assessment. Both Frequentist and Bayesian approaches will be applied for 
the interim analysis. Detailed approaches will be described in the interim statistical analysis plan 
and the Interim Analysis Committee (IAC) charter. 
The interim analysis results will be used to assess the study for futility and as such the study may 
be terminated early if the probability of success of the study is calculated to be very low. In 
addition, based on the results of hsCRP-response relationship, the study may continue with the 
enriched population using a selected hsCRP level. The decision rule for futility at the interim 
analysis will be detailed in the interim SAP and the IAC charter.    
In addition, the sample size for the study may be increased up to N=228 if the interim data 
suggest this is necessary to ensure robust conclusions.   
Analyses for primary efficacy
Analyses for primary efficacy will be done when all subjects have completed the 12-week 
double-blind treatment phase. Detailed statistical approaches are summarized below and will be 
described in more detail in the statistical analysis plan. The results will be used to assess the 
potential efficacy of sirukumab in the treatment of MDD and to make strategic internal decisions 
regarding the development of the compound. This will be the final analyses for the primary 
efficacy. The results will not impact the further conduct of the trial. 
Efficacy Analyses
Three analyses sets will be defined for efficacy analyses: the modified intent-to-treat 1 (mITT1), 
the modified intent-to-treat 2 (mITT2), and the modified intent-to-treat 3 (mITT3) analyses sets. 
The mITT1 analysis set is defined as all randomized subjects with hsCRP ≥0.300 mg/dL at 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
20
Approved, Date: 22 January 2018
screening and baseline who receive at least 1 dose of study drug and have both the baseline and 
at least one postbaseline HDRS17 total score measured within the double-blind treatment period. 
The mITT2 analysis set is defined as all randomized subjects (regardless of screening hsCRP 
level) who receive at least 1 dose of study drug and have both the baseline and at least one 
postbaseline HDRS17 total score measured within the double blind treatment period. The mITT3 
analysis set is defined as all randomized subjects with hsCRP≥ 0.300 mg/dL at screening who 
receive at least 1 dose of study drug and have both the baseline and at least one postbaseline 
HDRS17 total score measured within the double blind treatment period.
The primary efficacy analyses will be based on the mITT1 analysis set. The sirukumab treatment 
group will be compared with the placebo group using the primary efficacy endpoint, change 
from baseline in HDRS17 total score, with the comparison performed by means of a mixed-
effects model using repeated measures (MMRM), with time, treatment (placebo, sirukumab), 
country, hsCRP stratification levels [i.e., ≥3.00 to <5.00 mg/L (≥0.300 to <0.500 mg/dL), ≥5.00 
to <8.00 mg/L (≥0.500 to <0.800 mg/dL), and ≥8.00 mg/L (≥0.800 mg/dL)], and time-by-
treatment interaction as factors, baseline HDRS17 total score as a continuous covariate, and a 
random subject effect. An unstructured variance-covariance matrix will be used. The comparison 
of sirukumab versus placebo will be performed using the appropriate contrast. Subgroup analysis 
will be carried out for the primary efficacy endpoint based on TRD versus non-TRD status. 
Analyses of secondary efficacy endpoints will be based on the mITT2 analysis set. The change 
from baseline to 12-week endpoint for the secondary continuous efficacy endpoints will be
analyzed in the same way as for the HDRS17 total score. 
The hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) stratum will be compared with the 
hsCRP < 0.300 mg/dL (SI 3.00 mg/L) stratum using the primary efficacy endpoint, i.e., change 
from baseline to Week 12 in HDRS17 total score. A mixed effects model using repeated 
measures (MMRM), with time, hsCRP stratum (hsCRP ≥0.300 mg/dL (SI 3.00 mg/L), 
hsCRP < 0.300 mg/dL (SI 3.00 mg/L), treatment, country, and time-by-hsCRP stratum 
interaction as factors, baseline HDRS17 total score as a continuous covariate, and a random 
subject effect will be employed. An unstructured variance-covariance matrix will be used. The 
comparison of hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) versus hsCRP < 0.300 mg/dL 
(SI 3.00 mg/L) will be performed using the appropriate contrast. Note that subjects whose CRP 
drops from ≥ 0.300 mg/dL (SI 3.00 mg/L) at screening to <0.300 mg/dL (SI 3.00 mg/L) at 
baseline will be included in the 4th stratum hsCRP (< 0.300 mg/dL (SI 3.00 mg/L) group) for the 
analyses.
In addition to evaluating hsCRP as a categorical variable (hsCRP<0.300mg/dL; hsCRP ≥0.300 
to <0.500 mg/dL; hsCRP ≥0.500 to <0.800 mg/dL and hsCRP ≥0.800 mg/dL), hsCRP will be 
analyzed as a continuous variable and correlated with the primary efficacy endpoint (change 
from baseline to Week 12 in HDRS17 total score) using Pearson and Spearman methods.  
Sensitivity analyses of the primary endpoint will also be performed; these will be detailed further 
in the Statistical Analysis Plan. These will include analysis based on the mITT3 analysis set (that 
is, the mITT1 analysis set plus those subjects excluded for having a screening 
hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) but hsCRP <0.300 mg/dL (SI 3.00 mg/L) at baseline). 
These will also include an analysis of covariance (ANCOVA) model using the last observation 
carried forward (LOCF) imputation method, with factors for treatment, country, and hsCRP 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
21
Approved, Date: 22 January 2018
stratification levels, and baseline HDRS17 total score as a covariate. Other sensitivity analyses 
may also be performed to investigate the robustness of treatment estimates to the observed 
pattern of, and/or reason for, early withdrawals. Descriptive statistics for values and changes 
from baseline will be provided for all efficacy measures, including individual items for selected 
scales, subscales, and total score, at each time point of the double-blind treatment phase.
Sensitivity analyses of the secondary endpoints will also be performed; these will be detailed 
further in the Statistical Analysis Plan. These will include analysis based on the mITT1 and 
mITT3.
Details of the exploratory analyses will be provided in the SAP.
Safety analyses
All safety analyses will be performed based on the safety analysis set, which will include all 
randomized subjects who receive at least 1 dose of study drug. Adverse events will be coded 
using the current version of MedDRA and tabulated by system organ class and preferred term. 
Adverse events will also be tabulated by severity and relationship to study drug and will be 
presented by treatment group. Serious adverse events and treatment-limiting adverse events will 
be summarized separately.
Clinical laboratory test results, vital sign values, body weight and changes from baseline will be 
tabulated over time by treatment group, using descriptive statistics. Any treatment-emergent 
abnormalities will be presented. A listing of subjects with markedly abnormal results will also be 
provided. Subjects with changes from screening in physical examination findings from normal to 
abnormal will be listed.
The suicidality data collected from the C-SSRS using aggregate endpoints of suicidal behavior 
and suicidal ideation separately will be summarized descriptively at each scheduled visit by 
treatment group. Further details will be presented in the SAP.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
22
Approved, Date: 22 January 2018
TIME AND EVENTS SCHEDULE
Phase
Screening
Double-Blind Treatmenta
Early 
withdrawalb,s
Posttreatmenta,b
(Follow up 1)
Posttreatmenta,b
(Follow up 2)
Visit  
1
2
3
4
5
6
7
8
Week (end of)
-
-
1
4
8
12
16
22
Day
-28 to -1
1
7
28
56
84
112
154
Study Procedures
Screening/Administrative
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history and demographics
X
Prestudy therapy MGH-ATRQc
X
SAFER
Xe
Preplanned surgery/procedure(s)
X
MINI 
X
Study Drug Administration
Randomization
X
SC administration of sirukumab or placebof
X
X
X
Post-administration injection-site evaluation
X
X
X
Post-administration allergic reaction evaluation
X
X
X
Drug accountability
X
X
X
Safety Assessments
Physical examination
X
X
X
X
C-SSRS
Xd
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
Body weighth
X
X
X
X
X
Height
X
Clinical laboratory assessmentsi
X
X
X
X
X
X
X
Serology
X
Lipid panel (fasting)
X
X
X
X
X
TB test (QuantiFERON®-TB Gold Test)
X
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
23
Approved, Date: 22 January 2018
Phase
Screening
Double-Blind Treatmenta
Early 
withdrawalb,s
Posttreatmenta,b
(Follow up 1)
Posttreatmenta,b
(Follow up 2)
Visit  
1
2
3
4
5
6
7
8
Week (end of)
-
-
1
4
8
12
16
22
Day
-28 to -1
1
7
28
56
84
112
154
Chest x-rayj
Xe
TB evaluation
X
X
X
X
X
12-lead ECG
X
Urine drug screen 
Xk
X
Alcohol breath test
X
X
Pregnancy test l
X
X
X
X
X
X
Clinician-administered assessments
IDS-C30
Xd
X
X
X
X
X
X
X
X
HDRS17 – performed by remote independent rater
Xd
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
Patient-reported assessments
CTQ
X
PHQ-9
X
X
X
X
X
X
X
X
SHAPS
X
X
X
X
X
X
X
X
FACIT Fatigue
X
X
X
X
X
X
X
X
Pharmacokinetics and immunogenicity
Blood sample for sirukumab concentrationm
X
X
X
X
X
X
X
X
Blood sample for antibodies to sirukumabm
X
X
X
X
X
X
Blood sample for monoaminergic antidepressantsn
X
X
X
X
X
Biomarkers
hsCRP measuremento
X
X
X
X
X
Blood sample for biomarkerso
X
X
X
X
Blood sample for DNAp
X
X
X
X
Saliva sample for cortisolq
X
X
X
X
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
24
Approved, Date: 22 January 2018
Phase
Screening
Double-Blind Treatmenta
Early 
withdrawalb,s
Posttreatmenta,b
(Follow up 1)
Posttreatmenta,b
(Follow up 2)
Visit  
1
2
3
4
5
6
7
8
Week (end of)
-
-
1
4
8
12
16
22
Day
-28 to -1
1
7
28
56
84
112
154
Ongoing Subject Review
Adherence to baseline oral antidepressants
X
X
X
X
X
X
X
X
Concomitant therapy r
Continuous
Adverse events r
Continuous
Footnotes:
a.
Visits 2 and 3 should be conducted within +/-3 days of the scheduled day; all following visits should be conducted within +/-7 days of the scheduled day.
b.
If a subject discontinues treatment before the end of the double-blind treatment phase or withdraws from the study, early withdrawal and post-treatment assessments 
should be obtained. Follow-up visit will take place 8 and 14 weeks after last dose intake. 
c.
Prestudy therapy will include all medications taken within 3 months before screening.
d.
In case the first screening visit is conducted over two days, the following assessments must be performed on the same day: C-SSRS, IDS-C30 and HDRS17.
e.
To be done once all other screening assessments have been done and subject has been confirmed eligible according those assessments.
f.
All assessments should be done prior to SC administration of sirukumab or placebo, except for post-administration injection-site and allergic reaction evaluation and 
drug accountability.
g.
Supine blood pressure (after being in supine position for at least 5 minutes), pulse, and oral temperature. 
h.
Body weight will be measured with subjects lightly clothed.
i.
Serum chemistry (including thyroid-stimulating hormone and follicle-stimulating hormone, if applicable [at screening only]), hematology and urinalysis. At week 4 
no urinalysis, only serum chemistry and hematology.
j.
Chest x-ray taken up to 3 months prior to Day 1 may be used to qualify at screening.  
k.
Refer to study exclusion criteria for circumstances in which a repeat test during screening is permitted.
l.
Performed for all women of childbearing potential. Serum pregnancy test performed at screening and urine pregnancy test at other time points. For visits with study 
agent administration pregnancy test must be performed before the administration of the study agent. If the urine pregnancy test is positive, a serum β-hcg test will be 
performed. Investigators may perform additional pregnancy testing at their discretion as clinically needed.
m.
Venous blood samples will be collected for the analyses of serum sirukumab concentrations and antibodies to sirukumab. Each serum sample will be split into 3 
aliquots (1 aliquot for serum sirukumab concentration, 1 aliquot for antibodies to sirukumab, and 1 aliquot as a back-up). For visits with study agent administration 
(ie, Day 1, 28 and 56), blood samples MUST be collected BEFORE the administration of the study agent.
n.
Venous blood samples for analysis of plasma monoaminergic antidepressants concentrations will be collected on Day 1 and 7 before sirukumab administration and 
on Day 84, 112 and 154. Samples collected after Day 1 must be collected at the same time as samples on Day 1 (+/- 1 hour).
o.
Venous blood samples will be collected for biomarkers analysis. hsCRP measurement at screening will be used to assess eligibility. At visits at which an injection is 
scheduled, blood samples will be collected prior to dosing. Samples should be collected in the morning between 8 and 10 AM and under fasted conditions (for at 
least 8 hours), if feasible.  
p.
Venous blood samples will be collected for genetic research in this study.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
25
Approved, Date: 22 January 2018
q.
Saliva samples will be collected by the subject the day before their visit just before bed and again at waking. Saliva samples should be collected with a site-provided 
standard collection device.
r.
Concomitant therapies and adverse events must be recorded throughout the study beginning with signing of the informed consent to the final follow up visit       
(Visit 8).
s.
Early withdrawal visit evaluations will be performed in subjects who prematurely discontinue study treatment (see Section 10.2, Discontinuation of Study 
Treatment) and in subjects who withdraw consent from the study (see Section 10.3, Withdrawal from the Study). The Early Withdrawal visit evaluation should be 
performed as soon as possible after the last dose of study drug is taken.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
26
Approved, Date: 22 January 2018
ABBREVIATIONS
ACR
ADHD
ADR
AE
ALT
ANC
ANCOVA
AST
AUCinf.
BCG
CGI-S
CL
CLE
Cmax
CRF
CRP
CSSR-S
CTQ
American College of Rheumatology
Attention deficit hyperactivity disorder
Adverse drug reaction
Adverse event
alanine aminotransferase
Absolute neutrophil count
Analysis of Covariance
Aspartate aminotransferase
area under the concentration versus time curve extrapolated to infinity
Bacille Calmette-Guérin
Clinical Global Impression – Severity
Clearance
Cutaneous Lupus Erythematosus
Maximum observed serum concentration
case report form 
C-reactive protein
Columbia Suicide Severity Rating Scale
Childhood Trauma Questionnaire
DCF
data clarification form
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
ECG
eCRF
Electrocardiogram
Electronic case report form
eDC
FACIT
FSH
FT4
GAD
electronic data capture
Functional Assessment of Chronic Illness Therapy
Follicle stimulating hormone
Free thyroxine
Generalized Anxiety Disorder
GCP
Good Clinical Practice
HBsAg
HDL
HDRS
hepatitis B surface antigen
high-density protein
Hamilton Depression Rating Scale
HIV
HPA
hsCRP
human immunodeficiency virus
hypothalamic–pituitary–adrenal
high sensitivity C-Reactive Protein
IAC
Interim Analysis Committee
ICF
informed consent form
ICH
IDS-C30
International Conference on Harmonisation
Inventory of Depressive Symptomatology – Clinician Rated 30 Item Scale
IEC
IgG
IL-6
Independent Ethics Committee
Immunoglobulin G
Interleukin 6
IRB
IV
Institutional Review Board
intravenous
IWRS
LDL
LOCF
LPS
interactive web response system
low-density protein
last observation carried forward
lipopolysaccharide
mAb
MDD
monoclonal antibody
Major Depressive Disorder
MedDRA
MGH-ATRQ
MINI
mITT
MTX
NCI-CTCAE
Medical Dictionary for Regulatory Activities
Massachusetts General Hospital Antidepressant Treatment History Questionnaire
MINI International Neuropsychiatric Inventory
Modified Intent-to-Treat
Methotrexate
National cancer Institute Common Terminology Criteria for Adverse Events
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
27
Approved, Date: 22 January 2018
NOAEL
NSAID
PA
PSF
No observed adverse effect level
nonsteroidal anti-inflammatory drug
posterior-anterior
pre-filled syringe
PHQ-9
Patient Health Questionnaire
PK
PPD
Pharmacokinetic
purified protein derivative
PQC
PRN
Product Quality Complaint
Pro re nata / as needed
PRO
q2w
q4w
RA
SAA
SAP
SC
SHAPS
SI
SIGH-D
SLE
SUSAR
T1/2
TB
Tmax
TNFα
TRD
TSH
ULN
patient-reported outcome(s)
every 2 weeks
every 4 weeks
rheumatoid arthritis
serum amyloid A
Statistical Analysis Plan
subcutaneous
Snaith Hamilton Pleasure Scale
International System of Units
Structured Interview Guide for the Hamilton Depression Scale
Systemic Lupus Erythematosus
Suspected Unexpected Serious Adverse Reaction
Half-life
time corresponding to the maximum observed serum concentration (single dose), or the first time 
to reach the Cmax (multiple dose)
Tumor Necrosis Factor alpha
Treatment Resistant Depression
Thyroid stimulating hormone
upper limit of normal
Vz
WBC
volume of distribution based on terminal phase 
white blood cell
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
28
Approved, Date: 22 January 2018
1.
INTRODUCTION
Sirukumab (also known as CNTO 136) is a human immunoglobulin G1κ (IgG1κ) monoclonal 
antibody (mAb) that binds to human IL-6 with high affinity and specificity.  
Low grade systemic inflammation, characterized by mild elevations in peripheral cytokine levels 
and other chemokines, has been demonstrated in depressed mood states (Maes 1999; Dowlati et 
al., 2010; Hiles et al., 2012; Howren et al., 2009). Interleukin-6 (IL-6) is a cytokine known for its 
pleiotropic and proinflammatory functions which has been shown in two recent meta-analyses to 
be elevated in clinical depression (Dowlati et al., 2010; Hiles et al., 2012).  
Major Depressive Disorder (MDD) is well known to be a heterogeneous illness, and the 
approximately one-third of depressed patients who are deemed to be treatment resistant may 
have distinct mechanisms underlying their depression, including systemic inflammation, 
resulting in reduced responsiveness to traditional monoamine treatment approaches.  In fact, IL-6 
levels correlate with depression severity in patients who do not respond to conventional 
antidepressant treatments (Lanquillon et al., 2000), suggesting that a subset of depressed patients 
with treatment resistance may have an immune-mediated component to their illness which is 
evident in the periphery.  
Recent nonclinical data have demonstrated that rodents predisposed to develop a depressed 
phenotype in response to stress exhibit pre-existing evidence of immune dysregulation, including 
greater secretion of IL-6 in response to ex vivo lipopolysaccharide (LPS) stimulation (Hodes et 
al., 2014).  LPS challenge in humans is also associated with an acute increase in inflammatory
cytokines, including Tumor Necrosis Factor alpha (TNF-α) and IL-6, which correlates with 
increased anxiety and depression levels following LPS challenge (Reichenberg et al., 2003). 
Similarly, monocytes from depressed subjects show increased IL-6 production after incubation 
with LPS compared to control subjects (Lisi et al., 2013). Interestingly, a recent study in teachers 
suffering from chronic work stress showed that those teachers with the highest effort-reward 
imbalance display higher IL-6 production after ex-vivo LPS stimulation, suggesting an increased 
inflammatory potential similar to that demonstrated in rodents (Bellingrath et al., 2013). In 
addition, in the same study dexamethasone had a lower capacity to suppress IL-6 production in 
vitro.  This is not surprising in that clinical depression has long been associated with 
abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis. Interestingly, IL-6 has 
significant neuroendocrine effects, including being a strong activator of the HPA axis. In turn, 
cortisol inhibits IL-6 secretion, restraining the inflammatory response during and after stress.  
Chronic stress has been shown to induce glucocorticoid resistance, which may enable a relatively 
unchecked inflammatory state.  In fact, the normal phasic relationship between cortisol and IL-6 
has been shown to be disrupted in depression, potentially contributing to chronic inflammation 
(Alesci et al., 2005).  
These nonclinical and clinical data suggest that a genetic predisposition to heightened 
inflammatory response may be exacerbated by exposure to stress, and may be associated with a 
greater risk for developing depression-like behaviors in animals and depressive disorders in 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
29
Approved, Date: 22 January 2018
humans.  Neutralizing IL-6 is therefore an attractive target for antidepressant treatments.  This 
study will focus on investigating the efficacy of the anti-IL-6 monoclonal antibody (mAb), 
sirukumab, for the treatment of depression.
Although the most commonly prescribed antidepressant classes, the monoaminergic 
antidepressants, have been shown to exhibit some minor anti-inflammatory effects (Miller et al., 
2009), there is a significant subset of depressed patients who experience minimal response to 
these treatments.  According to the findings from the Sequenced Treatment Alternatives to 
Relieve Depression (STAR*D) study, response to the antidepressant treatment citalopram was 
less than 50%, with less than one-third of patients achieving remission (Trivedi et al., 2006).  
Recent studies suggest that this subset of patients, who do not respond to conventional 
antidepressant treatments, have elevated immune markers.  For example, this association was 
demonstrated in a study of depressed patients treated with the tricyclic antidepressant, 
amitriptyline.  Compared to healthy control subjects, baseline production of IL-6 was 
significantly lower in depressed patients responding to amitriptyline treatment, whereas IL-6 was 
significantly higher in treatment nonresponders. These data suggest that IL-6 levels or other 
inflammation-related biomarkers might dichotomize patients into subsequent responders and 
nonresponders prior to the initiation of treatment with
traditional, monamine-based 
antidepressant treatments (Lanquillon et al, 2000).  
Recent data also support the idea that failure to normalize elevations in peripheral IL-6 may 
characterize subjects who do not respond to conventional antidepressants: a study in 50 subjects 
with MDD showed that after 12 weeks of treatment with antidepressants, treatment-responders 
showed decreased IL-6 compared to baseline, while subjects who continued to fulfill MDD 
criteria did not (Dahl et al., 2014). Overall, these data suggest that elevation of peripheral 
cytokines, and IL-6 in particular, might characterize a subset of subjects less prone to respond to 
conventional antidepressants and who show persistence of IL-6 elevation after ineffective 
treatment. 
It remains unknown as to whether monotherapy treatments targeting specific aspects of the 
immune response will be effective in treating patients with suboptimal response to standard oral 
antidepressant therapy, or whether patients may respond best to an anti-inflammatory treatment 
given adjunctive to a background monoamine-based antidepressant.  In general, adjunctive 
treatment approaches are preferred by clinicians, as even minimal effects of a baseline 
monoaminergic antidepressant may be augmented with an adjunctive treatment (Nelson et al., 
2012, 2014), and may relieve depressive symptoms sooner versus switching to another 
monotherapy treatment (Al-Harbi 2012).  Therefore, in this proof-of-concept study, the anti-IL-6 
mAb sirukumab will be given adjunctively to a monoaminergic antidepressant in MDD subjects 
who have shown a suboptimal response to standard oral antidepressant therapy.  
Additionally, it is hypothesized that subjects with Treatment Resistant Depression (TRD) and 
relatively high levels of peripheral pro-inflammatory markers will be mechanistically most likely 
to respond to anti-inflammatory adjunctive treatment (Raison and Miller, 2013). Specifically, it 
is anticipated that subjects with a biomarker profile indicative of upregulated IL-6 signaling at 
screening will be most likely to respond to sirukumab. To this end, the subject population 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
30
Approved, Date: 22 January 2018
eligible for primary efficacy analysis will be enriched for higher levels of inflammation by
requiring a high sensitivity C-reactive protein (hsCRP) level ≥ 0.300 mg/dL (International 
System of Units (SI) 3.00 mg/L) at screening and at baseline. C- reactive protein (CRP) is an 
acute phase protein whose hepatic synthesis is induced by IL-6 and rapidly attenuated following 
sirukumab infusion (Data on file, Janssen Phase 2 Rheumatoid Arthritis (RA) data). High levels 
of plasma CRP have been strongly associated with risk for depression (Wium-Andersen et al., 
2013; Khandaker et al., 2014) and the assay for hsCRP is sensitive, reliable and practical in a 
multicenter study setting. The eligibility criterion of hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) for 
subjects eligible for the primary analysis is specified on the basis of the available literature and 
Janssen data (data on file, Janssen) which show that a level of hsCRP ≥0.300 mg/dL (SI 3.00 
mg/L) is consistent with a population of TRD subjects, as well as practical considerations 
regarding recruitment. Additionally, subjects will be stratified at randomization by country and
4 screening hsCRP levels: 0.00 to <0.300 mg/dL (0.000 to <3.00 mg/L), ≥0.300 to <0.500 mg/dL 
(≥3.00 to <5.00 mg/L), ≥0.500 to <0.800 mg/dL (≥5.00 to <8.00 mg/L), and ≥0.800 mg/dL 
(≥800 mg/L). By stratifying subjects on the basis of screening hsCRP values, and measuring 
change in inflammatory biomarkers throughout treatment, it will be possible to explore whether 
depressed subjects with more pronounced inflammation at screening are more responsive to 
treatment with sirukumab. Based on results from a planned interim analysis, the study may 
continue with an enriched population using a selected hsCRP level, if there is evidence from the 
first set of data that response is strongly correlated with hsCRP or the effect size of sirukumab is 
greater in subjects with higher hsCRP at screening 
Thus the current study will be conducted to assess the efficacy, safety and tolerability of 
sirukumab versus placebo, administered adjunctively to a baseline monoaminergic
antidepressant, in subjects with MDD who satisfy the additional eligibility criteria for 
screening hsCRP. During the 12-week double-blind treatment phase the subjects will receive a 
50 mg dose of sirukumab or placebo SC at Day 1, Day 28 and Day 56. An interim analysis will 
be conducted when 40-50% of planned number of subjects who are eligible to be included in the 
primary efficacy analysis complete the week 12 assessment. The results will be used to monitor 
safety data, assess the study for futility, sample size re-estimation and adaption of eligibility 
criteria. More details will be provided in the interim SAP.  
For the most comprehensive nonclinical and clinical information regarding sirukumab, refer to 
the latest version of the Investigator's Brochure and Addenda for sirukumab.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
1.1.1.
Nonclinical Studies
1.1.1.1.
Pharmacologic Profile
Sirukumab (also known as CNTO 136) is a human immunoglobulin G1κ (IgG1κ) monoclonal 
antibody (mAb) with a molecular weight of approximately 150,000 daltons.  Sirukumab binds to 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
31
Approved, Date: 22 January 2018
human IL-6 with high affinity and specificity.  The high affinity binding of sirukumab to IL-6 
(KD = 0.175 pM) prevents the association of IL-6 with the IL-6R, thereby blocking receptor 
signaling and biological activities attributed to IL-6 both in vitro and in vivo.  In vitro bioassays 
show that sirukumab neutralizes both cis- and trans-signaling of human IL-6 (mediated via cell 
surface IL-6R and soluble IL-6R, respectively) in a concentration-dependent manner.  
Sirukumab also blocks human IL-6-induced expression of the acute phase proteins haptoglobin 
and serum amyloid A (SAA) in mice; this effect is sirukumab-specific and dose-dependent.  An 
anti-murine IL-6 mAb, analogous to sirukumab, was shown to attenuate the severity of disease in 
mouse model of collagen-induced arthritis.  Thus, an IL 6-neutralizing antibody such as 
sirukumab may be an effective treatment in subjects with human autoimmune diseases such as 
RA.
1.1.1.2.
Toxicology
Sirukumab is able to neutralize the IL-6 dependent proliferation of murine hybridoma cell line 
(7TD1) cells that were stimulated by conditioned supernatants from peripheral blood 
mononuclear cells (PBMC) of human and cynomolgus monkeys to a similar degree.  Therefore, 
the cynomolgus monkey was selected as a pharmacologically relevant species for the nonclinical 
safety evaluation of sirukumab.
The nonclinical toxicology studies that have been conducted to support the sirukumab clinical 
studies include a 3 month multidose toxicity study and a 6-month multidose toxicity study 
conducted in cynomolgus monkeys, which included both IV and SC routes of administration and 
an investigation of the effects of sirukumab on embryo-fetal development in cynomolgus 
monkeys by weekly IV administration.  In the 6-month study, histopathological findings 
consisted of mononuclear cell infiltrates and small foci of acute or healed necrosis in the heart of 
5 monkeys (4 sirukumab-treated and 1 control).  These findings were of minimal to mild 
intensity, are commonly observed in cynomolgus monkeys, and occurred with similar incidence 
across all treatment groups including the control group.  These findings were not considered to 
be sirukumab treatment related.  One male in the high dose group had multiple cardiac 
abnormalities consisting of myofiber disarray and fibrosis.  This finding is likely a familial type 
of cardiomyopathy and therefore also not sirukumab treatment related.     
The completed toxicology studies in cynomolgus monkeys demonstrated that sirukumab 
appeared to be well tolerated at multiple doses of up to 50 mg/kg, with the exception of the 
embryo-fetal developmental toxicity study.  The results from the embryo-fetal developmental 
toxicity study demonstrated that the abortion/embryo-fetal death ratio was increased in the high 
dose 50 mg/kg group (35.7% at 50 mg/kg/week versus 20% in the control group).  This increase 
in abortion/embryo-fetal death ratio was possibly related to sirukumab.  In this study, the no 
observed adverse effect level (NOAEL) in dams and fetuses was 10 mg/kg weekly.
1.1.2 Clinical Studies
As of 23 Oct 2014, the following clinical studies were completed or in progress:
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
32
Approved, Date: 22 January 2018
Sirukumab was studied in the first-in-human, placebo-controlled, Phase 1 study (C0136T01), 
which was designed to evaluate the safety and PK of a single IV administration of sirukumab in 
healthy subjects. Trial duration was 9 months. Safety data from the C0136T01 study showed that 
sirukumab was generally well tolerated in 34 healthy subjects who received single IV infusions 
of sirukumab. There was no dose-relatedtrend across the dose groups. There were no clusters of 
adverse events (AEs). No anaphylaxis, severe allergic reactions, or delayed hypersensitivity 
reactions were observed. No subjects discontinued study agent due to AEs. Most AEs were of 
mild intensity and generally self-limiting in nature. One serious adverse event (SAE) was 
reported in a patient in the placebo group; no SAEs were reported in the sirukumab groups. 
There were no clinically important differences in hematology, clinical chemistry, vital signs, or 
ECG measurements among the dose groups. In the sirukumab 1 mg/kg, 3 mg/kg, and 6 mg/kg 
male treatment groups, 1 subject each had markedly abnormal decreases in post-treatment 
neutrophil counts, with the lowest values in the range of 0.90 to 0.93 x 109/L in absolute 
neutrophil count (ANC).
CNTO136NAP1001 was a Phase 1, randomized, parallel-group, placebo-controlled, open to 
dose-level and double-blinded active/placebo single-center study to evaluate the PK and safety of 
sirukumab following a single SC administration to healthy male Japanese and Caucasian 
subjects.  Trial duration was 7 months. Caucasian subjects reported more injection site reactions 
of erythema (37.5% vs. 12.0%) and upper respiratory tract infections (12.5% vs. 4.0%) than 
Japanese subjects. Absolute neutrophil counts decreased similarly in Japanese and Caucasian 
subjects treated with sirukumab, without evidence of dose dependency. Seven sirukumab-treated 
subjects had decreases to toxicity grade 2 ANC; 3 of the subjects returned to normal ANC and 
the other subjects were improving or showed stable values. No other relevant differences or 
changes from baseline were observed in any of the safety parameters.
CNTO136NAP1003: This is a Phase 1, randomized, open-label, parallel-design trial to assess 
absolute bioavailability and single-dose pharmacokinetics (PK) following SC administration of 
sirukumab delivered by a PFS fitted with Ultrasafe Passive™ delivery system or an Autoinjector 
in healthy male subjects. The trial is still ongoing.
CNTO136ARA1001: This is a Phase 1, open-label, multicenter, drug-drug interaction 12-week 
trial designed to evaluate the effect of a single SC dose of sirukumab on midazolam (cytochrome 
P450 [CYP]3A4), warfarin (CYP2C9), omeprazole (CYP2C19), and caffeine (CYP1A2), on the 
PK in subjects who have a diagnosis of RA and a screening C-reactive protein level of 
>8.00 mg/L (>0.8 mg/dL). The trial is ongoing.
C0136T03 was a Phase 1, 2-part, multicenter/multinational, randomized, double-blind, 
placebo-controlled study of sirukumab to evaluate the safety and PK of intravenously 
administered, multiple ascending doses of 1, 4, and 10 mg/kg in subjects with CLE and of 
10 mg/kg in subjects with SLE. The single death reported during the study was due to a car 
accident and not related to the administration of sirukumab. No dose-limiting SAEs were 
observed in this study. Six SAEs in 3 subjects were reported in Part A and 3 SAEs in 3 subjects 
were reported in Part B. Serious infections reported were pneumonia, in a subject with SLE and 
treatment-emergent neutropenia, which was considered to be related to sirukumab 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
33
Approved, Date: 22 January 2018
administration, and a bacterial infection of an iatrogenic wound, which was considered not 
related to sirukumab administration. Other infections were nonserious and most were mild upper 
respiratory tract infections. Subjects who received sirukumab showed immediate stable and 
sustained decreases compared with baseline in white blood cell count (WBC), ANC, and 
platelets at all individual dose levels, while subjects in the placebo group showed no change in 
results for all 3 parameters. The decreases were not dose dependent. There was little to no clear 
temporal association between low neutrophil counts and the occurrence of infections. Two 
subjects in the Part B SLE cohort were discontinued from administration because of low ANC 
and platelet counts, but no immediate apparent clinical symptoms were associated with these low 
values. Compared with the placebo subjects, sirukumab-treated CLE subjects in the 1 and 
4 mg/kg groups reported a relatively higher number of skin-related AEs that were considered 
reasonably related to sirukumab, whereas the 10 mg/kg group did not report any reasonably 
related skin events. Laboratory results for fasting lipids showed minor elevations of total 
cholesterol in the cohorts that received sirukumab. In subjects with CLE or SLE in all sirukumab 
treatment groups, complement C3 and C4 showed immediate, and for C4 almost maximal, 
decreases. All other safety parameters did not show a signal, clinically significant trend over time 
or change from baseline, or a difference between subjects who received sirukumab and those 
who received placebo. On clinical evaluation, none of the abnormal QTc intervals or any 
abnormal morphology was associated with clinically relevant pathology. No dose relationship 
was observed for AEs in Part A or Part B. In Part A, autoantibodies (antinuclear antibody [ANA] 
and anti-dsDNA) showed no changes in either sirukumab or placebo subjects. In Part B, changes 
in autoantibodies (ANA and anti-ds-DNA) showed lower titers for sirukumab subjects, where 
placebo subjects showed no change or increase of titers. None of the other autoantibodies 
showed any change from baseline.
C1377T04 was a Phase 2, 2-part, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled, proof-of-concept, and dose-finding study designed to evaluate the efficacy 
and safety of multiple doses of sirukumab administered subcutaneously in subjects with active 
RA despite methotrexate (MTX).  Part A was the proof-of-concept portion of the study, 
comparing sirukumab 100 mg SC or placebo injection every 2 weeks (q2w).  Part B was the 
dose-finding portion of the study.  Subjects received study agent administrations for 24 weeks.  
Dose regimens in Part B included sirukumab 25 mg SC every 4 weeks (q4w), 50 mg q4w, 
100 mg q4w, and 100 mg q2w.  Subjects enrolled in Part B were distinct from those enrolled in 
Part A.  
CNTO136LUN2001 was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 
proof-of-concept study to evaluate the efficacy and safety of sirukumab administered 
intravenously in subjects with active lupus nephritis.  As of 23 Oct 2014 all subjects (25) have 
been randomized and the study has been completed.
CNTO136ARA3001, is a 68-weeks Phase 3 study to evaluate the efficacy and safety of 
sirukumab administered SC, in Japanese subjects with active RA unresponsive to MTX or 
Sulfasalazine.  As of 23 Oct 2014, all subjects (122) were randomized and the study is ongoing.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
34
Approved, Date: 22 January 2018
CNTO136ARA3002, is a 120-weeks Phase 3 study to evaluate the efficacy and safety of 
sirukumab administered SC, in subjects with active RA despite disease-modifying antirheumatic 
drug (DMARD) therapy.  As of 23 Oct 2014, 1111 of 1650 planned subjects had been 
randomized and the study is ongoing.
CNTO136ARA3003, is a Phase 3 study to evaluate the efficacy and safety of sirukumab 
administered SC, in subjects with active RA despite anti-TNFα therapy.  As of 23 Oct 2014, 528 
of 840 planned subjects had been randomized and the study is ongoing.
CNTO136ARA3004, is a Phase 3 study to evaluate the long-term safety and efficacy of 
CNTO136 
(sirukumab) 
in 
subjects 
with 
RA 
who 
completed 
treatment 
in 
the 
CNTO136ARA3002 (SIRROUND-D) and CNTO136ARA3003 (SIRROUND-T) studies. As of 
23 Oct 2014, 173 of 2490 planned subjects had been randomized and the study is ongoing.
CNTO136ARA3005: This is a Phase 3, multicenter, randomized, double-blind, parallel-group 
trial of sirukumab administered SC as monotherapy compared with adalimumab monotherapy in 
subjects with active RA. As of 23 Oct 2014, 13 of 510 planned subjects had been randomized 
and the study is ongoing.
Cumulatively, the following adverse drug reactions (ADR) have been identified for sirukumab: 
neutropenia, thrombocytopenia, lipids increased (total cholesterol, low-density lipoprotein 
[LDL], high density lipoprotein [HDL], and triglycerides), alanine aminotransferase increased, 
aspartate aminotransferase increased, injection site reaction (including erythema, pain, pruritis, 
and/or swelling), serious hypersensitivity reaction (including anaphylaxis), cellulitis, pneumonia, 
sepsis and gastrointestinal perforation (see Section 1.1.2.2.2Safety).
1.1.2.1
Human Pharmacokinetics and Immunogenicity
The PK of sirukumab has been evaluated in healthy subjects following both IV (C0136T01) and 
SC (CNTO136NAP1001) administrations.  Following a single dose of either IV (0.3 to 
10 mg/kg) or SC (25, 50, or 100 mg) administration, the systemic exposure of sirukumab (Cmax
and AUCinf) increased in an approximately dose proportional manner.  Mean values of total 
systemic clearance (CL) ranged from 3.8 to 6.1 mL/day/kg; and mean values of volume of 
distribution during terminal phase (Vz) ranged from 121.3 to 247.6 mL/kg.  Following a single 
SC administration of sirukumab, median tmax ranged from 3 to 5 days; mean T1/2 values were 15 
to 18 days.  No apparent sex-related differences in PK were observed.  Sirukumab PK was 
generally comparable between Japanese and Caucasian healthy subjects. 
The PK of sirukumab was also evaluated in subjects with RA in Phase 2 study C1377T04. 
Overall, the PK of sirukumab after SC administration in subjects with RA is consistent with that 
observed in healthy subjects. Refer to latest version of the Investigator’s Brochure for a summary 
of PK parameters.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
35
Approved, Date: 22 January 2018
The effect of sirukumab on the pharmacokinetics of CYP enzyme substrates midazolam 
(CYP3A4), omeprazole (CYP2C19), S-warfarin (CYP2C9), and caffeine (CYP1A2) has been 
evaluated in subjects with active RA (CNTO136ARA1001). Twelve subjects received oral 
administrations of CYP probe cocktails consisting of 0.03 mg/kg midazolam, 10 mg warfarin, 
20 mg omeprazole, and 100 mg caffeine at 1 week before and at 1, 3, and 6 weeks after a single 
subcutaneous dose of 300 mg sirukumab. AUCinf for midazolam, omeprazole, and S-warfarin 
were reduced by 29.9%‒35.2%, 37.4%‒44.8%, and 18.0%‒19.1%, respectively, after sirukumab 
administration. Caffeine AUCinf was increased by 19.6%‒34.2% after sirukumab 
administration. The effect of sirukumab on CYP activities was sustained for at least 6 weeks 
following sirukumab administration. These results suggest that sirukumab may restore IL-6-
mediated suppression of CYP3A4, CYP2C9, and CYP2C19 activities in RA subjects.
Immunogenicity has been evaluated in 4 clinical studies:  C0136T01, CNTO136NAP1001, 
C0136T03, and C1377T04.  None of the subjects with evaluable serum samples tested positive 
for antibodies to sirukumab in C0136T01 (0/31), CNTO136NAP1001 (0/43), and C0136T03 
(0/32).  In C1377T04, 2 (1.2%) of 173 subjects tested positive for antibodies to sirukumab 
through Week 38.
1.1.2.2
Efficacy/Safety Studies 
1.1.2.2.1
Efficacy 
In Part A and Part B of C0136T03, C-reactive protein (CRP) levels were suppressed in subjects 
with CLE and SLE, in a manner similar to that observed for high-sensitivity CRP in the first-in-
humans study C0136T01.  Baseline CRP levels in the CLE and SLE subjects were normal to 
mildly elevated and after the first dose of sirukumab, the median CRP levels dropped to below 
the lower limit of normal (LLN) in subjects who received sirukumab IV at 1, 4, or 10 mg/kg.  
Sustained suppression of CRP in sirukumab-treated subjects was observed through the last CRP 
measurement at Week 14, approximately 8 weeks after the last dose of sirukumab. 
In Part B of the Phase 2 RA study C1377T04, sirukumab subcutaneous (SC) doses of 25, 50, and 
100 mg all rapidly suppressed the CRP levels by a median of 79 to 87% within 5 days and > 
90% within 8 days, and this level of CRP suppression was maintained in each of the 4 sirukumab 
treatment groups for 6 to 14 weeks after the last sirukumab administration at Week 24.  The 
change from baseline at Week 38 in CRP level suggested a dose-dependent effect on this acute 
phase marker, with the group that had received sirukumab 25 mg q4 weeks up to Week 24 
rebounding most toward the baseline CRP levels.
In Part B, a greater proportion of subjects achieved the primary endpoint of ACR 50 response at 
Week 12 in each of the 4 sirukumab treatment groups (sirukumab 100 mg q2 weeks, 27%; 
100 mg q4 weeks, 23%; 50 mg q4 weeks, 27%; 25 mg q4 weeks, 19%) compared with the 
placebo group (3.3%); subjects in the sirukumab 100 mg q2 weeks and 50 mg q4 weeks 
treatment groups achieved statistical significance (p < 0.05).  
A post-hoc analysis of the SF-36 Mental Health and Vitality domain items from the C1377T04 
study showed a beneficial effect of sirukumab on depressed mood at week 12, more pronounced 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
36
Approved, Date: 22 January 2018
than in the placebo group and at least partly independent on the clinical benefit on the target 
disease.  Patients with prevalent depressed mood and anhedonia receiving sirukumab but not 
placebo achieved significant improvements at week 12 in depressive symptoms (p=0.0006), and 
fatigue (p=0.0157). Significant improvements on depressed mood and anhedonia upon 
sirukumab treatment, but not placebo, were observed in both ACR50 responders (p=0.0024) and 
nonresponders (p=0.0014).
1.1.2.2.2
Safety
The sponsor’s medical experts evaluated safety reports from clinical studies with sirukumab 
using the definition of adverse drug reactions (ADRs) from the International Conference on 
Harmonisation (ICH) guideline entitled Guideline for Good Clinical Practices, E6(R1). Reviews 
by the Sponsor of cumulative safety data from completed sirukumab studies in healthy subjects 
and subjects with RA and CLE/SLE resulted in the identification of the following adverse drug 
reactions:  neutropenia, platelet count decreased, lipids increased (total cholesterol, low-density 
lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides), ALT increased, AST 
increased, injection site reaction (including erythema, pain, pruritus, and/or swelling), serious 
hypersensitivity 
reaction 
(including 
anaphylaxis), 
cellulitis, 
pneumonia, 
sepsis 
and 
gastrointestinal perforation (Table 1).
Overall, 252 healthy subjects and an estimated 3,015 subjects with lupus, LN, and RA have been 
enrolled in the sirukumab clinical program, of whom 2,419 subjects have received sirukumab 
(54 subjects with lupus/LN have received sirukumab and 2,365 subjects with RA have received 
sirukumab). Of these, 269 subjects were exposed to sirukumab in the Phase 1 trials, 203 subjects 
were exposed to sirukumab in the Phase 2 trials, and 1,947 subjects were exposed to sirukumab 
in the Phase 3 trials
A listing of adverse drug reactions (ADRs) determined for sirukumab based on a review of 
safety data through 27 April 2015 is provided in Table 1.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
37
Approved, Date: 22 January 2018
Table 1:
Adverse Drug Reactions with Sirukumab (CNTO136)
Adverse Drug Reactions Coded by MedDRA (Version 17.1) Associated with Sirukumab
MedDRA System Organ Class
Frequency
Preferred term(s) Ordered by 
Seriousness
Gastrointestinal Disorders
Uncommon:
Gastrointestinal Perforation
Infections and Infestations
Common:
Cellulitis
Pneumonia
Uncommon:
Sepsis
Immune System Disorders
Uncommon:
Serious hypersensitivity reaction 
(including anaphylaxis)
General disorders and 
administration site conditions
Very Common:
Injection site erythema
Common:
Injection site pain
Injection site pruritus
Injection site swelling
Investigations
Very Common:
Alanine aminotransferase increased
Aspartate aminotransferase   
increased
Blood cholesterol increased
Low density lipoprotein increased
High density lipoprotein increased
Common:
Triglycerides increased
Blood and lymphatic system 
disorders
Very Common: 
Neutropenia
Thrombocytopenia
IB Edition 10, Effective Date: 27 April 2015
The preferred terms presented in this table are ordered by seriousness within each frequency grouping.
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); 
very rare (<1/10,000).
Detailed description of safety and tolerability data is included in Section 4.4 (Safety and 
Tolerability) of the IB. Below a detailed description of the safety results only for the phase 2 
study C1377T04 is provided.
C1377T04
Data from the Phase 2 RA study (C1377T04) in subjects who had an inadequate response to 
MTX suggest a safety profile in subjects with RA to be similar to that of other IL-6 pathway 
inhibitors.  There was an increased incidence of infections and common occurrences of decreases 
in leukocytes and platelets, transient liver transaminase elevations, and increases in lipid 
parameters.
In Part A of the Phase 2 RA study, a single Serious Adverse Event (SAE) of staphylococcal 
cellulitis occurred in a subject treated with sirukumab 100 mg q2 weeks over the study.  In the 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
38
Approved, Date: 22 January 2018
initial 12-week, placebo controlled portion of the Phase 2 dose-ranging study (Part B), there were 
7 subjects with SAEs.  There was 1 malignancy: 1 subject reported fibrosarcoma of the right 
axillary and scapular regions after 4 weeks of participation, then withdrew from the study 
without providing any further details.  The proportion of RA subjects with treatment-emergent 
SAEs was higher in the placebo group (13.3%) compared with the combined sirukumab 
treatment groups (2.5%) and any individual sirukumab treatment group.  No dose-proportional 
relationship was observed between the sirukumab regimen and type or timing of SAE.  
After Week 12, 10 additional SAEs were reported in Part B, including 1 death.  The fatal case 
was a 59-year-female assigned to the placebo group, who per protocol crossed over to sirukumab 
100 mg q2 weeks from Week 12 to 24.  Approximately 6 weeks after the last study agent 
administration, she developed a severe headache, was diagnosed with a brain aneurysm and died 
during surgery.    
Subjects in the treatment groups who received sirukumab had a greater number of infections 
compared with those in the placebo group (33.3% vs 13.3%).  Most of the infections were upper 
respiratory tract infections.  There were no opportunistic infections or tuberculosis (TB).
In Part A, from Weeks 0 to 12, the incidence of injection-site reactions was higher in subjects 
who received sirukumab 100 mg q2 weeks (35.3%) compared with subjects who received 
placebo (10.5%).  In Part B, 15.7% of sirukumab-treated subjects reported at least 1 injection-site 
reaction compared with the 3.3% of placebo-treated subjects group (3.3%).  The proportion of 
injections resulting in injection-site reactions was highest in the sirukumab 100 mg q2 weeks 
treatment group in both Parts A and B (15.4% [28/128] and 6.9% [50/726] of injections, 
respectively), whereas only 0.9% of Part A and 0.6% of Part B placebo injections resulted in 
injection-site reactions.  All of the injection-site reactions were considered non-serious. 
No hypersensitivity or anaphylactic reactions were reported.
Hematologic effects occurred within the first 4 weeks of treatment and were sustained through at 
least Week 24.  In both Parts A and B, subjects in the sirukumab treatment groups (5.6% to 
17.2%) had markedly abnormala, decreased neutrophil counts compared with no subjects with 
neutropenia in the placebo group.
One subject in Part A and 2 subjects in Part B had Grade 3 neutropenia (< 1.0 x 103/µL).  Neither 
case of neutropenia was associated with infection.  No clear, dose-proportional relationship was 
observed between the sirukumab regimen and neutropenia.  In Part B, 11.6% of sirukumab 
treated subjects had absolute neutrophil count (ANC) < 1.5 x 103/µL.  Markedly abnormalb , 
decreased lymphocyte counts occurred in 3 (10.3%) of 29 subjects in the placebo group and 23 
(15.8%) of 146 sirukumab-treated subject.  In Part B, 1 subject had lymphopenia Grade 4 (< 0.5 
                                                
a Decrease ≥ 33% and value < 1.5 x 103/µL
b Decrease ≥ 33% and value < 1.0 x 103/µL
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
39
Approved, Date: 22 January 2018
x 103/µL).  Markedly abnormala , decreased platelet counts occurred in 2 subjects (1.7%): 1 was 
Grade 2   (< 75 - 50 x 103/µL) and one was Grade 4 (< 25 x 103/µL).  Neither subject had 
bleeding.  The subject with Grade 4 thrombocytopenia continued dosing with sirukumab and had 
normal platelets thereafter.  Neutrophil and platelet effects were resolving 14 weeks after the last 
dose. 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
toxicity Grade 1 ALT (Upper Level of Normal (ULN) – 2.5 x ULN) values were observed very 
commonly (48.6%) in the sirukumab-treated subjects compared with 10.3% in the placebo 
group.  Grade 3 ALT values (> 5 x ULN to 20 x ULN) were observed in 1 (6.3%) sirukumab-
treated subject in Part A and 8 (5.5%) sirukumab-treated subjects in Part B compared with none 
in placebo subjects.  No sirukumab dose relationship was observed.  No subjects had both ALT 
elevation ≥ 3 x ULN and total bilirubin ≥ 2 x ULN.  In a similar pattern but to a lesser degree, 
AST elevations were observed more often in sirukumab treatment groups.  A single Grade 3 and 
no Grade 4 AST elevations occurred.  Most of these liver transaminase abnormalities were 
transient, asymptomatic, and peaked within the first 8 weeks of treatment, and returned to normal 
upon further follow-up.  One subject was discontinued from study agent because ALT was 
persistently elevated by local laboratory testing.    
Total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides increased from baseline in 
the sirukumab treatment groups compared with the placebo group.  There was no apparent 
relationship between sirukumab dose and change in total, LDL cholesterol, or HDL cholesterol.  
Lipid increases occurred by Week 2 and were sustained through Week 24.  
Mean increases in HDL cholesterol at Week 24 were as follows:  Sirukumab 100 mg q2 weeks, 
9 mg/dL; 100 mg q4 weeks, 13 mg/dL; 50 mg q4 weeks, 10 mg/dL; 25 mg q4 weeks, 10 mg/dL. 
Mean increases in LDL cholesterol at Week 24 were as follows: Sirukumab 100 mg q2 weeks, 
13 mg/dL; 100 mg q4 weeks, 21 mg/dL; 50 mg q4 weeks, 23 mg/dL; 25 mg q4 weeks, 
12 mg/dL.
At Week 24, in Part B, of the subjects with normal baseline LDL (≤ 130 mg/dL), an abnormal 
LDL (> 130 mg/dL) occurred in 54 (62.1%) of 87 subjects in the sirukumab groups combined 
compared with 4 (20.0%) of 20 subjects in the placebo group. 
Laboratory data through Week 24 has shown a consistent pattern of hematologic parameter 
decreases, hepatic enzyme increases, and increases in lipid parameters.  No dose response has 
been observed to date.
1.2.
Overall Rationale for the Study
MDD is well known to be a heterogeneous illness, and the approximately one-third of depressed 
patients who are deemed to be treatment resistant may have distinct mechanisms underlying their 
                                                
a Decrease ≥ 50% and value < 75 x 103/µL
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
40
Approved, Date: 22 January 2018
depression, including systemic inflammation, resulting in reduced responsiveness to traditional 
monoamine treatment approaches.  In fact, IL-6 levels correlate with depression severity in 
patients who do not respond to conventional antidepressant treatment, suggesting that a subset of 
depressed patients with treatment resistance may have an immune-mediated component to their 
illness which is evident in the periphery (Dahl et al., 2014).  
Neutralizing IL-6 is therefore an attractive and rational target for antidepressant treatments.  This 
study will focus on investigating the efficacy of the anti-IL-6 mAb, sirukumab, for the treatment 
of depression. Analyses of the phase 2 sirukumab RA database both showed a beneficial effect 
on depressed mood, more pronounced than in the placebo group and at least partly independent 
on the benefit on the target disease, which provide further support to the peripheral route of 
administration as being potentially associated with antidepressant effects.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of sirukumab as adjunctive 
treatment to monoaminergic antidepressant therapy where sirukumab (administered as a 50 mg 
SC injection at Day 1, Day 28 and Day 56 during the 12 week double-blind treatment period) is 
compared to adjunctive placebo based on the change from baseline to 12-week endpoint in 
depressive symptoms as measured by the total score on the Hamilton Depression Rating Scale 
(HDRS17), in subjects diagnosed with MDD who have had a suboptimal response to the current 
standard oral antidepressant therapy and have a screening and baseline hsCRP ≥0.300 mg/dL 
(SI 3.00 mg/L).
Secondary Objectives

To evaluate the overall safety and tolerability of adjunctive sirukumab compared to 
adjunctive placebo in subjects with MDD.

To evaluate the impact of adjunctive sirukumab compared to adjunctive placebo on 
anhedonia as measured by the change from study baseline to 12-week endpoint on the 
Snaith 
Hamilton 
Pleasure 
Scale 
(SHAPS)
in 
subjects 
with 
MDD 
and 
screening hsCRP ≥0.300 mg/dL.

To evaluate the impact of treatment with adjunctive sirukumab compared to adjunctive 
placebo on global severity of symptoms of MDD, as measured by the change in the 
Clinical Global Impression - Severity (CGI-S) scale from study baseline to 12-week 
endpoint in subjects with MDD and screening hsCRP ≥0.300 mg/dL.

To evaluate the impact of treatment with adjunctive sirukumab compared to adjunctive 
placebo on remission and response rates at 12-week end point, defined as a HDRS17 total 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
41
Approved, Date: 22 January 2018
score ≤7 or a ≥ 50% improvement in HDRS17 total score from baseline, respectively in 
subjects with MDD and screening hsCRP ≥0.300 mg/dL.

To evaluate the impact of treatment with adjunctive sirukumab compared to adjunctive 
placebo on subject-reported severity of symptoms of MDD, as measured by the change in 
the Patient Health Questionnaire (PHQ-9) from study baseline to 1- week endpoint and to 
12-week endpoint in subjects with MDD and screening hsCRP ≥0.300 mg/dL.

To evaluate the impact of treatment with adjunctive sirukumab compared to adjunctive 
placebo on fatigue, as measured by the change from study baseline to 1-week, 4-week, 
8-week and 12-week endpoint in the Functional Assessment of Chronic Illness 
Therapy-Fatigue 
(FACIT 
Fatigue) 
scale
in 
subjects 
with 
MDD 
and 
screening hsCRP ≥0.300 mg/dL.

To evaluate the efficacy measured by change in the HDRS17 scores following adjunctive 
sirukumab compared to adjunctive placebo in the Treatment Resistant Depression (TRD) 
versus non-TRD subjects. TRD is defined as having being treated with ≥ 2 trials of 
antidepressants of adequate dose and duration [according to the Massachusetts General 
Hospital Antidepressant Treatment History Questionnaire (MGH-ATRQ)] during the 
current episode.

To evaluate pharmacokinetics and immunogenicity of sirukumab in subjects with MDD.

To evaluate the impact of treatment with adjunctive sirukumab in subjects with screening 
hsCRP≥0.300 mg/dL as compared to in those with screening hsCRP<0.300 mg/dL based 
on changes from baseline to Week 12 in HDRS17 total score.

To assess the efficacy of sirukumab compared to placebo as adjunctive therapy to an 
antidepressant in subjects with MDD with screening hsCRP levels <0.300 mg/dL versus 
those with screening hsCRP levels ≥ 0.300 mg/dL in improving response of depressive 
symptoms, defined as the proportion of subjects having a ≥50% improvement in HDRS17
total score from baseline to the end of Week 12. 

To assess the efficacy of sirukumab compared to placebo as adjunctive therapy to an 
antidepressant in subjects with MDD with screening hsCRP levels <0.300 mg/dL versus 
those with screening hsCRP levels ≥ 0.300 mg/dL in achieving remission of depressive 
symptoms, defined as the proportion of subjects having a HDRS17 total score ≤7 at the 
end of Week 12.

To evaluate whether hsCRP levels correlate with clinical efficacy as measured by the 
change from baseline to Week 12 in HDRS17 total score.
Exploratory Objectives
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
42
Approved, Date: 22 January 2018

To evaluate the efficacy of adjunctive sirukumab compared to adjunctive placebo, based 
on the change from baseline to 12-week endpoint in the Inventory of Depressive 
Symptomatology – Clinician Rated 30 Item Scale (IDS-C30) in subjects with MDD and 
screening hsCRP ≥0.300 mg/dL.

To explore immune-system related biomarkers (hsCRP, cytokines, chemokines), as well 
as other mood disorder related biomarkers (growth factors, hypothalamic–pituitary–
adrenal (HPA) axis markers, metabolic markers) and to explore the potential correlation 
between these biomarkers and the clinical response, non-response or safety parameters of 
sirukumab.

To explore genetic and epigenetic variation that may be related to clinical response, non-
response, or safety parameters of sirukumab.

To evaluate the effect of sirukumab on the pharmacokinetics of monoaminergic 
antidepressants.

To explore the relationship between the severity of childhood trauma as assessed through 
the Childhood Trauma Questionnaire and the change in HDRS17 scores following 
adjunctive sirukumab or placebo.
2.2.
Hypothesis
The primary hypothesis of this study is that sirukumab will determine significant improvement in 
depressive symptoms from baseline compared  to placebo when administered as an adjunctive 
treatment to a monoaminergic antidepressant in the treatment of patients with MDD who have 
shown a suboptimal response to standard oral antidepressant therapy and have a screening and 
baseline hsCRP ≥ 0.300 mg/dL (SI 3.00 mg/L), demonstrated by improvement in depressive 
symptoms from baseline to 12-week endpoint in the Hamilton Depression Rating Scale 
(HDRS17) total score.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind placebo-controlled multicenter study. A target of 
approximately 192 subjects will be randomly assigned in this study with approximately 96 
subjects planned per treatment group. The sample size may increase up to 228 if the interim 
analysis suggests so.
The target study population is male and female subjects with MDD who have had a suboptimal 
response to standard oral antidepressant therapy; have failed no more than 3 antidepressant 
treatments in the current major depressive episode; approximately 142 subjects with screening 
hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) and approximately 50 subjects with screening 
hsCRP<0.300 mg/dL (SI 3.00 mg/L) will be enrolled.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
43
Approved, Date: 22 January 2018
Determination of suboptimal response to the current standard oral antidepressant therapy will be 
made retrospectively using the structured MGH-ATRQ. Determination of the number of failed 
antidepressant treatments in the current episode will be made retrospectively using medical or
pharmacy records and documented on the MGH-ATRQ. Serum concentration of hsCRP will be 
measured from a venous blood sample at screening.
The study will consist of 3 phases: a screening phase of up to 4 weeks, consisting of 2 visits, a 12 
week double-blind treatment phase, and a 14 week posttreatment follow-up phase. The total 
duration of subject participation will be approximately 26 weeks. 
Screening Phase: Subjects with a Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition (DSM-5) diagnosis of MDD, confirmed by the MINI International Neuropsychiatric 
Inventory (MINI), who are currently being treated with a monoaminergic antidepressant and 
have failed no more than 3 antidepressants (of adequate dose and duration) in the current major 
depressive episode will be eligible for screening. Screening will include informed consent, 
evaluation for eligibility in the study, medical history, physical and psychiatric evaluations, 
venous blood sampling for hsCRP assay and standard lab safety tests. Determination of 
suboptimal response to the current standard oral antidepressant therapy will be made 
retrospectively using the structured MGH-ATRQ. Determination of failure of antidepressant 
treatments in the current episode will be made retrospectively using medical or pharmacy records 
and documented on the MGH-ATRQ.  Subjects with partial improvement (<50%) according to 
the MGH-ATRQ and moderate to severe depression (HDRS17 total score ≥18 at screening, as 
measured by a remote independent rater) will be eligible for inclusion. Subjects must be 
currently receiving no more than 2 of the following antidepressants for at least 6 weeks duration 
at screening with at least one antidepressant being at an adequate therapeutic dose, as determined 
by the MGH-ATRQ: bupropion, fluoxetine, citalopram, escitalopram, sertraline, paroxetine, 
venlafaxine, desvenlafaxine, duloxetine, vilazodone, mirtazapine, agomelatine, fluvoxamine,
amitriptyline, imipramine, nortriptyline, vortioxetine and levomilnacipram.
The screening phase will consist of 2 visits; the procedures scheduled during the first screening 
visit may be divided over two days, according to operational and/or site/country-specific needs.
In case the first screening visit is conducted over two days, the following assessments must be 
performed on the same day: C-SSRS, IDS-C30 and HDRS17.
The second visit will only be performed once all in- and exclusion criteria have been confirmed, 
except for the SAFER interview and chest X-ray (if applicable). These will only be performed at 
the second screening visit.
Double blind treatment phase: Subjects who continue to meet inclusion and exclusion criteria at 
the baseline visit will be eligible for randomization.  At the baseline visit, subjects must have a 
HDRS17 total score ≥18, as measured by a remote independent rater, and must not demonstrate 
an improvement of >25% on their HDRS17 total score from the screening to baseline visit. 
Randomization will be stratified by country and screening hsCRP level: 0.00 to <0.300 mg/dL 
(0.00 to <3.00 mg/L), ≥0.300 to <0.500 mg/dL (≥3.00 to <5.00 mg/L), ≥0.500 to <0.800 mg/dL 
(≥5.00 to <8.00 mg/L), and ≥0.800 mg/dL (≥8.00 mg/L). Subjects will receive either adjunctive 
placebo or adjunctive sirukumab in a 1:1 ratio. 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
44
Approved, Date: 22 January 2018
Refer to the Time and Events Schedule for a list of study evaluations that will be performed 
during the double-blind treatment phase.
Posttreatment Follow-Up: Subjects will have two follow-up safety visits, 8 and 14 weeks after 
last SC injection, to assess clinical condition, monitor safety and adverse events and record 
concomitant medications. Subjects with unresolved adverse events at Week 22 will be continued 
to be monitored as clinically appropriate to ensure subjects’ safety.
Pharmacogenomic blood samples will be collected to allow the identification of genetic and/or 
epigenetic factors that may influence the pharmacokinetics, pharmacodynamics, efficacy, safety, 
or tolerability of sirukumab and to identify genetic and/or epigenetic factors associated with 
MDD.
A diagram of the study design is provided below in Figure 1.
Figure 1:
Schematic Overview of the Study
3.2 
Study Design Rationale
Based on the known efficacy and safety profile of sirukumab and the time by which these are 
observed, the 12-week double-blind treatment phase should allow sufficient time to fully 
evaluate the effect of sirukumab as an add-on therapy to a monoaminergic antidepressant in 
MDD patients who have shown a suboptimal response to standard oral antidepressant therapy, on 
the clinical endpoints. In the RA phase 2 study C0136T03, sirukumab showed greater efficacy 
than placebo at week 12; additionally, post-hoc analyses of depressive symptom change 
following sirukumab in subjects with RA, showed greater improvement in sirukumab-treated 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
45
Approved, Date: 22 January 2018
subjects compared to placebo-treated subjects at week 12 (see Section 1.1.2.2.1 for additional 
details).
Patients will be stratified at randomization by country and 4 screening hsCRP levels: 0.00 to 
<0.300 mg/dL (SI 0.000 to <3.00 mg/L), ≥0.300 to <0.500 mg/dL (SI ≥3.00 to <500 mg/L), 
≥0.500 to <0.800 mg/dL (SI ≥5.00 to <8.00 mg/L), and ≥0.800 mg/dL (SI ≥8.00 mg/L). The 
hsCRP values defining those strata were derived by tertiles analyses of CRP distribution in 
depressed subjects with CRP >3.00 mg/L participating in two recent JRD-sponsored phase 2 
studies (data on file) and were consistent with CRP distribution reported in the literature
(Woloshin et al., 2005).  By stratifying patients on the basis of screening hsCRP values, and 
measuring change in inflammatory biomarkers throughout treatment, we will explore whether 
depressed patients with more pronounced inflammation at screening are more responsive to 
treatment with sirukumab, and whether treatment response is correlated with change in 
inflammatory processes, as reflected by changes in levels of inflammatory biomarkers. The 
0.00 to <0.300 mg/dL (SI 0.00 to <3.00 mg/L) stratum has been added to achieve a better 
understanding of the relationship between hsCRP – and potentially other inflammatory 
biomarkers- and the clinical response.
A placebo control will be used to maintain the blind and to establish the frequency and 
magnitude of changes in clinical endpoints that may occur in the absence of active study 
treatment in subjects with suboptimal response to monoaminergic antidepressant. Randomization 
will be used to minimize bias in the assignment of subjects to treatment groups, to increase the 
likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints.
The duration of the study is considered adequate to test the potential efficacy of sirukumab. Not 
allowed antidepressant medication will not be discontinued for the sole purpose of entering the 
study; subjects will be carefully monitored for potential worsening of the depressive symptoms 
and suicidality and appropriate actions will be taken to ensure the safety of the subjects 
participating in the study. Clinical studies with similar study design show that both partial and 
non-responders had significant improvement, even in the placebo arm (Thase et al., 2008). All 
subjects will receive clinical care while in the trial.
The HDRS17, IDS-C30, CGI-S and PHQ-9 are scales which capture depressive symptoms and 
severity and measure the magnitude of severity change following antidepressant interventions. 
The FACIT scale measures fatigue and will be used to investigate whether sirukumab decreases 
fatigue-related symptoms in subjects with depression, as elevation of inflammatory markers, 
including CRP, has been reported to be associated with greater fatigue severity.
The childhood trauma questionnaire will be used to investigate the potential association between 
the severity of childhood negative experiences and clinical change following sirukumab; 
preliminary evidence suggests that subjects with higher CTQ scores experience a greater level of 
depression and peripheral inflammation.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
46
Approved, Date: 22 January 2018
Length of Study Phases
All subjects will undergo a screening period of approximately 4 weeks, which will provide 
adequate time to assess their eligibility per inclusion/exclusion criteria for the study.  
The duration of the screening period of approximately 4 weeks is chosen to ensure that subjects 
are experiencing suboptimal response to the current antidepressant treatment regimen and that 
elevation of hsCRP is stable across time and does not represent a transient increase related to 
medical conditions other than depression. The screening phase has been split in 2 visits, so the 
more burdensome assessments for the subjects are only performed once all other screening 
criteria have been met. The procedures scheduled during the first screening visit may be divided 
over two days, according to operational and/or site/country-specific needs. In case the first 
screening visit is conducted over two days, the following assessments must be performed on the 
same day: C-SSRS, IDS-C30 and HDRS17.
The 12-week duration of the double-blind study is adequate to assess the potential efficacy of 
sirukumab in the treatment of MDD, as steady state is reached by approximately 12 weeks.
A posttreatment assessment visit 8 and 14 weeks after the last intake of study drug to determine 
the duration of the antidepressant effect and tolerability will be made to assess subject safety and 
mood symptoms A week 14 follow-up visit is deemed to be necessary to monitor potential risks 
of infections occurring after discontinuation of the study agent.
Study Population
The study population will consist of men and women, 21 to 64 years of age (inclusive), that meet 
the DSM-5 diagnosis of MDD, confirmed by the MINI, who are currently being treated with a 
monoaminergic antidepressant and have failed no more than 3 antidepressants (of adequate dose 
and duration) in the current major depressive episode. It is expected that this population will be 
representative for the targeted subject population for future clinical trials.
Dose selection
In a Phase 2 study in subjects with RA, all the doses tested (i.e., 100 mg q2w, 100 mg q4w,
50 mg q4w, and 25 mg q4w) showed a statistically significant reduction of serum CRP 
concentration compared to placebo which was maintained at least through week 24 (Smolen et 
al., 2014). The magnitude of CRP decrease in the sirukumab-treated subjects ranged from -81%
to -91% compared to baseline and was not different between dose groups. As sirukumab is 
hypothesized to exert its potential clinical effect in depressed subjects with elevated 
inflammatory markers through a reduction in IL-6 and other cytokines, the aforementioned data 
suggest that the doses tested in RA might be in the therapeutic range for MDD. Moreover, in the 
phase 2 RA study subjects were required to have CRP ≥10.00 mg/L, which is a CRP level more 
than 3-fold higher than what is required in the present study, where the CRP level for primary 
analysis needs to be ≥0.300 mg/dL (SI ≥3.00 mg/L). This additional consideration implies that 
50 mg q4w, a dose lower than the maximal dose tested in RA, might be sufficient in subjects 
with MDD to achieve suppression of the peripheral inflammatory component and there is no 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
47
Approved, Date: 22 January 2018
reason to suggest that 100mg might provide added benefit. Thus the sirukumab dose of 50 mg 
q4w has been chosen for this proof of concept study in subjects with MDD.
The 25mg q4w dose has not been chosen here as it is a dose not tested in the RA phase 3 
program. In case of unclear efficacy outcome in the present study it would be challenging to 
interpret ambiguous results as related to lack of compound efficacy in the depression indication 
or reflecting the use of a suboptimal dose of sirukumab. Further  studies in depressed subjects 
might need to test the efficacy of lower and higher doses than 50mg q4w, including 25mg q4w 
and 100 mg q2w.
Pharmacokinetics and Immunogenicity
To assess the pharmacokinetics of sirukumab in subjects with MDD, venous blood samples will 
be collected for the measurement of serum sirukumab concentration according to the Time and 
Events Schedule.  
Antibodies generated in response to sirukumab have the potential to accelerate the clearance of 
the drug and hence affect efficacy. To evaluate the immunogenicity of sirukumab in subjects 
with MDD, serum samples for the detection of antibodies to sirukumab will also be collected 
according to the Time and Events Schedule.
Inflammatory cytokines, including IL-6, are known to downregulate expression and activity of 
multiple CYP enzymes. Hypothetically, IL-6 inhibition in subjects with elevated inflammatory 
cytokines will restore CYP enzyme activities, and, in turn, increase the hepatic metabolism of 
drugs that are substrates for those enzymes. Since most of approved antidepressant medications 
are CYP substrates, effect of sirukumab on the pharmacokinetics of monoaminergic 
antidepressants will be evaluated. Venous blood samples will be collected for the assessment of 
plasma concentrations of monoaminergic antidepressants before and after sirukumab treatment 
as indicated in the Time and Events Schedule.
Safety assessments
The collection of adverse events and concomitant medications will start after the informed 
consent has been signed and will continue until the scheduled follow-up visit 14 weeks after last 
dose intake. Apart from this the following safety assessments will be done: physical examination 
(including temperature), body weight, vital signs, urine drug and pregnancy testing (female 
subjects only), clinical labs (hematology, chemistry panel, urinalysis, screening only: thyroid 
stimulating hormone (TSH) if applicable, follicle stimulating hormone (FSH) if applicable and
serology) and allergic and injection site reactions to SC injections. In addition the Columbia 
Suicide Severity Rating Scale (C-SSRS) will be conducted at each study visit to monitor suicidal 
ideation and behavior. See Time and Events schedule below for more details.
Additional blood and urine samples may be taken (not exceeding the stated maximum blood 
volume) or vital signs and electrocardiograms (ECG’s) recorded at the discretion of the 
investigators.   
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
48
Approved, Date: 22 January 2018
DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug. The goal of the pharmacogenomic component is to collect DNA to allow 
the identification of genetic factors that may influence the pharmacokinetics, pharmacodynamics,
efficacy, safety, or tolerability of sirukumab and to identify genetic factors associated with 
MDD. Specifically, genetic and epigenetic changes in genes known to be in pathways relevant to 
depression (HPA axis, inflammation, growth factors, monoamine transporters, ion channels, 
circadian rhythm) will be evaluated.
Biomarker samples will be collected to allow for exploratory immunophenotyping and for an 
exploratory pharmacodynamics evaluation.
DNA and biomarker samples may be used to help address emerging issues and to enable the 
development of safer, more effective, and ultimately individualized therapies.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 days before administration of the 
study drug. Chest X-ray (if applicable) and SAFER interview will only be performed (in a 
second screening visit) once all other screening criteria have been confirmed. If some in and/or 
exclusion criteria still have to be confirmed at the time of this second screening visit, this will be 
discussed prior to this second screening visit with the JRD responsible safety physician on a case 
by case basis.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study. 
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Male or female between 21 and 64 years of age, inclusive
2.
Criterion modified per Amendment INT-4
2.1. Subjects must have a primary DSM-5 diagnosis of MDD
a. Subjects with a diagnosis of comorbid Generalized Anxiety Disorder (GAD), Post-
Traumatic Stress Disorder, Persistent Depressive Disorder, Attention Deficit 
Hyperactivity Disorder (ADHD), Social Anxiety Disorder, Panic Disorder with or 
without agoraphobia, or Nicotine Dependence may be included, if the investigator 
considers MDD to be the primary diagnosis.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
49
Approved, Date: 22 January 2018
3.
Criterion modified per Amendment INT-4
3.1. Subjects must have a HDRS17 total score ≥18 at screening and predose at Day 1, as 
recorded by the remote independent rater and must not demonstrate an improvement of 
>25% on their HDRS17 total score from the screening to baseline visit.
4.
Criterion deleted per Amendment INT-4
4.1. Subjects must have a hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) at screening.
5.
Subject must be medically stable on the basis of physical examination, medical history, 
vital signs, clinical laboratory tests and 12-lead ECG performed at screening. If there are 
abnormalities, the subject may be included only if the investigator judges the 
abnormalities or deviations from normal to be not clinically significant. This 
determination must be recorded in the subject's source documents and initialed by the 
investigator.
6.
Subjects with hypothyroidism who are on stable treatment for 3 months prior to screening 
are required to have TSH and free thyroxine (FT4) obtained. If the TSH value is out of 
range, but FT4 is normal, such cases should be discussed directly with the JRD 
responsible safety physician before the subject is enrolled. If the FT4 value is out of 
range, the subject is not eligible.
7.
The subject’s major depressive episode and treatment response must be deemed "valid" 
using the SAFER criteria interview (which includes the HDRS17, a review of the 
MGH-ATRQ performed at screening, and the SAFER Criteria Inventory) administered 
by the remote independent rater.
8.
Subjects must have had an inadequate response to at least 1 antidepressant in the current 
episode of depression, as measured by the MGH-ATRQ. Inadequate response is defined 
as partial improvement (<50%) according to the MGH-ATRQ and moderate to severe 
depression (HDRS17 total score ≥18 at screening, as measured by a remote independent 
rater). The MGH-ATRQ and prior medication history will be used to determine 
antidepressant treatment response in prior episode(s).
9.
Criterion modified per Amendment INT-4
9.1. Subject must be currently receiving no more than 2 of the following antidepressants 
for at least 6 weeks duration at screening, with at least one being at an adequate 
therapeutic dose, as determined by the MGH-ATRQ and verified by medical or pharmacy
records and should remain on a stable dose throughout the study: bupropion, fluoxetine, 
citalopram, escitalopram, sertraline, paroxetine, venlafaxine, desvenlafaxine, duloxetine, 
vilazodone, 
vortioxetine, 
mirtazapine, 
fluvoxamine, 
agomelatine, 
nortriptyline, 
imipramine, amitriptyline and levomilnacipram.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
50
Approved, Date: 22 January 2018
10.
Women, sexually active or otherwise capable of pregnancy, must practice a method of 
birth control, including abstinence, intrauterine device, double barrier method (eg, 
condoms, diaphragm, or cervical cap with spermicidal foam, cream or gel) consistent 
with local regulations regarding the use of birth control methods for subjects participating 
in clinical trials. If using hormonal contraceptives, including oral contraceptives, 
injections and patches, a secondary method of contraception must be used. Contraception 
must be used for the duration of their participation in the study, and for 4 months after the 
last study agent administration. The exception to this restriction is if the subject or her 
male partner is sterilized; this situation does not require birth control. A woman must not 
donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and 
for 4 months after receiving the last dose of study agent.
Note: If childbearing potential of a subject changes after start of the study (e.g., a woman who is 
not heterosexually active becomes active) a woman must begin a highly effective method of birth 
control, as described above. Not of childbearing potential: postmenopausal (>45 years of age 
with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a 
serum follicle stimulating hormone (FSH) level >40 IU/mL); permanently sterilized (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy); or otherwise be incapable of pregnancy.
11.
A woman of childbearing potential must have a negative serum (β-human chorionic 
gonadotropin [β-hCG]) at screening and a negative urine pregnancy test prior to 
randomization on Day 1. 
12.
Men, if sexually active with women capable of pregnancy, are to use an effective method 
of birth control and to not donate sperm during the study and for 4 months after receiving 
the last dose of study agent. The exception to this restriction is if the subject or his female 
partner is sterilized; this situation does not require birth control.
13.
Subject must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol.
14. 
Subject must be able to read, understand and complete study questionnaires.
15.
Subjects will be included according to the following TB screening criteria:
a.
Have no history of latent or active TB prior to screening unless currently receiving 
treatment for latent TB for at least one month and showing no worsening in clinical status 
and there is no evidence of active TB. An exception is made for subjects who have a 
history of latent TB (defined for the purposes of this study as having had a positive result 
from either the tuberculin skin test (Attachment 2) or the QuantiFERON®-TB Gold test 
(Attachment 1) prior to screening) and documentation of having completed an adequate 
treatment regimen for latent TB within 3 years prior to the first administration of study 
agent under this protocol. These subjects do not need to be retested with the 
QuantiFERON-TB Gold test (or PPD) during screening. Adequate treatment for latent 
TB is defined according to local country guidelines for immunocompromised subjects. If 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
51
Approved, Date: 22 January 2018
no local guidelines for immunocompromised subjects exist, US guidelines must be 
followed. It is the responsibility of the investigator to verify the adequacy of previous 
anti-TB treatment and provide appropriate documentation.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical 
examination.
c.
Have had no recent close contact with a person with active TB or, if there has been such 
contact, will be referred to a physician specializing in TB to undergo additional 
evaluation and, if warranted, receive appropriate treatment for latent TB prior to the first 
administration of study agent.
d. Within 6 weeks prior to the first administration of study agent, have a negative 
QuantiFERON-TB Gold test result or have a newly identified positive QuantiFERON-TB 
Gold test result in which active TB has been ruled out and for which appropriate 
treatment for latent TB has been initiated prior to the first administration of study agent. 
A negative tuberculin skin test or a newly identified positive tuberculin skin test result in 
which active TB has been ruled out and for which appropriate treatment for latent TB has 
been initiated prior to the first administration of study agent is additionally required if the 
QuantiFERON-TB Gold test is not approved/registered in that country. An exception is 
made for subjects who have a history of latent TB (a positive result from either the 
tuberculin skin test or the QuantiFERON-TB Gold test prior to screening) and 
documentation of having completed an adequate treatment regimen for latent TB within 
3 years prior to the first administration of study agent. These subjects do not need to be 
retested with the QuantiFERON-TB Gold test (or PPD) during screening. Subjects with 
repeatedly indeterminate QuantiFERON-TB Gold test results from 2 samples tested in 
screening are ineligible (Section 9.1.2.).
e.
Have a chest radiograph (both posterior-anterior and lateral views), taken within 
12 weeks prior to the first administration of study agent and read by a qualified 
radiologist, with no evidence of current, active TB or old, inactive TB.
16.
Each subject must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of and procedures required for the study and is willing to 
participate in the study.
NOTE:

50 subjects must have a hsCRP < 0.300 mg/dL (SI <3.00 mg/L) at screening. Once 50 
subjects with a hsCRP level <0.300 mg/dL (SI <3.00 mg/L) have been enrolled, all 
further subjects to be randomized must have hsCRP levels ≥0.300 mg/d (SI ≥3.00 mg/L); 
sites will be notified by the study team when 50 subjects with hsCRP <0.300 mg/dL
(SI <3.00 mg/L) have been randomized and enrollment is completed in this stratum.
Subjects with <0.300 mg/dL (SI <3.00 mg/L) hsCRP in active screening once the 
enrollment in the hsCRP <0.300 mg/dL (SI <3.00 mg/L) will be completed, will be 
considered screening failures. 

Retesting of an abnormal laboratory value, at the discretion of the Investigator, that may 
lead to exclusion will be allowed only once during the screening phase. Retesting will 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
52
Approved, Date: 22 January 2018
take place during an unscheduled visit in the screening phase. After completion of the 
hsCRP < 0.300 mg/dL cohort, retesting for hsCRP will be allowed, but only for subjects 
who have hsCRP ≥ 0.250 mg/dL (SI ≥2.50 mg/L) and < 0.300 mg/dL (SI <3.00 mg/L) at 
screening. Retesting for hsCRP is only allowed once.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1. 
Criterion modified per Amendment INT-4
1.1. Any other current Axis I psychiatric condition, including, but not limited to, MDD 
with current psychotic features, bipolar disorder (including lifetime diagnosis), obsessive-
compulsive disorder, borderline personality disorder, eating disorder (eg, bulimia, 
anorexia nervosa), or schizophrenia (lifetime). The MINI will be used to screen for 
comorbid psychiatric diagnoses. As noted above, subjects with a diagnosis of comorbid 
GAD, Post-Traumatic Stress Disorder, Persistent Depressive Disorder, ADHD, Social 
Anxiety Disorder, Panic Disorder with or without agoraphobia or Nicotine/Caffeine 
Dependence may be included, if the investigator considers MDD to be the primary 
diagnosis.
Note: treatment with psychostimulants is not allowed
2.
Age of onset of depression after 55 years of age.
3.
A history of alcohol or substance use disorder (abuse/dependence) within 6 months prior 
to screening (nicotine and caffeine dependence are not exclusionary).
4.
A current or recent (within the past year) history of clinically significant suicidal ideation 
(corresponding to a score of ≥ 3 for ideation) or any suicidal behavior within the past 
year, as validated on the C-SSRS at screening or baseline. Subjects with a prior suicide 
attempt of any sort, or history of prior serious suicidal ideation/plan should be carefully 
screened for current suicidal ideation and only included at the discretion of the 
investigator. 
5.
More than 3 failed antidepressant treatments (of adequate dose and duration) in the 
current episode of depression (verified by the MGH-ATRQ).
6.
Criterion modified per Amendment INT-4
6.1. Length of current major depressive episode > 60 months.
7.
Criterion modified per Amendment INT-4
7.1. Subjects who demonstrate improvement of >25% on the HDRS17 between the 
screening and baseline visit.
8.
Lifetime history of treatment with a monoclonal antibody (biologic) for any reason.  
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
53
Approved, Date: 22 January 2018
9.
Organic brain disease or dementia.
10.
Known or suspected mental retardation.
11.
Subjects who have been treated with electroconvulsive therapy in the current episode or 
who have been treated with deep brain stimulation (lifetime) or who have been treated 
with repetitive transcranial magnetic stimulation within 4 weeks prior to baseline visit.
12.
Any clinically relevant medical condition that could potentially alter the absorption, 
metabolism, or excretion of the study medication, such as liver disease or renal disease.
13.
Relevant history of any significant immunologic disease including, but not limited to, 
Crohns Disease, Ulcerative Colitis, Rheumatoid Arthritis, Plaque Psoriasis, Psoriatic 
Arthritis, Lupus.  
14.
Relevant history of any significant and/or unstable cardiovascular, respiratory, 
neurological (including seizures - uncomplicated childhood febrile seizures with no 
sequelae are not exclusionary) or significant cerebrovascular, renal, hepatic, 
dermatologic, hematologic, gastrointestinal or endocrine diseases. Hospitalization for a 
cardiovascular event (myocardial infarction, unstable angina, stroke, transient ischemic 
attack) within 3 months prior to the first administration of study agent is exclusionary.

subjects with non-insulin dependent diabetes mellitus who are adequately 
controlled (not on insulin) may participate in the study.
15.
Have any known malignancy or has a history of malignancy within the previous 5 years 
(with the exception of a nonmelanoma skin cancer that has been treated with no evidence 
of recurrence for at least 3 months before the first study agent administration or cervical 
intraepithelial neoplasia with surgical cure).
16.
Female subjects who are pregnant or breastfeeding.
17.
Screening laboratory test result as follows:
a. Hemoglobin <10 g/dL (SI: <85 g/L) or < 5.3 mmol/L
b. White blood cells (WBC) <3.5 × 103 cells/μL (SI: <3.5 × 109 cells/L)
c. Neutrophils <1.95 × 103 cells/μL (SI: <1.95 × 109 cells/L)
d. Platelets <140 × 103 cells/μL (SI: <140 × 109 cells/L)
e. Serum ALT or AST >1.5 times the ULN for the central laboratory conducting  the test
f. Total bilirubin >ULN
g. Serum creatinine ≥2.0 mg/dL (SI: ≥177 μmol/L)
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
54
Approved, Date: 22 January 2018
18.
Subject has had a severe infection (including, but not limited to hepatitis, pneumonia, 
sepsis, or pyelonephritis); or has been hospitalized for an infection; or has been treated 
with intravenous antibiotics for an infection, within 2 months prior to the first 
administration of study agent.
19.
History of chronic or recurrent infectious disease or ongoing infection including, but  not 
limited to, chronic renal infection, chronic chest infection, recurrent urinary tract 
infection (eg, recurrent pyelonephritis, chronic non-remitting cystitis), or open, draining 
skin wound or an ulcer.
20.
Nontuberculous mycobacterial infection or opportunistic infection (eg, cytomegalovirus, 
pneumocystosis, aspergillosis) within 6 months prior to screening.
21.
Chest radiograph within 3 months prior to the first administration of study agent that 
shows an abnormality suggestive of a malignancy or current active infection, including 
TB.
22.
Criterion modified per Amendment INT-4
22.1. Subjects with uncontrolled hypertension – hypertension must be controlled for at 
least 3 months prior to screening; the dosage of any antihypertensive medication must 
have been stable for the past 3 months. Subjects with a supine systolic 
blood pressure >150 mmHg, a supine diastolic blood pressure >95 mmHg, or a pulse 
>100 bpm at screening or baseline will be excluded.
23.
Is infected with HIV (positive serology for HIV antibody), hepatitis B [positive serology 
for hepatitis B surface antigen (HBsAg)] or hepatitis C (positive serology for hepatitis C 
virus antibody). If seropositive, consultation with a physician with expertise in the 
treatment of HIV or hepatitis B and C virus infection is recommended.
24.
Criterion modified per Amendment INT-4
24.1. Positive urine drug screen for opiates, cocaine, barbiturates, methadone, marijuana 
and amphetamine/methamphetamine or positive alcohol screen at screening. In the case 
of a subject having a positive drug screen for marijuana, barbiturates or opioids, a one-
time repeat urine drug screen may be performed at the discretion of the investigator, 
provided the subject is willing to abstain from marijuana and other prohibited substances 
during the study.
25.
Clinically significant abnormal physical examination, vital signs or 12-lead ECG at 
screening. Minor deviations in ECG, which are not considered to be of clinical 
significance to the investigator, are acceptable. Clinically significant abnormal 
observations in ECG at screening are defined as:
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
55
Approved, Date: 22 January 2018
a.
A confirmed screening visit QTcB or QTcF, males or females, interval ≥470 ms), 
or >480 ms if bundle branch block and prolongation of the QTc interval are 
present; or a history of untreated second- or third-degree heart block.
26.
Diagnosis of congestive heart failure Class III or IV.
27.
History of known demyelinating diseases such as multiple sclerosis or optic neuritis.
28.
History of gastrointestinal perforation or currently has active diverticulitis.
29.
Has received, or is expected to receive, any live virus or bacterial vaccination within 
3 months before the first administration of study agent, during the study, or within 
4 months after the last administration of study agent. Have had a Bacille Calmette-Guérin 
(BCG) vaccination within 12 months of screening.
30.
Use of monoamine oxidase inhibitors within 4 weeks before screening.
31.
Criterion modified per Amendment INT-4
31.1 Use of benzodiazepines in dose in excess of 2mg/day equivalent of lorazepam (see 
section ‘prohibited medications’ below for equivalents)
32.
Use of mood stabilizers (e.g. anticonvulsants and/or lithium) or antipsychotics within 
2 weeks before screening. 
33.
Criterion modified per Amendment INT-4
33.1. Daily use of aspirin, ibuprofen, Cox-2 inhibitors, NSAIDs or other anti-
inflammatory drugs or combination treatments for headache or pain which contains those 
products within 2 weeks prior to screening (acetaminophen/paracetamol permitted) and 
unwilling to use acetaminophen/paracetamol only during study participation.
Note:
- PRN use of following NSAIDs is allowed: Ibuprofen up to 1600 mg/day; Diclofenac up to 75 
mg/day; Aspirin up to 1500 mg/day. NSAIDs must be discontinued 3 days before the in-clinic 
visits for biomarkers measurements.
- Prophylactic use of low dose aspirin prescribed for cardiovascular or cerebrovascular disease is 
allowed.
34. 
Current use of immunomodulators (eg azathioprine, tacrolimussulfasalazine)
35. 
Has received immunosuppressant agents, as follows:
a.
Has a history of cyclophosphamide or cytotoxic agent use. 
b.
Has received cyclosporine A, azathioprine, tacrolimus, mycophenolate 
mofetil, oral or parenteral gold, hydroxychloroquine and methotrexate 
within 4 weeks of the first study agent administration.  
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
56
Approved, Date: 22 January 2018
36.
Subjects with previous exposure to sirukumab.
37.
Known allergies, hypersensitivity, or intolerance to sirukumab or its excipients.
38.
History of severe allergic reaction to monoclonal antibodies or to murine, chimeric, or 
human proteins or their excipients.
39.
Major surgery, (eg, requiring general anesthesia) within 8 weeks before screening, or has 
not fully recovered from surgery, or has planned major surgery during the time the 
subject is expected to participate in the study. 
Note: subjects with planned surgical procedures to be conducted under local anesthesia may 
participate.
40.
Exposure to an experimental drug or experimental medical device within 90 days before 
screening.
41.
Criterion modified per Amendment INT-4
41.1. Involuntarily committed to psychiatric hospitalization in the current episode.
42.
Donation of 1 or more units (approximately 450 mL) of blood or acute loss of an 
equivalent amount of blood within 90 days prior to study drug administration.
43.
Any condition that, in the opinion of the investigator, would compromise the well-being 
of the subject or the study or that could prevent, limit or confound the protocol-specified 
assessments.
44.
Employees of the investigator or study center, persons with direct involvement in the 
proposed study or other studies under the direction of that investigator or study center, or 
family members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of study drug is given such that he or she no longer meets 
all eligibility criteria, then the subject should be excluded from participation in the study.
4.3.
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1. Subjects should abstain from using illegal drugs within 3 days prior to Day 1 and at any 
time during the study. Alcohol consumption should be limited to maximum 3 alcoholic 
beverages during the week prior to Day 1 and maximum 3 alcoholic beverages weekly 
throughout study. 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
57
Approved, Date: 22 January 2018
2. If a woman is of childbearing potential, she must remain on a highly effective method of 
birth control during the study and for 4 months after receiving the last dose of study 
agent. If she is using hormonal contraceptives, she must use an additional non-hormonal 
birth control method. The exception to this restriction is if the subject or her male partner 
is sterilized; this situation does not require birth control (see inclusion criteria #10). A 
woman must not donate eggs (ova, oocytes) for the purposes of assisted reproduction 
during the study and for 4 months after receiving the last dose of study agent.
3. If a man, he is to use an effective method of birth control and not donate sperm during the 
study and for 4 months after receiving the last dose of study agent. The exception to this 
is if the subject or his female partner is sterilized; this situation does not require birth 
control (see inclusion criteria #12).
4. For a list of prohibited medications, please see Prestudy and Concomitant Medication.
5. Must agree not to receive a live virus or live bacterial vaccination during the study. 
Subjects must also agree not to receive a live vaccine for 4 months after receiving the last 
administration of study agent.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by country and 4 screening hsCRP levels:
0.00 to <0.300 mg/dL (SI 0.00 to <3.00 mg/L), ≥0.300 to <0.500 mg/dL (SI ≥3.00 to 
<5.00 mg/L), ≥0.500 to <0.800 mg/dL (SI ≥5.00 to <8.00 mg/L), and ≥0.800 mg/dL 
(SI ≥8.00 mg/L). The interactive web response system (IWRS) will assign a unique treatment 
code, which will dictate the treatment assignment and matching study drug kit for the subject. 
The requestor must use his or her own user identification and personal identification number 
when contacting the IWRS, and will then give the relevant subject details to uniquely identify the 
subject.
Blinding
To maintain the study blind, the study drug container will have a label containing the study 
name, study drug number and reference number. The label will not identify the study drug in the 
container. However, if it is necessary for a subject's safety, the study blind may be broken and 
the identity of the study drug ascertained. The study drugs will be identical in appearance and 
will be packaged in identical containers.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
58
Approved, Date: 22 January 2018
The study agent kit number will be entered in the electronic case report form (eCRF) or other 
equivalent data capture method when the drug is administered.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, cholesterol, LDL, HDL, 
triglycerides and hsCRP) 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. Sponsor staff, 
investigators, site staff, subjects, and remote independent rater will all be blinded to the treatment 
assignment, as well as hsCRP, cholesterol, LDL, HDL and triglyceride values during the trial. 
The remote independent rater will be blinded to any adverse events (AEs) reported by subjects; 
subjects will be instructed not to discuss AEs with the rater.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IWRS. It is recommended that the investigator contact the sponsor or 
its designee if possible to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date and 
reason for the unblinding must be documented in the appropriate section of the case report form 
(CRF) and in the source document. The documentation received from the IWRS indicating the 
code break must be retained with the subject's source documents in a secure manner.
Subjects who have had their treatment 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. At the interim efficacy analysis, the randomization codes and, if 
required, the translation of randomization codes into treatment and control groups will be 
disclosed to those authorized and only for those subjects included in the interim analysis. The 
details about disclosure of randomization codes and treatment assignment at the interim efficacy 
analysis will be provided in the Interim Analysis Committee (IAC) charter. In addition, 
prespecified Clinical Pharmacology representatives may be unblinded prior to the clinical 
database lock for the purpose of performing PK and immunogenicity analyses.
At the time of the first database lock for the primary efficacy analyses, randomization codes will 
be disclosed fully. Unblinding after completion of the 12-week double-blind treatment phase will 
not impact the integrity of the study data, as only follow-up visits will be performed after the 
unblinding and those visits will not include the primary outcome measures of the study.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
59
Approved, Date: 22 January 2018
6.
DOSAGE AND ADMINISTRATION
Subjects will be randomly assigned in a 1:1 ratio to receive adjunctive treatment with a SC
injection of sirukumab 50 mg or placebo, while continuing on their baseline oral monoaminergic
antidepressant(s). The matching placebo injection will consist of an identical volume of placebo
solution, administered SC every 4 weeks. All subjects will receive 3 injections in total, one 
injection each at Day 1, Day 28 and Day 56. The study agent will be administered SC in the 
outer area of the upper arms. 
The study agent will be administered subcutaneously at the site by a healthcare professional who 
administers study agent through Week 8.
If an injection is missed every effort should be made to have the missed injection administered 
within 4 days after the scheduled study visit for that injection. 
In case it is not possible to administer an injection on time, the injection will be considered as 
missed for that visit, and the site personnel should discuss the issue with the JRD responsible 
safety physician. 
Time and date of dose administration will be recorded in the CRF.
7.
TREATMENT COMPLIANCE
Study agent administered at the site will be administered SC by an appropriately licensed and 
authorized health care professional.  Study personnel will maintain a log of all study agent 
administrations.  Study agent supplies for each subject will be inventoried and accounted for.  
All ongoing therapies administered at the time of screening must be recorded.  
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy oral antidepressant therapies, monoamine oxidase inhibitors, benzodiazepines and 
mood stabilizers, antipsychotics, immunosuppressants, immunomodulators, aspirin, ibuprofen, 
Cox-2 inhibitors, NSAIDs or other anti-inflammatory medication administered before first dose 
of study drug must be recorded at screening.
Concomitant therapies must be recorded throughout the study beginning with start of the first 
dose of study drug until last follow-up visit.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the CRF. Recorded 
information will include a description of the type of the drug, treatment period, dosing regimen,
route of administration, and its indication.
Subject’s baseline oral antidepressants (bupropion, fluoxetine, citalopram, escitalopram, 
sertraline, venlafaxine, desvenlafaxine, mirtazapine, fluvoxamine, agomelatine, amitriptyline
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
60
Approved, Date: 22 January 2018
imipramine, nortriptyline, vilazodone, vortioxetine and levomilnacipram) will be taken as 
prescribed (without dose change) throughout the screening and double-blind phase of the study.
Adherence to subject’s baseline oral antidepressants will be checked at each visit to the site.
Subjects must agree not to use any of the following medications with psychotropic properties, 
including but not limited to:
–
Psychiatric medications, including mood stabilizers, antipsychotics, psychostimulants and 
antidepressants other than their baseline monoaminergic antidepressant(s) (e.g., monoamine-
oxidase inhibitors (MAOIs) and milnacipram are prohibited).
–
Benzodiazepines in excess of the equivalent of 2 mg of lorazepam per day.  A subject 
may continue to take a benzodiazepine only if the subject has been taking a fixed daily dose of a 
benzodiazepine for at least 2 weeks prior to screening. As required (PRN) use of 
benzodiazepines is not allowed.
Benzodiazepine Equivalent Dosages:
Benzodiazepine
Oral Dose (mg)
Lorazepam
2
Clonazepam
1
Clorazepate 
30
Diazepam
10
Temazepam
20
Alprazolam
1
Phenazepam is also allowed in dosages up to 1.5 mg daily.
Allowable 
sleep 
medications 
include: 
zolpidem, 
zaleplon, 
zoplicone,
eszopliclone, 
diphenhydramine, and ramelteon. Continuous fixed dose or PRN use of sleep medications is 
allowed. Subjects with PRN use of sleep medications shall be advised not to take any sleep 
medications the day prior to the clinical visits and/or the remote ratings interview procedures 
(i.e., HDRS17 and SAFER interview). Other sleep aids such as chloral hydrate and sedating 
antipsychotics are prohibited.
A dosage of trazodone not exceeding 150 mg/day given as a sleep aid or for sexual dysfunction 
is allowed.
Other prohibited medications include:
-
S-adenosyl methionine (SAMe), St. John’s wort, ephedra, ginkgo, ginseng, or kava kava
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
61
Approved, Date: 22 January 2018
-
Opiates
-
Anticonvulsants
-
Antipsychotics (typical and atypical)
-
Cox-2 inhibitors, chronic use of NSAIDs or other anti-inflammatory drugs or 
combination treatments for headache or pain which contains those products 
(acetaminophen/paracetamol allowed, dose as recommended by the site staff, but not to 
exceed 3 g/day)
Note: PRN use of following NSAIDs is allowed: Ibuprofen up to 1600 mg/day; 
Diclofenac up to 75 mg/day; Aspirin up to 1500 mg/day. NSAIDs must be discontinued 3 
days before the in-clinic visits for biomarkers measurements.
-
Immunomodulators
-
Immunosuppressants
Subjects receiving psychotherapy can continue receiving psychotherapy provided this therapy 
has been stable in terms of frequency for the last 3 months prior to screening and will remain 
unchanged throughout study treatment. 
Cognitive behavioral therapy for ADHD is allowed.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Drugs Metabolized by Cytochrome P450
Inflammatory cytokines, including IL-6, are known to downregulate activity and expression of 
multiple CYP450 enzymes. Hypothetically, IL-6 inhibition in a subject with an inflammatory 
condition will restore or increase the CYP enzyme activity, and, in turn, increase the hepatic 
metabolism and clearance of drugs that are substrates for those enzymes. Therefore, upon 
initiation or discontinuation of sirukumab in subjects being treated with CYP450 substrates with 
a narrow therapeutic index, monitoring of the effect (eg, warfarin) or drug concentration (eg, 
theophylline) is recommended and the individual dose of the drug may be adjusted as needed. 
Since CYP3A4 is the major CYP enzyme and in vitro studies showed that IL-6 has a profound 
effect on CYP3A4, caution should also be exercised when sirukumab is coadministered with 
CYP3A4 substrate drugs, eg, oral contraceptives, certain statin medications (eg, simvastatin, 
atorvastatin, cerivastatin, lovastatin). Substrates with a narrow therapeutic range include 
alfentanil, 
astemizole, 
cisapride, 
dihydroergotamine, 
ergotamine, 
fentanyl, 
quinidine, 
terfenadine.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
62
Approved, Date: 22 January 2018
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy,
pharmacokinetic, immunogenicity, biomarker, pharmacogenomic, and safety measurements 
applicable to this study.
All visit-specific Patient-Reported Outcomes (PRO) assessments should be conducted/completed
before any tests, procedures, or other consultations for that visit to prevent influencing subject 
perceptions. Every effort should be made to perform all other assessments in the order specified 
in the Time and Events Schedule unless logistically not feasible, and if possible, the same 
individual(s) should perform the assessments at each visit.
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 subject's participation in the study.
For each subject, approximately 350 mL of blood will be drawn. The maximum amount of blood 
drawn from each subject in this study will not exceed 450 mL. Detailed blood volumes per blood 
sample will be provided in the lab manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
9.1.2.
Screening Phase
Within 4 weeks prior to Day 1, potential subjects will be screened to determine their eligibility 
for study participation. 
Prior to conducting any study procedure, the investigator (or designated study personnel) will 
review and explain the written ICF to each subject. No study procedures can be performed until 
after the subject signs the ICF.
The screening visit will include obtaining informed consent, assessment of inclusion and 
exclusion criteria, medical history and demographics, physical examination, psychiatric and 
safety evaluations and venous blood sampling for hsCRP assay and standard labs as described in 
the Time and Events Schedule.
The procedures scheduled during the first screening visit may be divided over two days, 
according to operational and/or site/country-specific needs. In case the first screening visit is 
conducted over two days, the following assessments must be performed on the same day: 
C-SSRS, IDS-C30 and HDRS17.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
63
Approved, Date: 22 January 2018
HDRS17 and SAFER will be done by an independent rater during the screening visit. The SAFER 
interview will only be performed (at a second screening visit) once subjects have been confirmed 
eligible for all other screening criteria. 
Adverse events will be collected starting after the ICF has been signed until the final study 
procedure at the final visit.
Subjects with a DSM-5 diagnosis of MDD, confirmed by the MINI, who are currently being 
treated with a monoaminergic antidepressant and have failed no more than 3 antidepressants (of 
adequate dose and duration) in the current major depressive episode will be eligible for 
screening. Determination of suboptimal response to the current standard oral antidepressant 
therapy will be made retrospectively using the structured MGH-ATRQ. Determination of failure 
of antidepressant treatments in the current episode will be made retrospectively using medical or 
pharmacy records and documented on the MGH-ATRQ. Subjects with partial improvement 
(<50%) according to the MGH-ATRQ and moderate to severe depression (HDRS17 total score 
≥18 at screening, as measured by a remote independent rater) will be eligible for inclusion. 
Subjects must be currently receiving no more than 2 of the following antidepressants for at least 
6 weeks duration at screening with at least one antidepressant being at an adequate therapeutic 
dose, as determined by the MGH-ATRQ: bupropion, fluoxetine, citalopram, escitalopram, 
sertraline, paroxetine, venlafaxine, desvenlafaxine, duloxetine, vilazodone,
vortioxetine
fluvoxamine, 
mirtazapine, 
agomelatine, 
nortiptyline, 
imipramine, 
amitriptyline
and 
levomilnacipram. hsCRP levels used for stratification during the randomization process are 
determined at screening.  Once 50 subjects with a hsCRP level <0.300 mg/dL have been 
enrolled, all further subjects to be randomized must have hsCRP levels ≥0.300 mg/dL; sites will 
be notified by the study team when 50 subjects with hsCRP <0.300 mg/dL have been 
randomized and enrollment is completed in this arm.
A chest radiograph (lateral and posterior-anterior view unless local guidelines recommend only 
single view) will be performed at screening to ensure that the subject does not have any 
abnormality suggestive of a malignancy or current active infection, including TB. This chest 
radiograph will only be performed (at a second screening visit) once subjects have been 
confirmed eligible for all other screening criteria. Chest x-rays taken up to 3 months prior to
Day 1 may also be used.
Subjects must undergo testing for TB (Attachment 1 and Attachment 2) and their medical history 
assessment must include specific questions about a history of TB or known occupational, or 
other personal exposure to individuals with active TB.  The subject should be asked about past 
testing for TB, including chest radiograph results and responses to tuberculin skin or other TB 
testing.
Subjects with a negative QuantiFERON-TB Gold test result (and a negative tuberculin skin test 
result in countries in which the QuantiFERON-TB Gold test is not approved/registered) are 
eligible to continue with prerandomization procedures.  Subjects with a newly identified positive 
QuantiFERON-TB Gold test (or tuberculin skin test) result must undergo an evaluation to rule 
out active TB and initiate appropriate treatment for latent TB prior to first dose.  An exception is 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
64
Approved, Date: 22 January 2018
made for subjects who have a history of latent TB (defined for the purposes of this study as 
having had a positive result from either the tuberculin skin test (Attachment 2) or the 
QuantiFERON TB Gold test (Attachment 1) prior to screening) and documentation of having 
completed an adequate treatment regimen for latent TB within 3 years prior to the first 
administration of study agent under this protocol. These subjects do not need to be retested with 
the QuantiFERON-TB Gold test (or PPD) during screening.  Appropriate treatment for latent TB 
is defined according to local country guidelines for immunocompromised subjects.  If no local 
country guidelines for immunocompromised subjects exist, US guidelines must be followed or 
the subject must be excluded from the study.  It is the responsibility of the investigator to verify 
the adequacy of previous anti-TB treatment and provide appropriate documentation.
A subject whose first QuantiFERON-TB Gold test result is indeterminate should have the test 
repeated.  In the event that the second QuantiFERON-TB Gold test result is also indeterminate, 
the subject should be excluded from the study.
Subject must not use a disallowed therapy (prior or concomitant), within 1 week (or longer, if 
specified) before the planned first dose of study drug. Refer to Section 8, Pre-trial and 
Concomitant Therapy for a list of prohibited therapies.
Subject-completed assessments should be completed before any clinical tests are taken or 
clinician-administered assessments associated with the study visit are conducted. 
9.1.3.
Double-Blind Treatment Phase
Subjects who continue to meet inclusion and exclusion criteria at the baseline visit will be 
eligible for randomization.  At the baseline visit, subjects must have a HDRS17 total score ≥18, 
as measured by a remote independent rater, and must not demonstrate an improvement of >25 % 
on their HDRS17 total score from the screening to baseline visit. Randomization will be stratified 
by country and screening hsCRP level: 0.00 to <0.300 mg/dL (SI 0.00 to <3.00 mg/L), ≥0.300 to 
<0.500 mg/dL (SI ≥3.00 to <5.00 mg/L), ≥0.500 to <0.800 mg/dL (SI ≥5.00 to <8.00 mg/L), and 
≥0.800 mg/dL (SI ≥8.00 mg/L). Subjects will receive either adjunctive placebo or adjunctive 
sirukumab in a 1:1 ratio.
During the treatment phase, efficacy, safety, tolerability, immunogenicity, PK, biomarker, and 
pharmacogenomic evaluations will be performed as per the Time and Events Schedule. 
On days when blood samples for lab safety or biomarkers are collected, subjects should come to 
the site fasted, whenever feasible.
Study drug will be administered on Day 1, Day 28 and Day 56. Refer to Section 6 (Dosage and 
Administration) for further details.
During the double blind treatment phase, at visits in which the subject-completed and clinician-
administered assessments, clinical tests and blood samples are scheduled at the same time point, 
the following sequence will be used:
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
65
Approved, Date: 22 January 2018
1. Subject-completed assessments
2. Clinician-administered assessments 
3. Clinical tests 
4. Blood samples 
The sequence of clinician-administered assessments will be:
1. IDS-C30
2. CGI-S
3. C-SSRS
HDRS17 will be done by an independent rater.
If a subject discontinues treatment before the end of the double-blind treatment phase, early 
withdrawal assessments should be obtained as soon as possible.
9.1.4.
Posttreatment Phase (Follow-Up)
Subjects will have follow-up assessments performed according to the Time and Events Schedule. 
In the event a subject discontinues study agent injections, but does not terminate study 
participation, the first safety and efficacy follow-up visit should occur 8 weeks after the date of 
discontinuation of the study agent.   The second safety and efficacy follow-up visit should occur 
14 weeks after the date of discontinuation of the study agent. The visit window for follow-up 
assessments is ± 7 days.
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigator until resolution or until a clinically stable endpoint is reached.
9.2.
Efficacy 
9.2.1.
Evaluations 
Every effort should be made to ensure that all clinician administered assessments are completed 
by the same individual who made the initial baseline determinations.
Hamilton Depression Rating Scale (HDRS17)
The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms 
in subjects diagnosed with depression (Hamilton M 1960) with a score range of 0 to 52. It is the 
most widely used symptom severity measure for depression. Each of the 17 items is rated by the 
clinician on either a 3- or a 5-point scale. The HDRS17 has an inter-rater reliability correlation of 
r = .90 and the internal consistency of the measure is reported to be high with a coefficient alpha 
of 0.88. Criterion-related validity for this measure is high (Knesevich J et al., 1977).  
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
66
Approved, Date: 22 January 2018
The original HDRS17 scale lacks instructions for administration and clear anchor points for the 
assignment of severity ratings. For this reason, the structured interview guide version of the 
HDRS17 (the Structured Interview Guide for the Hamilton Depression Scale [SIGH-D]) will be 
used in the current study to facilitate and standardize gathering clinical information from the 
subject.
An example of the HDRS17 is provided in Attachment 7.
CGI-S 
The CGI-S will provide an overall clinician-determined summary measure that takes into 
account all available information, including knowledge of the subject’s history, psychosocial 
circumstances, symptoms, behavior, and the impact of the symptoms on the subject’s ability to 
function (Guy 1976). The CGI evaluates the severity of psychopathology from 1 to 7.
An example of the CGI-S is provided in Attachment 3.
Patient Health Questionnaire (PHQ-9)
The PHQ-9 will be used as a subject-reported measure of depressive symptomatology 
(Spitzer 1999). The PHQ-9 is a 9-item scale, where each item is rated on a 4-point scale (0=Not 
at all, 1=Several Days, 2=More than half the days, and 3=Nearly every day), with a total score 
range of 0 to 27. The recall period is 2 weeks.
An example of the PHQ-9 is provided in Attachment 9.
Snaith–Hamilton Pleasure Scale (SHAPS)
Anhedonia, the inability to experience pleasure, is a core symptom of depression. The Snaith–
Hamilton Pleasure Scale (SHAPS) is a short, 14-item instrument to measure anhedonia, which 
has been shown to be valid and reliable in normal and clinical samples (Snaith et al, 1995).  Each 
of the 14 items has a set of four response categories:  Definitely Agree (= 1), Agree (= 2), 
Disagree (= 3), and Definitely Disagree (= 4). A higher total score indicates higher levels of state 
anhedonia.
An example of the SHAPS is provided in Attachment 10.
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT Fatigue)
The FACIT-Fatigue is a questionnaire that assesses self-reported tiredness, weakness, and 
difficulty conducting usual activities due to fatigue. The total FACIT-Fatigue score ranges from 
0 to 52, with a higher score indicating less fatigue (Webster et al., 1999).
An example of the FACIT is provided in Attachment 11.
Exploratory evaluation:
Inventory of Depressive Symptomatology – Clinician Rated 30 (IDS-C30)
The clinician-rated IDS is a 30-item, depression-specific symptom severity rating scale (Rush et 
al., 1986). The IDS is designed to measure the specific signs and symptoms of depression, 
including melancholic, atypical and anxious features. Scores range from 0 to 84 with higher 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
67
Approved, Date: 22 January 2018
scores representing greater severity of depressive symptoms. The inter-rater reliability and 
internal consistency coefficients are high (Rush et al., 1996).  The IDS-C and the IDS-self report 
have reasonable construct validity, and a concurrent validity index above 0.90, correlating well 
with the HDRS17 and the Beck Depressive Inventory (Rush et al., 1996).
An example of the IDS-C30 is provided in Attachment 8.
Childhood Trauma Questionnaire (CTQ)
The CTQ was developed as a screening tool for histories of abuse and neglect (Bernstein et al.
1998). The self-report includes a 28-item test that measures 5 types of maltreatment – emotional, 
physical, and sexual abuse, and emotional and physical neglect. A 5-point Likert scale is used for 
the responses which range from Never True to Very Often True.
An example of the CTQ is provided in Attachment 12.
9.2.2.
Endpoints 
Primary Endpoint
Efficacy will be based on the change from baseline to 12-week endpoint for the HDRS17 total 
score for the adjunctive sirukumab treatment group compared with the adjunctive placebo 
treatment group in subjects with hsCRP ≥0.300 mg/dL (SI ≥3.00 mg/L) at screening and 
baseline.
Secondary Endpoints
Secondary efficacy endpoints will include the change from baseline to 12-week endpoint 
between the adjunctive sirukumab group and the adjunctive placebo group in the SHAPS total 
score, CGI-S, PHQ-9 and FACIT as well as the distribution of remitters and responders in 
subjects with screening hsCRP ≥ 0.300 mg/dL (SI ≥3.00 mg/L) (the number and percentage of 
subjects in remission as measured by a HDRS17 total score ≤ 7 or responders defined as ≥ 50% 
improvement on the HDRS17 from baseline to 12 week endpoint). The same secondary efficacy 
endpoints will be compared between subjects with screening hsCRP≥0.300 mg/dL 
(SI ≥3.00 mg/L) and subjects with hsCRP<0.300 mg/dL (SI <3.00 mg/L). 
Exploratory Endpoints
Exploratory efficacy evaluations will include the change from baseline to 12-week endpoint in 
the IDS-C30 total score, evaluation of the association between change from baseline of the 
HDRS17, baseline and post-treatment biomarker measurements (including hsCRP), the effect of 
sirukumab on the pharmacokinetics of monoaminergic antidepressants, evaluation of the 
relationship between the severity of childhood trauma as assessed through the CTQ and the 
change in HDRS17 scores following adjunctive sirukumab or placebo and assessment of 
genes/genotypes.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
68
Approved, Date: 22 January 2018
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations 
Venous blood samples will be collected for measurement of serum sirukumab concentrations and 
immunogenicity of sirukumab (antibodies to sirukumab). Samples collected for analyses of 
sirukumab serum concentration and antibodies to sirukumab may additionally be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the study period, 
for further characterization of immunogenicity or for the evaluation of relevant biomarkers. 
Additionally, venous blood samples will be collected for measurement of plasma concentrations 
of monoaminergic antidepressants. Genetic analyses will not be performed on these serum 
samples. Subject confidentiality will be maintained.
9.3.2.
Pharmacokinetics
9.3.2.1.
Sample Collection and Handling
Venous blood samples for measurement of serum sirukumab concentrations and antibodies to 
sirukumab will be collected at the time points shown in the Time and Events Schedule. Subjects 
who terminate from study participation should have final visit samples collected at the time of 
termination. At visits where serum concentration and antibodies to sirukumab will be evaluated, 
termination. At visits where serum concentration and antibodies to sirukumab will be evaluated, 
1 blood draw can be used. Each serum sample will be divided into 3 aliquots (1 each for 
pharmacokinetics, antibodies to study drug, and a back-up). Samples must be collected before 
study drug administration at visits when study drug administration is scheduled. The exact dates 
and times of blood sample collection must be recorded in the laboratory requisition form. 
Additionally, venous blood samples for measurement of plasma concentrations of 
monoaminergic antidepressants will be collected at the time points shown in the Time and 
Events Schedule. Samples collected after Day 1 must be collected at the same time as samples on 
Day 1 (+/- 1 hour). On days when samples for concentrations of monoaminergic antidepressants 
are collected, date and time of the last 3 intakes of the monoaminergic antidepressants will be 
recorded in the CRF. If a monoaminergic antidepressant has less than 20 subjects taking it, 
samples for that antidepressant will not be analyzed since the small sample size may not provide 
useful data to evaluate the effect of sirukumab on the pharmacokinetics of monoaminergic 
antidepressants.
Additional information about the collection, handling, and shipment of biological samples can be 
found in the laboratory manual.
9.3.2.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of sirukumab using a validated, 
immunoassay method by or under the supervision of the sponsor.
Plasma samples will be analyzed to determine the concentrations of monoaminergic 
antidepressants using validated, specific and sensitive (eg, liquid chromatography mass 
spectrometry/mass spectrometry [LC-MS/MS]) methods by or under supervision of the sponsor.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
69
Approved, Date: 22 January 2018
9.3.3.
Immunogenicity Assessments (Antibodies to sirukumab)
Antibodies to sirukumab will be detected using a validated immunoassay method in serum 
samples collected from all subjects. Serum samples will be screened for antibodies binding to 
sirukumab and the titer of confirmed positive samples will be reported. Other analyses may be 
performed to further characterize the immunogenicity of sirukumab.
9.4.
Biomarkers 
During the study, blood and saliva will be collected for the assessment of biomarkers at the time 
points indicated in the Time and Events schedule. The biomarker blood samples will be collected 
between 08:00 and 10:00 am as indicated in the T&E schedule. Subjects should be fasting for at 
least 8 hours prior to blood draw (if feasible). Subjects should also refrain from strenuous 
exercise in 24 hours before blood collection (if feasible). Subjects should not consume any food 
or drink other than water (including use of toothpaste or mouthwash) for at least 60 min prior to 
saliva collections (if feasible).  
In blood, biomarkers related to the immune system activity, HPA axis activation, neurotrophic 
factors and metabolic factors will be investigated to allow for exploratory immunophenotyping 
and for an exploratory pharmacodynamics evaluation. 
Biomarkers may be added or deleted based on scientific information or technical innovations 
under the condition that the total volume of blood collected will not increase. 
Date and time of blood and saliva collection should be recorded on the laboratory requisition 
form.
Further information regarding handling, shipment, and labeling of biological samples will be 
provided in a separate lab manual.
Subject data
To evaluate the biomarker results, the following information needs to be documented on each 
day of collection of blood samples for biomarker analysis.
•
Diet (extremes during the previous week)
•
In women of childbearing potential: average duration of menstrual cycle in days and last 
date of menses to determine follicular phase
•
Any sickness or allergy in the previous 2 weeks
The 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.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
70
Approved, Date: 22 January 2018
9.5.
Pharmacogenomic (DNA) Evaluations 
DNA samples will be collected at the time points indicated in the Time and Events Schedule for 
the assessment of genetic and epigenetic changes in genes known to be in pathways relevant to 
depression (HPA axis, inflammation, growth factors, monoamine transporters, ion channels, 
circadian rhythm).
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 sirukumab or MDD. They may also be used to 
develop tests/assays related to sirukumab and MDD. Pharmacogenomic research may consist of 
the analysis of one or more candidate genes or of the analysis of genetic markers throughout the 
genome or analysis of the entire genome (as appropriate) in relation to sirukumab or MDD 
clinical endpoints.
9.6.
Safety Evaluations
Details regarding the Data Monitoring Committee are provided in Section 11.11.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 11.12, Adverse Event Reporting.
Clinical Laboratory Tests 
Blood samples for hsCRP, serum chemistry, serology and hematology and a random urine 
sample for urinalysis will be collected. The investigator must review the laboratory report, 
document this review, and record any clinically relevant changes occurring during the study in 
the adverse event section of the CRF. 
The following tests will be performed by the central laboratory:

hsCRP

Hematology Panel 
-hemoglobin
-platelet count
-hematocrit
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
71
Approved, Date: 22 January 2018
-red blood cell (RBC) count
-white blood cell (WBC) count with differential

Serum Chemistry Panel 
-sodium
-alkaline phosphatase
-potassium
-calcium
-chloride
-phosphate
-bicarbonate
-albumin
-blood urea nitrogen (BUN)
-total protein
-creatinine
-glucose
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)
-total bilirubin, with fractionation if 
hyperbilirubinemia

Lipid Panel (fasting)
-
Total cholesterol
-
Low-density lipoprotein (LDL)
-
High-density lipoprotein (HDL)
-
Triglycerides

Urinalysis
Dipstick
[Sediment (if dipstick result is
-specific gravity
abnormal)]
-pH
-red blood cells
-glucose
-white blood cells
-protein
-epithelial cells
-blood
-crystals
-ketones
-casts
-bilirubin
-bacteria
-urobilinogen
-nitrite
-leukocyte esterase
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen will be 
determined using a dipstick. If dipstick result is abnormal, flow cytometry will be used to 
measure sediment. Red blood cells, white blood cells, epithelial cells, crystals, casts, and bacteria 
will be measured using flowcytometry. In case of discordance between the dipstick results and 
the flow cytometric results, the sediment will be examined microscopically.

Serum Pregnancy Testing for women of childbearing potential only

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
72
Approved, Date: 22 January 2018

Urine Drug 
Screen: opiates, 
cocaine, barbiturates, methadone, marijuana
and 
amphetamine/methamphetamine

thyroid-stimulating hormone (if applicable)

follicle-stimulating hormone  (if applicable)
Electrocardiogram (ECG)
During the collection of ECG, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital signs measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG, vital signs, blood draw.
Vital Signs (oral temperature, pulse/heart rate, blood pressure)
Blood pressure and pulse/heart rate measurements will be assessed after being in supine position 
for at least 5 minutes with a completely automated device. Manual techniques will be used only 
if an automated device is not available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of 
rest in a quiet setting without distractions (eg, television, cell phones).
Physical Examination 
The study investigator, or other authorized and appropriately qualified designee, will perform the 
physical examinations.
Height will be measured at screening only. Body weight will be measured as per the Time and 
Events Schedule.
Suicidal Risk
Subjects of all ages with major MDD or bipolar disorder may experience worsening of their 
depression, the emergence of suicidal ideation and behaviour (suicidality), and/or unusual 
changes in behaviour whether or not they are taking antidepressant medications, and this risk 
may persist until significant remission occurs. Certain subjects, such as those with a history of 
suicidal behaviour or thoughts, young adults, and those subjects exhibiting a significant degree 
of suicidal ideation before beginning treatment, may be at a greater risk of suicidal thoughts or 
suicide attempts during the course of a clinical trial.
All subjects being treated with sirukumab should be monitored appropriately and observed 
closely for clinical worsening, suicidality and unusual changes in behaviour, especially at the 
beginning and end of the course of treatment, or at the time of dose changes, either increases or 
decreases. The following symptoms have been reported in some subjects being treated with 
antidepressants for major depressive disorder as well as for other indications: anxiety, agitation, 
panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia 
(psychomotor restlessness), hypomania, and mania. Although a causal link between the 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
73
Approved, Date: 22 January 2018
emergence of such symptoms and either the worsening of depression and/or the emergence of 
suicidal impulses has not been established, there is concern that such symptoms may represent 
precursors to emerging suicidality.
A major depressive episode may be the initial presentation of bipolar disorder. It is generally 
believed (though not established in controlled trials) that treating such an episode with an 
antidepressant alone may increase the likelihood of precipitating a mixed/manic episode in 
subjects at risk for bipolar disorder. Whether any of the symptoms described above represent 
such a conversion is unknown. However, prior to initiating treatment with sirukumab, subjects
should be adequately screened to determine if they are at risk for bipolar disorder. Screening 
should include a detailed psychiatric history.
Consideration should be given to discontinuing sirukumab in subjects whose depression is 
persistently worse or who are experiencing emergent suicidality or symptoms that might be 
precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt 
in onset, or were not part of the subject’s presenting symptomatology.
Families and caregivers of subjects being treated with sirukumab should be alerted about the 
need to monitor subjects for the emergence of agitation, irritability, unusual changes in 
behaviour and the other symptoms described above, as well as the emergence of suicidality, and 
to report such symptoms immediately to the study investigator. Baseline assessment of 
suicidality and treatment emergent suicidality will be monitored during this trial using the         
C-SSRS.
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation. It can also be used 
during treatment to monitor for clinical worsening. C-SSRS will be administered each visit to 
monitor suicidal ideation and behavior. An example of the C-SSRS is provided in Attachment 5
and Attachment 6.
Allergic Reactions 
All subjects will be observed carefully for symptoms of allergic reactions for at least 30 minutes 
after the SC injection of study agent at the study site.  If mild or moderate allergic reaction is 
observed, acetaminophen 650 mg orally and diphenhydramine 25 mg orally or IV may be 
administered.  If the reaction is not severe, subsequent injections at the appropriate treatment 
intervals may be undertaken with caution. Subjects with severe reactions following an injection 
such as bronchospasm with wheezing and/or dyspnea requiring ventilatory support, or 
symptomatic hypotension with a decrease in systolic blood pressure greater than 40 mm Hg will 
not be permitted to receive any additional study agent injections. In the case of such reactions, 
appropriate medical treatment should be administered.
Injection Site Reactions
An injection site reaction is any unfavorable or unintended sign that occurs at the study agent 
injection site.  All subjects must be carefully observed for symptoms of an injection site reaction.  
Subjects will be observed for at least 30 minutes after the SC injection of study agent at the site 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
74
Approved, Date: 22 January 2018
for symptoms of an injection-site reaction. If an injection site reaction is observed, the subject 
should be treated at the investigator’s discretion. Any adverse reaction (eg, pain, erythema, 
and/or induration) should be noted on the AE page of the eCRF.
Early Detection of Active Tuberculosis
To aid in the early detection of TB reactivation or new TB infection during study participation, 
subjects must be evaluated for signs and symptoms of active TB at scheduled visits (refer to the 
Time and Events Schedule). The following series of questions is suggested for use during the 
evaluation:  

“Have you had a new cough of >14 days’ duration or a change in a chronic cough?”

“Have you had any of the following symptoms:  

Persistent fever?

Unintentional weight loss?

Night sweats?”

“Have you had close contact with an individual with active TB?”  (If there is uncertainty as 
to whether a contact should be considered “close,” a physician specializing in TB should be 
consulted.)
If the evaluation raises suspicion that a subject may have TB reactivation or new TB infection, 
study agent administration should be interrupted and an immediate and thorough investigation 
should be undertaken, including, where possible, consultation with a physician specializing in 
TB. 
Investigators should be aware that TB reactivation in immunocompromised subjects may present 
as disseminated disease or with extra pulmonary features. Subjects with evidence of active TB 
must immediately discontinue study agent and should be referred for appropriate treatment.
Subjects who experience close contact with an individual with active TB during the conduct of 
the study must have a repeat chest radiograph, a repeat QuantiFERON®-TB Gold test, a repeat 
tuberculin skin test in countries in which the QuantiFERON-TB Gold test is not 
approved/registered, and, if possible, referral to a physician specializing in TB to determine the 
subject’s risk of developing active TB and whether treatment for latent TB is warranted. Study 
agent 
administration 
should 
be 
interrupted 
during 
the 
investigation. 
A 
positive 
QuantiFERON-TB Gold (or tuberculin skin) test result should be considered detection of latent 
TB. If the result is indeterminate, the test should be repeated. If recommended, treatment for 
latent TB must be initiated prior to the administration of further study agent. Subjects who 
discontinue treatment for latent TB prematurely or who are noncompliant with therapy must 
immediately discontinue further administration of study agent and should return for all 
subsequent scheduled study visits.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
75
Approved, Date: 22 January 2018
Hepatobiliary Abnormalities
In the event of hepatobiliary abnormalities such as AST or ALT 3 times ULN, confirmatory 
testing should be repeated using a liver chemistry kit (a kit put together by the central laboratory, 
containing all necessary tubes to do the require testing) and clinical assessment for symptoms of 
hepatic dysfunction done as soon as possible. A liver chemistry kit will include the following 
tests: ALT, AST, alkaline phosphatase, total and direct bilirubin. If the hepatobiliary laboratory 
abnormality is confirmed, then a thorough evaluation should be performed, including the 
following, as appropriate: 

Medical and family history 

Review of medications, alcohol, and other substance use 

Physical examination (including vital signs, examination of liver and abdomen, other 
stigmata of hepatic disease) 

Abdominal ultrasound with consideration of further imaging (eg, CT, MRI, MRCP, ERCP, 
Doppler studies of hepatic vessels, etc, if indicated based on ultrasound findings or clinical 
situation) 

Laboratory evaluation using a hepatobiliary abnormalities kit: complete blood counts with 
eosinophil count, international normalized ratio (INR), viral hepatitis serology testing 
(anti-Hepatitis A virus (HAV) IgM, HBsAg, anti-HBs, anti-HB core total, anti-HB core 
IgM, anti-HCV, HCV RNA, anti-Hepatitis E virus IgM, Epstein-Barr virus IgM, and 
Cytomegalovirus IgM), total protein and globulins, antinuclear antibody, anti-smooth 
muscle antibody, iron markers (iron, TIBC, ferritin)
See Section 10.2 for specific instructions regarding discontinuation of treatment guidelines and 
evaluation of hepatobiliary abnormalities.
Consultation with a specialist may be warranted. Temporary or permanent discontinuation of 
study agent may be required.  
9.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the laboratory requisition 
form.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Collection, handling, storage, and shipment of samples must be under the specified, and where 
applicable, controlled temperature conditions as indicated in the laboratory manual and 
instructions will be provided in the laboratory manual.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
Subjects must remain in the study until the last visit of the safety follow-up phase to be 
considered as having completed participation in the study. Subjects who completed the double-
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
76
Approved, Date: 22 January 2018
blind phase, but did not complete the follow-up visits, will be considered completers for efficacy. 
Subjects who prematurely discontinue study treatment for any reason before completion of the 
double-blind phase will not be considered to have completed the study.
10.2.
Discontinuation of Study Treatment 
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study. 
A subject's study treatment should be discontinued if:

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment

The subject becomes pregnant

Anaphylactic reaction resulting in bronchospasm with wheezing, or dyspnea requiring 
ventilatory support, or symptomatic hypotension with a greater than 40 mm Hg decrease in 
systolic blood pressure that occurs following a study agent administration.

Reaction suggestive of serum sickness occurring 1 to 14 days after study agent injection.  
These may be manifested by symptoms of myalgias, arthralgias, fever, rash, pruritus, facial, 
hand, or lip edema, dysphagia, urticaria, sore throat, and/or headache.

Opportunistic infection, ie, an infection by an organism that usually causes disease only in a 
host whose resistance is lowered (eg, Pneumocystis jirovecii, coccidioidomycosis, 
Mycobacterium avium).

Tuberculosis (TB)
a.
Active TB
b.
Subject with latent TB who discontinues treatment for latent TB prematurely or is 
not compliant with treatment for latent TB

Malignancy, excluding nonmelanoma skin cancer.

Demyelination, either central or peripheral.

Two confirmed consecutive absolute neutrophil counts of < 0.5 x 103/µ (SI: < 0.5×109
cells/L).

Two confirmed consecutive platelet counts < 50,000/µL (SI:  < 50 x 109 cells/L). 

The initiation of protocol-prohibited medications (see Section 8).

Acute diverticulitis requiring antibiotic treatment 

Gastrointestinal perforation

Drug induced liver injury, including any one of the following (see Section 10.2):
a. ALT or AST ≥5 x ULN but <8 x ULN and cannot be monitored weekly for ≥2 weeks.
b. ALT or AST ≥8 x upper limit of normal (ULN)
c. ALT or AST ≥5 x ULN for 2 or more weeks
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
77
Approved, Date: 22 January 2018
d. ALT or AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN (>35% direct bilirubin) (or ALT 
or AST ≥3 x ULN and INR >1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug for 
that subject if ALT or AST ≥3 x ULN and total bilirubin ≥2 x ULN. Serum bilirubin 
fractionation should be performed if testing is available.  If testing is unavailable, record the 
presence of detectable urinary bilirubin on dipstick as indicative of direct bilirubin elevations and 
suggestive of liver injury.
e. ALT or AST ≥3 x ULN accompanied by clinical symptoms believed to be related to 
hepatitis or hypersensitivity such as new or worsening of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, or rash.
When any of the liver chemistry stopping criteria a-e is met, do the following:
-
Immediately withdraw study agent for that subject
-
Report the event to the Sponsor within 24 hours of learning its occurrence (see 
Section 12.4)
-
All events that meet criteria as described below, must also be reported as an SAE.  
o
ALT or AST ≥3 x ULN and total bilirubin ≥2 x ULN (> 35% direct bilirubin) or 
o
ALT or AST ≥3 x ULN and INR > 1.5 (INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants) 
-
Perform liver event follow up assessments, and monitor the subject until liver chemistries 
resolve, stabilize, or return to baseline values as described below. 
-
Do not restart study agent 
-
Make every reasonable attempt to have subjects meeting liver chemistry criteria a - e to 
return to clinic within 24 hours for repeat liver chemistries, liver event follow up 
assessments (see below), and close monitoring.  
-
A specialist in hepatology consultation should be considered.  
-
Make every reasonable attempt to monitor subjects twice weekly until liver chemistries 
(ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline 
values.  Criterion e subjects should be monitored as frequently as possible.
-
Make every attempt to carry out the liver event follow up assessments described below:
Viral hepatitis serology (anti-Hepatitis A virus (HAV) IgM, HBsAg, anti-HBs, anti-HB 
core total, anti-HB core IgM, anti-HCV, HCV RNA, anti-Hepatitis E virus IgM, Epstein-
Barr virus IgM and Cytomegalovirus IgM).    
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
78
Approved, Date: 22 January 2018
o
If HBsAg or anti-HB core IgM is positive, or if anti-HBc total is the only positive 
test, a specialist in hepatology consultation should be obtained. 
o
If HBsAg is positive, perform hepatitis delta antibody assay. NOTE: if hepatitis 
delta antibody assay cannot be performed, it can be replaced with a PCR of 
hepatitis 
D 
RNA 
virus 
–
as 
outlined 
in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/
-
Blood sample for PK analysis, obtained within 24 hours of last dose. Record the 
date/time of the PK blood sample draw on the laboratory requisition form and the 
date/time of the last dose of study agent prior to blood sample draw on the CRF. If the 
date or time of the last dose is unclear, provide the subject’s best approximation. If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. 
-
Serum creatine phosphokinase, lactate dehydrogenase, and albumin.
-
Fractionate bilirubin, if total bilirubin ≥2 x ULN
-
Obtain complete blood count with differential to assess eosinophilia
-
Record the appearance or worsening of clinical symptoms of hepatitis or hypersensitivity, 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia as relevant on the AE report form
-
Record use of concomitant medications, acetaminophen/paracetamol, herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form.
-
Record alcohol use
The following are required for subjects that meet criteria of ALT or AST ≥ 3 x ULN and 
bilirubin ≥ 2 x ULN (> 35% direct) but are optional for subjects with other abnormal 
hepatobiliary chemistries as appropriate:
-
Screen for other causes of liver disease:  Total protein and globulins, ANA, anti-smooth 
muscle antibodies (ASMA), iron, TIBC, ferritin, alpha-1 anti-trypsin level, Type 1 anti-
liver kidney microsomal antibodies, and quantitative total immunoglobulin G (IgG or 
gamma globulins.  Additional testing should be performed if the following conditions are 
met:
o
If alkaline phosphatase > ALT, anti-mitochondrial antibody (AMA) should be 
tested.  
o
If subject is < 50 years of age, ceruloplasmin should also be tested.  
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
79
Approved, Date: 22 January 2018
o
If subject is sick enough to require hospitalization and less than 50 years old, 
24 hour urine copper should be tested.   
o
Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week).
o
Consider serum ethanol as clinically appropriate.
-
Liver ultrasound with consideration of further imaging (e.g. CT, MRI, MRCP, ERCP, 
Doppler studies of hepatic vessels, etc., if indicated based on ultrasound findings or 
clinical situation)
Subjects should not receive study agent administrations during the course of a serious infection.  
Discontinuation of study agent administration must be strongly considered for subjects who 
develop a serious infection such as sepsis or meningoencephalitis, and also should be considered 
for subjects who have serious infections requiring hospitalization or IV antibiotic therapy.  
Discontinuation of study agent administration should also be considered for severe injection-site 
reactions. 
Subjects who discontinued study agent administration should continue participating in the study 
for safety follow-up.
If a subject discontinues study treatment before the end of the double-blind phase, end-of-
treatment and posttreatment assessments should be obtained and scheduled assessments should 
be continued.
10.2.1.
Interruption of Study Agent Administration 
Values for liver transaminase levels (AST, ALT), absolute neutrophil count (ANC), and platelet 
count that require study agent interruption and/or permanent discontinuation of study agent 
administration are listed below in Table 2.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
80
Approved, Date: 22 January 2018
Table 2:
Values for liver transaminase levels, absolute neutrophil count, and platelet count that require 
study agent interruption and/or permanent discontinuation of study agent administration
ALT or AST increased
ALT or AST
Action
≥ 3 times the upper limit normal 
(≥3x ULN) for laboratory 
reference range.
Interrupt study agent administration, assess for symptoms, and 
repeat ALT/AST test as soon as possible using a liver chemistry 
kit as described in Section  Error! Reference source not 
found. Safety Evaluations below Hepatobiliary abnormalities.*  
May resume study agent when < 3x ULN** 
Criteria for drug-induced liver 
injury (Section Error! Reference 
source not found.,) 
Permanent discontinuation of study agent
Low Absolute Neutrophil Count (ANC)
Neutrophil count
Action
0.5 to ≤ 1.0 x 103/µL 
(SI: 0.5 to ≤ 1.0 x 109 cells/L)
Interrupt study agent administration, repeat ANC test as soon as 
possible*
May resume study agent when > 1.0 x 103/µL**
< 0.5 x 103/µL 
(SI: < 0.5 x 109 cells/L)
Interrupt study agent administration, repeat ANC test as soon as 
possible*
If confirmed to be < 0.5 x 103/µL, discontinue study agent 
permanently (Section Error! Reference source not found.)
Low Platelet Count
Platelet count
Action
50,000 to ≤ 100,000/µL 
(SI: 50 to ≤100 x 109 cells/L)
Interrupt study agent administration, repeat platelet count test as 
soon as possible*
May resume study agent when platelet count >100,000/µL **
< 50,000/µL
(SI: < 50 x 109 cells/L)
Interrupt study agent administration, repeat platelet count test as 
soon as possible*
If confirmed to be < 50,000/µL, discontinue study agent 
permanently (Section Error! Reference source not found.)
* Retesting should be done by Central laboratory
** In case of more than 3 subsequent injections are missed, and the PI wishes to resume study agent, please 
contact the JRD responsible safety physician.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
81
Approved, Date: 22 January 2018
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study before the end of the double-blind treatment phase, end-of-
treatment assessments should be obtained.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.1.5, Long-
Term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention 
for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the SAP.
This study will use an adaptive design to assess for futility, optimize the final sample size and 
review the hsCRP eligibility criterion based on interim data when 40-50% of the planned number 
of subjects who are eligible to be included in the primary efficacy analysis complete the week 12 
assessment. Depending on the results of the interim analysis, the study may be stopped for 
futility or it may continue to enroll up to an appropriate sample size which is expected to be 
N=192, but may go up to N=228 if in the interim data suggests this is necessary.  The hsCRP 
eligibility and/or stratification criteria may also be amended following the interim analysis. 
Details will be provided in the interim SAP.
11.1.
Subject Information
Three analyses sets will be defined for efficacy analyses: the modified intent-to-treat 1 (mITT1), 
the modified intent-to-treat 2 (mITT2), and the modified intent-to-treat 3 (mITT3) analyses sets. 
The mITT1 analysis set is defined as all randomized subjects with hsCRP  ≥ 0.300 mg/dL at 
screening and baseline who receive at least 1 dose of study drug and have both the baseline and 
at least one postbaseline HDRS17 total score measured within the double-blind treatment period. 
The mITT2 analysis set is defined as all randomized subjects (regardless of screening hsCRP 
level) who receive at least 1 dose of study drug and have both the baseline and at least one 
postbaseline HDRS17 total score measured within the double blind treatment period. The mITT3 
analysis set is defined as all randomized subjects with hsCRP≥ 0.300 mg/dL at screening who 
receive at least 1 dose of study drug and have both the baseline and at least one postbaseline 
HDRS17 total score measured within the double blind treatment period.
All safety analyses will be performed based on the safety analysis set, which will include all 
randomized subjects who receive at least 1 dose of study drug.
11.2.
Sample Size Determination
The expected sample size of 142 subjects with hsCRP ≥ 0.300 mg/dL (SI 3.00 mg/L) was 
determined based on the assumption of an effect size of at least 0.5 for the HDRS17 (difference in 
mean change from baseline to week 12 endpoint between the sirukumab and placebo groups of 4 
with SD=8).  This is considered to be a clinically relevant difference in a population with 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
82
Approved, Date: 22 January 2018
suboptimal response to standard oral antidepressant therapy. Power is set at 90.0%, with a 
1-sided alpha of 0.125 and a 12-week drop-out rate of 25%. It was also assumed that 10% of the 
randomized subjects would be excluded from the primary efficacy analysis due to having 
hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) at screening but not baseline.  The number of treatment 
resistant subjects will be monitored on an on-going basis to ensure enough sample size for a 
secondary efficacy analysis in the TRD population. If an insufficient number of TRD subjects is 
being enrolled in the study, the sponsor will encourage the sites to enroll more TRD subjects. 
Note that the study is not statistically powered for comparing effect sizes between treatment 
groups in the TRD population. Sample size for subjects with hsCRP ≥0.300 mg/dL 
(SI 3.00 mg/L) may be increased up to 178 if the interim analysis results suggest so.
Sample size determination for the additional stratum (screening hsCRP < 0.300 mg/dL 
(SI 3.00 mg/L):
Assuming a difference for the mean change from baseline to the week 12 endpoint of 4 between 
the hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) stratum and the hsCRP < 0.300 mg/dL (SI 3.00 mg/L)
stratum, and a SD of 8, a 1-sided alpha of 0.125, and a week 12 drop-out rate of 25%, a sample 
size of 71 subjects in the active treatment group (142 total) in the hsCRP ≥0.300 mg/dL 
(SI 3.00 mg/L) stratum and 25 subjects in the active treatment group (50 total) in the 
hsCRP < 0.300 mg/dL (SI 3.00 mg/L) stratum would provide 75% power to detect a difference 
between the two strata.   
11.3.
Efficacy Analyses 
The primary efficacy analyses will be based on the mITT1 analysis set. The sirukumab treatment 
group will be compared with the placebo group using the primary efficacy endpoint, change 
from baseline in HDRS17 total score, with the comparison performed by means of a mixed-
effects model using repeated measures (MMRM), with time, treatment (placebo, sirukumab), 
country, hsCRP stratification levels and time-by-treatment interaction as factors, baseline 
HDRS17 total score as a continuous covariate, and a random subject effect. An unstructured 
variance-covariance matrix will be used. The comparison of sirukumab versus placebo will be 
performed using the appropriate contrast. Subgroup analysis will be carried out for the primary 
efficacy endpoint based on TRD versus non-TRD status. 
Analyses of secondary efficacy endpoints will be based on the mITT2 analysis set. The change 
from baseline to 12-week endpoint for the secondary continuous efficacy endpoints will be 
analyzed in the same way as for the HDRS17 total score. 
For change from baseline in HDRS17 total score, the hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) 
stratum will be compared to the hsCRP < 0.300 mg/dL (SI 3.00 mg/L) stratum, using MMRM, 
with time, hsCRP stratum (hsCRP ≥0.300 mg/dL (SI 3.00 mg/L), hsCRP < 0.300 mg/dL 
(SI 3.00 mg/L), treatment, country, and time-by-hsCRP stratum interaction as factors, baseline 
HDRS17 total score as a continuous covariate, and a random subject effect. An unstructured 
variance-covariance matrix will be used. The comparison of hsCRP ≥0.300 mg/dL 
(SI 3.00 mg/L) versus hsCRP < 0.300 mg/dL (SI 3.00 mg/L) will be performed using the 
appropriate contrast. 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
83
Approved, Date: 22 January 2018
In addition to evaluating hsCRP as a categorical variable (hsCRP<0.300mg/dL; hsCRP ≥0.300 
to <0.500 mg/dL; hsCRP ≥0.500 to <0.800 mg/dL and hsCRP ≥0.800 mg/dL), hsCRP will be 
analyzed as a continuous variable and correlated with the primary efficacy endpoint (change 
from baseline to Week 12 in HDRS17 total score) using Pearson and Spearman methods.  
Sensitivity analyses of the primary endpoint will also be performed; these will be detailed further 
in the SAP. These will include analysis based on the mITT3 analysis set (that is, the mITT1 
analysis set plus those subjects excluded for having a screening hsCRP ≥0.300 mg/dL
(SI 3.00 mg/L) but hsCRP <0.300 mg/dL (SI 3.00 mg/L) at baseline). These will also include an 
analysis of covariance (ANCOVA) model using the last observation carried forward (LOCF) 
imputation method, with factors for treatment, country, hsCRP stratification levels, and baseline 
HDRS17 total score as a covariate. Other sensitivity analyses may also be performed to 
investigate the robustness of treatment estimates to the observed pattern of, and/or reason for, 
early withdrawals.
Sensitivity analyses of the secondary endpoints will also be performed; these will be detailed 
further in the Statistical Analysis Plan. These will include analysis based on the mITT1 and 
mITT3.
Descriptive statistics for values and changes from baseline will be provided for all efficacy 
measures, including individual items for selected scales, subscales, and total score, at each time 
point of the double-blind treatment phase.
Details of the exploratory analyses will be provided in the SAP.
11.4.
Pharmacokinetic Analyses 
Serum sirukumab concentrations will be summarized over time. Descriptive statistics, including 
arithmetic mean, standard deviation (SD), median, interquartile range, minimum, and maximum 
will be calculated at each sampling time point. Monoaminergic antidepressants concentration 
data before and after sirukumab treatment, will also be summarized.
If feasible, a population PK analysis using nonlinear mixed effects modeling (NONMEM) may 
be conducted to characterize the disposition characteristics of sirukumab using the data in the 
current study or combined data with other studies. Details will be given in a population PK 
analysis plan, and results of the population PK analysis will be presented in a separate technical 
report.
Data will be listed for all subjects with available serum concentrations. 
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All subjects and samples excluded from the analysis will be 
clearly documented in the study report.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
84
Approved, Date: 22 January 2018
11.5.
Immunogenicity 
The incidence of antibodies to sirukumab will be summarized for all subjects who received at 
least 1 administration of sirukumab and have appropriate samples for detection of antibodies to 
sirukumab (ie, subjects with at least 1 sample obtained after sirukumab treatment).
11.6.
Pharmacokinetic/Pharmacodynamic Analyses 
If data permit, the relationships between serum sirukumab concentration and efficacy or 
pharmacodynamic measures may be analyzed graphically.
11.7.
Biomarker Analyses 
Changes in biomarkers over time will be summarized by treatment group. 
Associations between baseline levels and changes from baseline in selected biomarkers and 
clinical endpoints will be explored. 
Exploratory analyses may be performed for additional biomarkers.  Results may be presented in 
a separate Biomarkers report.
11.8.
Pharmacogenomic Analyses 
A composite genotype will be derived from the raw genotyping data for the analyzed genes, as 
appropriate. 
The relationship between genetic subgroups and sirukumab PK endpoints and/or selected 
biomarkers and/or clinical endpoints may be examined through descriptive statistics or 
graphically, and association tests may be performed.
Results of the pharmacogenomic analysis will be summarized in a separate Pharmacogenomics 
report.
11.9.
Safety Analyses
All safety analyses will be performed based on the safety analysis set, which will include all 
randomized subjects who receive at least 1 dose of study drug. 
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are adverse events with onset during the treatment phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
included in the analysis. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized by treatment group. In addition, 
comparisons between treatment groups will be provided if appropriate.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
85
Approved, Date: 22 January 2018
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed 
values and changes from baseline at each scheduled time point. Changes from baseline results]
will be presented in pre- versus posttreatment cross-tabulations (with classes for below, within, 
and above normal ranges). A listing of subjects with any laboratory results outside the reference 
ranges will be provided. A listing of subjects with any markedly abnormal laboratory results will 
also be provided.
Vital Signs
Vital signs will be summarized by vital signs parameters (temperature, pulse/heart rate and blood 
pressure (systolic and diastolic, supine). 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.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point. 
Physical examination findings will be summarized at each scheduled time point. 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.
C-SSRS
The suicidality data collected from the C-SSRS using aggregate endpoints of suicidal behavior 
and suicidal ideation separately will be summarized descriptively at each scheduled visit by 
treatment group. Further details will be presented in the SAP.
11.10. Interim Analysis
An interim analysis will be conducted to monitor safety data, assess futility, sample size re-
estimation, and hsCRP enrichment criteria.  The interim analysis is planned when 40-50% of the 
planned number of subjects who are eligible to be included in the primary efficacy analysis 
complete the week 12 assessment. Both Frequentist and Bayesian approaches will be applied for 
the interim analysis. An internal IAC will be employed to review the unblinded efficacy and 
safety data at the interim analysis and to provide recommendations about the futility, sample size 
re-estimation, and hsCRP enrichment criteria. Detailed approaches will be described in the 
interim SAP and the IAC charter. 
The interim analysis results will be used to assess the study for futility and as such the study may 
be terminated early if the probability of success of the study is calculated to be very low. In 
addition, based on the results of hsCRP-response relationship, the study may continue with the 
enriched population using a selected hsCRP level. The decision rule for futility at the interim 
analysis will be detailed in the interim SAP and the IAC charter.    
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
86
Approved, Date: 22 January 2018
In addition the sample size for the study may be increased up to N=228 if the interim data 
suggests this is necessary to ensure robust conclusions.   
The interim analysis will be conducted such that the ongoing study integrity is maintained. Only 
the independent statistician and programmer responsible for providing the interim analysis 
results will be unblinded to the individual treatment group assignments. Individual and interim 
analysis results will not be shared with investigators, subjects or the sponsor staff who are 
involved in the conduct of the study before the final database lock.
Statistical procedures to be used, data to be analyzed, analysis method, p value adjustment will 
be provided in the interim SAP.
11.11. Interim Analysis Committee
An internal IAC will be established to monitor data on an ongoing basis to ensure the continuing 
safety of the subjects enrolled in this study and to meet efficacy objectives. 
The IAC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. 
To protect the integrity of the clinical study the IAC members (medical and statistical experts) 
will not be study team personnel or otherwise directly involved in the study conduct, data 
management, or statistical analysis for the study. 
The objectives and scope of the IAC and the operational and logistical procedures to perform the 
IAC activities will be documented in the IAC charter prior to the review of any data by the IAC. 
Only blinded information, conclusions, or recommendations will be communicated by the IAC 
chairperson while the study is ongoing.
The committee will meet periodically to review interim safety data. At the time of interim 
analysis the IAC will meet once to review the unblinded efficacy and safety data to make 
recommendations regarding futility, sample size re-estimation, and the hsCRP enrichment 
criteria.  The details will be provided in a separate IAC charter.
11.12. First Database Lock for the Primary Efficacy Analyses
Analyses for primary efficacy will be done when all subjects have completed the 12-week 
double-blind period. Detailed statistical approaches are summarized below and will be described 
in more detail in the statistical analysis plan. The results will be used to assess the potential 
efficacy of sirukumab in the treatment of MDD and to make strategic internal decisions 
regarding the development of the compound. The results will not impact the further conduct of 
the trial. 
At the the first database lock for the primary efficacy analyses, randomization codes will be 
disclosed fully. Sponsor staff will be unblinded to the individual treatment group assignments, 
however primary efficacy analyses results will not be shared with investigators and subjects 
before the final database lock.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
87
Approved, Date: 22 January 2018
Unblinding after completion of the 12-week double-blind treatment phase will not impact the 
integrity of the study data, as only follow-up visits will be performed after the unblinding and 
those visits will not include the primary outcome measures of the study.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
88
Approved, Date: 22 January 2018

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For sirukumab, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
89
Approved, Date: 22 January 2018
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety). Serious adverse 
events, including those spontaneously reported to the investigator within 4 months after the last 
dose of study agent, must be reported using the Serious Adverse Event Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
90
Approved, Date: 22 January 2018
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory 
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR 
summary, unless otherwise specified. 
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
91
Approved, Date: 22 January 2018

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the subject for the duration of 
the treatment period.
The cause of death of a subject in a study within 4 months of the last dose of study drug, whether 
or not the event is expected or associated with the study drug, is considered a serious adverse 
event.
12.3.3.
Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to 
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the 
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious 
adverse events and must be reported using the Serious Adverse Event Form. Any subject who 
becomes pregnant during the study must discontinue further study treatment. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Adverse Events of Special Interest
All initial reports of newly identified malignancies, active TB, hepatobiliary abnormalities (as 
defined below), and gastrointestinal perforations must be reported to the Sponsor by the 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
92
Approved, Date: 22 January 2018
investigational staff within 24 hours of their knowledge of the event even if these events do not 
meet the definition of an SAE.  
Investigators are also advised that active TB is considered a reportable disease in most countries.
These events are to be considered serious only if they meet the definition of a SAE.
Hepatobiliary events:
All events that meet criteria described below must be reported as an SAE. 
•
ALT or AST ≥3 x ULN and bilirubin ≥2 x ULN (>35% direct) or 
•
ALT or AST ≥3 x ULN and INR >1.5 (INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants) 
The following conditions should be considered AEs of special interest and require expedited 
reporting:
a.
ALT or AST ≥8 x ULN
b.
ALT or AST ≥5 x ULN for 2 or more weeks
c.
ALT or AST ≥3 x ULN and total bilirubin ≥2 x ULN (> 35% direct bilirubin) (or ALT or 
AST ≥3 x ULN and INR >1.5, if INR measured; see above)
d.
ALT or AST ≥3 x ULN accompanied by clinical symptoms believed to be related to 
hepatitis or hypersensitivity such new or as worsening of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, or rash.
e.
ALT or AST ≥5 x ULN but <8 x ULN and cannot be monitored at least weekly for          
≥ 2 weeks.
12.5.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
93
Approved, Date: 22 January 2018
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug
The sirukumab drug product provided for this study is supplied in a 1 mL Pre-Filled Syringe 
(PFS) fitted with a passive safety needle guard (UltraSafe Passive™ Delivery System, Safety 
Syringes, Inc.) that is permanently assembled on the syringe. The sirukumab PFS is aseptically 
filled to 50 mg/1.0 mL of sirukumab in a Becton-Dickinson (BD) Hypak®, 1 mL glass SCF™ 
(presiliconized) syringe barrel with a 26 gauge (G) ½ inch fixed needle, an elastomeric needle 
shield, and a fluoropolymer coated elastomeric plunger stopper. The needle shield on the PFS 
(assembled into UltraSafe needle guard) is made with a derivative of natural rubber latex, which 
may cause allergic reactions in individuals. For a list of excipients, refer to the Investigator’s 
Brochure for sirukumab.
Placebo for sirukumab PFS provided for this study is supplied in a 1 mL PFS fitted with a 
passive safety needle guard (UltraSafe Passive™ Delivery System, Safety Syringes, Inc.) that is 
permanently assembled on the syringe. Placebo for sirukumab PFS is aseptically filled to 1.0 mL 
of placebo solution in a BD Hypak®, 1 mL glass SCF™ (presiliconized) syringe barrel with a 
26 gauge (G) ½ inch fixed needle, an elastomeric needle shield, and a fluoropolymer coated 
elastomeric plunger stopper. The needle shield on the PFS (assembled into UltraSafe needle 
guard) is made with a derivative of natural rubber latex, which may cause allergic reactions in 
individuals. For a list of excipients, refer to the Investigator’s Brochure for sirukumab.
14.2.
Packaging
The sirukumab PFS and placebo for sirukumab PFS will be supplied with a passive safety needle 
guard (UltraSafe Passive™ Delivery System, Safety Syringes, Inc.) that is permanently assembled 
on the syringe.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
94
Approved, Date: 22 January 2018
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All sirukumab and sirukumab placebo study agent presentations should be stored in a secured 
refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Sirukumab should not be frozen or shaken. During 
extended storage, protect from excessive exposure to light. Protection from light is not required 
during administration. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever solution and container permit. If visibly opaque particles, 
discoloration, or other foreign particles are observed, the solution should not be used.
Refer to the study site investigational product manual for additional guidance on study drug 
preparation, handling, administration and storage.
14.5.
Drug Accountability
The study agents are to be prescribed only by the principal investigator or a qualified physician 
listed as a sub-investigator on required forms (eg, FDA Form 1572).
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug, or used returned study drug for destruction, will be documented on the drug return form. 
When the study site is an authorized destruction unit and study drug supplies are destroyed on-
site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
95
Approved, Date: 22 January 2018
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure and any addenda

Site Investigational Product Binder

Central Laboratory Manual 

PRO Questionnaires 

IVRS/IWRS Manual 

Electronic Data Capture (eDC) Manual

Sample ICF
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Clinical Study in Treatment-Resistant Major Depression
Major depressive disorder is a common, severe, chronic and often life-threatening illness. It is 
now the leading cause of disability worldwide. There is a clear need to develop novel and 
improved therapeutics for major depression. Whilst at present the clinical efficacy of sirukumab 
as an adjunctive treatment for depression is unknown many studies suggest that a subgroup of 
subjects may be characterized by elevated levels of circulating IL-6. Moreover, these subjects 
may benefit relatively less from treatment with monoaminergic antidepressant drug therapy (see 
introduction). These subjects are hypothesized to have a higher chance to respond to active 
treatment. Sirukumab showed a beneficial effect on depressed mood in the phase 2 sirukumab 
RA studies and has been well tolerated and safe in these clinical studies.
Selection of Subjects
The primary aim of the study is to evaluate the efficacy of subcutaneously administered 
sirukumab for the treatment of MDD. Thus, the study cannot be completed in healthy subjects. 
Subjects selected in the study will have adequate capacity to give consent for participation in the 
study.
Justification for Using Placebo
Some have considered it unethical to do placebo-controlled studies in major depression due to 
the potential risk of irreversible harm (Rothman and Michels, 1994). In a meta-analysis (Khan et 
al., 2000) of drug studies conducted in major depression, it was reported that adult subjects did 
not have higher rates of suicide behaviors or attempts in the placebo group compared with those 
receiving an active antidepressant. These studies show annual suicide rates of 0.8% on the 
investigational drug, 0.7% on the active comparator, and 0.4% on placebo. The risk of 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
96
Approved, Date: 22 January 2018
irreversible harm is not higher in the placebo arm compared to the active control arms. Some 
subjects may decide not to participate due to the potential for increased distress and dysfunction 
due to prolonged depression. 
Therefore, the use of a placebo-controlled study remains the gold standard for assessment of 
efficacy of new compound to allow for scientifically meaningful results. Placebo-controlled 
studies in major depression have been argued to be ethically and scientifically justifiable 
(Adam et al., 2005; Temple et al., 2000).
In this study the subjects will continue existing and allowed anti-depressant medications. Not 
allowed antidepressant medication will not be discontinued for the sole purpose of entering the 
study; subjects will be carefully monitored for potential worsening of the depressive symptoms 
and suicidality and appropriate actions will be taken to ensure the safety of the subjects 
participating in the study. Clinical studies with similar study design show that both partial and 
non-responders had significant improvement, even in the placebo arm (Thase et al., 2008). All 
subjects will receive clinical care while in the trial.
Precautions to Ensure Subject Safety in the Study 
Subjects may participate in the study only if they have adequate capacity to give consent and 
after fully understanding the potential risks and giving an informed consent. Determination of 
capacity will be made by the study investigator. Subjects may withdraw from the study at any 
time. The probability of receiving placebo and the concept of random assignment will be 
explained to the subject. Potential disadvantages and adverse events of participating in the study 
and alternative treatment options will be discussed. 
The subjects will visit the study site monthly during the double-blind study period and their 
symptoms will be carefully monitored during each study visit. Safety evaluations will include 
evaluation of suicidal ideation/behavior at each clinic visit. At any point in the study the subject 
may withdraw consent or be removed from the study by the investigator if there are any clinical 
concerns. 
A prospective assessment of suicidal ideation and behavior, the CSSR-S, will be conducted by 
the investigator/subinvestigator at every study visit. Subjects with a current or recent (within the 
past year) history of clinically significant suicidal ideation (corresponding to a score of ≥ 3 for 
ideation) or any suicidal behavior within the past year, as validated on the C-SSRS at screening 
or baseline will be excluded. 
Subjects receiving sirukumab are more susceptible to infections. Therefore it will be thoroughly 
evaluated during screening that subjects currently do not have or recently have not had any 
severe or chronic or recurrent infections. In addition a week 14 follow-up visit will be done to 
monitor potential risks of infections occurring after discontinuation of the study agent.
Subjects receiving sirukumab might experience an increase in transaminase levels. Therefore 
subjects with serum ALT or AST >1.5 times the ULN at screening will be excluded. Specific 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
97
Approved, Date: 22 January 2018
stopping criteria in case of drug induced liver injury are described in detail in Section 10.2 to 
ensure proper guidance and follow-up for subjects. 
Compensation for any procedure will be fair per local standards and approved by the 
participating sites IEC/IRB in order to not offer any undue incentive to participate in the study.
Subjects who are unable to tolerate study drug during the double-blind treatment phase will be 
discontinued from the study. If the investigator judges it to be necessary to immediately stop 
study drug, he or she has the option to do so.
Only subjects who have not adequately responded to their antidepressant where a clinician would 
consider changing it for lack of response or poor tolerability in addition to meeting the severity 
criteria for the study will be enrolled.
Only highly qualified and experienced investigators will participate in the study.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The study medication, sirukumab, will not be available after the study, however, following 
completion of the double-blind treatment phase, subjects can be treated according to standard of 
care.
The total blood volume to be collected is approximately 350 mL and will not exceed 450 mL, 
which is considered to be acceptable in comparison to a Red Cross blood donation.
16.1.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.1.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
98
Approved, Date: 22 January 2018

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
99
Approved, Date: 22 January 2018

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.1.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access and agrees to allow his or her study 
physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
100
Approved, Date: 22 January 2018
16.1.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, pharmacodynamics, biomarker, PK and immunogenicity, research is not 
conducted under standards appropriate for the return of data to subjects. In addition, the sponsor 
cannot make decisions as to the significance of any findings resulting from exploratory research. 
Therefore, exploratory research data will not be returned to subjects or investigators, unless 
required by law or local regulations. Privacy and confidentiality of data generated in the future 
on stored samples will be protected by the same standards applicable to all other clinical data.
16.1.5.
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 sirukumab, to 
understand MDD, to understand differential drug responders, and to develop tests/assays related 
to sirukumab and MDD.  The research may begin at any time during the study or the post-study 
storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Study).
16.1.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
101
Approved, Date: 22 January 2018
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
102
Approved, Date: 22 January 2018

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
103
Approved, Date: 22 January 2018
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
Subject- and investigator-completed scales and assessments designated by the sponsor will be 
recorded and will be considered source data.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg questionnaires) will be completed by the same individual who 
made the initial baseline determinations whenever possible. The investigator must verify that all 
data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. 
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 3 
different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
104
Approved, Date: 22 January 2018

Clinical data manager can generate a query for resolution by the study-site personnel.
17.5.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review CRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
105
Approved, Date: 22 January 2018
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques 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 CRFs with the hospital or clinic records (source 
documents); 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 documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
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.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
106
Approved, Date: 22 January 2018
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding sirukumab 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 sirukumab, 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 CRF data from all study sites that participated in the study and direct transmission of 
clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomics or
exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
107
Approved, Date: 22 January 2018
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
108
Approved, Date: 22 January 2018
REFERENCES
1.
Adam D, Kasper S, Moller HJ, Singer EA. Placebo-controlled trials in major depression are necessary and 
ethically justifiable: how to improve the communication between researchers and ethical committees. Eur Arch 
PsychiatryClin Neurosci. 2005;255(4):258-260.
2.
Alesci S, Martinez PE, Kelkar S, et al. Major depression is associated with significant diurnal elevations in 
plasma interleukin-6 levels, a  shift of its circadian rhythm, and loss of physiological complexity in its 
secretion: clinical implications. J Clin Endocrinol Metab 2005; 90(5):2522-30.
3.
Al-Harbi KS.  Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient 
Preference and Adherence 2012:6 369–388.
4.
Bellingrath S, Rohleder N, Kudielka BM.  Effort-reward-imbalance in healthy teachers is associated with 
higher LPS-stimulated production and lower glucocorticoid sensitivity of interleukin-6 in vitro.  Biological 
Psychology 2013; 92:403-409.
5.
Bernstein DP, Fink L. Childhood Trauma Questionnaire: A retrospective self-report manual. San Antonio, TX: 
Harcourt Brace & Company; 1998.
6.
Dowlati Y, Hermann N, Swardfager W, et al.  A meta-analysis of cytokines in major depression.  Biol 
Psychiatry 2010; 67(5):446-457. 
7.
Dahl J, Omstad H,AaSS HC et al.,The plasma levels of various cytokines are increased during ongoing 
depression and are reduced to normal levels after recovery.Pstchneuroendochronology2014; 45:77-96.
8.
Guy W (ed) (1976) ECDEU Assessment manual for psychopharmacology (revised). National Institute of 
Mental Health, Psychopharmacology Research Branch, Rockville, MD
9.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960 Feb; 23: 56-62.
10.
Hiles SA, Baker AL, de MT, Attia J.  A meta-analysis of differences in IL-6 and Il-10 between people with and 
without depression:  exploring the causes of heterogeneity.  Brain, Behavior, and Immunity 2012; 26:1180-
1188.  
11.
Hodes GE, Pfau ML, Leboeuf M, et al.  Individual differences in the peripheral immune system promote 
resilience versus susceptibility to social stress. Proc Natl Acad Sci 2014; 111(45):16136-16141.
12.
Howren MB, Lamkin DM, Suls J.  Associations of depression with C-reactive protein, IL-1, and IL-6:  a meta-
analysis.  Psychosomatic medicine 2009; 71:171-186.
13.
Khan A, Warner HA, Brown WA, Symptom reduction and suicide risk in patients treated with placebo in 
antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry. 
2000 Apr;57(4):311-7
14.
Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB: Association of serum interleukin 6 and C-
reactive protein in childhood with depression and psychosis in young adult life: A population based 
longitudinal study. JAMA Psychiatry: 2014; doi 10.1001/jamapsychiatry.2014.1332.
15.
Knesevich JW, Biggs JT, Clayton PJ, Ziegler VE. Validity of Hamilton Rating-Scale for depression. Br J
Psychiatry 1977 Jul; 131: 49-52.
16.
Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in 
major depressive disorder. Neuropsychopharmacology 2000; 22(4):370-9.
17.
Lisi L, Camardese G, Treglia M et al, Monocytes from depressed patients display an altered pattern of 
response to endotoxin challenge.PLos One 3013;8(1):e52585
18.
Maes M, Song C, Lin AH, et al.  Negative immunoregulatory effects of antidepressants:  inhibition of 
interferon-gamma and stimulation of interleukin-10 secretion.  Neuropsychopharmacology 1999; 20(4):370-
379.
19.
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the 
pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
109
Approved, Date: 22 January 2018
20.
National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) 
Study. Available from: http://www. nimh.nih.gov/trials/practical/stard/index.shtml.
21.
Nelson JC, Thase ME, Bellocchio EE, et al. Efficacy of adjunctive aripiprazole in patients with major 
depressive disorder who showed minimal response to initial antidepressant therapy. Int Clin Psychopharmacol 
2012; 27(3):125-33.
22.
Nelson JC, Rahman Z, Laubmeier KK, et al.  Efficacy of adjunctive aripiprazole in patients with major 
depressive disorder whose symptoms worsened with antidepressant monotherapy.  CNS Spectrums 2014; 1-7.
23.
Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, Pollmächer T. Cytokine-associated 
emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001 May;58(5):445-52. PubMed 
PMID: 11343523.
24.
Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994 Aug 
11;331(6):394-8.
25.
Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C: The Inventory for Depressive
Symptomatology (IDS): preliminary findings. Psychiatry Res 1986; 18(1):65-87.
26.
Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH: The Inventory of Depressive Symptomatology 
(IDS): Psychometric properties. Psychol Med 1996; 26(3):477-486.
27.
Smolen.JS, Weinblatt ME,Shengs S et al, Sirukumab, a human anti-interleukin-6 monoclonal antibody: a 
randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid 
arthritis despite methotrexate therapy. Ann Bheum Dis.2014;73(9):1616-1625.
28.
R P Snaith, M Hamilton, S Morley, A Humayan, D Hargreaves and P Trigwell. A scale for the assessment of 
hedonic tone the Snaith-Hamilton Pleasure Scale. BJP 1995, 167:99-103.
29.
Spitzer, R.L, Kroenke, K, Williams, J.B, and Patient Health Questionnaire Primary Care Study Group. 
Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. JAMA. 1999; 282: 
1737–1744
30.
Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. 
Part 1: ethical and scientific issues. Ann Intern Med. 2000;133(6):455-463. 
31.
Thase ME1, Trivedi MH, Nelson JC, Fava M, Swanink R, Tran QV, Pikalov A, Yang H, Carlson BX, Marcus 
RN, Berman RM: Examining the efficacy of adjunctive aripiprazole in major depressive disorder: a pooled 
analysis of 2 studies. Prim Care Companion J Clin Psychiatry. 2008;10(6):440-7
32.
Trivedi MH, Rush AJ, Wisniewski SR, et al.  Evaluation of Outcomes With Citalopram for Depression Using
Measurement-Based Care in STAR*D: Implications for Clinical Practice. Am J Psychiatry 2006;163:28-40
33.
Webster, K., Odom, L., Peterman, A., Lent, L., & Cella, D. (1999).  The Functional Assessment of Chronic 
Illness Therapy (FACIT) measurement system: Validation of version 4 of the core questionnaire. Quality of 
Life Research, 8(7), 604.
34.
Webster, K., & Cella, D., & Yost, K. (2003). The functional assessment of chronic illness therapy (FACIT) 
measurement system: Properties, applications, and interpretation. Health and Quality of Life Outcomes, 1(79), 
1-7.
35.
Wium-Andersen MK, Orsted DD, Nielsen SF, Nordestgaard BG: Elevated C-reactive protein levels, 
psychological distress and depression in 73,131 individuals. JAMA Psychiatry 2013; 70: 176-84
36.
Woloshin.S, Schwartz. LM : Distribution of C-Reactive Protein Values in the United States . N Engl J Med 
2005; 352:1611-1613 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
110
Approved, Date: 22 January 2018
Attachment 1: QuantiFERON®-TB Gold Testing
The QuantiFERON-TB Gold test is one of the interferon-(IFN-) based blood assays for TB screening 
(Cellestis, 2009). It utilizes the recently identified M. tuberculosis-specific antigens ESAT-6 and CFP-10 
in the standard format, as well as TB7.7 (p4) in the In-Tube format, to detect in vitro cell-mediated 
immune responses in infected individuals. The QuantiFERON-TB Gold assay measures the amount of 
IFN-produced by sensitized T-cells when stimulated with the synthetic M. tuberculosis-specific 
antigens. In M. tuberculosis-infected persons, sensitized T lymphocytes will secrete IFN-in response to 
stimulation with the M. tuberculosis-specific antigens and, thus, the QuantiFERON-TB Gold test should 
be positive. Because the antigens used in the test are specific to M. tuberculosis and not found in BCG, 
the test is not confounded by BCG vaccination, unlike the tuberculin skin test. However, there is some 
cross-reactivity with the 3 Mycobacterium species, M. kansasii, M. marinum, and M. szulgai. Thus, a 
positive test could be the result of infection with one of these 3 species of Mycobacterium, in the absence 
of M. tuberculosis infection.
In a study of the QuantiFERON-TB Gold test (standard format) in subjects with active TB, sensitivity has 
been shown to be approximately 89% (Mori et al, 2004). Specificity of the test in healthy BCG-
vaccinated individuals has been demonstrated to be more than 98%. In contrast, the sensitivity and 
specificity of the tuberculin skin test was noted to be only about 66% and 35% in a study of Japanese 
patients with active TB and healthy BCG-vaccinated young adults, respectively. However, sensitivity and 
specificity of the tuberculin skin test depend on the population being studied, and the tuberculin skin test 
performs best in healthy young adults who have not been BCG-vaccinated.
Data from a limited number of published studies examining the performance of the QuantiFERON-TB 
Gold assay in immunosuppressed populations suggest that the sensitivity of the QuantiFERON-TB Gold 
test is better than the tuberculin skin test even in immunosuppressed patients (Ferrara et al, 2005; Kobashi 
et al, 2007; Matulis et al, 2008). The ability of IFN--based tests to detect latent infection has been more 
difficult to study due to the lack of a gold standard diagnostic test; however, several TB outbreak studies 
have demonstrated that the tests correlated better than the tuberculin skin test with the degree of exposure 
that contacts had to the index TB case (Brock et al, 2004; Ewer et al, 2003). In addition, TB contact 
tracing studies have shown that patients who had a positive QuantiFERON-TB Gold test result and were 
not treated for latent TB infection were much more likely to develop active TB during longitudinal 
follow-up than those who had a positive tuberculin skin test and a negative QuantiFERON-TB Gold test 
result (Higuchi et al, 2007; Diel et al, 2008).
Although the performance of the new IFN--based blood tests for active or latent M. tuberculosis
infection have not been well validated in the immunosuppressed population, experts believe these new 
tests will be at least as, if not more, sensitive, and definitely more specific, than the tuberculin skin test 
(Barnes, 2004; personal communication, April, 2008 TB Advisory Board).
Performing the QuantiFERON-TB Gold In Tube Test
The QuantiFERON-TB Gold test In-Tube format will be provided for this study.  The In-Tube format 
contains 1 additional M. tuberculosis-specific antigen, TB7.7 (p4), which is thought to increase the 
specificity of the test. 
To perform the test using the In-Tube format, blood is drawn through standard venipuncture into supplied 
tubes that already contain the M. tuberculosis-specific antigens.  Approximately 3 tubes will be needed 
per subject, each requiring 1 mL of blood.  One tube contains the M. tuberculosis-specific antigens, while 
the remaining tubes contain positive and negative control reagents.  Thorough mixing of the blood with 
the antigens is necessary prior to incubation.  The blood is then incubated for 16 to 24 hours at 37°C, after 
which tubes are centrifuged for approximately 15 minutes at 2000 to 3000g.  Following centrifugation, 
plasma is harvested from each tube, frozen, and shipped on dry ice to the central laboratory.  The central 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
111
Approved, Date: 22 January 2018
laboratory will perform an ELISA to quantify the amount of IFN-present in the plasma using 
spectrophotometry and computer software analysis.
The central laboratory will analyze and report results for each subject, and sites will be informed of the 
results.  Subjects who have an indeterminate result should have the test repeated.
Adherence to Local Guidelines
Local country guidelines for immunocompromised patients should be consulted for acceptable 
antituberculous treatment regimens for latent TB.  If no local country guidelines for immunocompromised 
patients exist, US guidelines must be followed.
In countries in which the QuantiFERON-TB Gold test is not considered approved/registered, a tuberculin 
skin test is additionally required.
References
Barnes PF.  Diagnosing latent tuberculosis infection:  Turning glitter to gold [editorial].  Amer J Respir Crit Care 
Med. 2004;170:5-6.
Brock I, Weldingh K, Lillebaek T, et al.  Comparison of tuberculin skin test and new specific blood test in 
tuberculosis contacts.  Am J Respir Crit Care Med. 2004;170:65-69.
Cellestis.  QuantiFERON-TB Gold clinicians guide and QuantiFERON-TB Gold In-Tube Method package insert.  
Downloaded from www.cellestis.com, February 2009.
Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A.  Predictive value of a whole blood IFN-
assay for the development of active tuberculosis disease after recent infection with mycobacterium tuberculosis.  
Am J Respir Crit Care Med. 2008;177:1164-1170.
Ewer K, Deeks J, Alvarez L, et al.  Comparison of T-cell-based assay with tuberculin skin test for diagnosis of 
Mycobacterium tuberculosis infection in a school tuberculosis outbreak.  Lancet. 2003;361:1168-73.
Ferrara G, Losi M, Meacci M, et al.  Routine hospital use of a new commercial whole blood interferon-assay for 
the diagnosis of tuberculosis infection.  Am J Respir Crit Care Med. 2005; 172:631-635.
Higuchi K, Nobuyuki H, Mori T, Sekiya Y.  Use of QuantiFERON-TB Gold to investigate tuberculosis contacts in a 
high school.  Respirology.  2007;12:88-92.
Kobashi Y, Mouri K, Obase Y, et al.  Clinical evaluation of QuantiFERON TB-2G test for immunocompromised 
patients.  Eur Respir J. 2007; 30:945-950.
Matulis G, Jüni P, Villiger PM, Gadola SD.  Detection of latent tuberculosis in immunosuppressed patients with 
autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon assay.  Ann 
Rheum Dis. 2008;67:84-90
Mori T, Sakatani M, Yamagishi F, et al.  Specific detection of tuberculosis infection:  An interferon--based assay 
using new antigens.  Am J Respir Crit Care Med. 2004;170:59-64.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
112
Approved, Date: 22 January 2018
Attachment 2: Tuberculin Skin Testing
Administering the Mantoux Tuberculin Skin Test
The Mantoux tuberculin skin test (CDC, 2000) is the standard method of identifying persons infected 
with Mycobacterium tuberculosis.  Multiple puncture tests (Tine and Heaf) should not be used to 
determine whether a person is infected because the amount of tuberculin injected intradermally cannot be 
precisely controlled.  Tuberculin skin testing is both safe and reliable throughout the course of pregnancy.  
The Mantoux tuberculin test is performed by placing an intradermal injection of 0.1 mL of tuberculin into 
the inner surface of the forearm.  The test must be performed with tuberculin that has at least the same 
strength as either 5 tuberculin units (TU) of standard purified protein derivative (PPD) S or 2 TU of PPD 
RT 23, Statens Seruminstitut, as recommended by the World Health Organization.  PPD strengths of 
1 TU or 250 TU are not acceptable (Menzies, 2000).  Using a disposable tuberculin syringe with the 
needle bevel facing upward, the injection should be made just beneath the surface of the skin.  This 
should produce a discrete, pale elevation of the skin (a wheal) 6 mm to 10 mm in diameter.  To prevent 
needle-stick injuries, needles should not be recapped, purposely bent or broken, removed from disposable 
syringes, or otherwise manipulated by hand.  After they are used, disposable needles and syringes should 
be placed in puncture-resistant containers for disposal.  Institutional guidelines regarding universal 
precautions for infection control (eg, the use of gloves) should be followed.  A trained health care worker, 
preferably the investigator, should read the reaction to the Mantoux test 48 to 72 hours after the injection.  
Subjects should never be allowed to read their own tuberculin skin test results.  If a subject fails to show 
up for the scheduled reading, a positive reaction may still be measurable up to 1 week after testing.  
However, if a subject who fails to return within 72 hours has a negative test, tuberculin testing should be 
repeated.  The area of induration (palpable raised hardened area) around the site of injection is the 
reaction to tuberculin.  For standardization, the diameter of the induration should be measured 
transversely (perpendicular) to the long axis of the forearm.  Erythema (redness) should not be measured.  
All reactions should be recorded in millimeters, even those classified as negative.
Interpreting the Tuberculin Skin Test Results
In the US and many other countries, the most conservative definition of positivity for the tuberculin skin 
test is reserved for immunocompromised patients, and this definition is to be applied in this study to 
maximize the likelihood of detecting latent TB, even though the subjects may not be 
immunocompromised at baseline. In the US and Canada, an induration of 5 mm or greater in response to 
the intradermal tuberculin skin test is considered to be a positive result and evidence for either latent or 
active TB. In countries outside the US and Canada, country-specific guidelines for immunocompromised 
patients should be consulted for the interpretation of tuberculin skin test results.  If no local country 
guidelines for immunocompromised patients exist, US guidelines must be followed.
Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised patients should be consulted for acceptable 
antituberculous treatment regimens for latent TB.  If no local country guidelines for immunocompromised 
patients exist, US guidelines must be followed.
References
Centers for Disease Control and Prevention.  Core curriculum on tuberculosis:  What the clinician should know 
(Fourth Edition).  Atlanta, GA:  Department of Health and Human Services; Centers for Disease Control and 
Prevention; National Center for HIV, STD, and TB Prevention; Division of Tuberculosis Elimination; 2000:25-86. 
Menzies RI.  Tuberculin skin testing.  In:  Reichman LB, Hershfield ES (eds). Tuberculosis, a comprehensive 
international approach.  2nd ed.  New York, NY:  Marcel Dekker, Inc; 2000:279-322.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
113
Approved, Date: 22 January 2018
Attachment 3: Representative Example of the Clinical Global Impression Questionnaire-Severity
(CGI-S) questions that will be used in this study
Severity of illness 
Considering your total clinical experience with this particular population, how mentally ill is the 
patient at this time? 
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
Reproduced from Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976. Rockville, MD, U.S. Department of Health, 
Education, and Welfare 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
114
Approved, Date: 22 January 2018
Attachment 4: Representative Example of the Massachusetts General Hospital – Antidepressant 
Treatment Response Questionnaire questions that will be used in this study
(Non-Geriatric Population: 18 to 64 years of age)(Global)
Note: The minimum therapeutic dose for each antidepressant treatment  in Section I is based on prescribing 
information, relevant literature, and consultation with expert clinicians.
Section I. Antidepressant Medications
Instructions:
1.
Please check (√) the names of any medications that the patient has taken since the beginning of THIS 
CURRENT EPISODE of depression.
2.
Please check (√) if the daily dosage of the medication was equal to or greater than the minimum therapeutic 
dose for at least 6 weeks. 
3.
Only for those taken at the minimum therapeutic dose for at least 6 weeks, indicate the amount (%) of 
improvement in depression that the patient reported when they felt it was working at its best.
4.
If the subject initially experienced an improvement of ≥50% and then lost that response 
(tolerance/bradyphylaxis), that medication will not be counted towards a failed antidepressant trial.
Tricyclic Antidepressants
Generic Name
Taken during 
THIS current 
episode of 
depression(√)
Took at least this dose*
for at least 6 weeks? 
(√)
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks:
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best.
A.
75% to 100%
B.
50% to <75%
C.
26% to  <50%
D.
≤ 25%
doxepin
150mg/d           
clomipramine
150mg/d         
amoxapine
150mg/d          
amitriptyline   
150mg/d        
maprotiline  
150mg/d          
desipramine 
150mg/d          
nortriptyline     
75 mg/d            
doxepin    
150mg/d          
trimipramine    
150mg/d          
imipramine
150mg/d               
protriptyline      
30mg/d                  
pipofezine  
150mg/d            
noxiptiline  
100mg/d               
* If the dose is below the minimum dose required, a blood level that is within the therapeutic 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
115
Approved, Date: 22 January 2018
(antidepressant) range is also acceptable.
Monoamine Oxidase Inhibitors (MAOIs)
Generic Name
Taken during 
THIS current 
episode? (√)
Took at least this dose for at 
least 6 weeks? (√)
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks:
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best.
A.
75% to 100%
B.
50% to <75%
C.
26% to  <50%
D.
≤ 25%
isocarboxazid
30mg/d               
phenelzine      
45mg/d               
tranylcypromine 
30mg/d                 
selegiline patch 
6 mg/24 hrs
moclobemide
300 mg/d
pirlindole
200 mg/d
Selective Serotonin Reuptake Inhibitors (SSRIs)
Generic Name
Taken during 
THIS current 
episode? (√) 
Took at least this dose
at least 6 weeks? (√)
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks:
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best.
A.
75% to 100%
B.
50% to <75%
C.
26% to  <50%
D.
≤ 25%
fluvoxamine       
50mg/d           
paroxetine      
20/25mg/d        
fluoxetine    
20 mg/d           
sertraline      
50 mg/d           
citalopram          
20mg/d           
escitalopram          
10 mg/d           
vilazodone  
40 mg/d        
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
116
Approved, Date: 22 January 2018
vortioxetine  
10 mg/d        
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Generic Name
Taken during 
THIS current 
episode? (√)
Took at least this dose for at least 
6 weeks? (√)
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks:
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best.
A.
75% to 100%
B.
50% to <75%
C.
26% to  <50%
D.
≤ 25%
venlafaxine / 
venlafaxine XR        
150 mg/d         
duloxetine           
60mg/d         
desvenlafaxine       
50mg/d         
milnacipran          
100mg/d         
levomilnacipran     
40mg/d         
Other Antidepressants
Generic Name
Taken during 
THIS current 
episode? (√)
Took at least this dose for at 
least 6 weeks? (√)
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks:
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best.
A.
75% to 100%
B.
50% to <75%
C.
26% to  <50%
D.
≤25%
trazodone      
300mg/d         
bupropion    
300mg/d         
mirtazapine       
15 mg/d        
mianserin          
30 mg/d        
opipramol
150 mg/d
netazadone
300 mg/d
agomelatine
25 mg/d
tianeptine
37.5 mg/d
reboxetine
4 mg/d
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
117
Approved, Date: 22 January 2018
Section II. FDA-Approved Medications added to Augment /Boost Antidepressant Effect
Instructions:
1.
Please check (√) the names of any medication you have taken to augment or boost the antidepressant effect during 
THIS CURRENT EPISODE of depression.
2.
Please check (√) if the subject took at least this dose for at least 6 weeks in combination with an antidepressant treatment from 
Section I.
3.
Please indicate the name of antidepressant treatment from Section I this drug was taken with to augment /boost its antidepressant 
effect.
4.
Please indicate the amount (%) of improvement in depression that the patient reported when they felt this 
combination was working at its best.
Generic Name
Taken during 
THIS current 
episode? (√)
Took at least this 
dose for at least 6 
weeks in 
combination with 
an antidepressant 
treatment from 
Section I**?
(√)
Name of 
Antidepressant 
Treatment from 
Section I (see above) 
this drug was taken 
with
Only for those taken at 
minimum therapeutic dose 
for at least 6 weeks:
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression 
he/she reported when they 
feel the combination was 
working at its best.
A.
75% to 100%
B.
50% to <75%
C.
26% to  <50%
D.
≤ 25%
Aripiprazole
5 mg/d
Quetiapine
200 
mg/d
**The antidepressant treatment from Section I must also have been taken at the minimum therapeutic dose during 
the 6 weeks that the medication was taken to augment/boost antidepressant effect.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
118
Approved, Date: 22 January 2018
Attachment 5: Representative Example of the Columbia Suicide Severity Rating Scale – Baseline
questions that will be used in this study
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
119
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
120
Approved, Date: 22 January 2018
Attachment 6: Representative Example of the Columbia Suicide Severity Rating Scale (Since Last 
Visit) questions that will be used in this study
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
121
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
122
Approved, Date: 22 January 2018
Attachment 7: Representative Example of the 17-Item Hamilton Depression Rating Scale (HDRS17) 
questions that will be used in this study
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
123
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
124
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
125
Approved, Date: 22 January 2018
Attachment 8: Representative Example of the Inventory of Depressive Symptomatology -
Clinician (IDS-C30) questions that will be used in this study
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
126
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
127
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
128
Approved, Date: 22 January 2018
Attachment 9: Representative Example of the Patient Health Questionnaire questions that will be 
used in this study 
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
129
Approved, Date: 22 January 2018
Attachment 10: Representative Example of the Snaith Hamilton Pleasure Scale questions that will 
be used in this study
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
130
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
131
Approved, Date: 22 January 2018
Attachment 11: Representative Example of the Functional Assessment of Chronic Illness Therapy-
Fatigue questionnaire questions that will be used in this study
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
132
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
133
Approved, Date: 22 January 2018
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
134
Approved, Date: 22 January 2018
Attachment 12: Representative Example of the Childhood Trauma Questionnaire questions that 
will be used in this study
Instructions: These questions ask about some of your experiences growing up as a child and a 
teenager. For each question, circle the number that best describes how you feel. Although some 
of these questions are of a personal nature, please try to answer as honestly as you can. Your 
answers will be kept confidential.
When I was growing up,…
Never True
Rarely True
Sometimes True
Often True
Very Often True
1. I didn’t have enough to eat.
1
2
3
4
5
2. I knew there was someone to take care of me and protect me.
1
2
3
4
5
3. People in my family called me things like “stupid”, “lazy”, or “ugly”.
1
2
3
4
5
4. My parents were too drunk or too high to take care of me.
1
2
3
4
5
5. There was someone in my family who helped me feel important or special.
1
2
3
4
5
6. I had to wear dirty clothes.
1
2
3
4
5
7. I felt loved.
1
2
3
4
5
8. I thought that my parents wished I had never been born.
1
2
3
4
5
9. I got hit so hard by someone in my family that I had to see a doctor or go to the 
hospital.
1
2
3
4
5
10. There was nothing I wanted to change about my family.
1
2
3
4
5
11. People in my family hit me so hard that it left bruises or marks.
1
2
3
4
5
12. I was punished with a belt, a board, a cord, or some hard object.
1
2
3
4
5
13. People in my family looked out for each other.
1
2
3
4
5
14. People in my family said hurtful or insulting things to me.
1
2
3
4
5
15. I believe that I was physically abused.
1
2
3
4
5
16. I had the perfect childhood.
1
2
3
4
5
17. I got hit or beaten so badly that it was noticed by someone like a teacher, a 
neighbour, or doctor.
1
2
3
4
5
18. I felt that someone in my family hated me.
1
2
3
4
5
19. People in my family felt close to each other.
1
2
3
4
5
20. Someone tried to touch me in a sexual way, or tried to make me touch them.
1
2
3
4
5
21. Someone threatened to hurt me or tell lies about me unless I did something 
sexual with them.
1
2
3
4
5
22. I had the best family in the world.
1
2
3
4
5
23. Someone tried to make me do sexual things or make me watch sexual things.
1
2
3
4
5
24. Someone molested me.
1
2
3
4
5
25. I believe that I was emotionally abused.
1
2
3
4
5
26. There was someone to take me to the doctor if needed.
1
2
3
4
5
27. I believe that I was sexually abused.
1
2
3
4
5
28. My family was a source of strength and support
1
2
3
4
5
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
135
Approved, Date: 22 January 2018
Attachment 13:
Instructions for the Completion of the Patient-Reported Outcome (PRO) 
Case Report Forms
The following instructions are intended to assist investigators, study coordinators, and those with 
monitoring responsibilities with the completion of all patient self-administered (PRO) assessments.  
I.  General Instructions
1.
Patients should complete the patient-reported outcome (PRO) assessments in a quiet, semi-private 
location with access to study staff for questions.  
2.
Patients should be allowed approximately 30 minutes to orient him/herself and to self-administer all 
PRO assessments.
3.
Patients should be literate in the language of the PRO assessment(s).  Patients must not have any 
developmental, learning, or behavioral disabilities.  
4.
Patients should complete all PRO assessments using a black ballpoint pen.  Have the patient press 
firmly and print legibly when writing to ensure that all copies are clear and legible.  Have the patient 
place a piece of cardboard between the pages to ensure no ‘run through’ pages. 
5.
Explain to patients the reasons why they are being asked to complete the PRO assessment(s), i.e., 
they are part of the overall medical assessment and are designed to find out more information about 
how having their disease has affected their life. 
6.
Indicate to patients that all of the information on the PRO assessment(s) is confidential, and that 
someone from the study staff will only check for completeness and not share the results with other 
clinical staff.
7.
Indicate to patients that there are no right or wrong answers. 
8.
Provide patients with the set of instructions that are provided with the PRO assessment(s) materials.  
Have patients read the instructions prior to completing the assessment(s).  For almost all items, it is 
necessary for patients to check the box next to the answer that applies.  Occasionally, patients will be 
asked to write in some additional information.  Not all of the questions apply to every patient.  Where 
a particular question or set of questions does not apply, there will be instructions on which question to 
answer next. 
II. 
Assessment Times
1.
Each PRO assessment asks the patient for an evaluation of a specified period of time.  Therefore, it is 
important to minimize the influence of feedback from the clinic visit itself.  Insofar as it is possible, it 
is also important to have the PRO assessment(s) be conducted within the flow of the study visit.
2.
The PRO instruments have been placed in the correct order of completion in the study CRF.  Please 
ask the subject to complete the PROs in the sequence that they appear in the booklet.
Day -28 to -1 - Screening:
PRO assessment(s) during this time period should be completed immediately after the patient provides 
his/her informed consent, but before any clinical tests are taken or assessments associated with the study 
visit are conducted.  
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
136
Approved, Date: 22 January 2018
All other days:
PRO assessment(s) during this/these time period(s) should be completed before any clinical tests are 
taken or assessments associated with the study visit are conducted.
III. Quality Control
1.
Complete the ‘Subject Number,’ ‘date of birth,’ ‘Visit’ number, and ‘Visit Date’ at the bottom of 
every PRO assessment page.  
2.
Before the patient leaves following the study visit, check for any questions that might have been left 
blank.  If an item has been omitted, point this out and ask whether the item was left blank 
intentionally, and that these items be completed if appropriate.  Occasionally, patients mark more than 
one answer per item.  In such instances, ask the patient if he/she will reconsider the question and try 
to choose one answer only.
IV. Special Issues
1.
Patients should be instructed to complete the PRO assessment(s) without help from anyone, and 
relatives or caregivers should not be with the subject when the PROs are completed.  However, if a 
patient cannot read the PRO assessment(s) or complete it/them independently, then a designated 
person can read the items and response choices aloud and mark the appropriate response choices as 
verbally stated by the patient.  The designated person should read each question in its entirety in a 
neutral voice, avoiding any cues, even if interrupted by the patient with an answer.  The designated 
person should repeat each of the patient’s answers, e.g., “A little bit.”  The patient should not be 
prompted by the designated person in any other way.  No help should be offered to the patient in 
interpreting the questionnaire. 
2.
If a person is designated to assist the patient with the PRO assessment(s), this person should remain 
consistent across assessment instruments and across assessment periods.    
3.
If a designated person assists the patient with the PRO assessment(s), this should be noted in 
the footer section on the first page of each PRO assessment instrument.
NCT02473289


CNTO136 sirukumab
Amendment INT-5 CNTO136MDD2001
137
Approved, Date: 22 January 2018
INVESTIGATOR AGREEMENT
LAST PAGE
NCT02473289

SAP_001.pdf: 
1
Statistical Analysis Plan
A Double-Blind, Placebo-Controlled, Multicenter Study of Sirukumab as 
AdjunctiveTreatment to a MonoAminergic antidepressant in Adults with Major 
Depressive Disorder
Protocol CNTO136MDD2001; Phase 2a
CNTO136 (Sirukumab)
Final
Issue/Report Date:
Document No.:
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP).
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02473289
03 Dec 2018


CNTO136: Statistical Analysis Plan CNTO136MDD2001
2
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................2
ABBREVIATIONS.........................................................................................................................................4
1.
INTRODUCTION..................................................................................................................................6
1.1.
TRIAL OBJECTIVES ...........................................................................................................................6
1.2.
TRIAL DESIGN ....................................................................................................................................7
1.3.
STATISTICAL HYPOTHESIS FOR TRIAL OBJECTIVE(S) ...............................................................7
1.4.
SAMPLE SIZE JUSTIFICATION .........................................................................................................7
1.5.
RANDOMIZATION AND BLINDING....................................................................................................8
2.
GENERAL ANALYSIS DEFINITIONS.................................................................................................8
2.1.
TREATMENT GROUPS.......................................................................................................................8
2.2.
POOLING ALGORITHM ......................................................................................................................8
2.3.
ANALYSIS PHASES............................................................................................................................8
2.3.1.
Analysis Phase Start and End Dates ...............................................................................................9
2.3.2.
Study Reference Start and End Dates .............................................................................................9
2.3.3.
Study Day and Relative Days...........................................................................................................9
2.4.
VISIT WINDOWS ...............................................................................................................................10
2.5.
ANALYSIS SETS...............................................................................................................................11
2.5.1.
All Randomized Analysis Set..........................................................................................................11
2.5.2.
Efficacy Analysis Sets ....................................................................................................................12
2.5.3.
Biomarker Analysis Set ..................................................................................................................12
2.5.4.
Pharmacokinetic and Immunogenicity Analyses Sets....................................................................12
2.5.5.
Safety Analysis Set.........................................................................................................................12
2.6.
DEFINITION OF SUBGROUPS.........................................................................................................13
2.7.
INCOMPLETE/MISSING DATES FOR ADVERSE EVENTS............................................................13
3.
SUBJECT INFORMATION ................................................................................................................14
3.1.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS..............................................................14
3.2.
DISPOSITION INFORMATION..........................................................................................................15
3.3.
EXTENT OF EXPOSURE ..................................................................................................................15
3.4.
PROTOCOL DEVIATIONS ................................................................................................................15
3.5.
PRIOR AND CONCOMITANT MEDICATIONS.................................................................................15
4.
EFFICACY..........................................................................................................................................16
4.1.
ANALYSIS SPECIFICATIONS ..........................................................................................................16
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
3
4.1.1.
Level of Significance.......................................................................................................................16
4.1.2.
Data Handling Rules.......................................................................................................................16
4.1.3.
Imputation Methods for Missing Items............................................................................................16
4.2.
PRIMARY EFFICACY ENDPOINT ....................................................................................................17
4.2.1.
Definition.........................................................................................................................................17
4.2.2.
Analysis Methods ...........................................................................................................................17
4.2.3.
HDRS17 Total Score........................................................................................................................18
4.2.4.
Responders and Remitters.............................................................................................................18
4.2.5.
Clinical Global Impression-Severity Scale (CGI-S) ........................................................................18
4.2.6.
Patient Health Questionnaire (PHQ-9) ...........................................................................................19
4.2.7.
Snaith–Hamilton Pleasure Scale (SHAPS) ....................................................................................19
4.2.8.
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT Fatigue) ...............................20
4.3.
EXPLORATORY EFFICACY ENDPOINT .........................................................................................20
4.3.1.
Inventory of Depressive Symptomatology – Clinician Rated 30 (IDS-C30) ...................................20
4.3.2.
Childhood Trauma Questionnaire (CTQ) .......................................................................................20
4.3.3.
MINI International Neuropsychiatric Inventory (MINI) ....................................................................21
5.
BIOMARKERS...................................................................................................................................21
5.1.
BIOMARKER VARIABLES ...............................................................................................................21
5.2.
ANALYSIS METHODS ......................................................................................................................21
5.2.1.
hsCRP as a predictor of response .................................................................................................21
5.2.2.
Alternate predictors of response ....................................................................................................22
6.
PHARMACOKINETICS AND IMMUNOGENICITY ...........................................................................23
6.1.
PHARMACOKINETIC ANALYSES ...................................................................................................23
6.2.
IMMUNOGENICITY ANALYSES.......................................................................................................23
7.
SAFETY .............................................................................................................................................24
7.1.
ADVERSE EVENTS...........................................................................................................................24
7.2.
CLINICAL LABORATORY TESTS....................................................................................................25
7.3.
VITAL SIGNS, WEIGHT AND BMI....................................................................................................25
7.4.
OTHER SAFETY PARAMETERS .....................................................................................................25
7.4.1.
Columbia Suicide Severity Rating Scale........................................................................................25
8.
REFERENCES...................................................................................................................................29
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
4
LIST OF IN-TEXT TABLES
Table 1:
Analysis Visit Windows..............................................................................................................11
Table 2:
Demographic Variables and Baseline Characteristics ..............................................................14
Table 3:
Psychiatric History at Baseline Variables..................................................................................15
Table 4:
Efficacy Variables......................................................................................................................16
Table 5:
Treatment-Emergent Abnormality Categories for Vital Signs ...................................................25
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
5
ABBREVIATIONS 
AE
adverse event
BMI
body mass index
CI
CGI-S
confidence interval
Clinical Global Impression - Severity
CNS
central nervous system
C-SSRS
CTQ
Columbia-Suicide Severity Rating Scale
Childhood Trauma Questionnaire 
DB
double-blind
DRC
Data Review Committee
ECG
electrocardiogram
eCRF
electronic case report form
EOT
FACIT Fatigue
end of trial
functional assessment of chronic illness therapy-fatigue
FDA
FU
HDRS17
Food and Drug Administration
Follow-up
Hamilton Depression Rating Scale
hsCR
ICH
IDS-C30
high sensitivity C-Reactive Protein
International Conference on Harmonization
Inventory of Depressive Symptomatology – Clinician Rated 30 Item Scale
ITT
LOCF
LR
Intent-to-treat
last observation carried forward
likelihood ratio
MedDRA
Medical Dictionary for Regulatory Activities
MDD
Major Depressive Disorder
MMRM
mixed-effects model using repeated measures
PHQ-9
SAE
patient health questionnaire
serious adverse event
SAP
Statistical Analysis Plan
SD
SHAPS
standard deviation
Snaith–Hamilton pleasure scale
SOC
System Organ Class
TEMA
TRD
treatment-emergent markedly abnormal
treatment resistant depression
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
6
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, 
and statistical methods for the study CNTO136MDD2001.
1.1.
Trial Objectives
Primary Objective
To evaluate the efficacy of sirukumab as adjunctive treatment to antidepressant therapy 
(monoaminergic antidepressant) where sirukumab (administered as a 50mg subcutaneous 
(SC) injection at Day 1, Day 28 and Day 56 during the 12-week double-blind treatment 
period) is compared to adjunctive placebo based on the change from baseline to 12-week 
endpoint in depressive symptoms as measured by the total score on the Hamilton 
Depression Rating Scale (HDRS17), in subjects diagnosed with Major Depressive Disorder 
(MDD) who have had a suboptimal response to the current standard oral antidepressant 
therapy and have a screening high sensitivity C-Reactive Protein (hsCRP) ≥0.300 mg/dL 
(International System of Units (SI) 3.00 mg/L).
Secondary Objectives
The secondary objectives are to include the evaluation of the impact of treatment with 
adjunctive sirukumab compared to adjunctive placebo, on: (1) overall safety and 
tolerability (2) anhedonia (as measured by the change in the Snaith Hamilton Pleasure 
Scale [SHAPS] from baseline to week 12) (3) global severity of symptoms of MDD (as 
measured by the change in the Clinical Global Impression - Severity [CGI-S] scale from 
baseline to Week 12) (4) remission (HDRS17 total score ≤7) and response rates (≥ 50% 
improvement in HDRS17 total score from baseline) at 12-week end point (5) subject-
reported severity of symptoms of MDD ( as measured by the change in the Patient Health 
Questionnaire [PHQ-9] from baseline to  Week 1 and to Week 12) (6) fatigue (as measured 
by the change in the Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT 
Fatigue] scale from baseline to Weeks 1, 4, 8 and 12) and (7) to evaluate the efficacy 
measured by change in the HDRS17 scores following adjunctive sirukumab compared to 
adjunctive placebo in the Treatment Resistant Depression (TRD) versus non-TRD subjects.
(8) Evaluate pharmacokinetics and immunogenicity of sirukumab in subjects with MDD. 
(9) Evaluate the impact of treatment with adjunctive sirukumab in subjects with screening 
hsCRP≥3.00 mg/L and in those with screening hsCRP<3.00 mg/L based on changes from 
baseline to Week 12 in HDRS17 total score. (10) Assess the efficacy of sirukumab 
compared to placebo as adjunctive therapy to an antidepressant in subjects with MDD with 
screening hsCRP levels <0.300 mg/dL versus those with screening hsCRP levels ≥ 0.300 
mg/dL in improving response of depressive symptoms, defined as the proportion of 
subjects having a ≥50% improvement in HDRS17 total score from baseline to the end of 
Week 12. (11) Assess the efficacy of sirukumab compared to placebo as adjunctive therapy 
to an antidepressant in subjects with MDD with screening hsCRP levels <0.300 mg/dL 
versus those with screening hsCRP levels ≥ 0.300 mg/dL in achieving remission of 
depressive symptoms, defined as the proportion of subjects having a HDRS17 total score ≤7 
at the end of Week 12. (12) Evaluate whether hsCRP levels correlate with clinical efficacy 
as measured by the change from baseline to Week 12 in HDRS17 total score.  
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
7
Exploratory Objectives
(1) To explore the efficacy of adjunctive sirukumab compared to adjunctive placebo, based 
on the change from baseline to 12-week endpoint in the Inventory of Depressive 
Symptomatology – Clinician Rated 30 Item Scale (IDS-C30). (2) To explore immune-
system related biomarkers (hsCRP, cytokines, chemokines), as well as other mood disorder 
related biomarkers (growth factors, hypothalamic–pituitary–adrenal (HPA) axis markers, 
metabolic markers) and to explore the potential correlation between these biomarkers and 
the clinical response, non-response or safety parameters of sirukumab. (3) To explore 
genetic and epigenetic variation that may be related to clinical response, non-response, or 
safety parameters of sirukumab (4) To explore the effect of sirukumab on the 
pharmacokinetics of monoaminergic antidepressants. (5) To explore the relationship 
between the severity of childhood trauma as assessed through the Childhood Trauma 
Questionnaire and the change in HDRS17 scores following adjunctive sirukumab or 
placebo.
1.2.
Trial Design
This is a multicenter, double-blind, placebo-controlled study in male and female subjects, 
21 to 64 years of age inclusive, with major depressive disorder (MDD) who have had a 
suboptimal response to standard oral antidepressant therapy; have failed no more than 3 
antidepressant treatments in the current major depressive episode. 
The study will consist of 3 phases: a screening phase of up to 4 weeks, a 12-week double-
blind treatment phase, and a 14-week posttreatment follow-up phase. The total duration of 
subject participation will be approximately 26 weeks.
1.3.
Statistical Hypothesis for Trial Objective(s)
The primary hypothesis of this study is that sirukumab will determine significant 
improvement in depressive symptoms from baseline compared to placebo when 
administered as an adjunctive treatment to a monoaminergic antidepressant in the treatment 
of patients with MDD who have shown a suboptimal response to standard oral 
antidepressant therapy and have a screening hsCRP ≥0.300 mg/dL (SI 3.00 mg/L), 
demonstrated by improvement in depressive symptoms from baseline to 12-week endpoint 
in the Hamilton Depression Rating Scale (HDRS17) total score.
1.4.
Sample Size Justification
Approximately 192 subjects will be enrolled in this study, with approximately 96 subjects 
randomized per treatment group. 
The target study population is male and female subjects with MDD who have had a 
suboptimal response to standard oral antidepressant therapy; have failed no more than 3 
antidepressant treatments in the current major depressive episode; approximately 142 
subjects with screening hsCRP ≥0.300 mg/dL (SI 3.00 mg/L) and approximately 50 
subjects with screening hsCRP<0.300 mg/dL (SI 3.00 mg/L) will be enrolled.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
8
The expected final sample size of 142 for subjects with screening hsCRP ≥ 0.300 mg/dL
(SI 3.00 mg/L) was determined based on the assumption of an effect size of at least 0.5 for 
the HDRS17 (mean change from baseline to week 12 endpoint between the sirukumab and 
placebo groups of 4 with SD=8). This is considered to be a clinically relevant difference in 
a population with suboptimal response to standard oral antidepressant therapy. Power is set 
at 90.0%, with a 1-sided alpha of 0.125 and a 12-week drop-out rate of 25%. It was also 
assumed that 10% of the randomized subjects would be excluded from the primary efficacy 
analysis due to having hsCRP ≥3.00 mg/L at screening but not at baseline. 
1.5.
Randomization and Blinding
Central randomization was implemented in this study. Subjects were randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. The randomization was
balanced by using randomly permuted blocks and was stratified by country and 4 screening 
hsCRP levels: < 3.00 mg/L (0.300 mg/dL), ≥3.00 to <5.00 mg/L (≥0.300 to <0.500 mg/dL), 
≥5.00 to <8.00 mg/L (≥0.500 to <0.800 mg/dL), and ≥8.00 mg/L (≥0.800 mg/dL). The 
interactive web response system (IWRS) assigns a unique treatment code, which dictates
the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting 
the IWRS, and was then give the relevant subject details to uniquely identify the subject.
In general, randomization codes will be disclosed fully only if the study is completed and 
the clinical database is closed. At the interim analyses, the randomization codes and, if 
required, the translation of randomization codes into treatment and control groups will be 
disclosed to those authorized and only for those subjects included in the interim analysis.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Treatment Groups
Unless specified, the treatment groups are labeled as ‘Placebo’ and ‘Sirukumab’.
2.2.
Pooling Algorithm
Five counties are planned to enroll subjects: US, Canada, United Kingdom, Poland and 
Russia. To account for country variability, country will be used as a factor in the statistical 
models to analyze efficacy. 
2.3.
Analysis Phases 
There are 2 analysis phases defined in this study: Double-blind and Follow-up Phases. 
Each analysis phase has its own analysis reference start date and end dates.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
9
2.3.1.
Analysis Phase Start and End Dates
Double-Blind Phase
The analysis reference start date of the DB analysis phase is the date of the first dose of DB 
medication. The analysis reference end date of the DB analysis phase is the maximum of 
date of the last visit in the DB treatment phase or date of early termination from DB phase. 
For randomized subjects who did not receive any medication in the DB phase, the reference 
start date is missing.
Follow-Up Phase
The analysis reference start date of the Follow-up (Post-treatment) analysis phase is the day 
after the end of DB. The analysis reference end date is the maximum of the last follow-up 
visit date and end of trial date.
2.3.2.
Study Reference Start and End Dates
The overall reference start date for the study is defined as the date of the first dose of DB 
medication (the date is missing for screened subjects who did not receive a dose of DB 
medication). The overall reference end date for the study is maximum of the last follow-up 
visit date and end of trial date.
2.3.3.
Study Day and Relative Days
Study day is calculated relative to the overall reference start date for the study. Relative day 
is calculated relative to the analysis reference start date of the analysis phase in which the 
data are captured.
Study day for an event on or after the start of the study is calculated as:
Event date-study start date +1.
Study day for an event prior to the start of the study is calculated as:
Event date-study start date
Relative day for an event on or after a reference start date is calculated as:
Event date – reference start date + 1.
Relative day for an event prior to a reference start date is calculated as:
Event date – reference start date.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
10
2.4.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are 
applied to assign actual visits to protocol visits. Listed below are the visit windows and the 
target days for each visit. The reference day is Study Day 1 (which is the date of the first 
DB medication in the double-blind phase).
The baseline value is defined as the last observation before receiving the first dose of study 
drug on Day 1.
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. If 2 actual visits are equidistant 
from the target day within a visit window, the later visit is used. If a visit window has no 
scheduled visits but does have unscheduled visits, then the unscheduled visit closest to the 
scheduled visit will be used. If a visit window has both a scheduled and an unscheduled 
visit, then a scheduled visit will have a priority even an unscheduled visit is closer to the 
target day.
All assignments will be made in chronological order.  Once a visit is assigned to a visit 
window, it will no longer be used for a later time point except for the end point. Listed 
below are the visit windows and the target days (if applicable) for each visit defined in the 
protocol (Table 1).
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
11
Table 1:
Analysis Visit Windows
Parameter
Scheduled Visit Time
(label on output)
Time Interval 
(Day)
Target Time Point 
(Day)
HDRS17
Baseline
1/predose
1
Week 1 (DB)
2 - 17
7
Week 4 (DB)
18- 42
28
Week 8 (DB)
43 - 70
56
Week 12 (DB)
71 - end of DB
84
CGI-S, IDS-C30 and 
PHQ-9, SHAPS and 
FACIT Fatigue
Baseline
1/predose
1
Week 1 (DB)
2 - 17
7
Week 4 (DB)
18- 42
28
Week 8 (DB)
43 - 70
56
Week 12 (DB)
71 - end of DB
84
Week16 (FU)
End of DB+1 - 133
112
Week 22 (FU)
134 – end of FU
154
C-SSRS
Baseline
1/predose
1
Week 1 (DB)
2 - 17
7
Week 4 (DB)
18- 42
28
Week 8 (DB)
43 - 70
56
Week 12 (DB)
71 - end of DB
84
Week16 (FU)
End of DB+1 - 133
112
Week 22 (FU)
134 – end of FU
154
Vital signs (BP, HR, RR, 
temperature)
Baseline
1/predose
1
Week 4 (DB)
2 - 56
28
Week 12 (DB)
57 - end of DB
84
Week16 (FU)
End of DB+1 - 133
112
Week 22 (FU)
134 – end of FU
154
Body weight
Baseline
1/predose
1
Week 12
     2 – end of DB
84
Week 22 (FU)
End of DB+1 – end of FU
154
Clinical laboratory 
assessments: chemistry, 
hematology
Baseline
1/predose
1
Week 4
2 - 42
28
Week 8
43 - 70
56
Week 12
71 – end of DB
84
Week 22
End of DB+1 – end of FU
154
Clinical laboratory 
assessments: urinalysis
Baseline
1/predose
1
Week 8
2 - 70
56
Week 12
71 – end of DB
84
Week 22
End of DB+1 – end of FU
154
2.5.
Analysis Sets
Subjects will be classified mainly into the following analysis sets: all randomized analysis 
set, intent-to-treat analysis sets (with different variations) and safety analysis sets.
2.5.1.
All Randomized Analysis Set
This analysis set will include all subjects who were randomized (i.e., subjects who reported 
a randomization date, or were assigned a randomization number) regardless of whether or 
not the treatment was received.  This analysis set will be used for summarizing the overall 
study completion/withdrawal information using planned treatment group.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
12
2.5.2.
Efficacy Analysis Sets
Three analyses sets will be defined for efficacy analyses: the modified intent-to-treat 1 
(mITT1), the modified intent-to-treat 2 (mITT2) and the modified intent-to-treat 3 (mITT3) 
analyses sets. 
The mITT1 analysis set is defined as all randomized subjects with hsCRP ≥ 3.00 mg/L at 
screening and baseline who receive at least 1 dose of study drug and have both the baseline 
and at least one postbaseline HDRS17 total score measured within the double-blind 
treatment period. 
The mITT2 analysis set is defined as all randomized subjects who receive at least 1 dose of 
study drug and have both the baseline and at least one postbaseline HDRS17 total score 
measured within the double-blind treatment period.
The mITT3 analysis set is defined as all randomized subjects with hsCRP≥ 3.00 mg/L at 
screening who receive at least 1 dose of study drug and have both the baseline and at least 
one postbaseline HDRS17 total score measured within the double-blind treatment period.
Subjects who receive an incorrect treatment will be analyzed under the planned treatment 
received.
2.5.3.
Biomarker Analysis Set
Biomarker analyses will be performed on biomarker analysis set. It will include all 
randomized subjects who receive at least 1 dose of study drug in the double-blind phase 
and have at least 1 sample obtained.
2.5.4.
Pharmacokinetic and Immunogenicity Analyses Sets
Pharmacokinetic analyses will be performed on pharmacokinetic analysis set. It will 
include all randomized subjects who receive at least 1 administration of sirukumab in the 
double-blind phase and have at least 1 sample obtained after sirukumab treatment.
Immunogenicity analyses will be performed on immunogenicity analysis set.  It will 
include all randomized subjects who receive at least 1 administration of sirukumab and 
have appropriate samples for detection of antibodies to sirukumab (ie, subjects with at least 
1 sample obtained after sirukumab treatment).
2.5.5.
Safety Analysis Set
Safety analyses will be performed on the safety analysis set. It will include all randomized 
subjects who receive at least 1 dose of study drug in the double-blind phase. Analyses of 
change from baseline will include only subjects who have both baseline and at least 1 post-
baseline observation during the double-blind phase.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
13
Safety analyses for the follow up phase will be performed on the Safety (FU) analysis set. 
It will include all subjects who have at least 1 visit during the follow up phase. 
Screen failures and randomized subjects who received no double-blind study medication 
will be excluded from the safety analysis set. Subjects who received an incorrect treatment 
will be analyzed under the planned treatment.
2.6.
Definition of Subgroups
Descriptive statistics will be performed for the primary endpoint of HDRS17 change from 
baseline stratified by the following sub-groups.

Screening hsCRP stratification (<3.00 mg/L, ≥3.00 to <5.00 mg/L, ≥5.00 to <8.00 mg/L 
and ≥8.00 mg/L)

Treatment Resistant Depression (TRD) vs. non-TRD subjects. (TRD is defined as 
having be treated with ≥2 trials of antidepressants of adequate dose and duration 
during the current episode.)
Other subgroups such as 5 types of maltreatment (physical abuse, physical neglect, sexual 
abuse, emotional abuse and emotional neglect) based on CTQ and baseline BMI status 
(≤25 (normal) vs. >25 (abnormal) or ≤30 (normal) vs. >30 (abnormal)) may also be 
explored. 
2.7.
Incomplete/Missing Dates for Adverse Events
Treatment-emergent adverse events (AEs) for DB phase are those events with an onset date 
on or after the start of double-blind study medication, and occurred on or before the end of 
the double-blind phase.  A conservative approach will be used to handle the missing dates 
for adverse events.  
The rules for estimating incomplete AE onset dates will be as follows:
(1) The missing day of the month will be estimated as follows:  If the month and year are 
known and double-blind study medication started during that month then the estimated date 
is the start date of double-blind study medication.  If the month and year are known and 
double-blind study medication started prior to that month then the estimated date is the 1st
day of the month.  If the month and year are known and double-blind study medication 
started after the month, then no estimation will be done, and the AE will not be considered 
as treatment emergent for the double-blind phase.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
14
(2) If both the day and the month are missing: No estimation will be performed.  However, 
these AEs will be considered treatment emergent for the double-blind phase and will be 
included in the double-blind treatment summaries, except for the calculation of duration of 
the AE.  Attempts will be made to get at least the month for the adverse events. 
For incomplete AE resolution dates, the rules are:
(1) The missing day of the month will be estimated as follows:  If the month and 
year are known and the study medication was stopped before, or during that 
month, the estimated date is the last day of the month or the end of the double-
blind phase, whichever is earlier.  If the study medication stopped after that 
month then the estimated date is the last day of the month.
(2) If both the day and the month are missing:  the estimated resolution date is the 
end of the double-blind phase.
3.
SUBJECT INFORMATION
3.1.
Demographics and Baseline Characteristics
Demographic and baseline characteristics (Table 2) and psychiatric history at baseline 
(Table 3) will be summarized by treatment group for the All Randomized analysis set.
The continuous variables will be summarized using descriptive statistics (N, mean, 
standard deviation [SD], median, minimum, and maximum). The categorical variables will 
be summarized using a frequency distribution with the number and percentage of subjects 
in each category.
Table 2:
Demographic Variables and Baseline Characteristics
Continuous Variables:
Age (years) (informed consent date – date of birth + 1) / 365.25
Baseline weight (kg)
Baseline height (cm)
Baseline BMI (kg/m2) calculated as Weight (kg)/[Height (m)]2
Baseline hsCRP level
Categorical Variables:
Sex (male, female)
Racea (White, Black or African American, Asian, American Indian or Alaskan native,
   Native Hawaiian or Pacific islander, other)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
Baseline hsCRP (< 3.00 mg/L, ≥3.00 to <5.00 mg/L, ≥5.00 to <8.00 mg/L and ≥8.00 mg/L)
a:
If multiple race categories are indicated, then Race is recorded as “Multiple”.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
15
Table 3:
Psychiatric History at Baseline Variables
Continuous Variables:
Baseline HDRS17
Baseline IDS-C30 total score
Baseline CGI-S score
Categorical Variables:
Baseline CGI-S score
Antidepressant treatment history (as obtained in the MGH-ATRQ)
3.2.
Disposition Information
The distribution of the number of subjects who are randomized, receive double-blind 
treatment, and complete the Week 12 will be presented by treatment group for the double-
blind phase of the study. In addition, the distribution of trial termination reasons will be 
summarized. These summaries will include a total group. The All Randomized Subjects 
analysis set will be used to summarize this information. A subject will be considered to 
have completed the Week 12 treatment phase if he or she has completed assessments 
through Week 12 visit.
3.3.
Extent of Exposure
Total duration of exposure during the DB phase is defined as days between the first and the 
last dose of DB study medication. 
Descriptive statistics (N, mean, median, and range) of total duration of exposure will be 
presented for DB phase by treatment group in safety analysis set. A frequency distribution 
showing the number of doses received during the double-blind phase will also be provided.
3.4.
Protocol Deviations
Deviations that occurred during the study will be listed.  
3.5.
Prior and Concomitant Medications
The number and percent of subjects who receive concomitant therapies will be summarized 
by planned treatment group and by the generic term of the medication for the safety 
analysis set. Concomitant medications will be summarized in DB and FU separately.
A similar summary will be presented for antidepressants received prior to study entry 
according to responses to the MGH-ATRQ for the Safety analysis set.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
16
4.
EFFICACY
Efficacy data will be provided for the interim efficacy analysis; however, they will not be 
provided for the first DMC Safety Review meeting, except for Item 3 (Suicide) of HDRS17
and Item 18 (Suicide Ideation) of IDS-C30 which will be provided for DMC Safety Review 
meetings.
The efficacy variables in this study are listed in Table 4.
Table 4:
Efficacy Variables
Scale
End point
Change in HDRS17 total score from baseline to Week 12
Primary
Change in HDRS17 total score from baseline to Weeks 1, 4, 8, 16 or 22
Secondary
Response rate (≥50% improvement in HDRS17 total score from baseline) at Week 12
Remission rates (HDRS17 total score ≤7) at Week 12
Change in CGI-S score from baseline to Weeks 1, 4, 8, 12, 16 and 22
Change in SHAPS total score from baseline to Weeks 1, 4, 8, 12, 16 and 22
Change in FACIT Fatigue total score from baseline to Weeks 1, 4, 8, 12, 16 and 22
Change in IDS-C30 from baseline to Weeks 1, 4, 8, 12, 16 and 22
Exploratory
Change in PHQ-9 total score from baseline to Weeks 1, 4, 8, 12, 16 and 22
4.1.
Analysis Specifications
4.1.1.
Level of Significance
Unless otherwise specified, all statistical comparisons will be carried out at a 1-sided 
significance level of 12.5% and confidence intervals will be presented at 2-sided 
confidence level of 75% (ie. equivalent to 1-sided confidence level of 87.5%).
4.1.2.
Data Handling Rules
The last observation carried forward (LOCF) method will be applied to the HDRS17 total 
score in the sensitivity analysis. 
The LOCF approach will be used for imputing missing visit data in the ITT LOCF 
sensitivity efficacy analyses. The LOCF calculation will be performed for all scheduled 
post-baseline time windows in the double-blind phase.
4.1.3.
Imputation Methods for Missing Items
Imputation of missing individual item scores will apply only to the HDRS17, as described in 
the next section. For all other scales where multiple items are summed to create a total, if 
any item of the scale is missing on one visit, the total score for that scale at that visit will be 
left blank.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
17
4.2.
Primary Efficacy Endpoint
4.2.1.
Definition
The HDRS17 is a clinician-administered rating scale designed to assess the severity of 
symptoms in subjects diagnosed with depression with a score range of 0 to 52. Each of the 
17 items is rated by the clinician on either a 3- or a 5-point scale. The HDRS17 consists of 
17 items that cover all of the core depressive symptoms (depressed mood, feeling of guilt, 
suicide, insomnia early, insomnia middle, insomnia late, work and activities, retardation 
[psychomotor], agitation, anxiety [psychological], anxiety somatic, somatic symptoms 
general, genital symptoms, hypochondriasis, loss of weight and insight). A total score (0 to 
52) is calculated by adding the scores of all 17 items.  For each item as well as the total 
score, a higher score represents a more severe condition.  If 2 or more items are missing, no 
imputation will be performed and the total score will be left missing.  Otherwise, the total 
score will be calculated as the sum of the items present multiplied by the ratio of the 
maximum possible number of items (i.e., 17) to the number of items present.
4.2.2.
Analysis Methods
The primary efficacy analyses will be conducted using mITT1 analysis set.  The primary 
comparison will be between sirukumab and placebo using the primary efficacy endpoint, 
i.e., change in HDRS17 total score from baseline to Week 12.
A mixed effects model using repeated measures (MMRM) with time, treatment, country, 
screening hsCRP stratification and time-by-treatment interaction as factors, baseline 
HDRS17 total score as a continuous covariate, and a random subject effect, will be 
conducted. An unstructured variance-covariance matrix will be used (if there are 
convergence issues with the unstructured variance-covariance matrix, another suitable 
matrix structure will be chosen based on the LR test or the AIC).  The contrast on Week 12 
changes will be of primary interest, and tested at one-sided alpha level of 0.125. 
Descriptive statistics for values and changes from baseline will be provided for HDRS17
including individual items and total score, at each time point of the double-blind treatment 
phase. Time profile of HDRS17 total score for individual subjects will be represented 
graphically over time by treatment group.
Sensitivity analyses on the primary endpoint will also be conducted. Sensitivity analyses 
will be using the aforementioned MMRM using mITT3 and mITT2 analysis sets. 
The primary endpoint with the aforementioned MMRM analyses may also be explored in 
subgroups such as 5 types of maltreatment based on CTQ (physical abuse, physical neglect, 
sexual abuse, emotional abuse and emotional neglect) and baseline BMI status (≤25 
(normal) vs. >25 (abnormal) or ≤30 (normal) vs. >30 (abnormal)).
In addition, the primary endpoint using similar MMRM analyses with additional covariates 
such as CTQ total score or others may also be explored. 
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
18
Secondary Efficacy Endpoints
Analyses of secondary efficacy endpoints will be mainly based on the mITT2 analysis set. 
Analyses on the secondary efficacy endpoints may also be conducted using the 
aforementioned MMRM using mITT1 and mITT3 analysis sets. 
4.2.3.
HDRS17 Total Score
Changes in HDRS17 from baseline to Weeks 1, 4, and 8 will be analyzed using the same 
mixed-effects model with repeated measures (MMRM) as for the primary endpoint in all 3 
mITT analysis datasets. 
Summary statistics on HDRS17 (changes from baseline) over time by treatment group will 
be provided for the following subgroups:
(1) Screening hsCRP stratification;
(2) TRD status (TRD vs. non-TRD);
Other subgroups such as 5 types of maltreatment (physical abuse, physical neglect, sexual 
abuse, emotional abuse and emotional neglect) based on CTQ and baseline BMI status 
(≤25 (normal) vs. >25 (abnormal) or ≤30 (normal) vs. >30 (abnormal)) may also be 
explored. 
In addition, mean time profile plots of HDRS17 over time by treatment group will be 
provided.
4.2.4.
Responders and Remitters
Subjects who have HDRS17 score ≤ 7are considered as remitters while those who have ≥ 
50% improvement in HDRS17 total score from baseline at week 12 are considered 
responders. The response rate or remission rate at Week 12 in sirukumab will be compared 
with that in placebo using a logistic regression model including baseline HDRS17 score, 
screening hsCRP stratification, country and treatment.
Response rate or remission rate at Week 12 will be provided by treatment group for the 
following subgroups:
(1) Screening hsCRP stratification;
(2) TRD status (TRD vs. non-TRD).
4.2.5.
Clinical Global Impression-Severity Scale (CGI-S)
The CGI-S is a clinician -rated scale that assesses the severity of mental illness with scores 
as follows:
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.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
19
A higher score implies a more severe condition. Change from baseline in CGI-S score will 
be calculated.
Descriptive statistics (N, mean, median and range) of the numerical scores and as well 
changes from baseline will be provided by treatment group. 
A frequency distribution of severity scores may be provided by treatment group from Week 
1 to Week 12.
In addition, analyses on changes from baseline in CGI-S score may also be conducted using 
the similar aforementioned MMRM for the primary analyses.
4.2.6.
Patient Health Questionnaire (PHQ-9)
The PHQ-9 is used as a subject-reported measure of depressive symptomatology. The 
PHQ-9 is a 9-item scale, where each item is rated on a 4-point scale (0=Not at all,
1=Several Days, 2=More than half the days, and 3=Nearly every day), with a total score 
range of 0 to 27. The recall period is 2 weeks.
Descriptive statistics (N, mean, median and range) of total score and as well changes from 
baseline will be provided by treatment group.
In addition, analyses on changes from baseline in PHQ-9 total score may also be conducted 
using the similar aforementioned MMRM for the primary analyses.
4.2.7.
Snaith–Hamilton Pleasure Scale (SHAPS) 
Anhedonia, the inability to experience pleasure, is a core symptom of depression. The 
Snaith–Hamilton Pleasure Scale (SHAPS) is a short, 14-item instrument to measure 
anhedonia, which has been shown to be valid and reliable in normal and clinical samples.  
Each of the 14 items has a set of four response categories: Definitely Agree, Agree, 
Disagree, and Definitely Disagree. 
There will be two definitions for total score. The (protocol) definition 1: Definitely Agree 
(=1), Agree (= 2), Disagree (= 3), and Definitely Disagree (= 4). The definition 2: 
Definitely Agree (= 0), Agree (= 0), Disagree (= 1), and Definitely Disagree (= 1). A 
SHAPS total score will be calculated as the sum of the 14 item scores. A higher total score 
indicates higher levels of state anhedonia.
Descriptive statistics (N, mean, median and range) of total score (for both definitions) and 
as well changes from baseline will be provided by treatment group.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
20
4.2.8.
Functional Assessment of Chronic Illness Therapy-Fatigue
(FACIT Fatigue)
The FACIT-Fatigue is a questionnaire that assesses self-reported tiredness, weakness, and 
difficulty conducting usual activities due to fatigue. The subscale consists 13-item 
instrument to measure fatigue. Each of the 13 items has a set of five response categories:  
Not at all (=0), A little bit (=1), Somewhat (=2), Quite a bit (=3) and Very much (=4). A 
total FACIT-Fatigue subscale score will be calculated as the sum of the 13 item scores
(reserved scores [4 – score] for all except for 2 items: “I have energy” and “I am able to do 
my usual activities”), and ranges from 0 to 52, with a higher score indicating less fatigue.
Descriptive statistics (N, mean, median and range) of total score and as well changes from 
baseline will be provided by treatment group.
4.3.
Exploratory Efficacy Endpoint
4.3.1.
Inventory of Depressive Symptomatology – Clinician Rated 30 
(IDS-C30)
The clinician-rated IDS is a 30-item, depression-specific symptom severity rating scale. 
The IDS is designed to measure the specific signs and symptoms of depression, including 
melancholic, atypical and anxious features. Scores range from 0 to 84 with higher scores 
representing greater severity of depressive symptoms. Only one of items 11 or 12 and of 
items 13 or 14 need to be rated. If both item 11 and 12 (or 13 and 14) are completed by 
accident, the highest of the two item scores will be used for calculating the total score.
Change from baseline in IDS-C30 score will be calculated. Descriptive statistics (N, mean, 
median and range) of the numerical scores and as well changes from baseline will be 
provided by treatment group.
In addition, analyses on changes from baseline in IDS-C30 total score may also be 
conducted using the similar aforementioned MMRM for the primary analyses.
4.3.2.
Childhood Trauma Questionnaire (CTQ) 
The self-report includes a 28-item test that measures 5 types of maltreatment – emotional, 
physical, and sexual abuse, and emotional and physical neglect. A 5-point Likert scale is 
used for the responses which range from Never True to Very Often True. A total CTQ
score will be calculated as the sum of the 28 item scores (reserved scores for items 2, 5, 7, 
10, 13, 16, 19, 22, 26 and 28), and ranges from 28 to 140, with a higher score indicating a 
more server childhood trauma.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
21
Physical abuse is ‘yes’ if sum of CTQ items 9, 11, 12, 15, 17 is 8 or larger. Physical neglect 
is ‘yes’ if sum of CTQ items 1, 2 (R) (where R stands for reserving score), 4, 6, 26 (R) is 8 
or larger. Sexual abuse is ‘yes’ if sum of CTQ items 20, 21, 23, 24, 27 is 8 or larger. 
Emotional abuse is ‘yes’ if sum of CTQ items 3, 8, 14, 18, 25 is 10 or larger. Emotional 
neglect is ‘yes’ if sum of CTQ items 5 (R), 7 (R), 13 (R), 19 (R), 28 (R) is 15 or larger.
Descriptive statistics (N, mean, standard deviation, median and range) of the numerical 
total scores may be provided by treatment. A frequency distribution of CTQ will be 
provided by treatment group. Frequency distributions of physical abuse, physical neglect, 
sexual abuse, emotional abuse and emotional neglect will also be provided by treatment 
group.
4.3.3.
MINI International Neuropsychiatric Inventory (MINI) 
The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a short structured 
diagnostic interview for psychiatric disorders.
Frequency distributions of diagnostic psychiatric disorders will be provided by treatment 
group. 
5.
BIOMARKERS
5.1.
Biomarker Variables
Biomarkers consist of hsCRP, ACTH, Adiponectin, serum BDNF, IGF1, IL6R, Leptin, IL-
6, IL-1b, IL-10, TNFa, saliva Cortisol, serum Cortisol, Kynurenine pathway metabolites, 
and a total of 92 SNPs related to above HPA, metabolic, and inflammatory biomarkers. 
5.2.
Analysis Methods
5.2.1.
hsCRP as a predictor of response
HDRS17 changes and percent changes from screening on week 12 (∆w12
HDRS17) will be 
modeled as a function of screening hsCRP including BMI, sex, and age as covariates for 
subjects treated with sirukumab. hsCRP is determined to have significant predictive power 
if it models a significant amount of variance in ∆w12
HDRS17 from screening at p <= 0.1 
Scatter plots of ∆w12
HDRS17 versus hsCRP will be created and annotated with regression 
modeling results including regression coefficients for model variables and corresponding 
significance levels and coefficients of determination R2 and R2
partial and R2
reduced for the 
reduced model. The reduced model is the full model with the variable of interest (hsCRP) 
omitted. 
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
22
Logistic models will be used to gauge the potential of screening hsCRP as a predictor of 
remitters (week 12 HDRS17 <= 7) and responders with (50% improvement in HDRS17 on 
week 12). In both models, covariates will include BMI, sex, and age. Screening HDRS17 
levels will also be used as a covariate in the model predicting remission. ROC curves will 
be generated for each model in addition to AUC and model accuracies.
To demonstrate specificity of hsCRP predictive power, modeling is also carried out on 
placebo treated subjects and the outcomes are compared to those for subjects treated with 
sirukumab.
In order to enable comparison of hsCRP performance with that of other biomarkers which 
were measured at baseline, the above models will be repeated substituting screening visit 
with baseline.
5.2.2.
Alternate predictors of response
5.2.2.1 Tier A biomarker panel
The Tier A biomarkers panel consists of inflammation-related analytes:  IL-6, IL6R, IL-10, 
IL-1b, and TNFa. Kynurenine pathway metabolites kynurenine, tryptophan, 3-OH 
kynurenine, kynurenic acid, and quinolinic acid are also included in Tier A as this pathway 
has been shown to drive inflammatory processes. 
∆w12
HDRS17 will be modeled as a function of each analyte in the high-priority panel 
measured at baseline with BMI, sex, and age as covariates. Analyte levels that model a 
significant amount of variance (p≤ 0.1) in ∆w12
HDRS17 will be compared against performance 
of the baseline hsCRP model from Section 5.2.1 Model performance will be compared 
using Akaike Information Criterion (AIC) or non-parametric equivalent. Bonferroni Family 
Wise Error Rates (FWER) will be reported in addition to uncorrected p values. Models 
with FWER ≤0.1 and better performance than the hsCRP model are identified as alternate 
candidate predictive biomarkers. 
Logistic models for identified alternate candidate biomarkers, if any, will be generated for 
predicting remission and response and the results will be compared to the corresponding 
outcome of logistic models for baseline hsCRP in Section 5.2.1.  
Multivariate models using supervised machine learning will also be used to predict 
∆w12
HDRS17, response, and remission using hsCRP and Tier A analytes.  80% of the samples 
will be used for training with 20% set aside for model testing. ROC curves will be 
generated for each of model in addition to AUC and model accuracies.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
23
5.2.2.2 Full biomarker panel
If analysis of high-priority analytes fails to identify alternate candidate predictive 
biomarkers, exploratory univariate modeling of ∆w12
HDRS17 will be carried out with each of 
the remaining baseline biomarkers. Modeling outcomes will be tabulated including 
uncorrected p-values as well as p-values adjusted by controlling the Benjamini & Hochberg 
False Discovery Rate (BH FDR). Scatter plots for regression models with uncorrected p-
values ≤ 0.05 will be created and annotated with coefficients of determination (R2 and 
R2
partial) and R2
reduced for the reduced model.
Multivariate models using supervised machine learning will also be used to predict 
∆w12
HDRS17, response, and remission using all analytes that reach significance predicting 
∆w12
HDRS17 at uncorrected p≤0.1 in the univariate models.  80% of the samples will be used 
for training with 20% set aside for model testing. ROC curves will be generated for each of 
model in addition to AUC and model accuracies. Results from multivariate modeling will 
also be reported using all analytes regardless of univariate significance. 
6.
PHARMACOKINETICS AND IMMUNOGENICITY
6.1.
Pharmacokinetic Analyses
Serum sirukumab concentrations will be summarized over time. Descriptive statistics, 
including arithmetic mean, standard deviation (SD), median, interquartile range, minimum, 
and maximum will be calculated at each sampling time point. Monoaminergic 
antidepressants concentration data before and after sirukumab treatment, will also be 
summarized.
Data will be listed for all subjects with available serum concentrations. 
All concentrations below the lowest quantifiable concentration or missing data will be 
labeled as such in the concentration database. All subjects and samples excluded from the 
analysis will be clearly documented in the study report.
6.2.
Immunogenicity Analyses
The incidence of antibodies to sirukumab will be summarized for all subjects who received 
at least 1 administration of sirukumab and have appropriate samples for detection of 
antibodies to sirukumab (ie, subjects with at least 1 sample obtained after sirukumab 
treatment).
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
24
7.
SAFETY
7.1.
Adverse Events
Adverse events (AEs) are coded using the MedDRA dictionary (version 17.0 or above). 
Treatment-emergent adverse events (TEAEs) that occurred in the double-blind phase will 
be summarized by system organ class, preferred term, and treatment group. Adverse events 
that occurred in the follow up phase will be summarized separately.  
Adverse events in different phases of the study are defined as below:

Treatment-emergent adverse events during the double-blind phase are defined as AEs with 
an onset during the double-blind phase. In other words, treatment-emergent AE during the 
double-blind phase should satisfy the condition: Double-blind start date/time ≤ AE onset 
date/time < double-blind end date. If onset time is missing and AE onset date/time is the 
same as the double-blind start date/time, the AE is defined to be treatment emergent in the 
double-blind phase.

Adverse events during the follow up phase are defined as AEs with an onset during the 
follow up phase. AEs during the follow up phase should satisfy the condition: (follow up 
phase start date ≤AE onset date/time and AE onset date ≤ follow up phase end date). 
A TEAE is an event that is new in onset or increased in severity following treatment 
initiation. An event that starts prior to, and ends after the initiation of study medication will 
be considered treatment-emergent only if the severity increases after the start of 
medication. Adverse events will not be considered treatment-emergent if they occur or 
increase in severity during the follow up phase. Adverse events occurring during the follow 
up phase will be summarized separately. In addition, AEs will be summarized by severity 
and relationship to study drug using the preferred term. For the summaries of AEs by 
severity/relationship to study drug, the observation with the most severe occurrence/closest 
relationship to study drug will be chosen if there is more than one incident of an adverse 
event reported during the analysis phase by the subject.
Serious AEs (SAEs) and AEs that lead to study discontinuation will be summarized 
separately by treatment group, system organ class, and preferred term. Data listings will 
also be generated for deaths, other SAEs, and discontinuations due to AEs.  
Adverse Events of Special Interest
Clinically relevant TEAEs of special interest will be examined in malignancies, active TB, 
hepatobiliary abnormalities (as defined in the protocol), and gastrointestinal perforations.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
25
7.2.
Clinical Laboratory Tests
Descriptive statistics (N, mean, median and range) for values and changes from baseline 
will be provided for clinical laboratory tests (hsCRP, hematology, chemistry, lipid panel 
[fasting] and urinalysis) at each scheduled time point in the double-blind and follow up 
phases  
In addition, shift table from baseline to post-baseline values with respect to the normal 
range will be provided.
7.3.
Vital Signs, Weight and BMI
Descriptive statistics for values and changes from baseline at each scheduled time-point 
during the double-blind and follow up phases will be presented for Systolic Blood Pressure 
(mmHg), Diastolic Blood Pressure (mmHg), Pulse Rate (beats per minute), Weight (kg), 
and BMI. In addition, descriptive statistics of pulse rate and blood pressure (systolic and 
diastolic) values and changes from predose will be provided for each timepoint.
The proportion of subjects who have a treatment-emergent abnormality, as defined in 
Table 5 below, will be presented for the double-blind phase. The double-blind baseline will 
be used to determine abnormal values. A listing of subjects meeting any of the criteria will 
also be provided for the double-blind phase.
Table 5:
Treatment-Emergent Abnormality Categories for Vital Signs
Vital Parameter
Post-baseline value outside of normal limit if:
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from baseline of 
15 to a value 50
An increase from baseline of 
15 to a value 100
Systolic BP 
(mmHg)
A decrease from baseline of 
20 to a value 90
An increase from baseline of 
20 to a value 180
Diastolic BP  
(mmHg)
A decrease from baseline of 
15 to a value 50
An increase from baseline of 
15 to a value 105
BP = blood pressure
7.4.
Other Safety Parameters
7.4.1.
Columbia Suicide Severity Rating Scale 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior. It 
is a semi structured clinician-administered questionnaire designed to solicit the occurrence, 
severity, and frequency of suicide-related ideation and behaviors during the assessment 
period. 
As noted in the August 2012 draft guidance titled “Suicidal Ideation and Behavior: 
Prospective Assessment of Occurrence in Clinical Trials”,3 the FDA has outlined 11 
categories of interest, obtained by the C-SSRS instrument.  Some data collected on the C-
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
26
SSRS are not used for analysis, but are used for individual clinical management and safety 
monitoring (e.g., suicidal behavior lethality and suicidal ideation intensity). These data are 
not included in the proposed analysis tables.
The summaries of the C-SSRS outcomes will be based on the safety analysis set subjects 
who have at least 1 post-baseline C-SSRS measurement and a pre-treatment C-SSRS 
assessment (lifetime assessment at screening). The C-SSRS outcomes will be summarized 
in double-blind phase.
The following outcomes are C-SSRS categories and have binary responses (yes/no).  The 
categories have been re-ordered from the actual scale to facilitate the definitions of the 
composite and comparative endpoints, and to enable clarity in the presentation of the 
results.
Categories
Category 1 – Wish to be Dead  
Category 2 – Non-specific Active Suicidal Thoughts  
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt
Category 8 – Interrupted Attempt
Category 9 – Actual Attempt (non-fatal)
Category 10 – Completed Suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not 
suicide-related) and has a binary response (yes/no).
The following outcome is a numerical score derived from the C-SSRS categories.  The 
score is created at each assessment for each patient and is used for determining treatment 
emergence.  
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
27
•
Suicidal Ideation Score:  The maximum suicidal ideation category (1-5 on the C-
SSRS) present at the assessment.   Assign a score of 0 if no ideation is present.
Composite endpoints based on the above categories are defined below.
•
Suicidal ideation:  A “yes” answer at any time during treatment to any one of the 
five suicidal ideation questions (Categories 1-5) on the C-SSRS.
•
Suicidal behavior:  A “yes” answer at any time during treatment to any one of the 
five suicidal behavior questions (Categories 6-10) on the C-SSRS.
Comparative endpoints of interest are defined below.  “Treatment emergence” is used for 
outcomes that include events that first emerge or worsen.  “Emergence” is used for 
outcomes that include events that first emerge.
•
Treatment-emergent suicidal ideation compared to all prior history:
An increase in the maximum suicidal ideation score during treatment from the maximum 
suicidal ideation score prior to treatment.
•
Emergence of serious suicidal ideation compared to all prior history:  
An increase in the maximum suicidal ideation score to 4 or 5 during treatment from no 
suicidal ideation (scores of 0) prior to treatment.
•
Treatment-emergent serious suicidal ideation compared to all prior history:  
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS during 
treatment from not having serious suicidal ideation (scores of 0-3) prior to treatment.
•
Emergence of suicidal behavior compared to all prior history:  
The occurrence of suicidal behavior (any of the Categories 6-10) during treatment from not 
having suicidal behavior (any Categories 6-10) prior to treatment.
A summary of pre-treatment suicidal ideation and suicidal behavior will be presented in 
terms of percent of subjects with lifetime suicidal ideation, lifetime suicidal behavior, 
lifetime self-injurious behavior without suicidal intent.
Improvement in suicidal ideation compared to all prior history:  
The occurrence of a suicidal ideation score (any of the Categories 1-5) during treatment 
lower than the suicidal ideation score (Categories 1-5) prior to treatment. Subjects with a 
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
28
score of 0 prior to treatment (no ideation is present) will not be classified as having 
improved even if they did not experience any ideation during the study, ie, suicidal ideation 
score remains 0 post treatment.
The number and percent of subjects with treatment-emergent suicidal ideation, treatment 
emergent serious suicidal ideation, emergence of serious suicidal ideation and improvement 
in suicidal ideation and emergence of suicidal behavior in the double-blind phase will be 
summarized by treatment group in frequency and shift tables.  
A bar chart that will display in a visual graph the improvements in suicidal ideation score 
by treatment sequence over time may be provided.
Outcomes that can be used for clinical management and safety monitoring are described 
below and will be presented in data listings.
NCT02473289


CNTO136: Statistical Analysis Plan CNTO136MDD2001
29
8.
REFERENCES
1.
Mathew, S.J. et al., Riluzole for relapse prevention following intravenous ketamine in treatment-resistant 
depression:  a pilot randomized, placebo-controlled continuation trial, International Journal of 
Neuropsychopharmacology, 13, pp. 71-82, 2010.
2.
International Conference on Harmonization (ICH) Tripartite Guideline E14. The clinical evaluation of 
QT/QTc interval prolongation and proarrhythmic for non-antiarrhythmic drugs. London 2005
3.
FDA Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in 
Clinical Trials. August 2012
NCT02473289