Conditions: Arthritis, Rheumatoid
Keywords: Rheumatoid Arthritis Sirukumab CNTO 136 CNTO136ARA3002 SIRROUND-D CNTO136ARA3003 SIRROUND-T SIRROUND-LTE
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1820
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the long-term safety and efficacy of CNTO 136 (sirukumab) in participants with rheumatoid arthritis (RA) who are unresponsive to treatment with modifying antirheumatic drugs (DMARDs) or anti-TNF alpha agents.

Detailed description:
This is a multicenter, long-term study of sirukumab (CNTO 136) that will be conducted in two groups of participants at the same time (parallel-group study). The maximum duration of participation in this study is 208 weeks, followed by approximately 16 weeks of safety and efficacy follow-up after the administration of the final study agent injection of sirukumab. Participant safety will be monitored throughout the study.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Sirukumab 100 mg intervention 2: Sirukumab 50 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Sirukumab 100 mg subcutaneously (SC) at Weeks 0 (administered as the last dose in CNTO136ARA3002 or CNTO136ARA3003), 2, and every 2 weeks through Week 156 for participants who completed CNTO136ARA3002 and through Week 208 for participants who completed CNTO136ARA3003. intervention 2: Sirukumab 50 mg SC at Weeks 0 (administered as the last dose in CNTO136ARA3002 or CNTO136ARA3003), 4, and every 4 weeks through Week 156 for participants who completed CNTO136ARA3002 and through Week 208 for participants who completed CNTO136ARA3003. intervention 3: Between sirukumab 50 mg injections, placebo SC injections will be administered at Weeks 2, 6, and every 4 weeks until the study becomes open-label, and placebo injections are discontinued.

Protocol document:
Prot_000.pdf: 
Approved 06 Oct 2016
1
Janssen Research & Development*
Clinical Protocol
A Multicenter, Parallel-group Study of Long-term Safety and Efficacy of CNTO 136 
(sirukumab) for Rheumatoid Arthritis in Subjects Completing Treatment in 
Studies CNTO136ARA3002 (SIRROUND-D) and CNTO136ARA3003 (SIRROUND-T)
Protocol CNTO136ARA3004; Phase 3
AMENDMENT 3
CNTO 136 (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 R&D Ireland; 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:  2012-001176-10
Issue/Report Date:
Incorporates Amendment 3:  06 Oct 2016
Amendment 2:  01 May 2014
Amendment 1:  06 Mar 2013
Original Protocol: 20 Mar 2012
Prepared by:
Janssen Research & Development*
Document No.:
EDMS-ERI-34551602
Compliance: This study will be conducted in compliance with this protocol, 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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
2
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
SYNOPSIS.................................................................................................................................................... 7
TIME AND EVENTS SCHEDULE .............................................................................................................. 14
ABBREVIATIONS ...................................................................................................................................... 18
1
INTRODUCTION................................................................................................................................ 20
1.1
IL-6 as a Target in Rheumatoid Arthritis ........................................................................................ 20
1.2
Overall Rationale for the Study...................................................................................................... 22
2
OBJECTIVES AND HYPOTHESES.................................................................................................. 22
2.1
Objectives ...................................................................................................................................... 22
2.2
Hypothesis ..................................................................................................................................... 23
3
STUDY DESIGN AND RATIONALE ................................................................................................. 23
3.1
Overview of Study Design.............................................................................................................. 23
3.2
Study Design Rationale.................................................................................................................. 25
3.2.1
Study Population......................................................................................................................... 26
3.2.2
Treatment Groups, Dosage, and Dose Administration Interval.................................................. 26
3.2.3
Study Phases and Duration of Treatment .................................................................................. 26
3.2.4
Study Control, Randomization, and Blinding.............................................................................. 27
3.2.5
Efficacy Evaluations.................................................................................................................... 27
3.2.6
Safety Evaluations...................................................................................................................... 28
3.2.7
Pharmacokinetic Evaluations ..................................................................................................... 29
3.2.8
Immunogenicity Evaluations....................................................................................................... 29
3.2.9
Pharmacodynamic Evaluations .................................................................................................. 29
3.2.10
Pharmacogenetic (DNA) Evaluations......................................................................................... 29
3.2.11
Self-Administration...................................................................................................................... 30
3.2.12
Health Economics Data Collection ............................................................................................. 30
4
SUBJECT SELECTION..................................................................................................................... 30
4.1
Inclusion Criteria ............................................................................................................................ 30
4.2
Exclusion Criteria ........................................................................................................................... 31
4.3
Prohibitions and Restrictions ......................................................................................................... 31
5
TREATMENT ALLOCATION AND BLINDING................................................................................. 32
5.1
Treatment Allocation ...................................................................................................................... 32
5.2
Blinding .......................................................................................................................................... 32
6
DOSAGE AND ADMINISTRATION .................................................................................................. 33
6.1
Dosing Regimen............................................................................................................................. 33
6.2
Blinding .......................................................................................................................................... 34
6.3
Timing and Study Agent Administration......................................................................................... 35
6.4
DMARD/Oral Corticosteroid Initiation/Adjustment ......................................................................... 35
6.5
Self-Administration......................................................................................................................... 35
7
TREATMENT COMPLIANCE............................................................................................................ 36
8
CONCOMITANT THERAPY AND PROCEDURES .......................................................................... 36
8.1
Concomitant Therapy..................................................................................................................... 36
8.1.1
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics .................................................... 36
8.1.2
Disease Modifying Antirheumatic Drugs/Systemic Immunosuppressives.................................. 37
8.1.3
Corticosteroid Therapy ............................................................................................................... 37
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
3
8.1.4
Statin Therapy ............................................................................................................................ 37
8.1.5
Drugs Metabolized by Cytochrome P450................................................................................... 38
8.2
Prohibited Medications................................................................................................................... 38
8.3
Joint Procedures ............................................................................................................................ 38
9
STUDY EVALUATIONS .................................................................................................................... 39
9.1
Study Procedures........................................................................................................................... 39
9.1.1
Overview..................................................................................................................................... 39
9.1.2
Double-Blinded Treatment Phase .............................................................................................. 39
9.1.3
Open-Label Treatment Phase .................................................................................................... 39
9.1.4
Posttreatment Phase (Follow-Up) .............................................................................................. 40
9.2
Efficacy........................................................................................................................................... 40
9.2.1
Evaluations ................................................................................................................................. 40
9.2.1.1
Joint Assessments...................................................................................................................... 40
9.2.1.2
Pain Assessment........................................................................................................................ 41
9.2.1.3
Patient’s and Physician’s Global Assessment of Disease Activity ............................................. 41
9.2.1.4
Health Assessment Questionnaire – Disability Index................................................................. 41
9.2.1.5
Duration of Morning Stiffness ..................................................................................................... 42
9.2.1.6
36-Item Short Form Questionnaire ............................................................................................. 42
9.2.1.7
Work Limitations Questionnaire.................................................................................................. 42
9.2.1.8
Multidimensional Personality Questionnaire (MPSQ) ................................................................ 42
9.2.2
Definitions ................................................................................................................................... 43
9.2.2.1
American College of Rheumatology Responses........................................................................ 43
9.2.2.2
Disease Activity Index Score 28 ................................................................................................. 43
9.2.2.3
Simplified Disease Activity Index Score ..................................................................................... 44
9.2.2.4
Clinical Disease Activity Index Score ......................................................................................... 44
9.2.2.5
ACR/EULAR Remission ............................................................................................................. 45
9.2.3
Endpoints.................................................................................................................................... 45
9.3
Pharmacokinetics and Immunogenicity ......................................................................................... 46
9.3.1
Evaluations ................................................................................................................................. 46
9.3.2
Pharmacokinetics ....................................................................................................................... 46
9.3.2.1
Serum Collection and Handling .................................................................................................. 46
9.3.2.2
Analytical Procedures................................................................................................................. 46
9.3.2.3
Pharmacokinetic Parameters ..................................................................................................... 46
9.3.3
Immunogenicity Assessment (Antibodies to sirukumab)............................................................ 46
9.4
Pharmacodynamic Evaluations...................................................................................................... 47
9.5
Pharmacogenetics (DNA) Evaluations........................................................................................... 47
9.6
SmartJect™ Autoinjector Usability Substudy................................................................................. 47
9.7
Health Economics Evaluations ...................................................................................................... 48
9.8
Safety Evaluations ......................................................................................................................... 48
9.9
Sample Collection and Handling.................................................................................................... 52
10
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 52
10.1
Completion ..................................................................................................................................... 52
10.2
Discontinuation of Treatment ......................................................................................................... 52
10.2.1
Interruption of Study Agent Administration................................................................................. 56
10.3
Withdrawal from the Study............................................................................................................. 57
11
STATISTICAL METHODS................................................................................................................. 57
11.1
Subject Information ........................................................................................................................ 58
11.2
Efficacy and Safety Analyses......................................................................................................... 58
11.2.1
Primary Endpoint ........................................................................................................................ 58
11.2.2
Major Secondary Endpoints ....................................................................................................... 58
11.2.3
Other Secondary Endpoints ....................................................................................................... 59
11.3
Pharmacokinetic Analyses............................................................................................................. 59
11.4
Immunogenicity Analyses .............................................................................................................. 59
11.5
Pharmacodynamic Analyses.......................................................................................................... 59
11.6
Pharmacogenetics (DNA) Analyses............................................................................................... 60
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
4
11.7
Health Economics Analyses .......................................................................................................... 60
11.8
Safety Analyses ............................................................................................................................. 60
11.9
Interim Analysis.............................................................................................................................. 60
11.10
Data Monitoring Committee ........................................................................................................... 61
11.11
Clinical Events Committee ............................................................................................................. 61
12
ADVERSE EVENT REPORTING ...................................................................................................... 61
12.1
Definitions ...................................................................................................................................... 62
12.1.1
Adverse Event Definitions and Classifications ........................................................................... 62
12.1.2
Attribution Definitions.................................................................................................................. 63
12.1.3
Severity Criteria .......................................................................................................................... 63
12.2
Special Reporting Situations.......................................................................................................... 64
12.3
Procedures..................................................................................................................................... 64
12.3.1
All Adverse Events...................................................................................................................... 64
12.3.2
Serious Adverse Events ............................................................................................................. 65
12.3.3
Pregnancy................................................................................................................................... 66
12.4
Adverse Events of Special Interest................................................................................................ 66
12.5
Contacting Sponsor Regarding Safety........................................................................................... 67
13
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 67
13.1
Procedures..................................................................................................................................... 67
13.2
Contacting Sponsor Regarding Product Quality ............................................................................ 68
14
STUDY AGENT INFORMATION....................................................................................................... 68
14.1
Physical Description of Study Agent(s).......................................................................................... 68
14.2
Packaging ...................................................................................................................................... 68
14.3
Labeling.......................................................................................................................................... 68
14.4
Preparation, Handling, and Storage............................................................................................... 68
14.5
Drug Accountability ........................................................................................................................ 69
15
STUDY-SPECIFIC MATERIALS....................................................................................................... 70
16
ETHICAL ASPECTS ......................................................................................................................... 70
16.1
Study-Specific Design Considerations........................................................................................... 70
16.2
Regulatory Ethics Compliance....................................................................................................... 70
16.2.1
Investigator Responsibilities ....................................................................................................... 70
16.2.2
Independent Ethics Committee or Institutional Review Board ................................................... 70
16.2.3
Informed Consent ....................................................................................................................... 72
16.2.4
Privacy of Personal Data ............................................................................................................ 73
16.2.5
Country Selection ....................................................................................................................... 74
17
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 74
17.1
Protocol Amendments.................................................................................................................... 74
17.2
Regulatory Documentation ............................................................................................................ 74
17.2.1
Regulatory Approval/Notification ................................................................................................ 74
17.2.2
Required Prestudy Documentation............................................................................................. 74
17.3
Subject Identification, Enrollment, and Screening Logs ................................................................ 75
17.4
Source Documentation................................................................................................................... 75
17.5
Case Report Form Completion ...................................................................................................... 76
17.6
Data Quality Assurance/Quality Control ........................................................................................ 77
17.7
Record Retention ........................................................................................................................... 77
17.8
Monitoring ...................................................................................................................................... 78
17.9
Study Completion/Termination....................................................................................................... 79
17.9.1
Study Completion ....................................................................................................................... 79
17.9.2
Study Termination....................................................................................................................... 79
17.10
On-Site Audits ................................................................................................................................ 79
17.11
Use of Information and Publication................................................................................................ 79
REFERENCES............................................................................................................................................ 82
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
5
ATTACHMENT 1: PROTOCOL HISTORY ................................................................................................ 85
AMENDMENT 1 – 06 MARCH 2013 .......................................................................................................... 86
AMENDMENT 2 – 01 MAY 2014.............................................................................................................. 118
AMENDMENT 3 – 06 OCT 2016 .............................................................................................................. 122
ATTACHMENT 2:  ANTICIPATED EVENTS ........................................................................................... 134
APPENDIX A
QUANTIFERON-TB GOLD TESTING....................................................................... 135
APPENDIX B
TUBERCULIN SKIN TESTING ................................................................................... 137
APPENDIX C
GUIDELINES FOR MTX DOSE ADJUSTMENTS FOR MTX- TOXICITY .................. 139
INVESTIGATOR AGREEMENT ............................................................................................................... 141
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
6
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Times and Events in Long-term Extension............................................................................... 14
Table 2:
Times and Events in Safety and Efficacy Follow-up After Last Study Agent Injection or 
after Discontinuation of Study Agent ........................................................................................ 17
Table 3:
DAS28 (CRP) response criteria................................................................................................ 44
Table 4:
Values for liver transaminase levels, absolute neutrophil count, and platelet count that 
require study agent interruption and/or permanent discontinuation of study agent 
administration............................................................................................................................ 56
FIGURES
Figure 1:
CNTO136ARA3004 Study Design and Study Timeline............................................................ 25
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
7
SYNOPSIS
A Multicenter, Parallel-group Study of Long-term Safety and Efficacy of CNTO 136 (sirukumab) for
Rheumatoid Arthritis in Subjects Completing Treatment in Studies CNTO136ARA3002 (SIRROUND-D) 
and CNTO136ARA3003 (SIRROUND-T)
CNTO 136 (sirukumab) is a human anti-interleukin-6 (IL-6) mAb currently under development by the 
Sponsor in collaboration with GlaxoSmithKline, plc.  It binds to human IL-6 with high affinity and 
specificity, and has been shown to inhibit IL-6-mediated signal transducer and activator of transcription-3 
(STAT3) phosphorylation, resulting in the inhibition of the biological effect of IL-6.  The target 
indications for sirukumab are rheumatoid arthritis (RA) and lupus nephritis, both of which are diseases 
that involve IL-6. 
OBJECTIVES AND HYPOTHESIS
Primary Objective
To evaluate the long-term safety of sirukumab in subjects with RA who are refractory to DMARDs or 
anti-TNFα agents.
Secondary Objectives
The secondary objectives are to observe the following long-term effects of sirukumab in subjects with RA 
who are refractory to DMARDs or anti-TNFagents on: 

Efficacy 

Pharmacokinetics 

Immunogenicity

Pharmacodynamics

Pharmacogenetics

PFS-AI Usability (as defined in separate substudy protocol) 
Hypothesis
No hypothesis is being tested. 
OVERVIEW OF STUDY DESIGN
Subjects will become eligible to participate in this LTE study when they have completed participation in 
studies CNTO136ARA3002 (104 weeks) or CNTO136ARA3003 (52 weeks).  The purpose of this LTE 
study is to evaluate the safety, efficacy, and pharmacologic effects of sirukumab for a minimum duration 
of 1 additional year and a maximum total duration of approximately 5 years across the combined 
protocols (CNTO136ARA3002 (2 years) or CNTO136ARA3003 (1 year) + CNTO136ARA3004 (1 to 
4 years) = maximum of 5 years treatment). 
The SmartJect™ Autoinjector (PFS-AI) is expected to be used by the majority of subjects in study 
CNTO136ARA3004. In the event PFS-AIs are unavailable at the time of a subject’s enrollment in this 
protocol, sirukumab PFS-Ultrasafe (PFS-U), the same device used in the CNTO136ARA3002 and 
CNTO136ARA3003 studies, will be provided until such time as the PFS-AIs become available. Upon 
availability of PFS-AI trial supplies, subjects who are newly entering the CNTO136ARA3004 protocol 
will be trained on the operation of PFS-AI and perform self-administration of study agent using PFS-AI at 
the Week 2 study visit and return to the study site at Week 4 for self-administration with PFS-AI.  In the 
event PFS-AIs are unavailable at the time of a subject’s enrollment in this protocol, training on the use of 
a PFS-AI will be provided at the next study visit when the PFS-AI is available. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
8
During the Week 104 visit in CNTO136ARA3002 or the Week 52 visit in CNTO136ARA3003, subjects 
will sign the informed consent form (ICF) to enter study CNTO136ARA3004.  As a result, the Week 104 
visit in study CNTO136ARA3002 and the Week 52 visit in study CNTO136ARA3003 will correspond to 
the Week 0 visit in the CNTO136ARA3004 study.  
After a minimum of 1 year treatment in CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of treatment in CNTO136ARA3004 for subjects from 
CNTO136ARA3003, and after sirukumab is approved for the treatment of RA in the subject’s country of 
residence, the Sponsor may no longer offer study treatment in CNTO136ARA3004 for those specific 
subjects. At that point the subject will have the opportunity to discuss treatment options with their 
treating physician.   
The maximum duration of participation in this study is 208 weeks, followed by approximately 16 weeks 
of safety and efficacy follow-up after the administration of the final study agent injection of sirukumab.  
The study will end with the last visit for the last subject participating in the study.  
Study treatment will remain blinded in CNTO136ARA3004 until the following 3 conditions have been 
met: the Week 52 DBL occurs in study CNTO136ARA3002, the Week 24 DBL occurs in study 
CNTO136ARA3003, and the last AI usability substudy subject completes the Week 16 visit or terminates 
from the study. Thereafter treatment in study CNTO136ARA3004 becomes open-label, and placebo 
injections are discontinued in the SC sirukumab 50 mg treatment group.
Subject safety will be monitored and assessments will be done through the end of the study as delineated 
in the Time and Events Schedule (Table 1 and Table 2).
Only 1 DBL (at the end of the study) is planned. Additional data releases or locks may occur as needed.
An Independent Data Monitoring Committee (DMC) and Clinical Events Committee (CEC) will be 
commissioned for this study.  
SUBJECT SELECTION
To be eligible to enroll in this long-term extension study, subjects will have to have fulfilled the following 
conditions:

For subjects in study CNTO136ARA3002, have completed the Week 104 visit and study agent 
administration

For subjects in study CNTO136ARA3003, have completed the Week 52 visit and study agent 
administration.
Subjects who withdraw consent and/or have permanently discontinued study agent administration prior to 
the final visit in study CNTO136ARA3002 or CNTO136ARA3003 will be excluded from enrollment in 
the CNTO136ARA3004 study.
DOSAGE AND ADMINISTRATION
Dosing Regimen
Subjects will continue to receive the sirukumab dosing regimen they received at the end of the primary 
studies (CNTO136ARA3002, CNTO136ARA3003).
Group 1:
Sirukumab 100 mg SC at Weeks 0 (administered as the last dose in CNTO136ARA3002 
or CNTO136ARA3003), 2 and q2 weeks through Week 156 for subjects who enrolled 
after completing participation in CNTO136ARA3002 and through Week 208 for subjects 
who enrolled after completing participation in CNTO136ARA3003.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
9
Group 2:
Sirukumab 50 mg SC at Weeks 0 (administered as the last dose in CNTO136ARA3002 
or CNTO136ARA3003), 4 and q4 weeks through Week 156 for subjects who enrolled 
after completing participation in CNTO136ARA3002 and through Week 208 for subjects 
who enrolled after completing participation in CNTO136ARA3003.  Between sirukumab 
injections, placebo SC injections will be administered at Weeks 2, 6, and q4 weeks until 
the study becomes open-label and placebo injections will be discontinued.
After the study becomes open-label, subjects treated with SC sirukumab 100 mg q2 weeks will be offered 
the option to reduce the dose to 50 mg q4 weeks at the investigator’s discretion. This decision can be 
made at the subject’s first or second major resupply visit (up until approximately 7 months) after 
implementation of Amendment 3 at the study site. Once a subject’s dose is reduced to 50 mg q4 weeks, 
the subject will receive that dose for the remainder of the trial (ie, a return to 100 mg q2 weeks will not be 
allowed). If a subject opts to remain on the sirukumab 100 mg q2 weeks dose, he or she will remain on 
that dose for the duration of their participation in the study (ie, the subject will not have the option to 
reduce the dose at a subsequent timepoint).
If an injection is missed, every effort should be made to have the missed injection administered within 7 
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 medical monitor.
If sirukumab becomes approved in the subject’s country of residence, study agent administrations in 
CNTO136ARA3004 may be discontinued after 52 weeks of treatment for subjects who enrolled after 
completing participation in study CNTO136ARA3002, and after 104 weeks of treatment for subjects who 
enrolled after completing participation in CNTO136ARA3003. Therefore, all subjects in study 
CNTO136ARA3004 are expected to receive a minimum of 3 years of treatment with study agent (primary 
study + LTE study).
Blinding
To maintain the blind, all subjects will receive study agent as 1 SC injection as follows:  
Group 1 (sirukumab 100 mg):  1.0 mL sirukumab 100 mg injection q2 weeks.
Group 2 (sirukumab 50 mg): 1.0 mL sirukumab 50 mg injection q4 weeks. Between sirukumab injections, 
placebo SC injections will be administered at Weeks 2, 6, and q4 weeks until the study becomes open-
label, and placebo injections will be discontinued.
Timing and Study Agent Administration 
Through the end of the study, it is recommended that both the visit and the SC study agent administration 
occur within 7 days of the scheduled visit day. The SC study agent administrations must always be at 
least 7 days apart.
Self-Administration
The SmartJect™ Autoinjector (PFS-AI) is expected to be used by the majority of subjects in study 
CNTO136ARA3004. In the event PFS-AIs are unavailable at the time of a subject’s enrollment in this 
protocol, sirukumab PFS-Ultrasafe (PFS-U), the same device used in the CNTO136ARA3002 and 
CNTO136ARA3003 studies will be provided until such time as the PFS-AIs become available. Upon 
availability of PFS-AI trial supplies, subjects who are newly entering the CNTO136ARA3004 protocol 
will be trained on the operation of PFS-AI and perform self-administration of study agent using PFS-AI at 
the Week 2 study visit and return to the study site at Week 4 for self-administration with PFS-AI.  In the 
event PFS-AIs are unavailable at the time of a subject’s enrollment in this protocol, training on the use of 
a PFS-AI will be provided at the next study visit when the PFS-AI is available. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
10
The self-injection training consists of a face-to-face, “hands-on” training, with an explanation of each task 
in the Instructions For Use (IFU), a demonstration performed by the study site staff with the PFS-AI 
trainer device, followed by practice injections performed by the subject using the trainer device, until the 
study site staff and subject are satisfied that the injections can be performed as stated in the IFU. This 
mimics the typical training by a physician’s office staff that is likely to be received by a patient for the 
prescribed marketed product, per the final product’s labeling. The step-by-step Training Guide for 
investigators or site staff to follow when providing training of subjects will be provided in the Site IP 
Procedures Manual.   If subjects are competent in using PFS-AI, they will subsequently be provided with 
study agent for self-administration at home, and instructed how to transport and store medication for at-
home use as indicated for this protocol. Subjects will be instructed to contact the investigator promptly in 
the event of any signs of an allergic reaction, infection, or bleeding.  Subjects may continue to administer 
the study agent at home for the duration of the study. Although additional face-to-face training sessions 
after the first training session are not scheduled, the site staff will be available to provide additional 
training if needed. If subjects or health care providers are uncertain about how to administer the study 
agent, the Sponsor recommends a review of the IFU and performing practice injections with the PFS-AI 
trainer device, and if necessary, to ask for retraining at the study site. 
Subjects unable or unwilling to self-administer will continue to have study agent injections performed by 
a health care professional at the study site. A caregiver may also be trained to administer study agent at 
home.
Once the study becomes open-label, the Week 2 visit for training may be skipped by subjects who are to 
receive open label sirukumab 50 mg q4 weeks and training in the use of an PFS-AI will be provided at 
Week 4.
EFFICACY EVALUATIONS
The efficacy evaluations chosen for this study are as follows:
RA response evaluations include:

American College of Rheumatology (ACR) responses

Disease Activity Index Score 28 (DAS28)

Health Assessment Questionnaire-Disability Index (HAQ-DI)

ACR/The European League Against Rheumatism (EULAR) remission 
Patient Reported Outcome (PRO) evaluations include:

36-Item Short Form (SF-36)

Work Limitations Questionnaire (WLQ)

Health Economics Questionnaire (HECONQ)
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Blood samples for the measurement of serum sirukumab concentrations and the detection of antibodies to 
sirukumab will be collected according to the Time and Events Schedule (Table 1).
PHARMACODYNAMIC EVALUATIONS
Samples for the analysis of pharmacodynamic markers will be collected.  The samples will be used to 
better understand the biology of RA, to provide a biological assessment of the loss of response of subjects 
to treatment with sirukumab, and to determine if the markers can be used to classify patients as potential 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
11
responders to treatment.  The samples to be collected include whole blood for RNA and serum for the 
evaluation of inflammation-associated proteins and other analytes such as but not limited to microRNAs. 
PHARMACOGENETIC (DNA) EVALUATIONS
Pharmacogenetic testing will be undertaken in this study for only those subjects who have provided 
voluntary consent. Assessment of genetic factors such as DNA methylation testing will be performed to 
better understand the response of subjects to treatment with sirukumab.  A whole blood sample will be 
collected for DNA methylation testing. Only DNA research related to sirukumab or to the diseases for 
which this drug is developed will be performed.
SAFETY EVALUATIONS
Subject safety evaluations including the reporting of adverse events, clinical laboratory tests (hematology, 
serum chemistry including liver function tests, and lipid panels), pregnancy tests, and vital signs (blood 
pressure and body weight) etc. will be monitored through the end of the study as delineated in the Time 
and Events Schedules (Table 1 and Table 2).  
In addition, an independent DMC will review unblinded data periodically for the blinded portion of the 
study and whenever deemed necessary to monitor subject safety.  
The CEC is an independent committee composed of external specialists, blinded to treatment assignment, 
which will be commissioned to review case information on serious cardiovascular (CV) events 
(myocardial infarction, stroke, death, hospitalization for angina, hospitalization for transient ischemic 
attack [TIA]).  The operations, processes, and definitions to be employed by the committee will be 
defined in the CEC charter.  
SMARTJECT™ AUTOINJECTOR USABILITY SUBSTUDY
In this substudy, a select number of subjects at selected sites in English-speaking countries who are 
enrolled in CNTO136ARA3004 will be consented and enrolled in a SmartJect™ AI Usability substudy.  
Site personnel in this substudy will observe and document 2 scheduled self-administrations of study agent
by subjects using the PFS-AI. All substudy subjects will also complete an e-diary regarding their 
experiences with at-home use of PFS-AI.  
STATISTICAL METHODS 
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor.  
Subjects will continue to receive the same treatment regimen administered in studies CNTO136ARA3002 
and CNTO136ARA3003 at Weeks 104 and 52, respectively:

Group 1:  Sirukumab 100 mg SC q2 weeks 

Group 2:  Sirukumab 50 mg SC q4 weeks 
After the study becomes open-label, subjects in Group 1 will be offered the option (at the discretion of the 
investigator) to reduce the sirukumab dose to 50 mg q4 weeks for the remainder of the trial.
Since the treatment groups are not randomly assigned in this study, no formal hypothesis testing is 
planned. The efficacy, safety, and PK/PD/immunogenicity analyses will be performed separately for
subjects who complete studies CNTO136ARA3002 and CNTO136ARA3003. The analyses will include 
all subjects enrolled by study and by treatment group above.
Only 1 DBL (at the end of the study) is planned. Safety, efficacy, and PK/PD/immunogenicity 
assessments will be analyzed for subjects enrolled in the CNTO136ARA3004 by previous study and by 
treatment group.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
12
Additional data releases or locks may occur as needed.  The analyses based on these data releases or locks
intend to integrate data from CNTO136ARA3002 and CNTO136ARA3003 with this study for the long-
term PK, immunogenicity, safety and efficacy data of all subjects enrolled in these studies. A separate 
SAP for integration will be developed to specify the analyses and data handling rules. 

Sample Size Determination
All eligible subjects will be included in this LTE study. No power calculations were performed as there is 
no statistical hypothesis testing planned.

Interim Analysis
No formal interim analyses are planned, though analyses based on interim releases and locks may be 
carried out for integrated PK, immunogenicity, safety and efficacy data.

Primary Analyses
The number of subjects with each of the following long-term safety events: cardiovascular SAEs, 
malignancies, serious infections, and gastrointestinal perforations will be summarized. Serious 
cardiovascular events adjudicated by the CEC will be summarized by treatment group.  No hypothesis 
testing will be performed.

Secondary Analyses
The laboratory parameters of interest (neutrophils, platelets, hepatobiliary parameters, and lipid 
parameters) will be summarized by the treatment group over time. Baseline value is defined as the 
baseline value of study CNTO136ARA3002 or CNTO136ARA3003, respectively.

Other Planned Analyses

Safety Analyses
Additional analyses will be performed for the number of patients with cardiovascular SAEs by 
cardiovascular type and the number of patients with malignancies by malignancy type (eg, lymphoma, 
nonmelanoma skin cancers, other malignancies). 
Other safety data will be assessed by summarizing the proportion of subjects with AEs, the types of AEs, 
infections, SAEs, AEs leading to discontinuation, and changes in laboratory parameters.  

Efficacy Analysis 
The following efficacy endpoints will be summarized by treatment group over time:

ACR responses

DAS28 

HAQ-DI 

SF-36
Baseline value in efficacy is defined as the baseline value of study CNTO136ARA3002 or 
CNTO136ARA3003.  No missing data imputation will be used. 

Medical Resource Usage and Health Economics
WLQ and HECONQ data will be summarized over time.

Pharmacokinetic and Immunogenicity Analyses 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
13
Serum sirukumab concentration data including Ctrough will be summarized. PK data may be displayed 
graphically. If sufficient samples are collected, steady-state trough serum sirukumab concentrations 
before and after switching from PFS-U to PFS-AI will be evaluated.
The incidence of antibodies to sirukumab will be summarized for subjects with appropriate samples for 
detection of antibodies to sirukumab (ie, at least 1 sample obtained after sirukumab administration).

Pharmacodynamic Analyses 
Changes in the concentration of individual pharmacodynamic markers from baseline to the selected post 
treatment time points will be summarized. Association between baseline levels and changes from baseline 
in select biomarkers and clinical response will be explored. The pharmacodynamic analysis will 
characterize the response of subjects to sirukumab, to determine if loss of response to sirukumab can be 
predicted, and to better understand RA. Data will be summarized in a separate technical report.

Pharmacogenetic Analyses
Pharmacogenetic tests will be summarized by treatment group. Genetic factors and changes in expression 
of DNA methylation markers from baseline (CNTO136ARA3002 and CNTO136ARA3003 studies) to the
collection time point in study CNTO136ARA3004 will also be summarized. The pharmacogenetic 
analyses will be summarized in a separate technical report.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
14
TIME AND EVENTS SCHEDULE
Table 1:
Times and Events in Long-term Extension
Wk 
0
Wk
2b
Wk
4
Wk 
16
Wk 
28
Wk 
40
Wk 
52
Wk 
64
Wk
76
Wk
88
Wk 
104
Wk 
116
Wk
128
Wk 
140
Wk
156c
Wk 
168
Wk 
180
Wk 
192
Wk 
208d
Study Proceduresa
Administrative
Informed consent
X
Pharmacogenetic (DNA) 
consent
X
Training sessionb,e
X
Study Agent Administration
SC administration of study 
agent
X
←     administrations q2 or q4 weeks depending upon dosing regimen      →
Post-administration injection-
site evaluation 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments 
Urine pregnancy test (local)f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination  
X
X
X
X
Body weight measurement 
X
X
X
X
Blood pressure 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB evaluation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Joint assessment 
X
X
X
X
X
X
X
X
RA assessmentsg
X
X
X
X
X
X
X
X
SF-36
X
X
X
X
X
X
X
X
WLQ
X
X
X
X
X
X
X
X
Health Economics
X
X
X
X
X
X
X
X
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
15
Table 1: Times and Events in Long-term Extension
Wk 
0
Wk
2b
Wk
4
Wk 
16
Wk 
28
Wk 
40
Wk 
52
Wk 
64
Wk
76
Wk
88
Wk 
104
Wk 
116
Wk
128
Wk 
140
Wk
156c
Wk 
168
Wk 
180
Wk 
192
Wk 
208d
Exploration of Placebell©™ technology for RA
Placebell Multidimensional 
Personality Questionnaireh
←     optional at selected sites for consenting subjects at a single visit after implementation of Amendment 3   →
Clinical Laboratory Assessments
Hematology panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry panel  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid panel (fasting) 
X
X
X
X
X
X
X
X
CRP 
X
X
X
X
X
X
X
Pharmacokinetics / Immunogenicity
Sirukumab concentration 
(pharm serum sample)i,j
X
X
X
X
X
X
X
Xk
Antibodies to sirukumab 
(pharm serum sample)i,j
X
X
X
X
X
Xk
Pharmacodynamics
Pharmacodynamics serum 
sample
X
X
X
X
Whole blood sample for RNA
X
X
X
X
Pharmacogenetics(DNA)
Pharmacogenetics samplel
X
Ongoing Subject Review
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
16
Table 1: Times and Events in Long-term Extension
a. All assessments are to be completed prior to study agent administration, unless otherwise specified.  For subjects who discontinue study agent injections, see Table 2
for required follow-up assessments. Administration of study agent and visit windows should be within 7 days for all visits.  Administration of study agent must occur 
no less than 7 days apart throughout the study.
b. Once the study becomes open-label, the Week 2 visit will not be conducted for subjects in treatment Group 2.  The training session for these subjects will occur at 
Week 4 or at a subsequent visit following the availability of the PFS-AI.
c. Last study agent administration for subjects who enrolled after participating in CNTO136ARA3002.  These subjects will then have follow-up assessments as 
described in Table 2.
d. Last study agent administration for subjects who enrolled after participating in CNTO136ARA3003.  These subjects will then have follow-up assessments as 
described in Table 2.
e. Training in the use of a PFS-AI will be provided at the first scheduled visit that the subject receives the PFS-AI for the self-administration of study agent.
f. Urine pregnancy testing during the study for women of childbearing potential only.  Additional 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.  
g. RA assessments include the following:  patient pain assessment; patient global assessment of disease activity, physician global assessment of disease activity, Health 
Assessment Questionnaire-Disability Index, and duration of morning stiffness.
h. At selected sites, the MPSQ will be administered as an optional paper questionnaire to subjects who consent to participate after implementation of Amendment 3 at 
the study site.
i.
Pharm serum samples (sirukumab concentration and antibodies to sirukumab) will be collected from subjects who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 750 subjects randomized in CNTO136ARA3002 before 18 November 2013) and from all subjects enrolled after 
participating in study CNTO136ARA3003.
j.
On days of study agent administration, Pharm serum samples (sirukumab concentration and antibodies to sirukumab) must be collected prior to administration. Blood 
collected from one venipuncture will be divided into 3 serum aliquots (1 each sirukumab concentration, antibodies to sirukumab and a backup sample). Refer to the 
Central Laboratory Manual for more detailed instructions.
k. Pharm serum samples (sirukumab concentration and antibodies to sirukumab) will be collected only from those subjects who enrolled after participating in study 
CNTO136ARA3003.
l.
An optional pharmacogenetics blood sample will be collected from those subjects who sign a separate consent form (where local regulations permit).
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
17
Table 2:
Times and Events in Safety and Efficacy Follow-up After Last Study Agent Injection or after Discontinuation of Study Agent
Week 4
Week 8
Week 12
Week 16/Final 
Safety and 
Efficacy 
Follow-up Visit
Study Procedure a,b
Safety Assessments
Blood pressure
X
X
X
X
Efficacy Assessments
Patient pain assessment
X
X
Patient global assessment of disease
X
X
Physician global assessment of disease
X
X
Clinical Laboratory Assessments
Hematology panel
X
X
Chemistry panel
X
X
Lipid panel (fasting)
X
X
CRP
X
X
Pharmacokinetics/ Immunogenicity
Sirukumab concentration (pharm serum sample)c,d
X
Antibodies to sirukumab (pharm serum sample)c,d
X
Ongoing Subject Review
Injection-site evaluations
X
Adverse events
X
X
X
X
Concomitant medications
X
X
X
X
a.
Subjects who discontinue study agent injections and who are not terminating study participation should return for all scheduled follow-up assessments through 
approximately 16 weeks after the last study agent injection as specified in this table.
b.
The first safety and efficacy follow-up visit should occur 4 weeks 14 days after their last study agent injection.  The visit window for follow-up assessments is 
14 days.
c.
Pharm serum samples (sirukumab concentration and antibodies to sirukumab) will be collected at the final safety and efficacy follow up visit only from those 
subjects who had pharm serum samples collected at earlier time points in study CNTO136ARA3002 (approximately 750 subjects randomized in 
CNTO136ARA3002 before 18 November 2013) and from all subjects enrolled after participating in study CNTO136ARA3003.
d.
Blood collected from one venipuncture will be divided into 3 serum aliquots (1 each for sirukumab concentration, antibodies to sirukumab and a backup sample).  
Refer to the Central Laboratory Manual for more detailed instructions.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
18
ABBREVIATIONS
ACR
American College of Rheumatology
AE
adverse event
AI
Autoinjector
ALT
alanine aminotransferase
anti-HBc total
hepatitis B core antibody 
anti-HBs
hepatitis B surface antibody 
AST
aspartate aminotransferase
BD
Becton-Dickinson
BUN
blood urea nitrogen
CDAI
Clinical Disease Activity Index
CEC
Clinical Events Committee 
CQ
chloroquine
CRF
case report form
CRP
C-reactive protein
CSR
Clinical Study Report
Ctrough
Observed serum concentration immediately prior to the next administration
CV
cardiovascular
CYP
cytochrome P450
DAS28
Disease Activity Index Score 28
DBL
database lock
DMARD
disease modifying antirheumatic drugs
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSUR
Development Safety Update Report
ECG
electrocardiogram
eCRF
electronic case report form
eDC
Electronic Data Capture
EULAR
The European League Against Rheumatism
Fc
fragment crystallizable
FDA
Food and Drug Administration
G
gauge
GCP
Good Clinical Practice
GH
Patient’s Global Assessment of Disease Activity
GMS
Global Medical Safety
HAQ-DI
Health Assessment Questionnaire-Disability Index
HBsAg
hepatitis B surface antigen
HCQ
hydroxychloroquine
HDL
high-density lipoprotein
HECONQ
Health Economics Questionnaire
HIV
human immunodeficiency virus
IA
intra-articular
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG1
immunoglobulin G1
IL
interleukin
IL-6R
interleukin 6 receptor
sIL-6R
soluble interleukin 6 receptor
IM
intramuscular
INR
international normalized ratio
IRB
Institutional Review Board
IV
intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
JAK/STAT
janus kinase/signal transducer and activator of transcription
LDL
low-density lipoprotein
LE
lupus erythematosus
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
19
LN
Lupus Nephritis
LSLV
last subject’s last visit
LTE
long-term extension
mAb
monoclonal antibody
MACE
Major Adverse Cardiovascular Events
MCS
Mental Component Score 
MedDRA
Medical Dictionary for Regulatory Activities
MPSQ
Multidimensional Personality Questionnaire
MTX
methotrexate
NCEP
National Cholesterol Education Program
NK
natural killer
NSAID
nonsteroidal anti-inflammatory drug
PCS
Physical Component Score
PD
pharmacodynamics
PFS
Pre-filled Syringe
PFS-AI
Pre-filled Syringe Autoinjector
PFS-U
Pre-filled Syringe Ultrasafe Device
PGH
Physician’s Global Assessments of Disease Activity
PI
principal investigator
PK
pharmacokinetics
PO
by mouth
PQC
product quality complaint
PRO
Patient Reported Outcome
q2 
every 2 
q4 
every 4 
QT
the time between the beginning of the QRS complex and the end of the T-wave
QTc
the time between the beginning of the QRS complex and the end of the T-wave, adjusted for 
heart rate (normal 350-440 milliseconds)
RA
rheumatoid arthritis
RAS
rat sarcoma viral oncogene homolog 
RBC
red blood cell (count)
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SDAI
Simplified Disease Activity Index
SF-36
36-item short form health survey 
SI
International System of Units 
SSZ
sulfasalazine
STAT3
signal transducer and activator of transcription-3
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TIA
transient ischemic attack
TNFα
tumor necrosis factor alpha
ULN
upper limit of normal
US
United States
VAS
Visual Analogue Scale (Score)
WBC
white blood cell
WLQ
Work Limitations Questionnaire
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
20
1
INTRODUCTION
CNTO 136 (sirukumab) is a human anti-IL-6 mAb currently under development by the Sponsor
in collaboration with GlaxoSmithKline, plc.  It binds to human IL-6 with high affinity and 
specificity, and has been shown to inhibit IL-6-mediated signal transducer and activator of 
transcription-3 (STAT3) phosphorylation, resulting in the inhibition of the biological effect of 
IL-6.  The target indications for sirukumab are rheumatoid arthritis (RA) and lupus nephritis
(LN), both of which are diseases that involve IL-6.
IL-6 is a pleiotropic cytokine known for proinflammatory functions.19  The physiological and 
pathological role of IL-6 has been illustrated in many in vitro and in vivo studies which 
collectively suggest that IL-6 induces the differentiation of B cells into antibody-producing cells; 
promotes the development of cytotoxic T cells34; supports differentiation of Th17 cells; affects 
macrophage differentiation32; is an independent regulator of granulopoiesis24; increases hepatic 
acute-phase reactants, and promotes mesangial cell proliferation, keratinocyte growth, 
megakaryocytic differentiation, and thrombosis.16 IL-6 levels are increased in obesity, as IL-6 is 
produced from adipose tissue.46 Increased levels of IL-6 also correlate with insulin resistance.37
IL-6 blockade has been shown to have a potent effect on neutrophil recruitment.30
IL-6 knockout mice have a normal phenotype.  The animals are viable and fertile, but have a
slightly decreased number of T-cells and a decreased acute phase protein response to tissue 
injury.20
IL-6 deficient mice have been noted to be susceptible to infections with Listeria 
monocytogenes, Toxoplasma gondii, and Candida albicans.6,38,44
In contrast, transgenic mice 
that over-express IL-6 in lymphoid cells have massive plasmacytosis, increased megakaryocytes, 
and mesangial cell proliferation in the kidney.43 Over-expression of IL-6 in the brain results in 
neurologic disease such as neurodegeneration, astrocytosis, and proliferative angiopathy.5
Published studies have demonstrated the involvement of IL-6 in various disease processes 
including lupus erythematosus (LE), RA, anemia of chronic inflammation, insulin resistance, and 
cancer.
1.1
IL-6 as a Target in Rheumatoid Arthritis
Patients with RA often have increased levels of proinflammatory cytokines such as IL-6, IL-1, 
and tumor necrosis factor alpha (TNFα)3 in the synovial fluid and serum.  TNFα and IL-1 both 
can stimulate IL-6 production by multiple cell types in the RA synovium.13 Local concentrations 
of IL-6 may in turn stimulate leukocyte recruitment to the joint, promote osteoclast maturation 
and activation, suppress chondrocytes, and stimulate synovial proliferation, contributing to joint 
damage.11,23 Systemically, elevated IL-6 in patients with RA may induce hepatic production of 
acute phase proteins, increase platelet production, and the development of anemia of chronic 
inflammation via induction of hepcidin.31  It also may be chiefly responsible for autoimmune 
features in RA such as autoreactive T cell activation and hypergammaglobulinemia.17
Early studies focused on IL-6 signaling identified 2 mechanisms for signal transduction.  The 
first occurs when IL-6 binds specifically to the membrane-bound IL-6 receptor (IL-6R, or 
CD126).  This IL-6/IL-6R complex then binds 2 gp130 co-receptor molecules (CD130) on the 
cell membrane and triggers gp130-dependent intracellular signaling cascades via the janus 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
21
kinase/signal transducer and activator of transcription (JAK/STAT) and rat sarcoma viral 
oncogene homolog (RAS) pathways.  While gp130 is expressed on many cell types, the 
expression of membrane IL-6R is restricted to hepatocytes, neutrophils, monocytes, and other 
leukocyte populations and hence this classical or “cis” signaling mechanism is limited to these 
cell types.  However, a second mechanism was discovered when it was reported that soluble 
IL-6R (sIL-6R) can be secreted as a truncated form of the IL-6R in cells, or released from the 
cell surface due to proteolytic cleavage of membrane-bound IL-6R.25,29
IL-6 can form 
complexes with sIL-6R, and then initiate signaling on cells that express only the gp130 
co-receptor.26  This “trans” signaling therefore extends the effects of IL-6 to many other cell 
types that do not express endogenous IL-6R.39
Sirukumab binds to IL-6 and prevents its binding to both the membrane and soluble forms of 
IL-6R and therefore will provide similar inhibition of both “cis” and “trans” signaling due to 
IL-6.  In contrast, tocilizumab binds to the membrane and soluble forms of IL-6R in order to 
prevent IL-6 signaling.28 Tocilizumab inhibits signal transduction mediated by both mIL-6R and 
sIL-6R, but not by the receptors of other members of IL-6 cytokine family.28
As a result,
tocilizumab may not be as potent for the neutralization of “cis” signaling due to lower affinity for 
membrane IL-6R, or the cells expressing membrane IL-6R may be less accessible.  In addition, 
tocilizumab is a human IgG1 antibody that, when bound to membrane IL-6R, potentially can 
trigger cell lysis via complement or fragment crystallizable (Fc) receptor-expressing natural 
killer (NK) cells.4,14,40
IL-6 inhibition results in improvement in patients with active arthritis.21,33,51 The effectiveness of 
the anti-IL-6 receptor mAb, tocilizumab, in reducing joint swelling and tenderness, improving
physical function, and reducing the rate of radiographic progression was firmly established in 
pivotal registration studies.7,18,21,33,41
Additionally, in smaller RA studies biologic agents 
targeting the IL-6 cytokine ligand have also been shown to be efficacious.27,49
Safety issues related to the inhibition of IL-6 inhibition by tocilizumab include increased risk of 
serious infections and abnormalities in hematology, hepatobiliary, and lipid parameters. In 
addition, upper and lower gastrointestinal tract perforations occurred in the anti-IL-6 receptor 
(tocilizumab) Phase 3 program. The potential differences in safety or efficacy between agents
that bind to the IL-6 receptor versus ones that bind to the IL-6 ligand (sirukumab) remain 
unclear, but warrant further study.
In summary, IL-6 plays a major role in the pathophysiology of RA, and this is confirmed by the 
efficacy of IL-6 and IL-6 receptor inhibitors in clinical studies of patients with inflammatory 
arthritis.
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of sirukumab, refer to the latest version of the Investigator's Brochure 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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
22
1.2
Overall Rationale for the Study
This is a parallel-group long-term extension (LTE) trial of studies CNTO136ARA3002 and 
CNTO136ARA3003 to assess the long-term safety and efficacy of sirukumab in subjects with 
moderately to severely active RA.  Subjects who have completed participation in studies 
CNTO136ARA3002 or CNTO136ARA3003 will be eligible to enroll in this study.  Subjects are 
to continue to receive the identical sirukumab SC dose regimen of 100 mg every 2 (q2) weeks or 
50 mg every 4 (q4) weeks that they were receiving upon completion of participation in studies 
CNTO136ARA3002 and CNTO136ARA3003. 
Following the database lock for the primary endpoint, analysis of CNTO136ARA3002 and 
CNTO136ARA3003 PK and efficacy data showed that there was no clear dose response between 
the sirukumab SC 50 mg q4 weeks and sirukumab SC 100 mg q2 weeks dose groups across 
efficacy endpoints. Furthermore, there were a greater proportion of subjects with hypersensitivity 
reactions and injection site reactions in the sirukumab 100 mg q2 weeks dose group compared 
with the sirukumab 50 mg q4 weeks dose group. Therefore, to allow for minimization of the 
exposure to this immunosuppressant biologic agent, subjects treated with SC sirukumab 100 mg 
q2 weeks will be offered the option to reduce the sirukumab dose to 50 mg q4 weeks at the 
investigator’s discretion after the study becomes open-label. This decision can be made at the 
subject’s first or second major resupply visit (up until approximately 7 months) after 
implementation of Amendment 3 at the study site. Once a subject’s dose is reduced to 50 mg q4 
weeks, the subject will receive that dose for the remainder of the trial (ie, a return to 100 mg q2 
weeks will not be allowed). If a subject opts to remain on the sirukumab 100 mg q2 weeks dose, 
he or she will remain on that dose for the duration of their participation in the study (ie, the 
subject will not have the option to reduce the dose at a subsequent timepoint).
Additionally, a substudy of enrolled subjects in CNTO136ARA3004 will further assess the
usability of the SmartJect™ Autoinjector (PFS-AI).
2
OBJECTIVES AND HYPOTHESES
2.1
Objectives
Primary Objective
To evaluate the long-term safety of sirukumab in subjects with RA, who are refractory to disease 
modifying antirheumatic drugs (DMARD) or anti-TNFα agents.
Secondary Objectives
The secondary objectives are to observe the following long-term effects of sirukumab in subjects 
with RA who are refractory to DMARDs or anti-TNFagents on: 

Efficacy

Pharmacokinetics 

Immunogenicity

Pharmacodynamics
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
23

Pharmacogenetics

PFS-AI usability (as defined in a separate substudy protocol)
2.2
Hypothesis
No formal hypothesis is being tested.
3
STUDY DESIGN AND RATIONALE
3.1
Overview of Study Design
Subjects will become eligible to participate in this LTE study when they have completed 
participation in studies CNTO136ARA3002 (104 weeks) or CNTO136ARA3003 (52 weeks).  
The purpose of this LTE study is to evaluate the safety, efficacy, and pharmacologic effects of 
sirukumab for a minimum duration of 1 to 4 additional years and a maximum total duration of 
approximately 5 years across the combined protocols (CNTO136ARA3002 (2 years) or 
CNTO136ARA3003 (1 year) + CNTO136ARA3004 (1 to 4 years) = maximum of 5 years 
treatment). 
The SmartJect™ Autoinjector (PFS-AI) is expected to be used by the majority of subjects in 
study CNTO136ARA3004. In the event PFS-AIs are unavailable at the time of a subject’s 
enrollment in this protocol, sirukumab PFS-Ultrasafe (PFS-U), the same device used in the 
CNTO136ARA3002 and CNTO136ARA3003 studies, will be provided until such time as the 
PFS-AIs become available. Upon availability of PFS-AI trial supplies, subjects who are newly 
entering the CNTO136ARA3004 protocol will be trained on the operation of PFS-AI and 
perform self-administration of study agent using PFS-AI at the Week 2 study visit and return to 
the study site at Week 4 for self-administration with PFS-AI. In the event PFS-AIs are 
unavailable at the time of a subject’s enrollment in this protocol, training on the use of a PFS-AI 
will be provided at the next study visit when the PFS-AI is available. 
During the Week 104 visit in CNTO136ARA3002 or the Week 52 visit in CNTO136ARA3003, 
subjects will sign the informed consent form (ICF) to enter study CNTO136ARA3004.  As a 
result, the Week 104 visit in study CNTO136ARA3002 and the Week 52 visit in study 
CNTO136ARA3003 will correspond to the Week 0 visit in the CNTO136ARA3004 study.  
After a minimum of 1 year treatment in CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of treatment in CNTO136ARA3004 for subjects 
from CNTO136ARA3003, and after sirukumab is approved for the treatment of RA in the 
subject’s country of residence, the Sponsor may no longer offer study treatment in 
CNTO136ARA3004 for those specific subjects. At that point the subject will have the 
opportunity to discuss treatment options with their treating physician.   
The maximum duration of participation in this study is 208 weeks, followed by approximately 
16 weeks of safety and efficacy follow-up after the administration of the final study agent 
injection of sirukumab.  Only 1 database lock (DBL; at the end of the study) is planned.  
Additional data releases or locks may occur as needed. The study will end with the last visit for 
the last subject participating in the study. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
24
Study treatment will remain blinded in CNTO136ARA3004 until the following 3 conditions 
have been met: the Week 52 DBL occurs in study CNTO136ARA3002, the Week 24 DBL 
occurs in study CNTO136ARA3003, and the last AI usability substudy subject completes the 
Week 16 visit or terminates from the study.  Thereafter study CNTO136ARA3004 will become 
open-label and placebo injections will be discontinued in the SC sirukumab 50 mg treatment 
group. Once study CNTO136ARA3004 becomes open-label, study subjects will receive open-
label study agent through IVRS/IWRS.  However, when this study becomes open-label, any 
subjects who still remain in studies CNTO136ARA3002 and CNTO136ARA3003 due to 
staggered enrollment will continue to receive blinded treatment until they complete participation 
in those studies.
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns.  
Therefore, adherence to the study design requirements, including those specified in the Time and 
Events Schedules are essential and required for study conduct.  
Subject safety will be monitored through the end of the study as delineated in the Time and 
Events Schedules.
The primary endpoint is the number of subjects with each of the following long-term safety 
events through the end of the study: cardiovascular (CV) SAEs, malignancies, serious infections, 
and gastrointestinal perforations.
The major secondary endpoint is laboratory parameters of interest (neutrophils, platelets,
hepatobiliary parameters, and lipid parameters).
Serum samples will be collected for the evaluation of sirukumab PK and antibodies to 
sirukumab.  Other samples to be collected include serum and whole blood RNA for the 
evaluation of inflammation-associated proteins and other analytes.  These samples will be used 
to better understand the biology of RA, to analyze differences between responders and 
non-responders, and to assess loss of response.
A pharmacogenetics blood sample to assess genetic factors such as DNA methylation patterns 
will be collected from subjects who consent separately to the pharmacogenetics component of 
the study where local regulations permit. Participation in the pharmacogenetics research
component of this study is optional.
Health economics data including subject employability, daily work productivity, and reduced 
time lost from work will be collected.
Safety and tolerability will be assessed by monitoring AEs, clinical laboratory tests, vital signs, 
physical examinations, and concomitant medication review.
An independent Clinical Events Committee (CEC) will be established for this study to review 
case information on serious cardiovascular (CV) events (myocardial infarction, stroke, death, 
hospitalization for angina, hospitalization for transient ischemic attack (TIA); see Section 11.11).  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
25
An independent Data Monitoring Committee (DMC) will be commissioned for this study to 
review unblinded data periodically for the blinded portion of the study and whenever deemed 
necessary to monitor subject safety (see Section 11.10).
All assessments will be performed according to the Time and Events Schedules. A diagram of 
the study design is provided below (Figure 1).
Figure 1:
CNTO136ARA3004 Study Design and Study Timeline 
3.2
Study Design Rationale
This study is designed to examine the long-term safety and efficacy of sirukumab, the effects of 
sirukumab on physical function, pharmacokinetics, and immunogenicity of sirukumab in subjects 
with moderately to severely active RA who are refractory or intolerant to DMARDs or
anti-TNFtherapy.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
26
Additionally, this study is designed to obtain experience in the use of the SmartJect™ 
Autoinjector (PFS-AI) in all subjects enrolled in CNTO136ARA3004. More data regarding the 
usability of the autoinjector will be evaluated in the PFS-AI substudy.  Additional details are 
provided in Section 9.6.
3.2.1
Study Population
Subjects who complete the Week 104 (CNTO136ARA3002) visit and study agent administration 
or the Week 52 (CNTO136ARA3003) visit and study agent administration will be deemed to 
have completed participation in those studies and will be eligible to enroll in this long-term 
extension study.
3.2.2
Treatment Groups, Dosage, and Dose Administration Interval
Subjects will continue to receive the same dosing regimen they received at the Week 104 
(CNTO136ARA3002) and at Week 52 visit (CNTO136ARA3003) in blinded fashion until the 
following 3 conditions have been met: the Week 52 DBL occurs in study CNTO136ARA3002, 
the Week 24 DBL occurs in study CNTO136ARA3003, and the last AI usability substudy
subject completes the Week 16 visit or terminates from the study.  Thereafter the same treatment 
assignment will be continued, but the study will no longer be blinded and will become open-
label.
The 2 sirukumab doses to be administered in this study are as follows:

100 mg q2 weeks 

50 mg q4 weeks
Following the database lock for the primary endpoint, analysis of CNTO136ARA3002 and 
CNTO136ARA3003 PK and efficacy data showed that there was no clear dose response between 
the sirukumab SC 50 mg q4 weeks and sirukumab SC 100 mg q2 weeks dose groups across 
efficacy endpoints. Furthermore, there were a greater proportion of subjects with hypersensitivity 
reactions and injection site reactions in the sirukumab 100 mg q2 weeks dose group compared
with the sirukumab 50 mg q4 weeks dose group. Therefore, to allow for minimization of the 
exposure to this immunosuppressant biologic agent, subjects treated with SC sirukumab 100 mg 
q2 weeks will be offered the option to reduce the sirukumab dose to 50 mg q4 weeks at the 
investigator’s discretion after the study becomes open-label. This decision can be made at the 
subject’s first or second major resupply visit (up until approximately 7 months) after 
implementation of Amendment 3 at the study site.
3.2.3
Study Phases and Duration of Treatment
There will be 3 phases of this LTE study: Blinded active treatment, open-label treatment, and 
safety and efficacy follow-up. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
27
As described in Section 3.2.2, the blinded active treatment phase will continue until following 3 
conditions have been met: the Week 52 DBL occurs in study CNTO136ARA3002, the Week 24 
DBL occurs in study CNTO136ARA3003, and the last AI usability substudy subject completes 
the Week 16 visit or terminates from the study.
The open-label treatment phase of the study will begin after those 3 conditions have been met, 
and will continue through the last scheduled dose for all subjects.  The safety and efficacy 
follow-up will include approximately 16 weeks of study evaluations following the last 
administration of study agent, including follow-up for patients who discontinued study treatment 
prior to their last scheduled dose. The safety and efficacy follow-up allows for monitoring of the 
subject for a period of equivalent to at least 5 times the half-life of sirukumab.
The maximum duration of the study is expected to be 156 weeks for subjects enrolling after 
participation in study CNTO136ARA3002 and 208 weeks for subjects enrolling after 
participation in study CNTO136ARA3003, followed by approximately 16 weeks of safety and 
efficacy follow-up after the administration of the final study agent injection of sirukumab.   
After a minimum of 1 year treatment in CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of treatment in CNTO136ARA3004 for subjects 
from CNTO136ARA3003, and after sirukumab is approved for the treatment of RA in the 
subject’s country of residence, the Sponsor may no longer offer study treatment in 
CNTO136ARA3004 for those specific subjects. 
At that point the subject will have the 
opportunity to discuss treatment options with their treating physician.
3.2.4
Study Control, Randomization, and Blinding
Blinded matching placebo injections will be used to reduce potential bias during data collection 
and evaluation of clinical endpoints and will be maintained until the following 3 conditions have 
been met: the Week 52 DBL occurs in study CNTO136ARA3002, the Week 24 DBL occurs in 
study CNTO136ARA3003, and the last AI usability substudy subject completes the Week 16 
visit or terminates from the study.  Thereafter the CNTO136ARA3004 study will become open-
label.
3.2.5
Efficacy Evaluations
The efficacy evaluations chosen for this study are consistent with those in primary studies 
CNTO136ARA3002 and CNTO136ARA3003.
RA response evaluations include:

American College of Rheumatology (ACR) responses

Disease Activity Index Score 28 (DAS28)

Health Assessment Questionnaire-Disability Index (HAQ-DI)

ACR/The European League Against Rheumatism (EULAR) remission 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
28
Patient Reported Outcome (PRO) evaluations include: 

36-Item Short Form (SF-36)

Work Limitations Questionnaire (WLQ)

Health Economics Questionnaire (HECONQ)
The medical resource usage and health economics evaluations chosen for this study have also 
been used in studies CNTO136ARA3002 and CNTO136ARA3003.
3.2.6
Safety Evaluations
Based upon the emerging safety profile of other anti-IL-6 agents, as well as the sirukumab safety 
data to date, several AE of interest have been identified and will be monitored and assessed in 
this study.  These are: hematologic laboratory abnormalities (decreases in neutrophils and
platelets), hepatobiliary laboratory abnormalities, lipid parameter abnormalities, serious CV
events, infections, malignancies, and gastrointestinal perforations.1
Subject safety evaluations including the reporting of AEs, clinical laboratory tests (hematology, 
serum chemistry, and lipid panels), pregnancy tests, and vital signs (blood pressure and body 
weight) etc. will be monitored through the end of the study as delineated in the Time and Events 
Schedules.  In addition, an independent DMC will review unblinded data periodically for the 
blinded portion of the study and whenever deemed necessary to monitor subject safety.  
Laboratory parameter abnormalities:
IL-6 is a pleiotropic cytokine necessary for hematopoiesis and IL-6 inhibition has been shown to 
cause a reduction in both neutrophils and platelets. 
In addition, IL-6 inhibition has been 
associated with reversible elevation in liver enzymes.  Mechanisms by which this might occur 
include inhibition of the hepatoprotective effect of IL-6, leaving hepatocytes susceptible to 
effects of toxins and other stresses.  Lipid abnormalities have also been observed, both in the 
sirukumab Phase 2 study C1377T04, as well as with other anti-IL-6 agents.  The mechanism by 
which this occurs is not fully understood.  
Cardiovascular events:
Patients with RA are known to have an increased risk of serious CV events compared with the 
general population. In addition, in the sirukumab clinical programs, significant changes in lipid 
laboratory parameters have been observed, as with other agents that block IL-6. The clinical 
significance of these changes is not known.  Nonetheless, serious CV events are considered AEs 
of interest and will be closely monitored in the sirukumab program.  In order to fully understand 
CV events in this study, Major Adverse Cardiovascular Events (MACE), defined as myocardial 
infarction, stroke, death, hospitalization for unstable angina, and hospitalization for TIA, will be 
collected and prospectively adjudicated by an external CEC. The CEC is an independent 
committee composed of external specialists, blinded to treatment assignment, who will be 
commissioned to review case information on serious CV events (myocardial infarction, stroke, 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
29
death, hospitalization for angina, hospitalization for TIA).  The operations, processes, and 
definitions to be employed by the committee will be defined in the CEC charter.  This will allow 
external review of cases and determination of diagnosis prior to analysis.  See Section 11.11 for a 
complete discussion of the CEC.
Other events of interest:
Sirukumab, by its mechanism of action as an IL-6 inhibitor, would be expected to have some 
properties of immunosuppression. As such, increased susceptibility to certain infections is a 
potential risk. IL-6 deficient mice have been found to be susceptible to infections with Listeria 
monocytogenes, Toxoplasma gondii, and Candida albicans.6,38,44  In addition, as an IL-6 
inhibitor, sirukumab may have some effect on the risk of malignancy by affecting immune 
surveillance, particularly in a subject population (RA) already at increased risk for the 
development of lymphoma and leukemia. 
Further, gastrointestinal perforations have been 
reported with another anti-IL-6 agent at rates higher than the rate found in RA subjects.1
3.2.7
Pharmacokinetic Evaluations
To evaluate the PK of sirukumab in subjects with RA following long-term treatment, serum 
samples for the measurement of sirukumab concentrations will be collected according to the 
Time and Events Schedules.
3.2.8
Immunogenicity Evaluations
To evaluate the immunogenicity of sirukumab in subjects with RA following long-term 
treatment, serum samples for the detection of antibodies to sirukumab will be collected according 
to the Time and Events Schedules.
3.2.9
Pharmacodynamic Evaluations 
Whole blood and serum samples for the analysis of pharmacodynamic markers will be collected 
and analyzed for proteins, RNA, and other analytes such as but not limited to microRNAs.  The 
samples will be used to better understand the biology of RA, to provide a biological assessment 
of the response of subjects to treatment with sirukumab, to analyze responders, to assess loss of 
response, and to determine if the markers can be used to classify patients as potential responders 
to treatment. 
3.2.10
Pharmacogenetic (DNA) Evaluations 
Genetic variation and methylation status of DNA can be an important contributory factor to 
interindividual differences in drug disposition and response and may also serve as a marker for 
disease susceptibility and prognosis.  Pharmacogenetics research may help to explain 
interindividual variability in clinical outcomes and identify population subgroups that respond 
differently to a drug.  The goal of the pharmacogenetics component is to collect DNA to allow 
the identification of genetic factors or methylation patterns that may influence the 
pharmacokinetics, pharmacodynamics, efficacy, or tolerability of sirukumab and to identify 
genetic factors associated with RA.  DNA samples may be used to help address emerging issues 
and to enable the development of safer, more effective, and ultimately individualized therapies.  
For details, see Section 9.5.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
30
3.2.11
Self-Administration
Self-administration of SC products in subjects with RA is common practice and subjects with 
RA are familiar and comfortable with self-injection.  In addition, other biologic agents for the 
treatment of RA are approved for self-administration at home.  For additional details, see 
Section 6.5.
The SmartJect™ AI platform technology device, referred to as PFS-AI, is a prefilled, spring-
powered, single use, disposable device for the SC administration of a single dose of a liquid 
biologic drug product.  The PFS-AI was designed as a platform device for several liquid biologic 
drug products and has a simple, universal design that is suitable for use by clinicians, caregivers, 
and patients, including those with hand impairment and pain in the hands and wrists resulting 
from diseases such as rheumatoid arthritis (RA), and psoriatic arthritis (PsA). The PFS-AI is 
designed to operate effectively in a number of hand orientations. Since the needle is shielded 
from sight at all times, the PFS-AI also accommodates those patients with a needle phobia who 
cannot tolerate seeing injections administered.
3.2.12
Health Economics Data Collection
RA is a chronic, progressive, and disabling condition that significantly diminishes physical 
functioning and health related quality of life. Loss of physical function in RA patients can 
significantly affect their ability to work and perform other activities of daily living.
Indirect 
costs, primarily associated with loss of income among persons who have left work or reduced 
work, contribute substantially to the economic impact on patients, families and society.
Approximately half of all newly diagnosed RA patients had to stop working within the ensuing 
10 years.42,50  Hence, maintaining long-term function with resulting maintenance of productivity 
and employability is an important therapeutic goal in RA. 
Treatment of subjects with RA with sirukumab may have a positive impact on subjects’ 
employability, daily work productivity, and reduced time lost from work, compared among 
treatment groups.  For additional details, see Section 9.7.
4
SUBJECT SELECTION
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. 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
4.1
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study.  Each 
subject must:
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
31
1.
Have completed the final study agent administrations in the primary study (Week 104 
injection in CNTO136ARA3002 or Week 52 injection in CNTO136ARA3003) including all 
other assessments required for these visits.  The subject will then be deemed to have 
completed participation in those studies and will be eligible to enroll in this long-term 
extension study.
2.
Sign an informed consent form (ICF) indicating that they understand the purpose of and 
procedures required for the study and are willing to participate in the study.
3.
Sign an informed consent form (ICF) for pharmacogenetics research in order to participate 
in the optional pharmacogenetics component of this study, where local regulations permit.  
Refusal to give consent for this component does not exclude a subject from participation in 
this clinical study.  
4.2
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.  The subject will be excluded if he or she:
1.
Withdraws consent and/or discontinues participation in study CNTO136ARA3002 or 
CNTO136ARA3003.
2.
Is pregnant
3.
Has active diverticulitis.
4.
Has any condition that, in the opinion of the investigator, would make participation not be in 
the best interest (eg, compromise the well-being) of the subject or that could prevent, limit, 
or confound the protocol-specified assessments.
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.
If a woman 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 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.  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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
32
2.
Men must use an effective method of birth control 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. Also, men must not donate sperm during the study and for 4 
months after receiving the last dose of study agent.
3.
See Section 8.2 for prohibited medications.
4.
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.
Must agree not to receive an investigational medical device or other investigational 
drugs.
5
TREATMENT ALLOCATION AND BLINDING
5.1
Treatment Allocation
There will be 2 treatment groups for the duration of this study:
Group 1:  Sirukumab 100 mg q2 weeks through Week 156 for subjects who enrolled after 
completing participation in CNTO136ARA3002 and through Week 208 for subjects who 
enrolled after completing participation in CNTO136ARA3003.
Group 2:  Sirukumab 50 mg q4 weeks through Week 156 for subjects who enrolled after 
completing participation in CNTO136ARA3002 and through Week 208 for subjects who 
enrolled after completing participation in CNTO136ARA3003.
After the study becomes open-label, subjects treated with SC sirukumab 100 mg q2 weeks will 
be offered the option to reduce the sirukumab dose to 50 mg q4 weeks at the investigator’s 
discretion. This decision can be made at the subject’s first or second major resupply visit (up 
until approximately 7 months) after implementation of Amendment 3 at the study site.
5.2
Blinding
To maintain the study blind, the study agent container will have a multipart label with directions
for use and other information, but not the identity of the study agent, on each part.  One part of 
the label is designed to be torn off, separated from the study agent container, and attached to the 
subject’s source documents.  The rest of the label will remain affixed to the study agent 
container.  Thus, the study agent assigned to a subject will be linked between the container and 
the subject without breaking the study blind.  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. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
33
The investigator will not be provided with treatment codes, but the codes will be maintained 
within the IVRS/IWRS, which has the functionality to allow the investigator to break the blind 
for an individual subject when there is a need based on medical judgment.
The study will remain blinded until the following 3 conditions have been met: the Week 52 DBL 
occurs in study CNTO136ARA3002, the Week 24 DBL occurs in study CNTO136ARA3003, 
and the last AI usability substudy subject completes the Week 16 visit or terminates from the 
study.  
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 
determine the identity of the treatment from the IVRS/IWRS provider.
It is strongly 
recommended that the investigator contact the Sponsor or its designee if possible to discuss the 
particular situation prior to unblinding in IVRS/IWRS. 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 eCRF, and in the source document.  The 
documentation received from the IVRS/IWRS indicating the code break must be retained with 
the subject's source documents in a secure manner (eg, sealed envelope) so as not to unblind the 
treatment assignment to the subject, the study site, or Sponsor personnel.  The investigator is also 
advised not to reveal the study treatment assignment to the subject, the study site, or Sponsor 
personnel. 
Subjects who have had their treatment assignment unblinded are expected to continue to return 
for scheduled evaluations.  Further study agent administrations should be discussed with the 
study responsible physician.
Additionally, a given subject’s treatment assignment may be unblinded to the Sponsor, 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), and site personnel to 
fulfill regulatory reporting requirements for SUSARs.
A separate code break procedure will be available for use by Janssen Global Medical Safety 
(GMS) to allow for unblinding of individual subjects to comply with specific requests from 
regulatory or health authorities.
6
DOSAGE AND ADMINISTRATION
6.1
Dosing Regimen
Subjects will continue to receive the sirukumab dosing regimen they received at the end of the 
primary studies (CNTO136ARA3002, CNTO136ARA3003).
Group 1:
Sirukumab 100 mg SC at Weeks 0 (administered as the last dose in 
CNTO136ARA3002 or CNTO136ARA3003), 2, and q2 weeks through 
Week 156 for subjects who enrolled after completing participation in 
CNTO136ARA3002 and through Week 208 for subjects who enrolled 
after completing participation in CNTO136ARA3003.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
34
Group 2:
Sirukumab 50 mg SC at Weeks 0 (administered as the last dose in 
CNTO136ARA3002 or CNTO136ARA3003), 4, and q4 weeks through 
Week 156 for subjects who enrolled after completing participation in 
CNTO136ARA3002 and through Week 208 for subjects who enrolled 
after completing participation in CNTO136ARA3003.  Between 
sirukumab injections, placebo SC injections will be administered at 
Weeks 2, 6, and q4 weeks until the study becomes open-label and placebo 
injections will be discontinued.
After the study becomes open-label, subjects treated with SC sirukumab 100 mg q2 weeks will 
be offered the option to reduce the sirukumab dose to 50 mg q4 weeks at the investigator’s
discretion. This decision can be made at the subject’s first or second major resupply visit (up 
until approximately 7 months) after implementation of Amendment 3 at the study site. Once a 
subject’s dose is reduced to 50 mg q4 weeks, the subject will receive that dose for the remainder 
of the trial (ie, a return to 100 mg q2 weeks will not be allowed). If a subject opts to remain on 
the sirukumab 100 mg q2 weeks dose, he or she will remain on that dose for the duration of their 
participation in the study (ie, the subject will not have the option to reduce the dose at a 
subsequent timepoint).
If an injection is missed, every effort should be made to have the missed injection administered 
within 7 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 medical monitor.
After a minimum of 1 year treatment in CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of treatment in CNTO136ARA3004 for subjects 
from CNTO136ARA3003, and after sirukumab is approved for the treatment of RA in the 
subject’s country of residence, the Sponsor may no longer offer study treatment in 
CNTO136ARA3004 for those specific subjects.
At that point the subject will have the 
opportunity to discuss treatment options with their treating physician. 
For details on self-administration of study agent see Section 6.5.
6.2
Blinding
To maintain the blind, all subjects will receive study agent as 1 SC injection as follows:  
Group 1 (sirukumab 100 mg): 1.0 mL sirukumab 100 mg injection q2 weeks.
Group 2 (sirukumab 50 mg):  1.0 mL sirukumab 50 mg injection q4 weeks.  Between sirukumab 
injections, placebo SC injections will be administered at Weeks 2, 6, and q4 weeks until the 
study becomes open-label and placebo injections will be discontinued.
After the study becomes open-label, subjects treated with SC sirukumab 100 mg q2 weeks will 
be offered the option to reduce the sirukumab dose to 50 mg q4 weeks at the investigator’s 
discretion. This decision can be made at the subject’s first or second major resupply visit (up 
until approximately 7 months) after implementation of Amendment 3 at the study site.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
35
6.3
Timing and Study Agent Administration 
Through the end of the study, it is recommended that both the visit and the SC study agent 
administration occur within 7 days of the scheduled visit day.  The SC study agent 
administrations must always be at least 7 days apart.
6.4
DMARD/Oral Corticosteroid Initiation/Adjustment 
Subjects may adjust or initiate DMARDs and/or oral corticosteroids at the investigator’s 
discretion.  Permitted DMARDs include methotrexate (MTX), sulfasalazine (SSZ), 
hydrochloroquine (HCQ), chloroquine (CQ), and bucillamine.
Prohibited medications listed in Section 8.2 may not be initiated by subjects as long as they are 
receiving study agent administrations. 
6.5
Self-Administration
The SmartJect™ Autoinjector (PFS-AI) is expected to be used by the majority of subjects in 
study CNTO136ARA3004. In the event PFS-AIs are unavailable at the time of a subject’s 
enrollment in this protocol, PFS-U will be provided until such times as the PFA-AIs become 
available.
Upon availability of PFS-AI trial supplies, subjects who are newly entering the 
CNTO136ARA3004 protocol will be trained on the operation of PFS-AI and perform self-
administration of study agent using PFS-AI at the Week 2 study visit and return to the study site 
at Week 4 for self-administration with PFS-AI.  The self-injection training consists of a face-to-
face, “hands-on” training, with an explanation of each task in the Instructions For Use (IFU), a 
demonstration performed by the study site staff with the PFS-AI trainer device, followed by 
practice injections performed by the subject using the trainer device, until the study site staff and 
subject are satisfied that the injections can be performed as stated in the IFU.  This mimics the 
typical training by a physician’s office staff that is likely to be received by a patient for the 
prescribed marketed product, per the final product’s labeling.  The step-by-step Training Guide 
for investigators or site staff to follow when providing training of subjects will be provided in the 
Site IP Procedures Manual. If subjects are competent in using PFS-AI, they will subsequently be 
provided with study agent for self-administration at home and instructed how to transport and 
store medication for at-home use as indicated for this protocol.  Subjects will be instructed to 
contact the investigator promptly in the event of any signs of an allergic reaction, infection, or 
bleeding.  
Subjects may continue to administer the study agent at home for the duration of the study. 
Although additional face-to-face training sessions after the first training session are not 
scheduled, the site staff will be available to provide additional training if needed. If subjects or 
health care providers are uncertain about how to administer the study agent, the Sponsor 
recommends a review of the IFU and perform practice injections with the PFS-AI trainer device, 
and if necessary, to ask for retraining at the study site.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
36
Subjects unable or unwilling to self-administer will continue to have study agent injections 
performed by a health care professional at the study site. A caregiver may also be trained to 
administer study agent at home. In the event PFS-AIs are unavailable at the time of a subject’s 
enrollment in this protocol, training on the use of a PFS-AI will be provided at the next study 
visit when the PFS-AI is available. Once the study becomes open-label, the Week 2 visit for 
training may be skipped by subjects who are to receive open label sirukumab 50 mg q4 weeks 
and training in the use of an PFS-AI will be provided at Week 4.
7
TREATMENT COMPLIANCE
Study agent will be administered subcutaneously by the subject or a trained care-giver. Subjects 
will maintain a log of all study agent administrations.  Study agent supplies for each subject will 
be inventoried and accounted for.  
Study personnel will maintain a log of all study agent administrations.  Study agent supplies for 
each subject will be inventoried and accounted for.  
When subjects begin self-administration at home, the investigator or designated study personnel 
will maintain a log of all study agents dispensed and returned and the amount of study agent 
dispensed will be recorded and compared with the amount returned.
Subjects will receive instructions on compliance with study treatment when they begin self-
administration of study agent at home. During the course of the study, the investigator or 
designated study research personnel will be responsible for providing additional instruction to 
reeducate any subject who is not compliant with taking the study agent.
8
CONCOMITANT THERAPY AND PROCEDURES
8.1
Concomitant Therapy
All concomitant therapies must be recorded throughout the study, beginning at Week 0.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements) different from the study agent must be recorded in the concomitant therapy section 
of the eCRF. 
The concomitant medication dose may be changed at the discretion of the investigator. Disease-
modifying anti-rheumatic drug (DMARD) therapy is permitted at the discretion of the 
investigator (see Section 6.4), except for the specified prohibited medications (see Section 8.2).
8.1.1
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics
Subjects treated with NSAIDs, including aspirin and selective cyclooxygenase-2 inhibitors, and 
other analgesics should receive the usual marketed doses approved in the country in which the 
study is being conducted. In this study, aspirin is considered an NSAID, except for low-dose 
aspirin prescribed for CV or cerebrovascular disease.  The dose and the type of NSAIDs or other 
analgesics may be changed at the discretion of the investigator if the subject develops 
unacceptable side effects or a contraindication to their use.    
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
37
8.1.2
Disease Modifying Antirheumatic Drugs/Systemic Immunosuppressives
Acceptable non-biologic DMARDS are MTX, SSZ, HCQ, chloroquine (CQ) or bucillamine.  
DMARDs may be initiated or adjusted at the investigator’s discretion.  
Guidelines for MTX dose adjustment in the event of suspected MTX toxicity are provided in 
Appendix C.  The dose of MTX should be decreased 50% and/or a folic acid product should be 
started or increased in dose if AST/ALT increases 2 to < 3 times ULN during treatment.  The 
MTX dose may be increased back to the baseline dose if the AST/ALT decreases to < 2 times 
ULN.  The dose of MTX should be temporarily interrupted and a folic acid product should be 
started or increased in dose if AST/ALT increases to 3 times ULN and total bilirubin level is 
< 2 times ULN. See Section 10.3 for drug induced liver injury criteria that require permanent 
discontinuation of study agent administration.
All subjects using MTX at doses of ≥0.2 mg/kg weekly or who are at high risk of adverse 
reactions (eg, elderly age, renal impairment, chronic high-dose NSAIDs) should receive at least 
5 mg oral folic acid or oral folinic acid weekly.  Folic acid or folinic acid may also be initiated or 
increased for subjects using MTX for management of adverse events such as stomatitis, 
increased ALT/AST, leucopenia, or macrocytic anemia.  
8.1.3
Corticosteroid Therapy
Oral Corticosteroids
The dose and the type of oral corticosteroid may be changed at the discretion of the investigator 
if the subject develops unacceptable side effects.  
Intramuscular and Intravenous Corticosteroids
IM corticosteroids may be administered as needed throughout the course of the study, except not 
within 4 weeks prior to Weeks 52, 104, 156, and 208.  Every attempt should be made to avoid 
the use of IV corticosteroids, however for conditions other than RA, corticosteroid therapy 
should be limited to situations in which, in the opinion of the treating physician, there are no 
adequate alternatives. Subjects may receive short courses (2 weeks or less) of oral or IV 
corticosteroids for reasons such
as prophylactic therapy before surgery (stress-dose 
corticosteroids) or therapy for limited infections, exacerbation of asthma, or chronic obstructive 
pulmonary disease.
Intra-articular Corticosteroids
Intra-articular (IA) steroid injections should not be administered within 4 weeks prior to visits on 
Weeks 52, 104, 156, and 208.
8.1.4
Statin Therapy
Subjects are permitted to use statins (eg, pravastatin, rosuvastatin) for the treatment of 
hyperlipidemia as considered appropriate by National Cholesterol Education Program (NCEP) 
treatment guidelines
(http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf) or other 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
38
national cholesterol treatment guidelines.  Some statins are metabolized by cytochrome P450 
(CYP450) enzymes (see Section 8.1.5).
8.1.5
Drugs Metabolized by Cytochrome P450
Inflammatory cytokines, including IL-6, are known to down regulate activity and expression of 
multiple CYP450 enzymes.  Hypothetically, IL-6 inhibition in a patient 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 patients 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).  
8.2
Prohibited Medications
The use of the following drugs is not permitted concomitantly with SC study agent 
administration:

Systemic immunosuppressives or DMARDs (other than MTX, SSZ, HCQ, CQ, and 
bucillamine) including azathioprine, oral cyclosporine A, tacrolimus, mycophenolate 
mofetil, leflunomide, oral or parenteral gold, and IL-1ra (anakinra) 

Biologic agents targeted at reducing TNF(including but not limited to infliximab, 
golimumab, certolizumab pegol, etanercept, yisaipu, and adalimumab)

Tocilizumab (anti IL-6 receptor)

B-cell depleting agents (eg, rituximab)

Cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or other 
alkylating agents

Abatacept (ORENCIA)

Tofacitinib (XELJANZ)

Any other biologic therapy for the treatment of RA

Investigational drugs
8.3
Joint Procedures
Subjects undergoing a surgical joint procedure for the treatment of RA or receiving IA, tendon 
sheath, or bursal corticosteroid injections may continue to receive study agent administrations 
and undergo evaluations.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
39
9
STUDY EVALUATIONS
9.1
Study Procedures
9.1.1
Overview
The Time and Events Schedule (Table 1 and Table 2) summarizes the frequency and timing of 
efficacy, pharmacokinetic, immunogenicity, pharmacodynamics, pharmacogenetics, health 
economics, and safety measurements applicable to this study.
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.  Also additional TB tests or tests for other 
infections may be performed as determined necessary by the medical monitor, study investigator 
or as required by local regulation.
All visit-specific PRO assessments should be conducted before any tests, procedures, or other 
consultations for that visit to prevent influencing subjects’ 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.
Health economics data will be collected.  For details, see Section 9.7.
Serum for the analysis of pharmacodynamic markers and whole blood (for gene expression 
analysis) will be collected through Week 156 for subjects coming from the CNTO136ARA3002 
study and Week 208 from subjects coming from the CNTO136ARA3003 study.  A single whole 
blood sample for DNA analysis will be collected only from subjects who have consented to 
participate in the optional pharmacogenetics (DNA) component of the study.  
The total blood volume to be collected from each subject will be approximately 325 mL.  Repeat 
or unscheduled samples may be taken for safety reasons.
Blood samples for RNA and DNA analyses will only be collected if permitted by local 
regulations.
9.1.2
Double-Blinded Treatment Phase
Subjects will receive blinded study agent treatments according to the Time and Events Schedule 
until the following 3 conditions have been met: the Week 52 DBL occurs in study 
CNTO136ARA3002, the Week 24 DBL occurs in study CNTO136ARA3003, and the last AI 
usability substudy subject completes the Week 16 visit or terminates from the study.  
9.1.3
Open-Label Treatment Phase
The CNTO136ARA3004 study will become open-label after the following 3 conditions have 
been met: the Week 52 DBL occurs in study CNTO136ARA3002, the Week 24 DBL occurs in 
study CNTO136ARA3003, and the last AI usability substudy subject completes the Week 16 
visit or terminates from the study.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
40
After a minimum of 1 year treatment in CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of treatment in CNTO136ARA3004 for subjects 
from CNTO136ARA3003, and after sirukumab is approved for the treatment of RA in the 
subject’s country of residence, the Sponsor may no longer offer study treatment in 
CNTO136ARA3004 for those specific subjects.
At that point the subject will have the 
opportunity to discuss treatment options with their treating physician.
9.1.4
Posttreatment Phase (Follow-Up)
At the end of the study, subjects will return for follow-up assessments through approximately 
16 weeks after the last study agent administration.  Subjects who discontinue study agent 
injections but do not terminate study participation will continue to have assessments performed 
for 16 weeks following last injection according to the Time and Events Schedule (Table 2).
Note:  The visit that is approximately 16 weeks after the last study agent injection is 
referred to as the “final safety and efficacy follow-up visit” (Table 2).
In the event a subject discontinues study agent injections, the first safety and efficacy follow up 
visit should occur 4 weeks 14 days after the date of the last administration of the study agent.   
The visit window for follow-up assessments is 14 days.
9.2
Efficacy 
9.2.1
Evaluations 
9.2.1.1
Joint Assessments
Joint Assessor
Each of 68 joints will be evaluated for tenderness, and each of 66 joints will be evaluated for 
swelling (hips are excluded for swelling). All joints will be examined at visits as indicated in the 
Time and Events Schedule. 
A joint assessor with adequate training and experience in performing joint assessments will be 
designated at each study site to perform all joint assessments.  The joint assessor should 
preferably be a rheumatologist; however, if a rheumatologist is not available, the assessor should 
be a health care provider with at least 1 year of experience in performing joint assessments (for 
additional details, see Trial Center File).  Health care providers with less than 1 year of 
experience may serve as a joint assessor based upon the discretion and approval of the Sponsor.  
It is required that the designated joint assessor identify an appropriate back-up joint assessor to 
provide coverage if the designated joint assessor is absent.  However, it is strongly recommended 
that the joint assessor who performs the baseline joint assessments for a subject should also 
perform the joint assessments for that subject at every subsequent visit through the end of the 
study. 
The Sponsor will provide training for each site’s designated joint assessor prior to the [Week 0 
visit] of the first subject at each site. A back-up joint assessor must complete training before 
performing a joint assessment for a subject’s study visit. If an assessor was trained by the 
Sponsor in the primary studies (CNTO136ARA3002 and CNTO136ARA3003) or in a previous 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
41
clinical study within the last 3 years and there is adequate documentation of this training 
(certification), that training will be considered adequate for this study. Training documentation 
for each joint assessor should be maintained at the study site.   
All joint assessors performing joint evaluations at a site must be listed on the Delegation Log at 
the study site and should be documented in the source documents at each visit.
Nonevaluable Joints
Joints should only be designated as “non-evaluable” by the joint assessor on the Joint 
Assessment Worksheet if it is physically impossible to assess the joint (ie, joint inaccessible due 
to a cast, joint not present due to an amputation, joint deformed so as to make it impossible to 
assess). In all other cases, the joint assessor should assess each joint for tenderness and swelling 
(hips are excluded for swelling) and complete the worksheet with their assessments. This should 
be completed regardless of any visual indications of prior surgeries (eg, scars) or knowledge they 
may have of a subject’s prior joint procedures/injections (eg, if the subject was the joint 
assessor’s patient prior to study participation). 
9.2.1.2
Pain Assessment
Subjects will be asked to assess their average pain during the past week on a visual analogue 
scale (VAS).  The scale ranges from “no pain” to “the worst possible pain”.  This assessment 
should be completed prior to the joint examination.  The validity of this assessment has been 
evaluated and reviewed extensively as it is a component of the ACR response score.8,15 Specific 
magnitudes of change in the VAS correspond to prespecified ACR score calculations (ie, a 20% 
improvement in the VAS corresponds to an ACR 20).
9.2.1.3
Patient’s and Physician’s Global Assessment of Disease Activity
The Patient’s and Physician’s Global Assessments of Disease Activity9 will be recorded on a 
VAS.  The scale for the subject’s assessment ranges from “very well” to “very poor”.  The scale 
for the physician’s assessment ranges from “no arthritis activity” to “extremely active arthritis”.  
The evaluating physician and subject must complete the global assessment independently of each 
other.  The physician should preferably be the same person at every study visit for a given 
subject.  The results of the joint assessment performed by the joint assessor will be available to 
the physician assessing the subject’s global disease.
9.2.1.4
Health Assessment Questionnaire – Disability Index
The functional status of the subject will be assessed using the HAQ-DI.12
This 20-question 
instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional 
areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily
living).  Responses in each functional area are scored from 0, indicating no difficulty, to 3,
indicating inability to perform a task in that area.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
42
9.2.1.5
Duration of Morning Stiffness
The average duration of morning stiffness during the previous week in minutes will be assessed.  
If a subject has stiffness that lasts the entire day, this should be recorded as 1440 minutes of 
morning stiffness.
9.2.1.6
36-Item Short Form Questionnaire
The Medical Outcome Study health measure entitled the 36-item Short-Form (SF-36) health 
survey questionnaire was developed as part of the Rand Health Insurance Experiment and 
consists of 8 multi-item scales.

Limitations in physical functioning due to health problems

Limitations in usual role activities due to physical health problems

Bodily pain

General mental health (psychological distress and well-being)

Limitations in usual role activities due to personal or emotional problems

Limitations in social functioning due to physical or mental health problems

Vitality (energy and fatigue)

General health perception
These scales are scored from 0 to 100 with higher scores indicating better health.  Another 
algorithm yields 2 summary scores, the Physical Component Score (PCS) and Mental 
Component Score (MCS).  These summary scores are also scaled with higher scores indicating 
better health.47
The concepts measured by the SF-36 are not specific to any age, disease, or 
treatment group, allowing comparison of relative burden of different diseases and the relative 
benefit of different treatments.48
9.2.1.7
Work Limitations Questionnaire
The WLQ has been selected from existing instruments in order to generate estimates of work 
productivity and absenteeism.  The WLQ is a brief, self-report questionnaire designed to enable 
investigators to obtain a sensitive measure of the degree to which employed individuals are 
experiencing limitations on-the-job due to their health problems and health-related productivity 
loss.22 The WLQ has 25 items that ask respondents to rate their level of difficulty or ability to
perform specific job demands. The 25 items are aggregated into 4 scales, time management, 
physical demands, mental-interpersonal, and output.  Scale scores range from 0 (limited none of 
the time) to 100 (limited all of the time) and represent the reported amount of time in the prior 
2 weeks that respondents were limited on-the-job. 
9.2.1.8
Multidimensional Personality Questionnaire (MPSQ)
The Placebell©™ technology will be explored in this study of rheumatoid arthritis. The 
Multidimensional Personality Questionnaire (MPSQ) is a questionnaire contributing to the 
evaluation of individual patient response to placebo by assessing patients's personality, well-
being as well as attitudes and beliefs on disease therapies.35,36 It has been developed by 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
43
Tools4patient SA. MPSQ is self-reported by patient and made of 114 items. Each of them is 
rated by patient on a 5-point scale ranging from 1 (strongly disagree) to 5 (strongly agree).
At selected sites, the MPSQ will be administered as an optional paper questionnaire to subjects 
who consent to participate after implementation of Amendment 3.
9.2.2
Definitions
9.2.2.1
American College of Rheumatology Responses
ACR responses are presented as the numerical measurement of improvement in multiple disease 
assessment criteria.  For example, an ACR 20 response9 is defined as: 
1.
≥20% improvement from baseline in both swollen joint count (66 joints) and tender joint 
count (68 joints), 
AND
2.
≥20% improvement from baseline in 3 of the following 5 assessments:
Patient’s assessment of pain (VAS)
Patient’s Global Assessment of Disease Activity (VAS)
Physician’s Global Assessment of Disease Activity (VAS)
Patient’s assessment of physical function as measured by HAQ-DI
C-reactive protein (CRP)
ACR 50 and ACR 70 are similarly defined except improvement threshold from baseline is 50% 
and 70%, respectively.
9.2.2.2
Disease Activity Index Score 28
9.2.2.2.1
Disease Activity Index Score 28 Using CRP
The Disease Activity Index Score 28 using CRP [DAS28 (CRP)] is a derived score combining 
tender joints (28 joints), swollen joints (28 joints), CRP, and Patient’s Global Assessment of 
Disease Activity (GH).45 The DAS28 (CRP) is a continuous parameter and is defined as follows:
DAS28 (CRP) = 0.56 x SQRT(TEN28) + 0.28 x SQRT(SW28) + 0.36 x ln (CRP + 1) + 0.014 x
GH + 0.96 where:

The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, MCP1, MCP2, 
MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of both the upper right extremity 
and the upper left extremity as well as the knee joints of lower right and lower left 
extremities. 

TEN28 is 28 joint count for tenderness.

SQRT (TEN28) is square root of TEN28.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
44

SW28 is 28 joint count for swelling.  

SQRT (SW28) is square root of SW28

Ln (CRP+1) is natural logarithm of (CRP value [mg/L] + 1).

GH is Patient’s Global Assessment of Disease Activity on VAS.
9.2.2.2.1.1
DAS28 (CRP) Response

DAS28 (CRP) response is defined in Table 3.45
Table 3:
DAS28 (CRP) response criteria


Improvement from Baseline

DAS28 (CRP) at the 
visit

> 1.2

> 0.6 – 1.2

0.6

3.2

Good response

Moderate response

No response

> 3.2 – 5.1

Moderate response

Moderate response

No response

> 5.1

Moderate response

No response

No response
9.2.2.2.1.2
DAS28 (CRP) Remission
DAS28 (CRP) remission is defined as a DAS28 (CRP) value of 2.6 at a visit.
9.2.2.3
Simplified Disease Activity Index Score
The Simplified Disease Activity Index (SDAI) score is a derived score combining tender joints 
(28 joints), swollen joints (28 joints), GH, Physician’s global assessments of disease activity 
(PGH), and CRP.2
SDAI is defined as follows:
SDAI = TEN28 + SW28 + GH + PGH + CRP (mg/dL) where:

TEN28 and SW28 were defined the same as in Section 9.2.2.2.1

GH is Patient’s Global Assessment of Disease Activity on VAS.

PGH is Physician’s Global Assessment of Disease Activity on VAS.
9.2.2.4
Clinical Disease Activity Index Score
Clinical Disease Activity Index (CDAI) score is a derived score combining tender joints 
(28 joints), swollen joints (28 joints), GH, and PGH.2
CDAI is defined as follows:
CDAI = TEN28 + SW28 + GH + PGH where:
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
45

TEN28 and SW28 were defined the same as in Section 9.2.2.2.1

GH is Patient’s Global Assessment of Disease Activity on VAS.

PGH is Physician’s Global Assessment of Disease Activity on VAS.
Note: CDAI is the same as SDAI, except that CRP is not included.
9.2.2.5
ACR/EULAR Remission
9.2.2.5.1
SDAI-Based ACR/EULAR Remission
SDAI-based ACR/EULAR remission is defined as a SDAI value of ≤ 3.3 at a visit10:
9.2.2.5.2
Boolean-Based ACR/EULAR Remission
A subject is considered as having achieved the Boolean-based ACR/EULAR remission at a visit 
if he/she meets all of the following 4 criteria at that visit10:

Tender joint count (68 joints) 1.

Swollen joint count (66 joints) 1.

CRP 1 mg/dL

Patient’s Global Assessment of Disease Activity on VAS ≤ 1 on a 0 to 10 scale.
9.2.3
Endpoints
Primary Endpoint
The primary endpoint is the number of subjects with each of the following long-term safety
events through the end of the study: cardiovascular SAEs, malignancies, serious infections, and 
gastrointestinal perforations.
Major Secondary Endpoints
Laboratory parameters of interest (neutrophils, platelets, hepatobiliary parameters, and lipid 
parameters) will be observed.
Other secondary endpoints

ACR responses

DAS28 

HAQ-DI

SF-36

WLQ

HECONQ

Morning stiffness
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
46
9.3
Pharmacokinetics and Immunogenicity
9.3.1
Evaluations 
Serum samples will be used to evaluate the pharmacokinetics, as well as the immunogenicity of 
sirukumab (antibodies to sirukumab).  Serum collected for sirukumab serum concentration and 
antibodies to sirukumab analyses may additionally be used to evaluate safety or efficacy aspects 
that address concerns arising during or after the study period.  Genetic analyses will not be 
performed on these serum samples.  Subject confidentiality will be maintained.  At visits where 
sirukumab serum concentration and antibodies to sirukumab will be evaluated, 1 blood draw of 
sufficient volume can be used. Venous blood samples will be collected and each serum sample 
will be divided into 3 aliquots (1 each for pharmacokinetics, antibodies to study agent, and a 
back-up). Subjects who discontinue study participation should have serum samples collected at 
the last safety follow-up visit.
Instructions for the collection, handling, and shipment of these samples are found in the 
Laboratory Manual.
9.3.2
Pharmacokinetics
9.3.2.1
Serum Collection and Handling
Blood samples for the measurement of serum sirukumab concentrations will be collected at visits 
as shown in the Time and Events Schedules (Table 1 and Table 2).  For subjects who had serum 
samples collected at earlier time points in study CNTO136ARA3002 (approximately 750 
randomized subjects in CNTO136ARA3002) and all subjects who enrolled after participating in 
study CNTO136ARA3003, serum samples will be collected at Weeks 2, 4, 16, 28, 52, 104, 156 
and the final safety and efficacy follow-up visit (Table 1 and Table 2). One additional sample 
will be collected at Week 208 for subjects who enrolled after participating in study 
CNTO136ARA3003.
The exact dates and times of blood sampling must be recorded on the laboratory requisition 
form.  Note that if the subject is to receive an administration of study agent at that visit, blood 
samples will be collected prior to study agent administration.  
9.3.2.2
Analytical Procedures
Serum samples will be analyzed to determine concentrations of sirukumab using a validated, 
immunoassay method. 
The Sponsor, or its designee, under conditions in which the subjects’ identity remains blinded, 
will assay these samples.
9.3.2.3
Pharmacokinetic Parameters 
Serum sirukumab concentration including Ctrough will be summarized.  
9.3.3
Immunogenicity Assessment (Antibodies to sirukumab)
To assess the immunogenicity of sirukumab, serum samples for the detection of antibodies to 
sirukumab will be collected at visits as shown in the Time and Events Schedules (Table 1 and 
Table 2).
For subjects who had serum samples collected at earlier time points in study 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
47
CNTO136ARA3002 (approximately 750 randomized subjects in CNTO136ARA3002) and all 
subjects who enrolled after participating in study CNTO136ARA3003, serum samples will be 
collected at Weeks 16, 28, 52, 104, 156 and the final safety and efficacy follow-up visit. One 
additional sample will be collected at Week 208 for subjects who enrolled after participating in 
study CNTO136ARA3003.
Antibodies to sirukumab will be detected using a validated immunoassay method.  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 verify the stability of antibodies 
to sirukumab and/or further characterize the immunogenicity of sirukumab.  These samples will 
be analyzed by the Sponsor or its designee.
Subjects will be classified as positive for antibodies to sirukumab if any post-treatment samples 
tested positive for antibodies to sirukumab. Subjects will be classified as negative for antibodies 
to sirukumab if antibodies were not detected in any post-treatment samples.
9.4
Pharmacodynamic Evaluations 
Serum and whole blood samples for the analysis of pharmacodynamic markers will be collected 
according to the Time and Events Schedule.  These samples will be used to better understand the 
biology of RA, to analyze differences between responders and non-responders, and to assess loss 
of response.  The samples to be collected include whole blood for RNA and serum for the 
evaluation of inflammation-associated proteins and other analytes such as but not limited to 
microRNAs.
9.5
Pharmacogenetics (DNA) Evaluations 
Assessment of genetic factors such as DNA methylation will be completed.  Only DNA research 
related to sirukumab or to the diseases for which this drug is developed will be performed. 
Subjects who agree to participate in this optional portion of the study must sign a separate 
pharmacogenetics informed consent. Further, a subject may withdraw such consent at any time 
without affecting their participation in other aspects of the study, or their future participation in 
the study.
9.6
SmartJect™ Autoinjector Usability Substudy
In this substudy, a select number of subjects at selected sites in English-speaking countries who 
are enrolled in CNTO136ARA3004 will be consented and enrolled in a SmartJect™ AI Usability 
substudy.  Subjects will not be required to participate in the substudy, and can enter the 
CNTO136ARA3004 LTE study independent of participation in the substudy. 
Subjects 
completing the substudy will return to the LTE study for the remainder of their study treatments. 
Site personnel in the substudy will observe and document 2 scheduled self-administrations of 
study agent by subjects using the PFS-AI.  All substudy subjects will also complete an e-diary 
regarding their experiences with at-home use of PFS-AI for an additional 12 weeks of study 
treatment.  A subset of these subjects will also have a detailed interview at their final substudy
visit regarding their at-home-use experience. 
For additional details, refer to the PFS-AI 
Usability Substudy Protocol.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
48
9.7
Health Economics Evaluations
Health economics evaluations on employment status, impact of disease on daily productivity, 
and time lost from work will be collected.  The impact of disease on patients’ daily work 
productivity will be measured using a VAS. The scale ranges from “not at all affected” to 
“affected very much”.
9.8
Safety Evaluations
Details regarding the DMC and CEC are provided in Sections 11.10 and 11.11, respectively.
As noted in Section 3.2.6, AEs of interest have been identified.  These are: hematologic 
laboratory abnormalities (decreases in neutrophils and platelets), hepatobiliary laboratory 
abnormalities, lipid parameter abnormalities, serious CV events, infections, malignancies, and 
gastrointestinal perforations.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally-acceptable representative) for the duration of the study.  Adverse events 
will be followed by the investigator as specified in Section 12.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology 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 AE section of the CRF.  The following tests will be performed 
by the central laboratory:   

Hematology Panel 
-hemoglobin
-hematocrit
- RBC count
- WBC count with differential
-platelet count

Serum Chemistry Panel 
-sodium
- AST
-potassium
- ALT
-chloride
-alkaline phosphatase
-bicarbonate
-calcium
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
49
- BUN
-phosphate
-creatinine
-albumin
-glucose
-total protein
-total bilirubin, with fractionation if 
hyperbilirubinemia

Lipid Panel (fasting)
-total cholesterol
-high-density lipoprotein (HDL)
-low-density lipoprotein (LDL)
-triglycerides

Urine Pregnancy Testing for women of childbearing potential only.
Additional assays may be performed on lipid panel specimens to further characterize the changes 
in lipid profile following treatment with sirukumab. Additional laboratory tests may be 
performed as determined by the Sponsor for the further evaluation of subjects. 
Subject Lab Data Access
Subjects at selected sites in the US will be offered the opportunity to consent to join a secure, 
web-based platform managed by a third party vendor so that they may access results to select 
clinical laboratory tests collected during the study (as defined above with the exception of RBC 
count). More details will be provided in the Informed Consent Form for these subjects.
Pathology  
If a subject requires tissue sampling for the evaluation of an adverse event, the Sponsor may 
request that the sample be sent for additional central evaluation.
Vital Signs 
Blood pressure and body weight will be measured.
Physical Examination 
A general physical examination will be performed as indicated in Table 1.  Clinically significant 
findings should be reported as AEs.
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 at least until the study becomes open-label.   
If mild or moderate allergic reaction is observed, acetaminophen 650 mg PO or NSAIDS and 
diphenhydramine 25 mg PO or IV may be administered.  If the reaction is not severe, subsequent 
injections at the appropriate treatment intervals may be undertaken with caution.  Subjects who 
self-inject the study agent away from the study site will receive detailed instructions on how to 
monitor and report AEs.
Subjects with severe reactions following an injection such as bronchospasm with wheezing 
and/or dyspnea requiring ventilator support, or symptomatic hypotension with a decrease in 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
50
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 for 
symptoms of an injection-site reaction at least until the study becomes open-label. 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 extrapulmonary 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
(Appendix A), a repeat tuberculin skin test (Appendix B) 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 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
51
investigation.  A positive QuantiFERON-TB Gold (or tuberculin skin) test result should be 
considered detection of latent TB.  Appropriate treatment for latent TB is defined according to 
local country guidelines for immunocompromised patients.  If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed or the subject must be 
excluded from the study.  If recommended, treatment for latent TB must be initiated prior to or 
simultaneously with 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 (see Section 10.2). 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.
Hepatitis B Monitoring
Subjects who are HBsAg- /HBcAb+ only, without detectable HBV DNA, should be monitored 
according to local guidelines. If local guidelines do not exist for HBV monitoring in these types 
of patients, monitoring should be performed following consultation with a hepatitis B specialist.
HBsAg- /HBsAb+ subjects who are HBcAb- or +, and without detectable HBV DNA, should be 
monitored if recommended under local guidelines related to HBV and biologic anti-rheumatic 
agents.
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 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)
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
52
Consultation with a specialist may be warranted. See Section 10.2 for specific instructions 
regarding discontinuation of treatment guidelines and evaluation of hepatobiliary abnormalities.  
Temporary or permanent discontinuation of study agent may be required (see Section 10.2).  
Temporary discontinuation or dose adjustment of MTX may be required (see Section 8.1.2).
9.9
Sample Collection and Handling
The actual dates and times of sample collection must be recorded on the laboratory requisition 
form. 
Refer to the Time and Events Schedules for the timing and frequency of all sample collections.
Instructions for the collection, handling, and shipment of samples are found in the laboratory 
manual that will be provided for sample collection and handling.
10
SUBJECT COMPLETION/WITHDRAWAL
10.1
Completion
Subjects must remain in the study until the last scheduled visit followed by 16 weeks of safety 
and efficacy follow up to be considered as having completed participation in the study.
10.2
Discontinuation of 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. 
Study agent administration to a subject must be permanently discontinued if any of the following 
occur:
1.
The investigator (in consultation with the medical monitor) believes that for safety reasons 
(eg, adverse event) it is in the best interest of the subject to stop treatment.
2.
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.
3.
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.
4.
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).
5.
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
6.
Malignancy, excluding nonmelanoma skin cancer.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
53
7.
Demyelination, either central or peripheral.
8.
Pregnancy during study participation.
9.
Drug induced liver injury, including any one of the following:
a.
Alanine transferase (ALT) or aspartate transferase (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
d.
ALT or AST 3 x ULN and total bilirubin 2 x ULN (upper limit of normal) (> 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)

Complete the Hepatobiliary Event Information Form and SAE form if the event also 
meets the criteria for an SAE.  All events that meet criteria as described below must be 
reported as an SAE.  

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 (INR measurement is not required and the 
threshold value stated will not apply to patients 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.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
54

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).    

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. 

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 (CPK), lactate dehydrogenase (LDH) 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, herbal remedies, other over the 
counter medications, or putative hepatotoxins, on the concomitant medications report 
form.

Record alcohol use 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
55
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, ASMA 
(anti-smooth muscle antibodies), 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:

If alkaline phosphatase > ALT, AMA (anti-mitochondrial antibody) should be 
tested.  

If patient is < 50 years of age, ceruloplasmin should also be tested.  

If patient is sick enough to require hospitalization be hospitalized and is under age 
less than 50 years old, 24 hour urine copper should be tested.   

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week 

Consider serum ethanol as clinically appropriate.

Liver 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)
10.
Two confirmed consecutive absolute neutrophil counts of < 0.5 x 103/µL (SI:  < 0.5 × 
109 cells/L). 
11.
Two confirmed consecutive platelet counts < 50,000/µL (SI:  < 50 x 109 cells/L). 
12.
QTc > 500 msec* or uncorrected QT > 600 msec, Change from baseline: QTc >60 msec* 
*based on average QTc value of triplicate ECGs
13.
The initiation of protocol-prohibited medications. (see Section 8.2).
14.
Acute diverticulitis requiring antibiotic treatment 
15.
Gastrointestinal perforation
16.
If sirukumab becomes approved in the subject’s country of residence, it may no longer be 
offered by the Sponsor in CNTO136ARA3004. In this case, study agent administrations 
will be discontinued after 52 weeks of treatment for subjects who enrolled after completing 
participation in study CNTO136ARA3002, and after 104 weeks of treatment for subjects 
who enrolled after completing participation in CNTO136ARA3003. At that point the 
subject will have the opportunity to discuss treatment options with their treating physician.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
56
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 and efficacy follow-up (Table 2).
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 4.
Table 4:
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 9.8 Safety Evaluations below Hepatobiliary abnormalities.*  
May resume study agent when < 3x ULN** 
Criteria for drug-induced liver injury 
(Section 10.2, #9)
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 10.2 #10)
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 10.2 #11)
* Retesting should be done by Central laboratory
** In case more than 3 subsequent injections are missed, and the PI wishes to resume study agent, please contact the Medical 
Monitor.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
57
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 discontinues study agent administration before the end of the study, follow-up 
assessments should be obtained as per the Time and Events Schedule described in Table 2.
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 agent assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
Withdrawal from Pharmacodynamic Research
The subject may withdraw consent for pharmacodynamics research while remaining in the 
clinical study.  In such a case, any stored samples will be destroyed upon communication from 
the site to the Sponsor.  No pharmacogenetics testing will be conducted on these samples.  This 
does not include those samples specifically collected for pharmacogenetic analysis for which 
separate optional consent was obtained.
Withdrawal from Pharmacogenetics Research 
The subject may withdraw consent for pharmacogenetics research while remaining in the clinical 
study.  In such a case, any DNA extracted from the subject's blood will be destroyed upon 
communication from the site to the Sponsor.  If requested, the investigator will receive written 
confirmation from the Sponsor that the sample has been destroyed.
11
STATISTICAL METHODS
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor.  
Descriptive statistics (eg, mean, median, standard deviation, interquartile range, minimum, and 
maximum) will be used to summarize continuous variables. Counts and percentages will be used 
to summarize categorical variables.
Subjects will continue to receive the same treatment regimen administered in studies 
CNTO136ARA3002 and CNTO136ARA3003 at Weeks 104 and 52, respectively:

Group 1:  Sirukumab 100 mg SC q2 weeks 

Group 2:  Sirukumab 50 mg SC q4 weeks
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
58
After the study becomes open-label, subjects treated with SC sirukumab 100 mg q2 weeks will 
be offered the option to reduce the sirukumab dose to 50 mg q4 weeks at the investigator’s 
discretion. This decision can be made at the subject’s first or second major resupply visit (up 
until approximately 7 months) after implementation of Amendment 3 at the study site.
Since the treatment groups are not randomly assigned in this study, no formal hypothesis testing 
is planned. The efficacy, safety, and PK/PD/immunogenicity analyses will be performed 
separately for subjects who complete studies CNTO136ARA3002 and CNTO136ARA3003. The 
analyses will include all subjects enrolled by study and by treatment group above.
Additional data releases or locks may occur periodically as needed.  The analyses based on these 
data 
releases 
or 
locks 
intend 
to 
integrate 
data 
from 
CNTO136ARA3002 
and 
CNTO136ARA3003 with this study for the long-term PK, immunogenicity, safety and efficacy 
data of all subjects enrolled in these studies.  A separate SAP for integration will be developed to 
specify the analyses and data handling rules. 
An independent DMC will monitor the safety of the blinded portion of the study in unblinded 
fashion on a regular basis and whenever deemed necessary.  Additional details are provided in 
Section 11.10.
11.1
Subject Information
Unless otherwise stated, in general, all subjects who enrolled this study will be included in 
analyses. Analyses will be performed based on the treatment groups defined in Section 11.  
11.2
Efficacy and Safety Analyses
Baseline value in efficacy
and
safety
is defined as the baseline value of study 
CNTO136ARA3002 or CNTO136ARA3003.  No missing data imputation will be used.
11.2.1
Primary Endpoint
The number of subjects with each of the following long-term safety events through the end of 
study: cardiovascular SAEs, malignancies, serious infections, and gastrointestinal perforations 
will be summarized.  
Serious cardiovascular events adjudicated by the CEC will be summarized by treatment group.
No hypothesis testing will be performed.  
11.2.2
Major Secondary Endpoints
Laboratory parameters of interest (neutrophils, platelets, hepatobiliary parameters, and lipid 
parameters) will be observed. Toxicity grade will be summarized by treatment group over time 
through the end of the study.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
59
11.2.3
Other Secondary Endpoints
In addition to the primary and major secondary efficacy endpoints, the following efficacy 
endpoints will be summarized by treatment group over time through the end of the study:
1.
Proportion of subjects who achieve ACR 20 response
2.
Proportion of subjects who achieve ACR 50 response
3.
Proportion of subjects who achieve ACR 70 response
4.
Proportion of subjects with DAS28 (CRP) response
5.
Proportion of subjects with DAS28 (CRP) remission
6.
Change from baseline in DAS28 (CRP)
7.
Proportion of subjects with SDAI-based ACR/EULAR remission
8.
Proportion of subjects with Boolean-based ACR/EULAR remission
9.
Change from baseline in SDAI
10. Change from baseline in CDAI
11. Change from baseline in HAQ-DI
12. Proportion of HAQ-DI responders (ie, those who have a change from baseline of > 0.22 in 
HAQ-DI score)
13. Change from baseline in PCS and MCS and in domain scores of SF-36
14. Change from baseline in duration of morning stiffness
11.3
Pharmacokinetic Analyses 
Blood samples for the measurement of serum sirukumab concentrations and the detection of 
antibodies to sirukumab will be collected and analyzed.
Serum sirukumab concentration data including Ctrough will be summarized by visit. PK data may 
be displayed graphically. If sufficient samples are collected, steady-state trough serum 
sirukumab concentrations before and after switching from PFS-U to PFS-AI will be evaluated.
11.4
Immunogenicity Analyses 
The incidence of antibodies to sirukumab will be summarized for all subjects who have 
appropriate samples.  Additional analysis may be performed as needed.
11.5
Pharmacodynamic Analyses 
Changes in the concentration of individual pharmacodynamic markers from baseline to the 
selected post treatment time points will be summarized.  Association between baseline levels and 
changes from baseline in select biomarkers and clinical response will be explored. Baseline value 
is defined as the baseline value of study CNTO136ARA3002 or CNTO136ARA3003, 
respectively. The pharmacodynamic analysis will characterize the response of subjects to 
sirukumab, to determine if loss of response to sirukumab can be predicted, and to better 
understand RA.  Data will be summarized in a separate technical report.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
60
11.6
Pharmacogenetics (DNA) Analyses 
Pharmacogenetics tests will be summarized by treatment group.  Genetic factors and changes in 
expression 
of 
DNA 
methylation markers 
from baseline (CNTO136ARA3002 
and 
CNTO136ARA3003 studies) to the collection time point in study CNTO136ARA3004 will also 
be summarized. The pharmacogenetic analyses will be summarized in a separate technical report.
11.7
Health Economics Analyses 
Change from baseline in total and domain scores of the WLQ and HECONQ will be summarized
over time. Baseline value is defined as the baseline value of study CNTO136ARA3002 or 
CNTO136ARA3003, respectively.
11.8
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
MedDRA dictionary. 
All reported AEs with onset during the treatment phase (ie, 
treatment-emergent AEs and AEs that have worsened since baseline) will be included in the 
analysis. For each AE, the percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized by treatment group.  Other safety analyses include the 
proportion of subjects with infections, SAE, AE leading to discontinuation.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or a 
serious adverse event (SAE).
Additional analyses will be performed for the number of subjects with cardiovascular SAEs by 
cardiovascular type and the number of subjects with malignancies by malignancy type (eg, 
lymphoma, nonmelanoma skin cancers, and other malignancies).
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. NCI-CTCAE grades will be used 
in the summary of laboratory data. For some laboratory data, which are not covered in the NCI-
CTCAE grading criteria, shift tables and/or other abnormal cutoff levels may be used for 
summaries.  Descriptive statistics will be calculated for selected laboratory analyte at baseline 
and at each scheduled time point. A listing of subjects with post-baseline abnormal laboratory 
results based on NCI-CTCAE grades will also be provided.
Vital Signs
The proportion of subjects with markedly abnormal post-baseline values will be summarized.
11.9
Interim Analysis
No formal interim analyses are planned, though analyses based on interim releases and locks 
may be carried out for integrated PK, immunogenicity, safety and efficacy data.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
61
11.10
Data Monitoring Committee
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study.  The committee will meet periodically to 
review interim data.  After the review, the DMC will make recommendations regarding the 
continuation of the study.
The DMC will have 3 to 6 members who are independent of the Sponsor. None of the members 
will be participating in the current study. The DMC will consist of at least 1 medical expert in 
the relevant therapeutic area and at least 1 statistician.  The members of the committee will be 
specified prior to study initiation. The major function of this committee will be to monitor the 
safety of the study agent and to provide recommendations for placing the study on hold or 
stopping the study in the event that any unanticipated serious events occur.  
The DMC will conduct periodic safety reviews that will occur every 4 months until at a 
minimum, the study becomes open-label. The DMC may change the frequency or number of 
reviews based on interim safety findings. The safety reviews will focus on particular AEs, SAEs, 
and mortality.
SAE reports will be provided to the DMC members on an ongoing basis. The DMC will have 
access to unblinded data and review tabulated safety summaries (if appropriate) and any 
additional data that the DMC may request during the conduct of the study. No formal statistical 
hypothesis testing is planned. In addition, during the study, the Sponsor's study responsible 
physician (or designee) will regularly review blinded safety data from the sites and notify the 
DMC and appropriate Sponsor personnel of any issues.  
The content of the safety summaries, the DMC role and responsibilities, and the general 
procedures (including communications) and their recommendations on the study conduct will be 
defined and documented in the DMC charter prior to the first DMC review.
11.11
Clinical Events Committee
The CEC is an independent committee composed of external specialists, blinded to treatment 
assignment, which will be commissioned to review case information on serious CV events 
(myocardial infarction, stroke, death, hospitalization for angina, hospitalization for TIA).  The 
operations, processes, and definitions to be employed by the committee will be defined in the 
CEC charter.
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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
62
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 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 (see 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A SAE based on ICH is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is medically important*
*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 as unlisted, if the nature or severity is not consistent with the 
applicable product reference safety information. 
For an investigational product, the 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
63
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).
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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
64
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 medicinal product that may require expedited reporting 
and/or safety evaluation include, but are not limited to:

Overdose of a Sponsor medicinal product

Suspected abuse/misuse of a Sponsor medicinal product

Inadvertent or accidental exposure to a Sponsor medicinal product

Medication error involving a Sponsor product (with or without subject/patient exposure to 
the Sponsor medicinal product, eg, name confusion)

Adverse events that require expedited reporting include: cardiovascular AEs (myocardial 
infarction, stroke, death, hospitalization for angina, and hospitalization for TIA), newly 
identified malignancies, active TB, gastrointestinal perforations, and certain hepatobiliary 
events (that meet the criteria described in Section 10.2).  Adverse events of special interest 
will be reported in the same timeframe as an SAE, even if they do not meet the requirements 
to be an SAE.  Of note, all hepatobiliary events that meet criteria as described below, must 
be reported as an SAE (see Section 12.4).

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 patients receiving anticoagulants) 
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a SAE should be recorded on the SAE 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 visit (which may include contact for follow-up of safety).  SAEs, 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 SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments. Anticipated events will be recorded and reported as described 
in Attachment 2. All adverse events, regardless of seriousness, severity, or presumed relationship
to study therapy, must be recorded using medical terminology in the source document and the 
CRF. Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection"). Investigators must record in the CRF their opinion 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
65
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 all SAEs that are unlisted 
(unexpected) and associated with the use of the drug. The investigator (or Sponsor where 
required) must report these events to the appropriate IEC/IRB that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
Subjects (or their designees, if appropriate) must be provided with a "study card" indicating the 
following:

Subject number

Study site number

Study number

Sponsor’s emergency contact name and 24-hour telephone number (for medical staff only)

Investigator's name and contact information

Statement in the local language(s) that the subject is participating in a clinical trial.
12.3.2
Serious Adverse Events
All SAEs occurring during clinical studies must be reported to the appropriate Sponsor contact 
person by investigational staff within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the Sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a member of the investigational staff, and 
transmitted to the Sponsor within 24 hours. The initial and follow-up reports of a SAE should be 
made by facsimile (fax).
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study agent 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)
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
66
Suspected transmission of an infectious agent by a medicinal product will be reported as a SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a clinical study must be reported as a SAE, except 
hospitalizations for the following:

Social reasons in the absence of an adverse event

Surgery or procedure planned before entry into the study (must be documented in the CRF)
The cause of death of a subject in a clinical study within 4 months of the last dose, whether or 
not the event is expected or associated with the investigational agent, is considered a SAE.
12.3.3
Pregnancy 
All initial reports of pregnancy must be reported to the Sponsor by the investigational staff 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital 
anomaly) are considered SAEs 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 agent on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported by the investigational staff 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 after the subject’s consent has been obtained.

For women: The study doctor will ask for your permission to stay in contact with you 
throughout the length of the pregnancy.

For men: The study doctor will ask for your permission and your partner’s to stay in contact 
with your partner throughout the pregnancy.
12.4
Adverse Events of Special Interest 
All initial reports of cardiovascular AEs (myocardial infarction, stroke, death, hospitalization for 
angina, hospitalization for TIA), newly identified malignancies, active TB, hepatobiliary 
abnormalities (as defined below), and gastrointestinal perforations must be reported to the 
Sponsor by the 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 as described below must be reported as an SAE.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
67

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 patients 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.  PQCs may have 
an impact on the safety and efficacy of the product. The timely, accurate, and complete 
reporting and analysis of PQC 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 procedures in conformity with regulatory requirements worldwide 
to ensure appropriate reporting of PQC information; all clinical 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 investigational staff within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the investigational staff must report the PQC to the 
Sponsor according to the SAE reporting timelines (see Section 12.3.2) in addition to reporting 
the SAE to the Sponsor. A sample of the suspected product should be maintained for further 
investigation if requested by the Sponsor.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
68
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 AGENT INFORMATION
14.1
Physical Description of Study Agent(s)
The sirukumab drug product provided for this study is supplied in a 1 mL PFS fitted with either: 
(1) a passive safety needle guard (UltraSafe Passive™ Delivery System, Safety Syringes, Inc.) 
that is permanently assembled on the syringe or (2) a spring-powered, disposable autoinjector 
device for SC administration of liquid biologic drug products (SmartJect™ Autoinjector) that is 
permanently assembled on the syringe.  The sirukumab PFS is aseptically filled to 50 mg/1.0 mL 
and 100 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, a non-latex-based 
elastomeric needle shield, and a fluoropolymer coated elastomeric plunger stopper.  For a list of 
excipients, refer to the Investigator’s Brochure for sirukumab.
Until the study is unblinded, study agent will be supplied in a 1 mL PFS fitted with either: (1) a
passive safety needle guard (UltraSafe Passive™ Delivery System, Safety Syringes, Inc.) that is 
permanently assembled on the syringe or (2) a spring-powered, disposable autoinjector device 
for SC administration of liquid biologic drug products (SmartJect™ Autoinjector) 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 G ½ inch fixed needle, a non-latex-based elastomeric needle shield, and a 
fluoropolymer coated elastomeric plunger stopper.  For a list of excipients, refer to the 
Investigator’s Brochure for sirukumab.
14.2
Packaging
The sirukumab PFS-U will be supplied with a passive safety needle guard (UltraSafe Passive™ 
Delivery System, Safety Syringes, Inc.) that is permanently assembled on the syringe.
Once available, the sirukumab PFS-AI will be supplied with a spring-powered, disposable device 
for SC administration of liquid biologic drug products (SmartJect™ Autoinjector) that is 
permanently assembled on the syringe.
14.3
Labeling
Study agent labels will contain information to meet the applicable regulatory requirements.
14.4
Preparation, Handling, and Storage
All study agent presentations should be stored in a secured refrigerator at 2ºC to 8ºC (36ºF to 
46ºF).  Study agent should not be frozen or shaken.  During extended storage, protect from 
excessive exposure to light.  Protection from light is not required during administration.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
69
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.
Study agent should be administered according to the instructions provided in the Site 
Investigational Product Procedures Manual.
Subjects who are able and who have been appropriately trained in the self-administration of 
study agent may self-administer study agent at home in accordance with Section 6.5.  Study 
personnel will instruct subjects on how to transport, store and administer medication for at-home 
use as indicated for this protocol.  Details will be provided in the Site Investigational Product 
Procedures Manual.  
14.5
Drug Accountability
The study agents are to be prescribed only by the principal investigator (PI) or a qualified 
physician listed as a subinvestigator on required forms (eg, FDA Form 1572).  Records should be 
kept on the study agent accountability form provided by the Sponsor or its designee.  
Administration of the study agent must be recorded in the subject’s permanent record.  The study 
agent may not be used for any purpose other than that outlined in this protocol, including other 
human studies, animal investigations, or in vitro testing.
Upon termination of the study or at the request of the Sponsor or its designee, the investigator 
must return all unused study agent to the Sponsor or its designee or if approved by the Sponsor, 
unused study agent can be destroyed directly at the site or locally by an approved destruction unit 
as described in the Site Investigational Product Procedures Manual.
The investigator is responsible for ensuring that all study agent received at the site is inventoried 
and accounted for throughout the study.  The dispensing of study agent to the subject, and the 
return of study agent from the subject (if applicable), must be documented on the drug 
accountability form.  Subjects must be instructed to return all used or unused study agent, 
whether empty or containing study agent.  Subjects will receive a sharps container to dispose of 
used PFS fitted with UltraSafe Passive™or autoinjector.  Subjects will be instructed to return 
the sharps container and/or unused cartons with PFS-UltraSafe Passive™or autoinjector.  The 
study agent administered to the subject must be documented on the drug accountability form.  
All study agents will be stored and disposed of according to the Sponsor's instructions. Site staff 
must not combine contents of the study agent containers.
Study agent 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 agent must be available for verification by the 
Sponsor's site monitor during on-site monitoring visits.  The return to the Sponsor of unused 
study agent, or used returned study agent for destruction, will be documented on the drug return 
form.  When the site is an authorized destruction unit and study agent supplies are destroyed on 
site, this must also be documented on the drug return form.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
70
Study agent should be dispensed under the supervision of the investigator or a qualified member 
of the investigational staff, or by a hospital/clinic pharmacist. Study agent will be supplied only 
to subjects participating in the study. Returned study agent must not be dispensed again, even to 
the same subject. Study agent may not be relabeled or reassigned for use by other subjects.  The 
investigator agrees neither to dispense the study agent from, nor store it at, any site other than the
study sites agreed upon with the Sponsor.
15
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following:

Investigator Brochure

Site Investigational Product Procedures Manual

Central Laboratory Manual

ePRO Device and Manual

MTX Toxicity Guidelines (Appendix C)  

IVRS/IWRS User Guides and Worksheets
16
ETHICAL ASPECTS  
16.1
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study, and during 
the study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
16.2
Regulatory Ethics Compliance
16.2.1
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on GCP, and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects.
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the clinical study data are credible.
16.2.2
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or Sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents:
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
71

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 (unless not required, as documented by the 
IEC/IRB)

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), ICF, applicable recruiting materials, and subject compensation 
programs, and the Sponsor has received a copy of this approval. This approval letter must be 
dated and must clearly identify the IEC/IRB and the documents being approved.
Approval for the pharmacogenetics research component of the clinical study and for the 
pharmacogenetics ICF must be obtained from the IEC/IRB.  Approval for the protocol can be 
obtained independent of approval for pharmacogenetics research.
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

Revisions 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 
investigational 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
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
72

Notification if a new PI is responsible for the study at the site

Development Safety Update Report (DSUR) Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or trial 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 clinical 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.
16.2.3
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The consent form must be signed before performance of any 
study-related activity. The consent form that is 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 investigational 
staff 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 to not 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 staff or delegate(s) 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, and subsequent disease-related treatments, or to obtain information 
about his or her survival status.
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 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
73
by means of the subject's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the subject.
Subjects will be asked to consent to participate in a pharmacogenetics research component of the 
study where local regulations permit. After informed consent for the clinical study is 
appropriately obtained, the subject will be asked to sign and personally date a separate 
pharmacogenetics informed consent form indicating agreement to participate in optional 
pharmacogenetics research. A copy of the signed pharmacogenetics informed consent form will 
be given to the subject. Refusal to participate in the pharmacogenetics research component of the 
study will not result in ineligibility for the clinical study.
A limited number of subjects will be asked to consent to participate in the Subject Lab Data 
Access and/or to complete the Placebell Multidimensional Personality Questionnaire. Refusal to 
participate in either the Subject Lab Access program or to complete the Placebell 
Multidimensional Personality Questionnaire will not result in ineligibility for the clinical study.
16.2.4
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of study subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator to allow direct access to his or her original medical records 
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 and biomarker research will not be 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. 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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
74
16.2.5
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.
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 or its designee. 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
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2
Required Prestudy Documentation
The following documents must be provided to the Sponsor before shipment of study agent to the 
investigational site:

Protocol and amendment(s), if any, signed and dated by the PI

A copy of the dated and signed, 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 
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, 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
75
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the investigational staff is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the PI, 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 clinical subinvestigators

Documentation of sub investigator 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 ID 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 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 informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all AEs and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; study agent administration information; and date of study 
completion and reason for early discontinuation of study agent or withdrawal from the study, if 
applicable. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
76
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 study subject should be 
consistent with that commonly recorded at the site as a basis for standard medical care.  Specific 
details required as source data for the study will be reviewed with the investigator before the 
study and will be described in the monitoring guidelines (or other equivalent document).
Data which may be recorded directly into the CRF, if in accordance with site capabilities and/or 
in compliance with local regulations, will be considered source data, and will include but not be 
limited to the following:

Blood pressure

Weight
The following subject- and investigator-completed RA scales and assessments designated by the 
Sponsor will be recorded directly into an electronic device and will be considered source data.

Swollen and tender joint assessments

Patient’s Global Assessment of Disease Activity

Physician’s Global Assessment of Disease Activity

Patient’s Assessment of Pain

HAQ-DI

SF-36

Duration of Morning Stiffness

WLQ

HECONQ
Multidimensional Personality Questionnaire recorded on paper will also be considered source 
data.
During the “at home administration” (AHA) phase of the study, subjects will enter information 
on their study agent administration on a patient diary.
17.5
Case Report Form Completion
Case report forms are provided for each subject in electronic format.  
Electronic Data Capture will be used for this study. The study data will be transcribed by study 
personnel from the source documents onto an electronic CRF (eCRF), and transmitted in a 
secure manner to the Sponsor within the timeframe agreed upon between the Sponsor and the 
site. The electronic file will be considered to be the eCRF.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
77
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation.  All data relating to the 
study must be recorded in eCRFs prepared by the Sponsor. Data must be entered into eCRFs in 
English. Designated site personnel must complete the eCRF as soon as possible after a subject 
visit, and the forms should be available for review at the next scheduled monitoring visit.
The investigator must confirm that all data are accurate and correct.
All eCRF 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. The 
investigator or an authorized member of the investigational staff must adjust the eCRF (if 
applicable) and complete the query. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways:

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)

Site manager can generate a query for resolution by the investigational staff

Clinical data manager can generate a query for resolution by the investigational staff 
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 
associated personnel before the study, and periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the Sponsor's designee’s 
data base. Written instructions will be provided for collection, preparation, and shipment of 
samples.
Guidelines for CRF completion will be provided and reviewed with study personnel before the 
start of the study.  Whenever possible, all subjective measurements (eg, pain scale information or 
other questionnaires) should be completed as consistently as possible and preferably by the same 
individual who made the initial baseline determinations.  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 clinical 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).
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
78
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. 
It is the responsibility of the Sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the Sponsor.
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports.
17.8
Monitoring
The Sponsor will perform on-site monitoring visits as frequently as necessary.  At these 
monitoring visits, the monitor will compare the data entered into the CRFs with the hospital or 
clinic records (source documents).  The monitor will record dates of the visits in a study site visit 
log that will be kept at the site.  
Although the data for all subjects is eligible to be monitored, a streamlined approach to 
monitoring may be implemented, whereby a subset of subjects and/or critical data points will be 
verified as defined in the monitoring plan.  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 investigational staff and are accessible for verification by the Sponsor site 
contact. If electronic records are maintained at the investigational site, the method of verification 
must be discussed with the investigational staff. 
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 investigational staff. 
The Sponsor expects that, during monitoring visits, the relevant investigational staff 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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
79
17.9
Study Completion/Termination
17.9.1
Study Completion
The study is considered completed with the last visit for the last subject participating in the 
study.  The final data from the investigational site will be sent to the Sponsor (or designee) after 
completion of the final subject visit at that site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2
Study Termination
The Sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Investigational sites will be closed upon 
study completion or after a formal DBL if the site has no active subjects.  An investigational site 
is considered closed when all required documents and study supplies have been collected and a 
site closure visit has been performed.
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of an investigational 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 the subjects by the investigator

Discontinuation of further drug development
17.10
On-Site Audits
Representatives of the Sponsor's clinical quality assurance department may visit the 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 staff are responsible for being present and 
available for consultation during routinely scheduled 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 they have 
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, generated as a result of this study, are considered 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
80
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 clinical 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 CSR generated by the Sponsor and will contain 
CRF data from all investigational sites that participated in the study, clinical laboratory data from 
a central laboratory, and other data such as IVRS/IWRS data and x-ray data into the Sponsor's 
designee’s database.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR.  The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results at the Sponsor’s site or other mutually-agreeable location.
The Sponsor will also provide all investigators with the summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as appropriate.  
The Sponsor will provide each investigator with the unblinding codes for their site only after 
completion of the full statistical analysis.   Results of exploratory biomarker analyses performed 
after the CSR has been issued may be reported in a separate report and will not require a revision 
of the CSR. Study subject identifiers will not be used in publication of exploratory biomarker 
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. 
The Sponsor shall have the right to publish such data and information without approval from the 
investigator. 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 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 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
81
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.  The Sponsor aims to post results summary to the appropriate publicly available 
registers no later than 8 months after the last subject’s last visit (LSLV).  In addition, the aim is 
to submit a manuscript to a peer-reviewed journal for publication within 12 months of LSLV.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
82
REFERENCES
1.
ACTEMRA® [prescribing information]. South San Francisco, CA: Genentech, Inc; 2011
2.
Aletaha D, Smolen JS. The definition and measurement of disease modification in inflammatory rheumatic 
diseases. Rheum Dis Clin North Am. 2006;32(1):9-44, vii.
3.
Arend WP, Dayer JM.  Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis.  Arthritis 
Rheum.  1990;33(3):305-315.
4.
Beum PV, Lindorfer MA, Taylor RP.  Within peripheral blood mononuclear cells, antibody-dependent cellular 
cytotoxicity of rituximab-opsonized Daudi cells is promoted by NK cells and inhibited by monocytes due to 
shaving. J Immunol. 2008;181(4):2916-2924.
5.
Campbell IL, Abraham CR, Masliah E, et al.  Neurologic disease induced in transgenic mice by cerebral 
overexpression of interleukin 6.  Proc Natl Acad Sci U S A.  1993;90(21):10061-10065.
6.
Dalrymple SA, Lucian LA, Slattery R, et al.  Interleukin-6-deficient mice are highly susceptible to Listeria 
monocytogenes infection: correlation with inefficient neutrophilia.  Infect Immun. 1995;63(6):2262-2268. 
7.
Emery P, Keystone E, Tony HP, et al.  IL-6 receptor inhibition with tocilizumab improves treatment outcomes 
in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week 
multicentre randomised placebo-controlled trial.  Ann Rheum Dis. 2008;67(11):1516-1223.
8.
Felson DT, Anderson JJ, Boers M, et al.  The American College of Rheumatology preliminary core set of 
disease activity measures for rheumatoid arthritis clinical trials.  The Committee on Outcome Measures in 
Rheumatoid Arthritis Clinical Trials.  Arthritis Rheum.  1993;36(6):729-740.
9.
Felson DT, Anderson JJ, Boers M, et al.  American College of Rheumatology.  Preliminary definition of 
improvement in rheumatoid arthritis.  Arthritis Rheum.  1995;38(6):727-735.
10. Felson DT, Smolen JS, Wells G, et al; American College of Rheumatology; European League Against 
Rheumatism. American College of Rheumatology/European League Against Rheumatism provisional 
definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63(3):573-586.
11. Flannery CR, Little CB, Hughes CE, Curtis CL, Caterson B, Jones SA.  IL-6 and its soluble receptor augment 
aggrecanase-mediated proteoglycan catabolism in articular cartilage.  Matrix Biol.  2000;19(6):549-553.
12. Fries JF, Spitz P, Kraines RG, Holman HR.  Measurement of patient outcomes in arthritis.  Arthritis Rheum.
1980;23:137-145.
13. Guerne PA, Zuraw BL, Vaughan JH, Carson DA, Lotz M.  Synovium as a source of interleukin 6 in vitro.  
Contribution to local and systemic manifestations of arthritis.  J Clin Invest.  1989;83(2):585-592.
14. Harjunpää A, Junnikkala S, Meri S. Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement 
killing is superior to cellular effector mechanisms. Scand J Immunol. 2000;51(6):634-641. 
15. Hawley DJ, Wolfe F.  Sensitivity to change in the Health Assessment Questionnaire (HAQ-DI) and other 
clinical and health status measures in rheumatoid arthritis.  Arthritis Care Res.  1992;5(3):130-136.
16. Hirano T, Matsuda T, Nakajima K.  Signal transduction through gp130 that is shared among the receptors for 
the interleukin 6 related cytokine subfamily.  Stem Cells.  1994;12(3):262-277.
17. Ishihara K, Hirano T.  IL-6 in autoimmune disease and chronic inflammatory proliferative disease.  Cytokine 
Growth Factor Rev.  2002;13(4-5):357-368.
18. Jones G, Sebba A, Gu J. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients 
with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010 69: 88-96.
19. Kishimoto T.  Interleukin-6:  from basic science to medicine - 40 years in immunology.  Annu Rev Immunol.  
2005;23:1-21.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
83
20. Kopf M, Baumann H, Freer G, et al.  Impaired immune and acute-phase responses in interleukin-6-deficient 
mice.  Nature.  1994;368(6469):339-342.
21. Kremer J, Fleischmann R, Brzezicki J, et al.  Tocilizumab Inhibits Structural Joint Damage, Improves Physical 
Function, and Increases DAS28 Remission Rates in RA Patients Who Respond Inadequately to Methotrexate:  
the Lithe Study.  Ann Rheum Dis. 2009;68(Suppl3):122.
22. Lerner D, Rogers WH and Chang H.  The Work Limitations Questionnaire.  MAPI Research Institute Quality of 
Life News Letter.  2002;28:9-10.
23. Lipsky PE.  Interleukin-6 and rheumatic diseases.  Arthritis Res Ther.  2006;8 Suppl 2:S4.
24. Liu F, Poursine-Laurent J, Wu Huai, Link D.  Interleukin-6 and the Granuloycte Colony-Stimulating Factor 
Receptor Are Major Independent Regulators of Granulopoiesis In Vivo but are not Required for Lineage 
Commitment or Terminal Differentiation.  Blood.  Vol 90, No 7 (October 1), 1997: pp 2583-2590.
25. Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ. Isolation of an mRNA encoding a soluble 
form of the human interleukin-6 receptor. Cytokine. 1992;4(2):96-100.
26. Mackiewicz A, Schooltink H, Heinrich PC, Rose-John S. Complex of soluble human IL-6-receptor/IL-6 up-
regulates expression of acute-phase proteins. J Immunol. 1992;149(6):2021-2027.
27. Mease P, Strand V, Shalamberidze L, et al.  Inhibition of IL-6 with ALD518 Improves Disease Activity in 
Rheumatoid Arthritis in a Randomized, Double-Blind, Placebo-controlled, Dose Ranging Phase 2 Clinical Trial.  
Ann Rheum Dis.  2010;69(Suppl3):98.
28. Mihara M, Kasutani K, Okazaki M, et al.  Tocilizumab inhibits signal transduction mediated by both mIL-6R 
and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol. 
2005;5(12):1731-1740.
29. Müllberg J, Schooltink H, Stoyan T, et al. The soluble interleukin-6 receptor is generated by shedding. 
Eur J Immunol. 1993;23(2):473-480.
30. Nakamura I, Omata Y, Naito M, Ito K.  Blockade of interleukin 6 signaling induces marked neutropenia in 
patients with rheumatoid arthritis.  J Rheumatol.  2009;36(2):459-460.
31. Nemeth E, Rivera S, Gabayan V, et al.  IL-6 mediates hypoferremia of inflammation by inducing the synthesis 
of the iron regulatory hormone hepcidin.  J Clin Invest.  2004;113(9):1271-1276.
32. Nicola NA, Matsumoto M, Metcalf D, Johnson GR.  Molecular properties of a factor inducing differentiation in 
murine myelomonocytic leukemic cells.  Haematol Blood Transfus.  1983;28:345-347.
33. Nishimoto N, Hashimoto J, Miyasaka N, et al.  Study of active controlled monotherapy used for rheumatoid 
arthritis, an IL-6 inhibitor (SAMURAI):  evidence of clinical and radiographic benefit from an x ray reader-
blinded randomised controlled trial of tocilizumab.  Ann Rheum Dis.  2007;66(9):1162-1167.
34. Park JY, Pillinger MH. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bull NYU Hosp Jt Dis.
2007;65(Suppl 1):S4-S10. 
35. Pereira A, Branders S, Duale C, Clermont F, Gramme P, Gossuin C, Demolle D. Multifactorial aspect of the 
placebo analgesia response in peripheral neuropathic patients. IASP 16th World Congress on Pain 2016.
36. Pereira A, Duale C, Clermont F, Gramme P, Branders S, Gossuin C, Demolle D. (171) Characterization and 
prediction of placebo responders in peripheral neuropathic patients in a 4-week analgesic clinical trial. J. Pain 
2016;17:S18. doi:10.1016/j.jpain.2016.01.074.
37. Pittas AG, Joseph NA, Greenberg AS.  Adipocytokines and insulin resistance.  J Clin Endocrinol Metab.  
2004;89(2):447-452.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
84
38. Romani L, Mencacci A, Cenci E, et al.  Impaired neutrophil response and CD4+ T helper cell 1 development in 
interleukin 6-deficient mice infected with Candida albicans.  J Exp Med. 1996;183(4):1345-1355.  
39. Rose-John S. Heinrich PC. Soluble receptors for cytokines and growth factors: generation and biological 
function. Biochemical J. 1994;300 (Pt 2):281-290.
40. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J.  Chimeric anti-TNF-alpha monoclonal antibody cA2 
binds
recombinant transmembrane TNF-alpha and activates immune effector functions.  Cytokine.  
1995;7(3):251-259.
41. Smolen JS, Beaulieu A, Rubbert-Roth A, et al, for the OPTION Investigators. Effect of interleukin-6 receptor 
inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-
controlled, randomised trial.  Lancet.  2008;371(9617):987-997.
42. Sokka T, Kautiainen H, Mottonen T, Hannonen P.  Work disability in rheumatoid arthritis 10 years after the 
diagnosis.  J Rheumatol.  1999;26(8):1681-1685.
43. Suematsu S, Matsuda T, Aozasa K, et al.  IgG1 plasmacytosis in interleukin 6 transgenic mice.  Proc. Natl. 
Acad. Sci. USA.  1989;86:7547-7551.  
44. Suzuki Y, Rani S, Liesenfeld O, et al.  Impaired resistance to the development of toxoplasmic encephalitis in 
interleukin-6-deficient mice.  Infect Immun. 1997;65(6):2339-2345.  
45. van Riel PL, van Gestel AM, Scott DL.  EULAR Handbook of Clinical Assessments in Rheumatoid Arthritis.  
Alphen Aan Den Rijn, The Netherlands:  Van Zuiden Communications B.V.; 2000:40.
46. Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE. Circulating interleukin-6 in relation 
to adiposity, insulin action, and insulin secretion. Obes Res. 2001;9(7):414-417.
47. Ware JE, Kosinski M, Keller SD.  Interpretation: Norm-Based.  In: SF-36 Physical and Mental Health Summary 
Scales: A User’s Manual.  Boston, MA: The Health Institute; 1994:8:1-8:42.  
48. Ware JE Jr, Sherbourne CD.  The MOS 36-item short-form health survey (SF-36), I: conceptual framework and 
item selection.  Med Care.  1992;30(6):473-483
49. Wendling D, Racadot E, Wijdenes J.  Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal 
antibody.  J Rheumatol.  1993;20:259-262.
50. Yelin E, Henke C, Epstein W.  The work dynamics of the person with rheumatoid arthritis.  Arthritis Rheum. 
1987;30(5):507-512.
51. Yokota S, Miyamae T, Imagawa T, et al.  Therapeutic efficacy of humanized recombinant anti-interlukin-6 
receptor antibody in children with systemic-onset juvenile idiopathic arthritis.  Arthritis Rheum.  
2005;52(3):818-825.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
85
ATTACHMENT 1: PROTOCOL HISTORY
Original Protocol:  20 March 2012
Amendment 1:  06 Mar 2013
Amendment 2:  01 May 2014
Amendment 3:  06 Oct 2016
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
86
AMENDMENT 1 – 06 MARCH 2013
The protocol has been revised to incorporate this amendment, which applies to all study centers.  The rationale and description of the 
changes to the protocol are provided below.  Minor formatting and typographical errors have also been corrected to improve the clarity 
and accuracy of the protocol text; these changes do not affect the overall conduct of the study.
1.  The overall rationale for the study has been updated
An additional rationale for the study has been added.
Sections Affected
Original Content
Amended/New Content
1.2 Overall Rationale of the Study
3.2 Study Design Rationale
This is a parallel-group long-term extension (LTE) trial of 
studies CNTO136ARA3002 and CNTO136ARA3003 to 
assess safety and efficacy of sirukumab in subjects with 
moderately to severely active RA.  
  
None
None
This is a parallel-group long-term extension (LTE) trial of 
studies CNTO136ARA3002 and CNTO136ARA3003 to 
assess the long-term safety and efficacy of sirukumab in 
subjects with moderately to severely active RA.  
Additionally, a substudy of enrolled subjects in 
CNTO136ARA3004 will further assess the usability of 
the SmartJect™ Autoinjector (PFS-AI).
Additionally, this study is designed to obtain experience 
in the use of the SmartJect™ Autoinjector (PFS-AI) in 
all subjects enrolled in CNTO136ARA3004. More data 
regarding the usability of the autoinjector will be 
evaluated in the PFS-AI substudy.  Additional details 
are provided in Section 9.6.
2.  Clarification of the primary objective has been made
Clarification of the primary objective has been made
Sections Affected
Original Content
Amended/New Content
Synopsis Primary Objective
2.1 Primary Objective
To evaluate the long-term safety of sirukumab in subjects 
with RA.
To evaluate the long-term safety of sirukumab in subjects 
with RA who are refractory to DMARDs or anti-TNFα 
agents.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
87
3.  The secondary objectives have been updated
An additional secondary objective has been added
Sections Affected
Original Content
Amended/New Content
Synopsis Secondary Objectives
Synopsis Secondary Objectives
2.1 Primary Objective
None
None
None
Pharmacogenetics
PFS-AI usability (as defined in a separate substudy
protocol
PFS-AI usability (as defined in a separate substudy 
protocol
4.  The duration of blinded/open-label treatment has been described
Clarification of the duration of blinded/open-label treatment has been made.
Sections Affected
Original Content
Amended/New Content
Synopsis Overview of Study Design
3.1 Overview of Study design
3.2.2 Treatment Groups, Dosage, 
and Dose Administration Interval
3.2.4 Study Control, Randomization, 
and Blinding
Subjects will receive blinded treatment in this study until 
after the Week 52 DBL occurs in CNTO136ARA3002 and 
the Week 24 DBL occurs in CNTO136ARA3003.
Subjects will continue to receive the dosing regimen they 
received at the Week 104 (CNTO136ARA3002) and at 
Week 52 visit (CNTO136ARA3003) in blinded fashion 
until after the Week 52 DBL in CNTO136ARA3002 and 
the Week 24 DBL in CNTO136ARA3003.
Blinded matching placebo injections will be used to reduce 
potential bias during data collection and evaluation of 
clinical endpoints and will be maintained until after the 
Study treatment will remain blinded in 
CNTO136ARA3004 until the following 3 conditions 
have been met: the Week 52 DBL occurs in study 
CNTO136ARA3002, the Week 24 DBL occurs in study 
CNTO136ARA3003, and the last AI usability substudy
subject completes the Week 16 visit or terminates from 
the study.  
Subjects will continue to receive the same dosing regimen 
they received at the Week 104 (CNTO136ARA3002) and 
at Week 52 visit (CNTO136ARA3003) in blinded fashion 
until the following 3 conditions have been met: the 
Week 52 DBL occurs in study CNTO136ARA3002, the 
Week 24 DBL occurs in study CNTO136ARA3003, and 
the last AI usability substudy subject completes the 
Week 16 visit or terminates from the study.   Thereafter 
the same treatment assignment will be continued, but 
the study will no longer be blinded and will become 
open-label.  
Blinded matching placebo injections will be used to reduce 
potential bias during data collection and evaluation of 
clinical endpoints and will be maintained until the 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
88
5.2 Blinding
9.1.2 Double-Blinded Treatment 
Phase
9.1.3 Open-Label Treatment Phase
Week 52 DBL in CNTO136ARA3002 and the Week 24 
DBL in CNTO136ARA3003.  
The study will remain blinded until after the Week 52 DBL 
in CNTO136ARA3002 and the Week 24 DBL in 
CNTO136ARA3003.  
Subjects will have clinic visits per the Time and Events 
Schedule until after the Week 52 DBL in 
CNTO136ARA3002 and the Week 24 DBL in 
CNTO136ARA3003 to receive blinded active study agent 
treatment.
After the Week 52 DBL in CNTO136ARA3002 and the 
Week 24 DBL in CNTO136ARA3003 subjects will receive 
open-label study agent treatment through the end of study.  
following 3 conditions have been met: the Week 52 DBL 
occurs in study CNTO136ARA3002, the Week 24 DBL 
occurs in study CNTO136ARA3003, and the last AI 
usability substudy subject completes the Week 16 visit 
or terminates from the study.  
The study will remain blinded until the following 3 
conditions have been met: the Week 52 DBL occurs in 
study CNTO136ARA3002, the Week 24 DBL occurs in 
study CNTO136ARA3003, and the last AI usability 
substudy subject completes the Week 16 visit or 
terminates from the study.
Subjects will receive blinded study agent treatments 
according to the Time and Events Schedule until the 
following 3 conditions have been met: the Week 52 DBL 
occurs in study CNTO136ARA3002, the Week 24 DBL 
occurs in study CNTO136ARA3003, and the last AI 
usability substudy subject completes the Week 16 visit 
or terminates from the study.
The CNTO136ARA3004 study will become open-label 
after the following 3 conditions have been met: the 
Week 52 DBL occurs in study CNTO136ARA3002, the 
Week 24 DBL occurs in study CNTO136ARA3003, and 
the last AI usability substudy subject completes the 
Week 16 visit or terminates from the study.   
5.  A short summary of the SmartJect™autoinjector has been added
A short summary of the SmartJect™ autoinjector to be introduced in this study has been added.
Sections Affected
Original Content
Amended/New Content
Synopsis Overview of Study design
Synopsis Self-administration
3.1 Overview of Study Design
None
The SmartJect™ Autoinjector (PFS-AI) is expected to 
be used by the majority of subjects in study 
CNTO136ARA3004. In the event PFS-AIs are 
unavailable at the time of a subject’s enrollment in this 
protocol, sirukumab PFS-Ultrasafe (PFS-U), the same 
device used in the CNTO136ARA3002 and 
CNTO136ARA3003 studies, will be provided until such 
time as the PFS-AIs become available. Upon 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
89
availability of PFS-AI trial supplies, subjects who are 
newly entering the CNTO136ARA3004 protocol will be 
trained on the operation of PFS-AI and perform self-
administration of study agent using PFS-AI at the 
Week 2 study visit and return to the study site at 
Week 4 for self-administration with PFS-AI.  In the 
event PFS-AIs are unavailable at the time of a subject’s 
enrollment in this protocol, training on the use of a
PFS-AI will be provided at the next study visit when the 
PFS-AI is available. 
6.  Clarification  on the overview of the study design have been made
Clarifications on the overview of the study design have been made.
Sections Affected
Original Content
Amended/New Content
Synopsis Overview of Study Design
3.1 Overview of Study Design
In study CNTO136ARA3002, after the completion of the 
Week 104 visit (evaluations and study agent 
administration), the subject will sign the informed consent 
form (ICF) and enter the long-term extension (LTE) study 
CNTO136ARA3004.  As a result, the Week 104 visit in 
study CNTO136ARA3002 will correspond to the Week 0 
visit in the CNTO136ARA3004 study.  The duration of 
study CNTO136ARA3002 is 2 years and the duration of 
study CNTO136ARA3004 is approximately 3 years for a 
total of 5 years.
The long-term extension (LTE) study will start after 
subjects have completed participation in studies 
CNTO136ARA3002 or CNTO136ARA3003.  The purpose 
of this LTE study is to evaluate the safety, efficacy, and 
pharmacologic effects of sirukumab for a minimum 
duration of 3 years and a maximum duration of 
approximately 5 years. 
In study CNTO136ARA3002, after the completion of the 
Week 104 visit (evaluations and study agent 
During the Week 104 visit in CNTO136ARA3002 or the 
Week 52 visit in CNTO136ARA3003, subjects will sign 
the informed consent form (ICF) to enter the LTE 
study CNTO136ARA3004.  As a result, the Week 104 
visit in study CNTO136ARA3002 and the Week 52 visit 
in study CNTO136ARA3003 will correspond to the 
Week 0 visit in the CNTO136ARA3004 study.  
Subjects will become eligible to participate in this LTE 
study when they have completed participation in 
studies CNTO136ARA3002 (104 weeks) or 
CNTO136ARA3003 (52 weeks).  The purpose of this 
LTE study is to evaluate the safety, efficacy, and 
pharmacologic effects of sirukumab for a minimum 
duration of 1 to 4 additional years and a maximum total 
duration of approximately 5 years across the combined 
protocols (CNTO136ARA3002 (2 years) or 
CNTO136ARA3003 (1 year) + CNTO136ARA3004 (1 to 
4 years) = maximum of 5 years treatment). 
During the Week 104 visit in CNTO136ARA3002 or the 
Week 52 visit in CNTO136ARA3003, subjects will sign 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
90
administration), the subject will sign the informed consent 
form (ICF) and enter the long-term extension (LTE) study 
CNTO136ARA3004.  As a result, the Week 104 visit in 
study CNTO136ARA3002 will correspond to the Week 0 
visit in the CNTO136ARA3004 study.  The duration of 
study CNTO136ARA3002 is 2 years and the duration of 
study CNTO136ARA3004 is approximately 3 years for a 
total of 5 years.
Similarly, in study CNTO136ARA3003, after the 
completion of the Week 52 visit (evaluations and study 
agent administration), the subject will sign the ICF and 
enter the LTE study CNTO136ARA3004.  As a result, the 
Week 52 visit in study CNTO136ARA3003 will 
correspond to the Week 0 visit in the CNTO136ARA3004 
study.  The duration of study CNTO136ARA3003 is 1 year 
and the duration of study CNTO136ARA3004 is 
approximately 4 years for a total of 5 years.
If sirukumab becomes approved and available for use for 
RA in the subject’s country of residence, the subject may 
be discontinued from study agent administrations and will 
have the opportunity to discuss treatment options with their 
treating physician under the following conditions: 

For subjects from study CNTO136ARA3002, 
after a minimum of 1 year in this study 

For subjects from study CNTO136ARA3003, 
after a minimum of 2 years in this study 
The maximum duration of this study is expected to be 208 
weeks, followed by approximately 16 weeks of safety and 
efficacy follow-up after the administration of the final 
study agent injection of sirukumab.  
the informed consent form (ICF) to enter the LTE 
study CNTO136ARA3004.  As a result, the Week 104 
visit in study CNTO136ARA3002 and the Week 52 visit 
in study CNTO136ARA3003 will correspond to the 
Week 0 visit in the CNTO136ARA3004 study.  
After a minimum of 1 year treatment in 
CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of 
treatment in CNTO136ARA3004 for subjects from 
CNTO136ARA3003, and after sirukumab is approved 
for the treatment of RA in the subject’s country of 
residence, the Sponsor may no longer offer study 
treatment in CNTO136ARA3004 for those specific 
subjects. At that point the subject will have the 
opportunity to discuss treatment options with their 
treating physician.   
The maximum duration of participation in this study is 
208 weeks, followed by approximately 16 weeks of safety 
and efficacy follow-up after the administration of the final 
study agent injection of sirukumab.   
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
91
7.  Clarification on pharmacogenetics blood sample has been made
Clarification on pharmacogenetics blood sample has been made.
Sections Affected
Original Content
Amended/New Content
3.1 Overview of Study Design
A pharmacogenetics blood sample to assess DNA 
methylation will be collected from subjects who consent 
separately to the pharmacogenetics component of the study 
where local regulations permit.  Participation in the 
pharmacogenetics research is optional.
A pharmacogenetics blood sample to assess genetic 
factors such as DNA methylation patterns will be 
collected from subjects who consent separately to the 
pharmacogenetics component of the study where local 
regulations permit.  Participation in the pharmacogenetics
research component of this study is optional.
8.  Figure 1 representing the study design has been updated
Panel A in Figure 1 describing the study design has been updated.
Sections Affected
Original Content
Amended/New Content
3.1 Overview of Study Design
CNTO136ARA3004 will become an open-label study after 
the 52-Week DBL in CNTO136ARA3002 and the 24-
Week DBL in CNTO136ARA3003 have occurred.
Deleted.
9.  Clarification on the study phases and duration of treatment have been made
Clarifications on the study phases and duration of treatment have been made.
Sections Affected
Original Content
Amended/New Content
3.2.3 Study Phases and Duration of 
Treatment
There will be 3 phases of this LTE study: Blinded active 
treatment, open-label treatment, and safety and efficacy 
follow-up. 
The blinded active treatment phase of the study will be 
from Week 0 until after the Week 52 DBL in 
CNTO136ARA3002 and the Week 24 DBL in 
CNTO136ARA3003. 
The open-label treatment phase of the study will begin 
after the Week 52 DBL in CNTO136ARA3002 and the 
Week 24 DBL in CNTO136ARA3003.  
The safety and efficacy follow-up phase of the study will 
be approximately 16 weeks from the last administration of 
study agent or is discontinued permanently from study 
agent (early).  The safety and efficacy follow-up allows for 
There will be 3 phases of this LTE study: Blinded active 
treatment, open-label treatment, and safety and efficacy 
follow-up. 
As described in Section 3.2.2, the blinded active 
treatment phase will continue until following 3 
conditions have been met: the Week 52 DBL occurs in 
study CNTO136ARA3002, the Week 24 DBL occurs in 
study CNTO136ARA3003, and the last AI usability 
substudy subject completes the Week 16 visit or 
terminates from the study.
The open-label treatment phase of the study will begin 
after those 3 conditions have been met, and will 
continue through the last scheduled dose for all 
subjects.  The safety and efficacy follow-up will include 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
92
monitoring of the subject for a period of equivalent to at 
least 5 times the half-life of sirukumab.
The duration of the study is expected to be 156 weeks for 
subjects enrolling after participation in 
CNTO136ARA3002 and 208 weeks for subjects enrolling 
after participation in CNTO136ARA3003, followed by 
approximately 16 weeks of safety and efficacy follow-up 
after the administration of the final study agent injection of 
sirukumab.   
approximately 16 weeks of study evaluations following 
the last administration of study agent, including follow-
up for patients who discontinued study treatment prior 
to their last scheduled dose. The safety and efficacy 
follow-up allows for monitoring of the subject for a 
period of equivalent to at least 5 times the half-life of 
sirukumab.
The maximum duration of the study is expected to be 
156 weeks for subjects enrolling after participation in 
study CNTO136ARA3002 and 208 weeks for subjects 
enrolling after participation in study 
CNTO136ARA3003, followed by approximately 16 
weeks of safety and efficacy follow-up after the 
administration of the final study agent injection of 
sirukumab.   
After a minimum of 1 year treatment in 
CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of 
treatment in CNTO136ARA3004 for subjects from 
CNTO136ARA3003, and after sirukumab is approved 
for the treatment of RA in the subject’s country of 
residence, the Sponsor may no longer offer study 
treatment in CNTO136ARA3004 for those specific 
subjects. At that point the subject will have the 
opportunity to discuss treatment options with their 
treating physician.   
9.  Figure 1 representing the study design has been updated
Panel A in Figure 1 describing the study design has been updated.
Sections Affected
Original Content
Amended/New Content
3.1 Overview of Study Design
CNTO136ARA3004 will become an open-label study after 
the 52-Week DBL in CNTO136ARA3002 and the 24-
Week DBL in CNTO136ARA3003 have occurred.
Deleted.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
93
10.  Clarification of study status for the CNTO136ARA3002 and CNTO136ARA3003
Clarification of the status for the CNTO136ARA3002 and CNTO136ARA3003 has been made
Sections Affected
Original Content
Amended/New Content
3.2.5 Efficacy Evaluations
Synopsis Dosing Regimen
6.1 Dosing Regimen
9.2.1.1 Joint Assessments
The efficacy evaluations chosen for this study are 
consistent with those in main studies CNTO136ARA3002 
and CNTO136ARA3003.
Subjects will continue to receive the sirukumab dosing 
regimen they received at the end of the main primary 
studies (CNTO136ARA3002, CNTO136ARA3003).
If an assessor was trained by the Sponsor in the main 
studies (CNTO136ARA3002 and CNTO136ARA3003) or 
in a previous clinical study within the last 3 years and there 
is adequate documentation of this training (certification), 
that training will be considered adequate for this study.  
The efficacy evaluations chosen for this study are 
consistent with those in primary studies 
CNTO136ARA3002 and CNTO136ARA3003.
Subjects will continue to receive the sirukumab dosing 
regimen they received at the end of the primary studies 
(CNTO136ARA3002, CNTO136ARA3003).
If an assessor was trained by the Sponsor in the primary 
studies (CNTO136ARA3002 and CNTO136ARA3003) or 
in a previous clinical study within the last 3 years and there 
is adequate documentation of this training (certification), 
that training will be considered adequate for this study.  
11.  The paragraph detailing the CEC has been deleted
A paragraph regarding the CEC has been deleted as the information and consolidated under the heading ‘Cardiovascular events’
Sections Affected
Original Content
Amended/New Content
3.2.6 Safety Evaluations
Cardiovascular events
The CEC is an independent committee composed of 
external specialists, blinded to treatment assignment, which 
will be commissioned to review case information on 
serious CV events (myocardial infarction, stroke, death, 
hospitalization for angina, hospitalization for TIA).  The 
operations, processes, and definitions to be employed by 
the committee will be defined in the CEC charter.
None.
Deleted.
The operations, processes, and definitions to be 
employed by the committee will be defined in the CEC 
charter.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
94
12.  Additional details regarding the PFS-AI are provided
Additional details about the PFS-AI have been added.
Sections Affected
Original Content
Amended/New Content
3.2.11 Self-Administration
None.
The SmartJect™ AI platform technology device, 
referred to as PFS-AI, is a prefilled, spring-powered, 
single use, disposable device for the SC administration 
of a single dose of a liquid biologic drug product.  The 
PFS-AI was designed as a platform device for several 
liquid biologic drug products and has a simple, 
universal design that is suitable for use by clinicians, 
caregivers, and patients, including those with hand 
impairment and pain in the hands and wrists resulting 
from diseases such as rheumatoid arthritis (RA), and 
psoriatic arthritis (PsA). The PFS-AI is designed to 
operate effectively in a number of hand orientations. 
Since the needle is shielded from sight at all times, the 
PFS-AI also accommodates those patients with a needle 
phobia who cannot tolerate seeing injections 
administered.
13.  Inclusion criteria #3 has been deleted
Inclusion criteria #3 has been deleted.
Sections Affected
Original Content
Amended/New Content
4.1 Inclusion Criteria #3
4.1 Inclusion Criteria#4
Must be willing and able to complete the subject diaries 
correctly.
Sign the informed consent form (ICF) for 
pharmacogenetics research indicating willingness to 
participate in the pharmacogenetics component of the study 
(in order to participate in the optional pharmacogenetics 
component of this study) where local regulations permit.  
Refusal to give consent for this component does not 
exclude a subject from participation in the clinical study.  
Deleted.
Sign an informed consent form (ICF) for 
pharmacogenetics research in order to participate in 
the optional pharmacogenetics component of this study, 
where local regulations permit.  Refusal to give consent
for this component does not exclude a subject from 
participation in this clinical study.  
The numbering has been appropriately cascaded.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
95
14.  Prohibitions and Restrictions #1, #2, and #5 have been revised
Clarifications of Prohibitions and Restrictions #1, #2, and #5 have been made.
Sections Affected
Original Content
Amended/New Content
4.3 Prohibitions and Restrictions #1
4.3 Prohibitions and Restrictions#2
4.3 Prohibitions and Restrictions#5
If a woman 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 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.  
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 #11).
Must agree not to receive an investigational medical 
device.
If a woman 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 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.  A woman must not to 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.
Men must use an effective method of birth control
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.  Also, men must not 
donate sperm during the study and for 4 months after 
receiving the last dose of study agent.
Must agree not to receive an investigational medical device 
or other investigational drugs.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
96
15.  Clarifications to the dosing regimen have been made
Clarifications to the dosing regimen have been made. 
Sections Affected
Original Content
Amended/New Content
6.1 Dosing Regimen
Group 1: Sirukumab 100 mg SC at Weeks 0, 2, and q2 
weeks through Week 156 for subjects who enrolled after 
completing participation in CNTO136ARA3002 and 
through Week 208 for subjects who enrolled after 
completing participation in CNTO136ARA3003.
Group 2:  Sirukumab 50 mg SC at Weeks 0, 4, and q4 
weeks through Week 156 for subjects who enrolled after 
completing participation in CNTO136ARA3002 and 
through Week 208 for subjects who enrolled after 
completing participation in CNTO136ARA3003.  Between 
sirukumab injections, placebo SC at Weeks 2, 6, and q4 
weeks until the study becomes open-label.
None
Group 1: Sirukumab 100 mg SC at Weeks 0 (administered 
as the last dose in CNTO136ARA3002 or 
CNTO136ARA3003), 2, and q2 weeks through Week 156 
for subjects who enrolled after completing participation in 
CNTO136ARA3002 and through Week 208 for subjects 
who enrolled after completing participation in 
CNTO136ARA3003.
Group 2: Sirukumab 50 mg SC at Weeks 0 (administered 
as the last dose in CNTO136ARA3002 or 
CNTO136ARA3003), 4, and q4 weeks through Week 156 
for subjects who enrolled after completing participation in 
CNTO136ARA3002 and through Week 208 for subjects 
who enrolled after completing participation in 
CNTO136ARA3003.  Between sirukumab injections, 
placebo SC injections will be administered at Weeks 2, 6, 
and q4 weeks until the study becomes open-label and 
placebo injections will be discontinued.
After a minimum of 1 year treatment in 
CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of 
treatment in CNTO136ARA3004 for subjects from 
CNTO136ARA 3003, and after sirukumab is approved 
for the treatment of RA in the subject’s country of 
residence, the Sponsor may no longer offer study 
treatment in CNTO136ARA3004 for those specific 
subjects. At that point the subject will have the 
opportunity to discuss treatment options with their 
treating physician.   
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
97
16.  Details regarding the training in the use of the PFS-AI have been added
Additional details regarding the training in the use of the PFS-AI have been made.
Sections Affected
Original Content
Amended/New Content
Synopsis
6.5 Self-Administration
Subjects who enrolled after completing participation in 
CNTO136ARA3002 may continue to administer the study 
agent at home for the duration of the study.  Subjects who 
enrolled after participation in CNTO136ARA3003 may 
start at home administration (AHA) of the study agent after 
Week 0.  
Subjects unable or unwilling to self-administer will 
continue to have study agent injections performed by a 
health care professional at the study site.  A caregiver may 
also be trained to administer study agent at home.  
Study personnel will instruct subjects on how to self-
administer and on how to transport and store medication 
for at-home use as indicated for this protocol. 
The SmartJect™ Autoinjector (PFS-AI) is expected to 
be used by the majority of subjects in study 
CNTO136ARA3004. In the event PFS-AIs are 
unavailable at the time of a subject’s enrollment in this 
protocol, PFS-U will be provided until such times as the 
PFS-AIs become available.
Upon availability of PFS-AI trial supplies, subjects who 
are newly entering the CNTO136ARA3004 protocol 
will be trained on the operation of PFS-AI and perform 
self-administration of study agent using PFS-AI at the 
Week 2 study visit and return to the study site at 
Week 4 for self-administration with PFS-AI.  The self-
injection training consists of a face-to-face, “hands-on” 
training, with an explanation of each task in the 
Instructions For Use (IFU), a demonstration performed 
by the study site staff with the PFS-AI trainer device, 
followed by practice injections performed by the 
subject using the trainer device, until the study site staff 
and subject are satisfied that the injections can be 
performed as stated in the IFU.  The step-by-step 
Training Guide for investigators or site staff to follow 
when providing training of subjects will be provided in 
the Site IP Procedures Manual.   If subjects are 
competent in using PFS-AI, they will subsequently be 
provided with study agent for self-administration at 
home and instructed how to transport and store 
medication for at-home use as indicated for this 
protocol.
Subjects may continue to administer the study agent at 
home for the duration of the study. Although 
additional face-to-face training sessions after the first 
training session are not scheduled, the site staff will be 
available to provide additional training if needed. If 
subjects or health care providers are uncertain about 
how to administer the study agent, the Sponsor 
recommends a review of the IFU and perform practice 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
98
injections with the PFS-AI trainer device, and if 
necessary, to ask for retraining at the study site.
Subjects unable or unwilling to self-administer will 
continue to have study agent injections performed by a 
health care professional at the study site. A caregiver 
may also be trained to administer study agent at home.
In the event PFS-AIs are unavailable at the time of a 
subject’s enrollment in this protocol, training on the use 
of a PFS-AI will be provided at the next study visit 
when the PFS-AI is available. Once the study becomes 
open-label, the Week 2 visit for training may be skipped 
by subjects who are to receive open label sirukumab 
50 mg q4 weeks and training in the use of an PFS-AI 
will be provided at Week 4.
17.  The subsection on autoinjectors has been deleted
The section on autoinjectors has been deleted and the content been added to Section 6.5.
Sections Affected
Original Content
Amended/New Content
6.6 Autoinjector
At selected sites, study agent packaged in an autoinjector 
will be introduced for use in the study. At the Week 4 visit, 
a selected number of subjects (who have not been 
previously trained in one of the main studies) will be 
trained in the use of an autoinjector for the self-
administration of the study agent.  
Deleted.
18.  Clarification on the coadministration of certain class of drugs has been made
Clarification on the coadministration of CYP3A4 substrate drugs has been made.
Sections Affected
Original Content
Amended/New Content
8.1.5 Drugs Metabolized by 
Cytochrome P450
Caution should also be exercised when sirukumab is 
coadministered with CYP3A4 substrate drugs, eg, oral 
contraceptives, certain statin medications (eg, simvastatin, 
atorvastatin, cerivastatin, lovastatin).  
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).  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
99
19.  The total blood volume to be collected has been revised
As a result of content change in Table 1, the total blood volume to be collected has been revised.
Sections Affected
Original Content
Amended/New Content
9.1.1 Overview
Also additional TB tests may be performed as determined 
necessary by the investigator or as required by local 
regulation.
The total blood volume to be collected from each subject 
will be approximately 235 mL.  
Also additional TB tests or tests for other infections may 
be performed as determined necessary by the medical 
monitor, study investigator or as required by local 
regulation.
The total blood volume to be collected from each subject 
will be approximately 325 mL.  
20.  Clarifications on the posttreatment phase have been made
Clarifications on the posttreatment phase have been made.
Sections Affected
Original Content
Amended/New Content
9.1.4 Posttreatment Phase 
(Follow-Up)
Paragraph 1
Paragraph 3
Subjects who discontinue study agent injections but do not 
terminate study participation, should also return for follow-
up assessments through approximately 16 weeks after the 
last study agent injection as specified below. 
Subjects who discontinue study agent injections will have 
assessments performed according to the Time and Events 
Schedule (Table 2). 
Subjects who discontinue study agent injections but do 
not terminate study participation will continue to have 
assessments performed for 16 weeks following last 
injection according to the Time and Events Schedule 
(Table 2). 
Deleted.
21.  Clarification on the training for the joint assessor and back-up joint assessor have been made
Clarifications on training for the JA and back-up JA have been made.
Sections Affected
Original Content
Amended/New Content
9.2.1.1 Joint Assessments
Joint Assessor
9.2.1.3  Patient’s and Physician’s 
Global Assessment of Disease 
Activity
The Sponsor will provide training for each site’s joint 
assessors and back-up joint assessors prior to the Week 0 
visit of the first subject at each site. 
In addition, the physician performing the global assessment 
cannot be the joint assessor described in Section 9.2.1.1.  
The Sponsor will provide training for each site’s 
designated joint assessor prior to the Week 0 visit of the 
first subject at each site. A back-up joint assessor must 
complete training before performing a joint assessment 
for a subject’s study visit.
Deleted.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
100
22.  Clarification on the Work Limitations Questionnaire have been made
Questions in addition to the Work Limitations Questionnaire will not be added.
Sections Affected
Original Content
Amended/New Content
9.2.1.7 Work Limitations 
Questionnaire
The WLQ has been selected from existing instruments in 
order to generate estimates of work productivity and 
absenteeism.  The WLQ is a brief, self-report questionnaire 
designed to enable investigators to obtain a sensitive 
measure of the degree to which employed individuals are 
experiencing limitations on-the-job due to their health 
problems and health-related productivity loss.22  The WLQ 
has 25 items that ask respondents to rate their level of 
difficulty or ability to perform specific job demands.  The 
25 items are aggregated into 4 scales, time management, 
physical demands, mental-interpersonal, and output.  Scale 
scores range from 0 (limited none of the time) to 
100 (limited all of the time) and represent the reported 
amount of time in the prior 2 weeks that respondents were 
limited on-the-job.  Additionally, 3 questions added to the 
beginning of the WLQ collect information on the amount 
of time in hours that an individual typically works per 
week and whether any time in hours was missed from work 
due to health problems.  
The WLQ has been selected from existing instruments 
in order to generate estimates of work productivity and 
absenteeism.  The WLQ is a brief, self-report 
questionnaire designed to enable investigators to obtain 
a sensitive measure of the degree to which employed 
individuals are experiencing limitations on-the-job due 
to their health problems and health-related 
productivity loss.22  The WLQ has 25 items that ask 
respondents to rate their level of difficulty or ability to 
perform specific job demands.  The 25 items are 
aggregated into 4 scales, time management, physical 
demands, mental-interpersonal, and output.  Scale 
scores range from 0 (limited none of the time) to 
100 (limited all of the time) and represent the reported 
amount of time in the prior 2 weeks that respondents 
were limited on-the-job.  
23.  Clarifications on the collection of the last sample have been made
Clarifications on the timing of the collection of the last serum sample have been made.
Sections Affected
Original Content
Amended/New Content
9.3.1 Evaluations
Subjects who discontinue study participation should have 
serum samples collected at the final safety and efficacy 
follow-up visit.
Subjects who discontinue study participation should have 
serum samples collected at the last safety follow-up visit.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
101
24.  Clarifications on the schedule for collection of blood samples have been made
Clarifications on the schedule for collection of blood samples have been made.
Sections Affected
Original Content
Amended/New Content
Synopsis Pharmacokinetic and 
Immunogenicity Evaluations
9.3.2.1  Serum Collection and 
Handling
Blood samples for the measurement of serum sirukumab 
concentrations and the detection of antibodies to sirukumab 
will be collected from subjects who also had samples 
collected at earlier time points in studies 
CNTO136ARA3002 and CNTO136ARA3003 according to 
the Time and Events Schedule (Table 1). 
Blood samples for the measurement of serum sirukumab 
concentrations will be collected as follows:

For subjects who enrolled after participating in study 
CNTO136ARA3002 and had samples collected at 
earlier time points in that study will have a sample 
collected at Week 156 and the final safety and 
efficacy follow-up visit;

For subjects who enrolled after participating in study 
CNTO136ARA3003, samples will be collected at 
Weeks 4, 16, 28, 52, 208, and the final safety and 
efficacy follow-up visit. 
The exact dates and times of blood sampling must be 
recorded on the laboratory requisition form.  Note that if 
the subject is to receive an administration of study agent at 
that visit, blood samples will be collected prior to study 
agent administration.  
Blood samples for the measurement of serum 
sirukumab concentrations and the detection of 
antibodies to sirukumab will be collected according to 
the Time and Events Schedule (Table 1). 
Blood samples for the measurement of serum 
sirukumab concentrations will be collected at visits as 
shown in the Time and Events Schedules (Table 1 and 
Table 2).  For subjects who had serum samples 
collected at earlier time points in study 
CNTO136ARA3002 (approximately 50% of 
randomized subjects in CNTO136ARA3002) and all 
subjects who enrolled after participating in study 
CNTO136ARA3003, serum samples will be collected at 
Weeks 2, 4, 16, 28, 52, 104, 156 and the final safety and 
efficacy follow-up visit (Table 1 and Table 2).  One 
additional sample will be collected at Week 208 for
subjects who enrolled after participating in study 
CNTO136ARA3003. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
102
25.  Clarifications on the collection of blood samples for immunogenicity evaluation have been made
Clarifications on the collection of blood samples for immunogenicity evaluation have been made.
Sections Affected
Original Content
Amended/New Content
9.3.3  Immunogenicity Assessment 
(Antibodies to Sirukumab)
To assess the immunogenicity of sirukumab, blood 
samples for the detection of antibodies to sirukumab will 
be collected as follows:

For subjects who enrolled after participating in study 
CNTO136ARA3002 and had samples collected at 
earlier time points in that study will have a sample 
collected at Week 156 and the final safety and 
efficacy follow-up visit;

For subjects who enrolled after participating in study 
CNTO136ARA3003, samples will be collected at 
Weeks 52, 208, and the final safety and efficacy 
follow-up visit. 
To assess the immunogenicity of sirukumab, serum 
samples for the detection of antibodies to sirukumab 
will be collected at visits as shown in the Time and 
Events Schedules (Tables 1 and 2). For subjects who 
had serum samples collected at earlier time points in 
study CNTO136ARA3002 (approximately 50% of 
randomized subjects in CNTO136ARA3002) and all 
subjects who enrolled after participating in study 
CNTO136ARA3003, serum samples will be collected at 
Weeks 16, 28, 52, 104, 156 and the final safety and 
efficacy follow-up visit. One additional sample will be 
collected at Week 208 for subjects who enrolled after 
participating in study CNTO136ARA3003. 
26.  Clarification on the planned pharmacodynamics evaluations have been made
Clarifications on the planned pharmacodynamics evaluations have been made.
Sections Affected
Original Content
Amended/New Content
Synopsis Pharmacodynamic 
Evaluations
9.4 Pharmacodynamic Evaluations
The samples will be used to better understand the biology 
of RA, to provide a biological assessment of the response 
of patients to treatment with sirukumab, to analyze 
responders and to determine if the markers can be used to 
classify patients as potential responders to treatment.  
Serum and whole blood samples for the analysis of 
pharmacodynamic markers will be collected according 
to the Time and Events Schedule.  These samples will 
be used to better understand the biology of RA, to 
analyze differences between responders and 
non-responders, and to assess loss of response.  The 
samples to be collected include whole blood for RNA, 
and serum for the evaluation of inflammation-
associated proteins and other analytes such as but not 
limited to microRNAs.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
103
27.  Clarification on the planned pharmacogenetics evaluations have been made
Clarifications on the planned pharmacogenetics evaluations have been made
Sections Affected
Original Content
Amended/New Content
Synopsis Pharmacogentics (DNA) 
Evaluations
9.5 Pharmacogenetics (DNA) 
Evaluations
DNA methylation testing will be performed to better 
understand the response of subjects to treatment with 
sirukumab.  A whole blood sample will be collected for 
DNA methylation testing. Only DNA research related to 
sirukumab or to the diseases for which this drug is 
developed will be performed. Pharmacogenetic testing will 
be undertaken in this study in consenting subjects only.
Assessment of DNA methylation will be completed.  Only 
DNA research related to sirukumab or to the diseases for 
which this drug is developed will be performed. Subjects 
participating in this portion of the study must sign a 
separate pharmacogenetics informed consent. 
Pharmacogenetic testing will be undertaken in this 
study for only those subjects who have provided 
voluntary consent. Assessment of genetic factors such as 
DNA methylation testing will be performed to better 
understand the response of subjects to treatment with 
sirukumab. A whole blood sample will be collected for 
DNA methylation testing. Only DNA research related to 
sirukumab or to the diseases for which this drug is 
developed will be performed. 
Assessment of genetic factors such as DNA methylation 
will be completed.  Only DNA research related to 
sirukumab or to the diseases for which this drug is 
developed will be performed. Subjects who agree to 
participate in this optional portion of the study must sign 
a separate pharmacogenetics informed consent.
28.  Details regarding the SmartJect™Autoinjector substudy have been added
Details regarding the SmartJect™ Autoinjector substudy have been added.
Sections Affected
Original Content
Amended/New Content
Synopsis SmartJect™ Autoinjector 
substudy
9.6 SmartJect™ Autoinjector 
substudy
None
None
In this substudy, a select number of subjects at selected 
sites in English-speaking countries who are enrolled in 
CNTO136ARA3004 will be consented and enrolled in 
the SmartJect™ AI Usability substudy.  Site personnel
in this substudy will observe and document 2 scheduled 
self-administrations of study agent by subjects using the 
PFS-AI.  All substudy subjects will also complete an e-
diary regarding their experiences with at-home use of 
PFS-AI.  
In this substudy, a select number of subjects at selected 
sites in English-speaking countries who are enrolled in 
CNTO136ARA3004 will be consented and enrolled in a 
SmartJect™ AI Usability substudy.  Subjects will not 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
104
be required to participate in the substudy, and can 
enter the CNTO136ARA3004 LTE study independent 
of participation in the substudy.  Subjects completing 
the substudy will return to the LTE study for the 
remainder of their study treatments. Site personnel in 
the substudy will observe and document 2 scheduled 
self-administrations of study agent by subjects using the 
PFS-AI.  All substudy subjects will also complete an e-
diary regarding their experiences with at-home use of 
PFS-AI for an additional 12 weeks of study treatment.  
A subset of these subjects will also have a detailed 
interview at their final substudy visit regarding their at-
home-use experience. For additional details, refer to the 
PFS-AI Usability Substudy Protocol.
29.  Clarifications on safety evaluations have been added
Clarifications on hepatitis B monitoring have been added.
Sections Affected
Original Content
Amended/New Content
9.8 Safety Evaluations
None
Hepatitis B Monitoring
Subjects who are HBsAg- /HBcAb+ only, without 
detectable HBV DNA, should be monitored according 
to local guidelines. If local guidelines do not exist for 
HBV monitoring in these types of patients, monitoring 
should be performed following consultation with a 
hepatitis B specialist.
HBsAg- /HBsAb+ subjects who are HBcAb- or +, and 
without detectable HBV DNA, should be monitored if 
recommended under local guidelines related to HBV 
and biologic anti-rheumatic agents.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
105
30.  Clarification on the withdrawal from the pharmacodynamics and pharmacogenetics research
Clarifications on the withdrawal from the pharmacodynamics and pharmacogenetics research have been made.
Sections Affected
Original Content
Amended/New Content
10.3 Withdrawal from the Study
The samples may be used in method development or to 
better understand processes in the underlying disease.  No 
pharmacogenetics testing will be conducted on these 
samples.  This does not include those samples specifically 
collected for pharmacogenetic analysis for which separate 
optional consent was obtained.
Withdrawal from Pharmacodynamic Research 
The subject may withdraw consent for 
pharmacodynamics research while remaining in the 
clinical study.  In such a case, any stored samples will 
be destroyed upon communication from the site to the 
Sponsor.  No pharmacogenetics testing will be 
conducted on these samples.  This does not include 
those samples specifically collected for 
pharmacogenetic analysis for which separate optional 
consent was obtained.
Withdrawal from Pharmacogenetics Research 
The subject may withdraw consent for 
pharmacogenetics research while remaining in the 
clinical study.  In such a case, any DNA extracted from 
the subject's blood will be destroyed upon 
communication from the site to the Sponsor.  If 
requested, the investigator will receive written 
confirmation from the Sponsor that the sample has 
been destroyed. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
106
31. Clarifications on the pharmacokinetic analyses have been made
Clarifications on the pharmacokinetic analyses have been made.
Sections Affected
Original Content
Amended/New Content
Synopsis Pharmacokinetic and 
Immunogenicity Analyses
11.3 Pharmacokinetic Analyses
Serum sirukumab concentration data will be summarized 
by visit for each study.  PK data may be displayed 
graphically. If sufficient samples are collected, trough 
serum sirukumab concentrations before and after switching 
from PFS to Autoinjector will be evaluated.
Blood samples for the measurement of serum sirukumab 
concentrations and the detection of antibodies to sirukumab 
will be collected from subjects who had samples collected 
at earlier time points in studies CNTO136ARA3002 and 
CNTO136ARA3003 as delineated in the Time and Events 
Schedule (Table 1).
Serum sirukumab concentration data will be summarized 
by visit for each study.  PK data may be displayed 
graphically. If sufficient samples are collected, trough 
serum sirukumab concentrations before and after switching 
from pre-filled syringe (PFS) to Autoinjector will be 
evaluated.
Serum sirukumab concentration data including Ctrough will 
be summarized by visit.  PK data may be displayed 
graphically. If sufficient samples are collected, steady-
state trough serum sirukumab concentrations before and 
after switching from PFS-U to PFS-AI will be evaluated.
Blood samples for the measurement of serum sirukumab 
concentrations and the detection of antibodies to sirukumab 
will be collected and analyzed. 
Serum sirukumab concentration data including Ctrough will 
be summarized by visit.  PK data may be displayed 
graphically. If sufficient samples are collected, steady-
state trough serum sirukumab concentrations before and 
after switching from PFS-U to PFS-AI will be evaluated.
32.  Clarifications on the immunogenicity analyses have been made
Clarifications on the immunogenicity analyses have been made.
Sections Affected
Original Content
Amended/New Content
11.4 Immunogenicity Analyses
The incidence of antibodies to sirukumab will be 
summarized through the end of study for all subjects who 
have appropriate samples.  
The incidence of antibodies to sirukumab will be 
summarized for all subjects who have appropriate 
samples.  Additional analysis may be performed as 
needed.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
107
33.  Clarifications on the pharmacodynamic analyses have been made
Clarifications on the pharmacodynamic analyses have been made.
Sections Affected
Original Content
Amended/New Content
Synopsis Pharmacodynamic 
Analyses
11.5 Pharmacodynamic Analyses
The pharmacodynamic analysis will characterize the 
response of subjects to sirukumab, loss of response, to 
determine if response to sirukumab can be predicted, and 
to understand RA.  The analysis, along with the RNA 
analysis will be summarized in a separate technical report.
The pharmacodynamic analysis will characterize the 
response of subjects to sirukumab, to determine if loss of
response to sirukumab can be predicted, and to better
understand RA.  Data will be summarized in a separate 
technical report.
34.  Clarifications on the pharmacogenetics (DNA) analyses have been made
Clarifications on the pharmacogenetics (DNA) analyses have been made.
Sections Affected
Original Content
Amended/New Content
Synopsis Pharmacogenetics 
Analyses
11.6 Pharmacogenetics (DNA) 
Analyses
Pharmacogenetics data will be descriptively summarized 
by treatment group.  Results will be presented in a separate 
technical report.  
Pharmacogenetics tests will be summarized by 
treatment group.  Genetic factors and changes in 
expression of DNA methylation markers from baseline 
(CNTO136ARA3002 and CNTO136ARA3003 studies) 
to the collection time point in study CNTO136ARA3004 
will also be summarized. The pharmacogenetic analyses 
will be summarized in a separate technical report.
35.  Clarifications on source documentation have been made
Clarifications on source documentation have been made.
Sections Affected
Original Content
Amended/New Content
17.4 Source Documentation
The following data may be recorded directly into the CRF, 
if in accordance with site capabilities and/or in compliance 
with local regulations, and will be considered source data:

Race

History of smoking

Blood pressure

Height and weight
Deleted.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
108
36.  Clarifications on data quality assurance and quality control have been made
Clarifications data quality assurance and quality control have been made
Sections Affected
Original Content
Amended/New Content
17.6 Data Quality Assurance/Quality 
Control
None
Whenever possible, all subjective measurements 
(eg, pain scale information or other questionnaires) 
should be completed as consistently as possible and 
preferably by the same individual who made the initial 
baseline determinations.   
37.  Clarifications on monitoring have been made
Clarifications on monitoring have been made
Sections Affected
Original Content
Amended/New Content
17.8 Monitoring
The Sponsor will perform on-site monitoring visits as 
frequently as necessary.  The monitor will record dates of 
the visits in a study site visit log that will be kept at the 
site.  The first post-initiation visit will be made as soon as 
possible after enrollment has begun.  At these visits, the 
monitor will compare the data entered into the CRFs with 
the hospital or clinic records (source documents).  
The Sponsor will perform on-site monitoring visits as 
frequently as necessary.  At these monitoring visits, the 
monitor will compare the data entered into the CRFs 
with the hospital or clinic records (source documents).  
The monitor will record dates of the visits in a study 
site visit log that will be kept at the site.  
Although the data for all subjects is eligible to be 
monitored, a streamlined approach to monitoring may 
be implemented, whereby a subset of subjects and/or 
critical data points will be verified as defined in the 
monitoring plan.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
109
38.  Revisions in Table 1 have been summarized
Revisions within Table 1 and the accompanying legends are summarized.
Sections Affected
Original Content
Amended/New Content
Table 1 Times and Events in Long-
term Extension
a.
All assessments are to be completed prior to study 
agent administration, unless otherwise specified.  For 
subjects who discontinue study agent injections, see 
Table 2 for required follow-up assessments. 
Administration of study agent and visit windows will 
be within 7 days for all visits.  Administration of study 
agent must occur no less than 7 days apart throughout 
the study.
b.
Last study agent administration for subjects who 
enrolled after participating in CNTO136ARA3002.  
These subjects will then have assessments as described 
in Table 2.
c.
For a select number of subjects, training in the use of 
an autoinjector will be provided for the self-
administration of study agent.
d.
Urine pregnancy testing during the study for women of 
childbearing potential only.
e.
RA assessments include the following:  patient pain 
assessment; patient global assessment of disease 
activity, physician global assessment of disease 
activity, Health Assessment Questionnaire-Disability 
Index, and duration of morning stiffness.
f.
Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected only from 
those subjects who enrolled after participating in study 
CNTO136ARA3003.
g.
On days of study agent administration, Pharm serum 
samples (sirukumab concentration and antibodies to 
sirukumab) must be collected prior to administration. 
Blood collected from one venipuncture will be divided 
into multiple aliquots of serum for Pharm serum 
(sirukumab concentration and antibodies to 
sirukumab) and backup samples. Refer to the Central 
Laboratory Manual for more detailed instructions.
a.
All assessments are to be completed prior to study 
agent administration, unless otherwise specified.  For 
subjects who discontinue study agent injections, see 
Table 2 for required follow-up assessments. 
Administration of study agent and visit windows 
should be within 7 days for all visits.  Administration 
of study agent must occur no less than 7 days apart 
throughout the study.
b.
Once the study becomes open-label, the Week 2 
visit will not be conducted for subjects in treatment 
Group 2.  The training session for these subjects 
will occur at Week 4 or at a subsequent visit 
following the availability of the PFS-AI.
c.
Last study agent administration for subjects who 
enrolled after participating in CNTO136ARA3002.  
These subjects will then have follow-up assessments 
as described in Table 2.
d.
Last study agent administration for subjects who 
enrolled after participating in CNTO136ARA3003.  
These subjects will then have follow-up assessments 
as described in Table 2.
e.
Training in the use of a PFS-AI will be provided at 
the first scheduled visit that the subject receives the 
PFS-AI for the self-administration of study agent.
f.
Urine pregnancy testing during the study for 
women of childbearing potential only.  Additional 
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.  
g.
RA assessments include the following:  patient pain 
assessment; patient global assessment of disease 
activity, physician global assessment of disease 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
110
h.
Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected only from 
those subjects who enrolled after participating in study 
CNTO136ARA3002 and had samples collected at 
earlier time points in study CNTO136ARA3002.
i.
An optional pharmacogenetics blood sample will be 
collected from those subjects who sign a separate 
consent form (where local regulations permit).
activity, Health Assessment Questionnaire-
Disability Index, and duration of morning stiffness.
h.
Pharm serum samples (sirukumab concentration 
and antibodies to sirukumab) will be collected from 
subjects who had pharm serum samples collected at 
earlier time points in study CNTO136ARA3002 
(approximately 50% of randomized subjects in 
CNTO136ARA3002) and from all subjects enrolled 
after participating in study CNTO136ARA3003.
i.
On days of study agent administration, Pharm serum 
samples (sirukumab concentration and antibodies to 
sirukumab) must be collected prior to administration.
Blood collected from one venipuncture will be 
divided into 3 serum aliquots (1 each sirukumab 
concentration, antibodies to sirukumab and a 
backup sample). Refer to the Central Laboratory 
Manual for more detailed instructions.
j.
Pharm serum samples (sirukumab concentration 
and antibodies to sirukumab) will be collected only 
from those subjects who enrolled after 
participating in study CNTO136ARA3003.
k.
An optional pharmacogenetics blood sample will be 
collected from those subjects who sign a separate 
consent form (where local regulations permit).
The legend alphabets were cascaded appropriately.
Xs for urine pregnancy test, TB testing, and blood 
pressure evaluations have been removed from Week 2 
and placed in Week 4.  Additional Xs have been 
inserted for pharm serum samples for sirukumab 
concentration at Week 104 and for antibodies to 
sirukumab at Weeks 16, 28, and 104.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
111
Table 2 Times and Events in Safety 
and Efficacy Follow-up After Last 
Study Agent Injection or after 
Discontinuation of Study Agent
c Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected at the final 
safety and efficacy follow up visit only from those subjects 
who had samples collected at earlier time points in studies 
CNTO136ARA3002 and CNTO136ARA3003.
d Blood collected from one venipuncture will be divided 
into multiple aliquots of serum for Pharm serum 
(sirukumab concentration and antibodies to sirukumab) and 
backup samples.  Refer to the Central Laboratory Manual 
for more detailed instructions.
c Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected at the final 
safety and efficacy follow up visit only from those subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 50% 
of randomized subjects in CNTO136ARA3002) and
from all subjects enrolled after participating in study 
CNTO136ARA3003.
d Blood collected from one venipuncture will be divided 
into 3 serum aliquots (1 each for sirukumab 
concentration,  antibodies to sirukumab and a backup 
sample).  Refer to the Central Laboratory Manual for more 
detailed instructions.
39.  Editorial changes made throughout the protocol
A substantial number of editorial changes have been made throughout the protocol for clarity.  These changes do not alter the meaning of the original text.
Sections Affected
Original Content
Amended/New Content
Title page
Synopsis
Synopsis
3.1 Overview of Study Design
A Multicenter, Parallel-group Study of Long-term Safety 
and Efficacy of CNTO 136 (sirukumab) for Rheumatoid 
Arthritis in Subjects Completing Treatment in 
CNTO136ARA3002 and CNTO136ARA3003
The long-term extension (LTE) study will start after 
subjects have completed participation in studies 
CNTO136ARA3002 or CNTO136ARA3003.  The purpose 
of this LTE study is to evaluate the safety, efficacy, and 
pharmacologic effects of sirukumab for a minimum 
duration of 3 years and a maximum duration of 
approximately 5 years.
A Multicenter, Parallel-group Study of Long-term Safety 
and Efficacy of CNTO 136 (sirukumab) for Rheumatoid 
Arthritis in Subjects Completing Treatment in Studies
CNTO136ARA3002 (SIRROUND-D) and 
CNTO136ARA3003 (SIRROUND-T)
Subjects will become eligible to participate in this LTE 
study when they have completed participation in 
studies CNTO136ARA3002 (104 weeks) or 
CNTO136ARA3003 (52 weeks).  The purpose of this 
LTE study is to evaluate the safety, efficacy, and 
pharmacologic effects of sirukumab for a minimum 
duration of 1 additional year and a maximum total 
duration of approximately 5 years across the combined 
protocols (CNTO136ARA3002 (2 years) or 
CNTO136ARA3003 (1 year) + CNTO136ARA3004 (1 to 
4 years) = maximum of 5 years treatment).
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
112
3.1 Overview of Study Design
3.2.7 Pharmacokinetic Evaluations
Synopsis Blinding
6.2 Blinding
Thereafter this study (CNTO136ARA3004) becomes open-
label. Once this study becomes open-label, subjects in this 
study will receive unblinded study agent through 
IVRS/IWRS.  However, when this study becomes open-
label, those subjects who remain in studies 
CNTO136ARA3002 and CNTO136ARA3003 due to 
staggered enrollment will continue to receive blinded 
treatment until they complete participation in those studies.
Serum samples will be used to evaluate PK and antibodies 
to sirukumab.  Samples to be collected include serum and 
whole blood RNA for the evaluation of inflammation-
associated proteins and other analytes. These samples will 
be used to better understand the biology of RA, to provide 
a biological assessment of the response of subjects to 
treatment with sirukumab, to analyze differences between 
responders and non-responders, to assess loss of response, 
and to determine if the markers can be used to classify 
patients as potential responders prior to treatment.
Only 1 DBL (at the end of the study) is planned.  
Additional data releases or locks may occur periodically as 
needed. 
Serum samples will be collected for evaluation of 
pharmacokinetics of sirukumab in subjects with RA 
according to the Time and Events Schedules.
To maintain the blind, all subjects will receive each 
administration of study agent as 1 SC injection as follows:  
Group 1 (sirukumab 100 mg):  1.0 mL sirukumab 100 mg 
injection q2 weeks until the study becomes open-label.
Group 2 (sirukumab 50 mg):  1.0 mL sirukumab 50 mg 
Thereafter study CNTO136ARA3004 will become open-
label and placebo injections are discontinued in the SC 
sirukumab 50 mg treatment group.  Once study 
CNTO136ARA3004 becomes open-label, study subjects 
in this study will receive open-label study agent through 
IVRS/IWRS.  However, when this study becomes open-
label, any subjects who still remain in studies 
CNTO136ARA3002 and CNTO136ARA3003 due to 
staggered enrollment will continue to receive blinded 
treatment until they complete participation in those studies.
Serum samples will be collected for the evaluation of 
sirukumab PK and antibodies to sirukumab.  Other 
samples to be collected include serum and whole blood 
RNA for the evaluation of inflammation-associated 
proteins and other analytes. These samples will be used 
to better understand the biology of RA, to analyze 
differences between responders and non-responders, 
and to assess loss of response. 
Only 1 DBL (at the end of the study) is planned.  
Additional data releases or locks may occur as needed. 
To evaluate the PK of sirukumab in subjects with RA 
following long-term treatment, serum samples for the 
measurement of sirukumab concentrations will be 
collected according to the Time and Events Schedules.
To maintain the blind, all subjects will receive study
agent as 1 SC injection as follows:  
Group 1 (sirukumab 100 mg):  1.0 mL sirukumab 100 
mg injection q2 weeks 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
113
Synopsis Timing and Study Agent 
Administration
6.3 Timing and Study Agent 
Administration
7 Treatment Compliance
Paragraph 3
8.1 Concomitant Therapy
Paragraph 1
Paragraph 3
8.1.3 Intra-articular Corticosteroids
9.1.1 Overview
injection q4 weeks until the study becomes open-label.  
Between sirukumab injections, placebo SC at Weeks 2, 6, 
and q4 weeks until the study becomes open-label.
Through the end of the study, it is recommended that both 
the visit and the SC study agent administration be within 7 
days from the scheduled visit day.  The SC study agent 
administrations must always be at least 7 days apart. 
When subjects begin self-administration at home, the 
investigator or designated study personnel will maintain a 
log of all study agent dispensed and returned. When study 
agent is self-administered by subjects at home, the amount 
of study agent dispensed will be recorded and compared 
with the amount returned.
All concomitant therapies must be recorded throughout the 
study, beginning with the administration of the first dose of 
the study agent at Week 0.
The concomitant medication dose may be changed at the 
discretion of the investigator. Disease-modifying anti-
rheumatic drug (DMARD) therapy is permitted at the 
discretion of the investigator (see Section 6.4), except for 
the specified prohibited medications (biologic 
immunosuppressive agents, cytotoxic drugs, and 
investigational agents; see Section 8.2). 
No intra-articular (IA) steroid injections should be 
administered between Weeks 48 and 52, between Weeks 
100 and 104, between Weeks 152 and 156, and between 
Weeks 204 and 208 of this study.
Group 2 (sirukumab 50 mg):  1.0 mL sirukumab 50 mg 
injection q4 weeks until the study becomes open-label.  
Between sirukumab injections, placebo SC injections 
will be administered at Weeks 2, 6, and q4 weeks until 
the study becomes open-label, and placebo injections 
will be discontinued.
Through the end of the study, it is recommended that 
both the visit and the SC study agent administration 
occur within 7 days of the scheduled visit day.  The SC 
study agent administrations must always be at least 7 
days apart.
When subjects begin self-administration at home, the 
investigator or designated study personnel will 
maintain a log of all study agent dispensed and 
returned and the amount of study agent dispensed will 
be recorded and compared with the amount returned.
All concomitant therapies must be recorded throughout 
the study, beginning at Week 0. 
The concomitant medication dose may be changed at 
the discretion of the investigator. Disease-modifying 
anti-rheumatic drug (DMARD) therapy is permitted at 
the discretion of the investigator (see Section 6.4), 
except for the specified prohibited medications (see 
Section 8.2). 
Intra-articular (IA) steroid injections should not be 
administered within 4 weeks prior to visits on 
Weeks 52, 104, 156, and 208.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
114
9.1.1 Overview
Paragraph 5
9.1.3 Open-label Treatment Phase
At Week 0, a single whole blood sample for DNA analysis 
will be collected only from subjects who have consented to 
participate in the optional pharmacogenetics (DNA) 
component of the study. 
No intra-articular (IA) steroid injections should be 
administered between Weeks 48 and 52, between Weeks 
100 and 104, between Weeks 152 and 156, and between 
Weeks 204 and 208 of this study.
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.  Also additional TB tests may be performed as 
determined necessary by the investigator or as required by 
local regulation.
After the Week 52 DBL in CNTO136ARA3002 and the 
Week 24 DBL in CNTO136ARA3003 subjects will receive 
open-label study agent treatment through the end of study.  
If sirukumab becomes approved and available for use for 
RA in the subject’s country of residence, the subject may 
be discontinued from study agent administrations and will 
have the opportunity to discuss treatment options with their 
treating physician under the following conditions:     

For subjects from study CNTO136ARA3002, after a 
minimum of 1 year in this study 

For subjects from study CNTO136ARA3003, after a 
minimum of 2 years in this study 
A single whole blood sample for DNA analysis will be 
collected only from subjects who have consented to 
participate in the optional pharmacogenetics (DNA) 
component of the study. 
Intra-articular (IA) steroid injections should not be 
administered within 4 weeks prior to visits on Weeks 
52, 104, 156, and 208.
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. Also additional TB tests or tests for other 
infections may be performed as determined necessary by 
the medical monitor, study investigator or as required by 
local regulation.
The CNTO136ARA3004 study will become open-label 
after the following 3 conditions have been met: the 
Week 52 DBL occurs in study CNTO136ARA3002, the 
Week 24 DBL occurs in study CNTO136ARA3003, and 
the last AI usability substudy subject completes the 
Week 16 visit or terminates from the study.   
After a minimum of 1 year treatment in 
CNTO136ARA3004 for subjects from study 
CNTO136ARA3002, or a minimum of 2 years of 
treatment in CNTO136ARA3004 for subjects from 
CNTO136ARA3003, and after sirukumab is approved 
for the treatment of RA in the subject’s country of 
residence, the Sponsor may no longer offer study 
treatment in CNTO136ARA3004 for those specific 
subjects. At that point the subject will have the 
opportunity to discuss treatment options with their 
treating physician.   
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
115
9.7 Health Economics Evaluations
10.3 Withdrawal from the Study
11 Statistical Methods
Paragraph 3
Paragraph 4
Synopsis Interim Analysis
11.9 Interim Analyses
Health economics evaluations on employment status, 
impact of disease on daily productivity, and time lost from 
work will be collected at Weeks 28, 52, 76, 104, 128, 156, 
and 208. The impact of disease on patients’ daily work 
productivity will be measured using a VAS. The scale 
ranges from “not at all affected” to “affected very much”.
If a subject discontinues study agent administration before 
the end of the study, follow-up assessments should be 
obtained as per the Time and Events Schedule described in 
Table 2.  For details, see Section 10.3.
Since the treatment groups are not randomly assigned in 
this study, no formal hypothesis testing is planned. The 
efficacy, safety, and PK/PD/immunogenicity analyses will 
be performed separately for subjects who complete each 
study of CNTO136ARA3002 and CNTO136ARA3003. 
The analyses will include all subjects enrolled in this study 
by study and by treatment group above.
Additional data releases or locks may occur periodically as 
needed.  The analyses based on these data releases or locks 
intend to integrate data from CNTO136ARA3002 and 
CNTO136ARA3003 with this study for the long-term 
safety and efficacy data of all subjects enrolled in these 
studies.  A separate SAP for integration will be developed 
to specify the analyses and data handling rules. 
No formal interim analyses are planned, though analyses 
based on interim releases and locks may be carried out for 
integrated safety and efficacy data.
Health economics evaluations on employment status, 
impact of disease on daily productivity, and time lost 
from work will be collected.  The impact of disease on 
patients’ daily work productivity will be measured 
using a VAS. The scale ranges from “not at all 
affected” to “affected very much”.     
If a subject discontinues study agent administration 
before the end of the study, follow-up assessments 
should be obtained as per the Time and Events 
Schedule described in Table 2.  
Since the treatment groups are not randomly assigned in 
this study, no formal hypothesis testing is planned. The 
efficacy, safety, and PK/PD/immunogenicity analyses 
will be performed separately for subjects who complete 
studies CNTO136ARA3002 and CNTO136ARA3003. 
The analyses will include all subjects enrolled by study 
and by treatment group above.
Additional data releases or locks may occur periodically as 
needed.  The analyses based on these data releases or locks 
intend to integrate data from CNTO136ARA3002 and 
CNTO136ARA3003 with this study for the long-term PK, 
immunogenicity, safety and efficacy data of all subjects 
enrolled in these studies.  A separate SAP for integration 
will be developed to specify the analyses and data handling 
rules.
No formal interim analyses are planned, though analyses 
based on interim releases and locks may be carried out for 
integrated PK, immunogenicity, safety and efficacy data.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
116
11.10 Data Monitoring Committee
Paragraph 3
14.1 Physical Description of Study 
Agent
14.2 Packaging
14.4 Preparation, Handling, and 
Storage
Paragraph 1
Paragraph 3
The DMC will conduct periodic safety reviews that will 
occur every 4 months until the study becomes open-label.  
The DMC may change the frequency or number of reviews 
based on interim safety findings.  The safety reviews will 
focus on particular AEs, SAEs, and mortality. 
The sirukumab drug product provided for this study is 
supplied in a 1 mL PFS fitted with either: (1) a passive 
safety needle guard (UltraSafe Passive™ Delivery System, 
Safety Syringes, Inc.) that is permanently assembled on the 
syringe or (2) a spring-powered, disposable autoinjector 
device for SC administration of liquid biologic drug 
products (SmartJect™ Autoinjector) that is permanently 
assembled on the syringe.  
The 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.
Once available, the sirukumab PFS may also be supplied 
with a spring-powered, disposable device for SC 
administration of liquid biologic drug products 
(SmartJect™ Autoinjector) that is permanently assembled 
on the syringe. 
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.
Sirukumab should be administered according to the 
instructions provided in the Site Investigational Product 
Binder.  
The DMC will conduct periodic safety reviews that will 
occur every 4 months until at a minimum, the study 
becomes open-label.  The DMC may change the frequency 
or number of reviews based on interim safety findings.  
The safety reviews will focus on particular AEs, SAEs, and 
mortality. 
Until the study is unblinded, study agent will be 
supplied in a 1 mL PFS fitted with either: (1) a passive 
safety needle guard (UltraSafe Passive™Delivery System, 
Safety Syringes, Inc.) that is permanently assembled on the 
syringe or (2) a spring-powered, disposable autoinjector 
device for SC administration of liquid biologic drug 
products (SmartJect™ Autoinjector) that is permanently 
assembled on the syringe.  
The sirukumab PFS-U will be supplied with a passive 
safety needle guard (UltraSafe Passive™ Delivery System, 
Safety Syringes, Inc.) that is permanently assembled on the 
syringe.
Once available, the sirukumab PFS-AI will be supplied 
with a spring-powered, disposable device for SC 
administration of liquid biologic drug products 
(SmartJect™ Autoinjector) that is permanently assembled 
on the syringe. 
All study agent presentations should be stored in a 
secured refrigerator at 2ºC to 8ºC (36ºF to 46ºF).  Study 
agent should not be frozen or shaken.  During extended 
storage, protect from excessive exposure to light.  
Protection from light is not required during 
administration.
Study agent should be administered according to the 
instructions provided in the Site Investigational Product 
Binder.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
117
17.5 Case Report Form Completion
Paragraph 4
All subjective measurements (eg, pain scale information or 
other questionnaires) will be completed by the same 
individual who made the initial baseline determinations 
whenever possible. The investigator must confirm that all 
data entries in the CRFs are accurate and correct.
The investigator must confirm that all data are 
accurate and correct.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
118
AMENDMENT 2 – 01 MAY 2014
The protocol has been revised to incorporate this amendment, which applies to all study centers.  The rationale and description of the 
changes to the protocol are provided below.  Minor formatting and typographical errors have also been corrected to improve the clarity and 
accuracy of the protocol text; these changes do not affect the overall conduct of the study.
1.  A change from percent to a number of randomized subjects for PK and immunogenicity analyses has been made.
Pharmacokinetic and immunogenicity analyses will be performed in approximately 750 randomized subjects from study CNTO136ARA3002.
Sections Affected
Original Content
Amended/New Content
Table 1 Times and Events in Long-
term Extension
Footnote h
Table 2 Times and Events in Safety 
and Efficacy Follow-up After Last 
Study Agent Injection or after 
Discontinuation of Study Agent
Footnote c
9.3.2.1 Serum Collection and 
Handling
Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected from subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 50% 
of randomized subjects in CNTO136ARA3002) and from 
all subjects enrolled after participating in study 
CNTO136ARA3003.
Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected at the final 
safety and efficacy follow up visit only from those subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 50%
of randomized subjects in CNTO136ARA3002) and from 
all subjects enrolled after participating in study 
CNTO136ARA3003.
For subjects who had serum samples collected at earlier 
time points in study CNTO136ARA3002 (approximately 
50% of randomized subjects in CNTO136ARA3002) and 
all subjects who enrolled after participating in study 
CNTO136ARA3003, serum samples will be collected at 
Weeks 2, 4, 16, 28, 52, 104, 156 and the final safety and 
efficacy follow-up visit (Table 1 and Table 2).  
Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected from subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 750 
randomized subjects in CNTO136ARA3002) and from all 
subjects enrolled after participating in study 
CNTO136ARA3003.
Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected at the final 
safety and efficacy follow up visit only from those subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 750 
randomized subjects in CNTO136ARA3002) and from all 
subjects enrolled after participating in study 
CNTO136ARA3003.
For subjects who had serum samples collected at earlier 
time points in study CNTO136ARA3002 (approximately 
750 randomized subjects in CNTO136ARA3002) and all 
subjects who enrolled after participating in study 
CNTO136ARA3003, serum samples will be collected at 
Weeks 2, 4, 16, 28, 52, 104, 156 and the final safety and 
efficacy follow-up visit (Table 1 and Table 2).  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
119
9.3.3 Immunogenicity Assessment
(Antibodies to Sirukumab)
For subjects who had serum samples collected at earlier 
time points in study CNTO136ARA3002 (approximately 
50% of  randomized subjects in CNTO136ARA3002) and 
all subjects who enrolled after participating in study 
CNTO136ARA3003, serum samples will be collected at 
Weeks 16, 28, 52, 104, 156 and the final safety and 
efficacy follow-up visit.  
For subjects who had serum samples collected at earlier 
time points in study CNTO136ARA3002 (approximately 
750 randomized subjects in CNTO136ARA3002) and all 
subjects who enrolled after participating in study 
CNTO136ARA3003, serum samples will be collected at 
Weeks 16, 28, 52, 104, 156 and the final safety and 
efficacy follow-up visit.  
2.  Efficacy assessments at Week 180 have been added.
Efficacy assessments (joint assessment, RA assessments, SF-36, WLQ, and health economics) have been added at Week 180.
Sections Affected
Original Content
Amended/New Content
Table 1 Times and Events in Long-
term Extension
None
Xs noted for:

Joint assessment

RA assessments

SF-36

WLQ

Health economics
3.  The guidelines for the discontinuation of treatment have been revised.
Per DMC recommendation, GI perforation and acute diverticulitis have been added to the list of conditions that would result in the permanent discontinuation of 
study agent administrations.
Sections Affected
Original Content
Amended/New Content
10.2 Discontinuation of Treatment
None
14. Acute diverticulitis requiring antibiotic treatment 
15. Gastrointestinal perforation
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
120
4.  Clarification on subject study card content.
The subject’s name and date of birth are not included on the study card.
Sections Affected
Original Content
Amended/New Content
12.3.1 All Adverse Events
Paragraph 4
Subjects (or their designees, if appropriate) must be 
provided with a "study card" indicating the following:

Subject's name

Subject number

Subject's date of birth

Study site number

Investigator's name and 24-hour contact information

Statement that the subject is participating in a clinical 
trial.
Subjects (or their designees, if appropriate) must be 
provided with a "study card" indicating the following:

Subject number

Study site number

Study number

Sponsor’s emergency contact name and 24-hour 
telephone number (for medical staff only)

Investigator's name and contact information

Statement in the local language(s) that the subject is 
participating in a clinical trial.
5.  Prohibited medications have been revised.
Additions have been made to the list of prohibited medications.
Sections Affected
Original Content
Amended/New Content
8.2 Prohibited Medications
None

Tofacitinib (XELJANZ)

Any other biologic therapy for the treatment 
of RA
6.  The time frame for reporting all initial PQCs has been revised.
A clarification on the time frame for the reporting all initial PQCs has been revised.
Sections Affected
Original Content
Amended/New Content
13.1 Procedures
All initial PQCs must be reported to the Sponsor by the 
investigational staff as soon as possible after being made 
aware of the event.
All initial PQCs must be reported to the Sponsor by 
the investigational staff within 24 hours after being 
made aware of the event.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
121
7.  Criteria for planned statistical analyses for clinical laboratory data have been revised.
Clarifications on the criteria for the planned statistical analyses of clinical laboratory data have been made.
Sections Affected
Original Content
Amended/New Content
11.8 Safety Analyses
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory 
test.  NCI-CTCAE grades will be used in the summary of 
laboratory data.  Descriptive statistics will be calculated for 
selected laboratory analyte at baseline and at each 
scheduled time point.  A listing of subjects with any 
markedly abnormal laboratory results will also be 
provided.
Laboratory data will be summarized by type of laboratory 
test. NCI-CTCAE grades will be used in the summary of 
laboratory data. For some laboratory data, which are 
not covered in the NCI-CTCAE grading criteria, shift 
tables and/or other abnormal cutoff levels may be used 
for summaries. Descriptive statistics will be calculated 
for selected laboratory analyte at baseline and at each 
scheduled time point. A listing of subjects with post-
baseline abnormal laboratory results based on NCI-
CTCAE grades will also be provided.
8.  Clarifications for contacting the investigator by subjects who self-administer study agent have been made.
Clarifications for contacting the investigator by subjects who upon self-administration study agent experience any signs of allergic reaction, infection, or 
bleeding have been made.
Sections Affected
Original Content
Amended/New Content
Synopsis  Self Administration
Paragraph 2
6.5 Self Administration
None
None
Subjects will be instructed to contact the investigator 
promptly in the event of any signs of an allergic 
reaction, infection, or bleeding.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
122
AMENDMENT 3 – 06 OCT 2016
The protocol has been revised to incorporate this amendment, which applies to all study centers. The rationale and description of the 
changes to the protocol are provided below. Minor formatting and typographical errors have also been corrected to improve the clarity and 
accuracy of the protocol text; these changes do not affect the overall conduct of the study.
1.  Language has been included for optional dose reduction from 100 mg SC q2 weeks to 50 mg SC q4 weeks.
Based on data from Phase 3 studies, subjects treated with SC sirukumab 100 mg q2 weeks will be offered the option to reduce the sirukumab dose to 50 mg q4 
weeks after the study becomes open-label. Figure 1 was also updated accordingly.
Sections Affected
Original Content
Amended/New Content
Synopsis (Dosing and 
Administration: Dosing Regimen)
Synopsis (Statistical Methods)
1.2 Overall Rationale for the Study
(paragraph 2)
None
None
None
After the study becomes open-label, subjects treated 
with SC sirukumab 100 mg q2 weeks will be offered the 
option to reduce the dose to 50 mg q4 weeks at the 
investigator’s discretion. This decision can be made at 
the subject’s first or second major resupply visit (up 
until approximately 7 months) after implementation of 
Amendment 3 at the study site. Once a subject’s dose is 
reduced to 50 mg q4 weeks, the subject will receive that 
dose for the remainder of the trial (ie, a return to 
100 mg q2 weeks will not be allowed). If a subject opts 
to remain on the sirukumab 100 mg q2 weeks dose, he 
or she will remain on that dose for the duration of their 
participation in the study (ie, the subject will not have 
the option to reduce the dose at a subsequent 
timepoint).
After the study becomes open-label, subjects in Group 1 
will be offered the option (at the discretion of the 
investigator) to reduce the sirukumab dose to 50 mg q4 
weeks for the remainder of the trial.
Following the database lock for the primary endpoint, 
analysis of CNTO136ARA3002 and 
CNTO136ARA3003 PK and efficacy data showed that 
there was no clear dose response between the 
sirukumab SC 50 mg q4 weeks and sirukumab SC 
100 g q2 weeks dose groups across efficacy endpoints. 
Furthermore, there were a greater proportion of 
subjects with hypersensitivity reactions and injection 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
123
3.1 Overview of Study Design
(Figure 1)
[Figure labels as follows]
Wk 0**
Wk 156*
Wk 208*
Group 1
[Footnotes as follows]
*Subjects from study CNTO136ARA3002 will have 
completed 104 weeks of study agent treatment prior to 
enrolling in this study. Subjects from study 
CNTO136ARA3003 will have completed 52 weeks of 
study agent treatment prior to enrolling in this study.
**Subjects from study CNTO136ARA3002 will receive 
the last study agent administration at Week 156 and 
subjects from study CNTO136ARA3003 will receive the 
last study agent administration at Week 208.
site reactions in the sirukumab 100 mg q2 weeks dose 
group compared with the sirukumab 50 mg q4 weeks 
dose group. Therefore, to allow for minimization of the 
exposure to this immunosuppressant biologic agent, 
subjects treated with SC sirukumab 100 mg q2 weeks 
will be offered the option to reduce the sirukumab dose 
to 50 mg q4 weeks at the investigator’s discretion after 
the study becomes open-label. This decision can be 
made at the subject’s first or second major resupply 
visit (up until approximately 7 months) after 
implementation of Amendment 3 at the study site. Once 
a subject’s dose is reduced to 50 mg q4 weeks, the 
subject will receive that dose for the remainder of the 
trial (ie, a return to 100 mg q2 weeks will not be 
allowed). If a subject opts to remain on the sirukumab 
100 mg q2 weeks dose, he or she will remain on that 
dose for the duration of their participation in the study 
(ie, the subject will not have the option to reduce the 
dose at a subsequent timepoint).
[Asterisks corrected for the footnotes; one footnote added:]
Wk 0**
Wk 156**
Wk 208**
Group 1†
*Subjects from study CNTO136ARA3002 will have 
completed 104 weeks of study agent treatment prior to 
enrolling in this study. Subjects from study 
CNTO136ARA3003 will have completed 52 weeks of 
study agent treatment prior to enrolling in this study.
**Subjects from study CNTO136ARA3002 will receive 
the last study agent administration at Week 156 and 
subjects from study CNTO136ARA3003 will receive the 
last study agent administration at Week 208.
†After the study becomes open-label, subjects in Group 
1 will be offered the option (at the discretion of the 
investigator) to reduce the sirukumab dose to 50 mg q4 
weeks for the remainder of the trial.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
124
3.2.2 Treatment Groups, Dosage, 
and Dose Administration Interval
(paragraph 3)
5.1 Treatment Allocation (paragraph 
4); 6.2 Blinding (paragraph 4);
11 Statistical Methods (paragraph 4)
6.1 Dosing Regimen (paragraph 4)
None
None
None
Following the database lock for the primary endpoint, 
analysis of CNTO136ARA3002 and 
CNTO136ARA3003 PK and efficacy data showed that 
there was no clear dose response between the 
sirukumab SC 50 mg q4 weeks and sirukumab SC 
100 mg q2 weeks dose groups across efficacy endpoints. 
Furthermore, there were a greater proportion of 
subjects with hypersensitivity reactions and injection 
site reactions in the sirukumab 100 mg q2 weeks dose 
group compared with the sirukumab 50 mg q4 weeks 
dose group. Therefore, to allow for minimization of the 
exposure to this immunosuppressant biologic agent, 
subjects treated with SC sirukumab 100 mg q2 weeks 
will be offered the option to reduce the sirukumab dose 
to 50 mg q4 weeks at the investigator’s discretion after 
the study becomes open-label. This decision can be 
made at the subject’s first or second major resupply 
visit (up until approximately 7 months) after 
implementation of Amendment 3 at the study site.
After the study becomes open-label, subjects treated 
with SC sirukumab 100 mg q2 weeks will be offered the 
option to reduce the sirukumab dose to 50 mg q4 weeks 
at the investigator’s discretion. This decision can be 
made at the subject’s first or second major resupply 
visit (up until approximately 7 months) after 
implementation of Amendment 3 at the study site.
After the study becomes open-label, subjects treated 
with SC sirukumab 100 mg q2 weeks will be offered the 
option to reduce the sirukumab dose to 50 mg q4 weeks 
at the investigator’s discretion. This decision can be 
made at the subject’s first or second major resupply 
visit (up until approximately 7 months) after 
implementation of Amendment 3 at the study site. Once 
a subject’s dose is reduced to 50 mg q4 weeks, the 
subject will receive that dose for the remainder of the 
trial (ie, a return to 100 mg q2 weeks will not be 
allowed). If a subject opts to remain on the sirukumab 
100 mg q2 weeks dose, he or she will remain on that 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
125
dose for the duration of their participation in the study 
(ie, the subject will not have the option to reduce the 
dose at a subsequent timepoint).
2.  Additional mentions of Patient Reported Outcome (PRO) evaluations and endpoints were added to the appropriate sections for completeness 
throughout the document.
The additional mentions of the PRO evaluations and endpoints (eg, Health Economics Questionnaire and morning stiffness) were added to various sections of the 
document for clarity and completeness.
Sections Affected
Original Content
Amended/New Content
Synopsis (Efficacy Evaluations), 
3.2.5 Efficacy Evaluations
(paragraph 3)
Synopsis (Statistical Methods –
Medical Resource Usage and Health 
Economics)
9.2.3 Endpoints (Other secondary 
endpoints)
11.2.3 Other Secondary Endpoints
Patient Reported Outcome (PRO) evaluations include:

36-Item Short Form (SF-36)

Work Limitations Questionnaire (WLQ)
WLQ data will be summarized over time.
Other secondary endpoints

ACR responses

DAS28 

HAQ-DI

SF-36

WLQ
In addition to the primary and major secondary efficacy 
endpoints, the following efficacy endpoints will be 
summarized by treatment group over time through the end 
of the study:
1. Proportion of subjects who achieve ACR 20 response
2. Proportion of subjects who achieve ACR 50 response
3. Proportion of subjects who achieve ACR 70 response
4. Proportion of subjects with DAS28 (CRP) response
5. Proportion of subjects with DAS28 (CRP) remission
6. Change from baseline in DAS28 (CRP)
Patient Reported Outcome (PRO) evaluations include:

36-Item Short Form (SF-36)

Work Limitations Questionnaire (WLQ)

Health Economic Questionnaire (HECONQ)
WLQ and HECONQ data will be summarized over time.
Other secondary endpoints

ACR responses

DAS28 

HAQ-DI

SF-36

WLQ

HECONQ

Morning stiffness
In addition to the primary and major secondary efficacy 
endpoints, the following efficacy endpoints will be 
summarized by treatment group over time through the end 
of the study:
1. Proportion of subjects who achieve ACR 20 response
2. Proportion of subjects who achieve ACR 50 response
3. Proportion of subjects who achieve ACR 70 response
4. Proportion of subjects with DAS28 (CRP) response
5. Proportion of subjects with DAS28 (CRP) remission
6. Change from baseline in DAS28 (CRP)
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
126
11.7 Health Economics Analyses
7. Proportion of subjects with SDAI-based ACR/EULAR 
remission
8. Proportion of subjects with Boolean-based 
ACR/EULAR remission
9. Change from baseline in SDAI
10. Change from baseline in CDAI
11. Change from baseline in HAQ-DI
12. Proportion of HAQ-DI responders (ie, those who have 
a change from baseline of > 0.22 in HAQ-DI score)
13. Change from baseline in PCS and MCS and in domain 
scores of SF-36
Change from baseline in total and domain scores of WLQ 
will be summarized over time.
7. Proportion of subjects with SDAI-based ACR/EULAR 
remission
8. Proportion of subjects with Boolean-based 
ACR/EULAR remission
9. Change from baseline in SDAI
10. Change from baseline in CDAI
11. Change from baseline in HAQ-DI
12. Proportion of HAQ-DI responders (ie, those who have 
a change from baseline of > 0.22 in HAQ-DI score)
13. Change from baseline in PCS and MCS and in domain 
scores of SF-36
14. Change from baseline in duration of morning 
stiffness.
Change from baseline in total and domain scores of WLQ 
and HECONQ will be summarized over time.
3.  Placebell©™ technology for RA was incorporated into the study.
Language regarding the incorporation of the Placebell©™technology was added to account for its exploration in this study.
Sections Affected
Original Content
Amended/New Content
Time and Events Schedule (Table 1)
9.2.1.8 Multidimensional 
Personality Questionnaire (MPSQ)
None
None
Exploration of Placebell©™technology for RA
Placebell Multidimensional Personality Questionnaireh:
optional at selected sites for consenting subjects at a 
single visit after implementation of Amendment 3;
Wk 16 through Wk 208
h.  At selected sites, the MPSQ will be administered as 
an optional paper questionnaire to subjects who 
consent to participate after implementation of 
Amendment 3 at the study site.
The Placebell©™ technology will be explored in this 
study of rheumatoid arthritis. The Multidimensional 
Personality Questionnaire (MPSQ) is a questionnaire 
contributing to the evaluation of individual patient 
response to placebo by assessing patients's personality, 
well-being as well as attitudes and beliefs on disease 
therapies. It has been developed by Tools4patient SA.
MPSQ is self-reported by patient and made of 114 
items. Each of them is rated by patient on a 5-point 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
127
9.8 Safety Evaluations
16.2.3 Informed Consent (paragraph 
5)
None
None
scale ranging from 1 (strongly disagree) to 5 (strongly 
agree).
At selected sites, the MPSQ will be administered as an 
optional paper questionnaire to subjects who consent to 
participate after implementation of Amendment 3.
Subject Lab Data Access
Subjects at selected sites in the US will be offered the 
opportunity to consent to join a secure, web-based 
platform managed by a third party vendor so that they 
may access results to select clinical laboratory tests 
collected during the study (as defined above with the 
exception of RBC count). More details will be provided 
in the Informed Consent Form for these subjects.
A limited number of subjects will be asked to consent to 
participate in the Subject Lab Data Access and/or to 
complete the Placebell Multidimensional Personality 
Questionnaire. Refusal to participate in either the 
Subject Lab Access program or to complete the
Placebell Multidimensional Personality Questionnaire 
will not result in ineligibility for the clinical study.
4.  Specifying language was added regarding what is considered source data during source documentation.
Language was added to the source documentation section to specify the data that will be considered source data. 
Sections Affected
Original Content
Amended/New Content
17.4 Source Documentation
(paragraph 4)
None
Data which may be recorded directly into the CRF, if in 
accordance with site capabilities and/or in compliance 
with local regulations, will be considered source data, 
and will include but not be limited to the following:

Blood pressure

Weight
The following subject- and investigator-completed RA 
scales and assessments designated by the Sponsor will 
be recorded directly into an electronic device and will 
be considered source data.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
128

Swollen and tender joint assessments

Patient’s Global Assessment of Disease Activity

Physician’s Global Assessment of Disease Activity

Patient’s Assessment of Pain

HAQ-DI

SF-36

Duration of Morning Stiffness

WLQ

HECONQ
Multidimensional Personality Questionnaire recorded 
on paper will also be considered source data.
5.  Clarification was made in the Time & Events Schedules regarding the timing of the collection of pharm serum samples.
A cut-off date for randomization was added to provide further specification of the subject population from CNTO136ARA3002 from which samples will be 
collected.
Sections Affected
Original Content
Amended/New Content
Time and Events Schedule (Table 1)
Time and Events Schedule (Table 2)
i.  Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected from subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 750 
randomized subjects in CNTO136ARA3002) and from all 
subjects enrolled after participating in study 
CNTO136ARA3003.
c.  Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected at the final 
safety and efficacy follow up visit only from those subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 750 
randomized subjects in CNTO136ARA3002) and from all 
subjects enrolled after participating in study 
CNTO136ARA3003.
i.  Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected from subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 750 
randomized subjects randomized in CNTO136ARA3002 
before 18 November 2013) and from all subjects enrolled 
after participating in study CNTO136ARA3003.
c.  Pharm serum samples (sirukumab concentration and 
antibodies to sirukumab) will be collected at the final 
safety and efficacy follow up visit only from those subjects 
who had pharm serum samples collected at earlier time 
points in study CNTO136ARA3002 (approximately 750 
randomized subjects randomized in CNTO136ARA3002 
before 18 November 2013) and from all subjects enrolled 
after participating in study CNTO136ARA3003.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
129
6.  A clarification regarding joint assessors was made.
The joint assessors are not required to be indepenedent.
Sections Affected
Original Content
Amended/New Content
9.2.1.1 Joint Assessments (Joint 
Assessor paragraph 3)
The Sponsor will provide training for each site’s 
designated IJA prior to the [Week 0 visit] of the first 
subject at each site. A back-up IJA must complete training 
before performing a joint assessment for a subject’s study 
visit.
The Sponsor will provide training for each site’s 
designated IJA joint assessor prior to the [Week 0 visit] of 
the first subject at each site. A back-up IJA joint assessor
must complete training before performing a joint 
assessment for a subject’s study visit.
7.  A specification was made regarding how long subjects are required to be monitored for allergic and injection site reactions throughout the study.
Clarifying language was added to the Safety Evaluations to specify that subjects only need to undergo monitoring for symptoms of allergic reactions and 
injection site reactions at least until the study becomes open-label.
Sections Affected
Original Content
Amended/New Content
9.8 Safety Evaluations (Allergic 
Reactions)
9.8 Safety Evaluations (Injection 
Site 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.
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 for 
symptoms of an injection-site reaction.
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 at least until the 
study becomes open-label.
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 for 
symptoms of an injection-site reaction at least until the 
study becomes open-label.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
130
8.  A criterion was added to the Subject Completion / Withdrawal criteria for completeness.
A criterion for discontinuation of study treatment was added to address the potential future approval of sirukumab in the subject’s country of residence. This is 
already mentioned earlier in the document, but is being added to this list for completeness.
Sections Affected
Original Content
Amended/New Content
10.2 Discontinuation of Treatment
None
16. If sirukumab becomes approved in the subject’s 
country of residence, it may no longer be offered by the 
Sponsor in CNTO136ARA3004. In this case, study 
agent administrations will be discontinued after 52 
weeks of treatment for subjects who enrolled after 
completing participation in study CNTO136ARA3002, 
and after 104 weeks of treatment for subjects who 
enrolled after completing participation in 
CNTO136ARA3003. At that point the subject will have 
the opportunity to discuss treatment options with their 
treating physician.
9.  The list of anticipated events was updated and language was moved to an attachment at the end of the protocol.
Language was added to include synovitis in the list of anticipated events, which was moved from section 12.3.2 to a new attachment (Attachment 2) at the end of 
the protocol. A reference to this attachment was included in section 12.3.1 (All Adverse Events).
Sections Affected
Original Content
Amended/New Content
12.3.1 All Adverse Events
(paragraph 2)
All events that meet the definition of a SAE will be 
reported as SAEs, regardless of whether they are protocol-
specific assessments. All adverse events, regardless of 
seriousness, severity, or presumed relationship to study 
therapy, must be recorded using medical terminology in the 
source document and the CRF. Whenever possible, 
diagnoses should be given when signs and symptoms are 
due to a common etiology (eg, cough, runny nose, 
sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection"). Investigators 
must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All 
measures required for adverse event management must be 
recorded in the source document and reported according to 
Sponsor instructions.
All events that meet the definition of a SAE will be 
reported as SAEs, regardless of whether they are protocol-
specific assessments. Anticipated events will be recorded 
and reported as described in Attachment 2. All adverse 
events, regardless of seriousness, severity, or presumed 
relationship to study therapy, must be recorded using 
medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs 
and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion 
should be reported as "upper respiratory infection"). 
Investigators must record in the CRF their opinion 
concerning the relationship of the adverse event to study 
therapy. All measures required for adverse event 
management must be recorded in the source document and 
reported according to Sponsor instructions.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
131
12.3.2 Serious Adverse Events
(paragraphs 7, 8)
Attachment 2: Anticipated Events
SAEs related to the disease under study will be collected 
per protocol but will not be unblinded and expedited if they 
fall into the following categories:
•  Exacerbations of RA
•  Worsening joint pain or swelling due to RA
These events will be reviewed periodically at the time of 
database locks in an unblinded fashion, if unblinded data is 
available. In addition, the DMC will review unblinded data 
during the blinded portions of the study (Section 11.10). If 
the review finds an association with the use of the drug to 
be a reasonable possibility, the assessment and all single 
cases not yet reported will be sent to FDA in an expedited 
manner.
None
SAEs related to the disease under study will be collected 
per protocol but will not be unblinded and expedited if they 
fall into the following categories:
•  Exacerbations of RA
•  Worsening joint pain or swelling due to RA
These events will be reviewed periodically at the time of 
database locks in an unblinded fashion, if unblinded data is 
available. In addition, the DMC will review unblinded data 
during the blinded portions of the study (Section 11.10). If 
the review finds an association with the use of the drug to 
be a reasonable possibility, the assessment and all single 
cases not yet reported will be sent to FDA in an expedited 
manner.
An anticipated event is an adverse event (serious or 
non-serious) that commonly occurs as a consequence of 
the underlying disease or condition under investigation 
(disease related) or background regimen.
For the purposes of this study the following events will 
be considered anticipated events:

Exacerbations of rheumatoid arthritis (RA)

Worsening joint pain or swelling due to RA

Synovitis
Reporting of Anticipated Events
These events will be captured on the CRF and in the 
database, and will be reported to the sponsor as 
described in Section 12.3.1, All Adverse Events. Any 
event that meets serious adverse event criteria will be 
reported to the sponsor within the appropriate timeline 
as described in Section 12.3.2, Serious Adverse Events. 
These anticipated events are exempt from expedited 
reporting as individual single cases to Health 
Authorities. However, if based on an aggregate review, 
it is determined that an anticipated event is possibly 
related to study drug, the sponsor will report these 
events in an expedited manner.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
132
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be 
established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a 
safety committee within the sponsor’s organization that 
is independent of the sponsor’s study team. The ARC 
will meet to aid in the recommendation to the sponsor’s 
study team as to whether there is a reasonable 
possibility that an anticipated event is related to the
study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, 
including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will 
be provided in a separate Anticipated Events Safety 
Monitoring Plan (ASMP).
10.  Language for consent regarding pregnancy was updated for greater specification.
Language was added regarding consent guidelines for male and female subjects involved in pregnancy during the study.
Sections Affected
Original Content
Amended/New Content
12.3.3 Pregnancy (paragraph 3)
Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be 
required.
Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be 
required after subject’s consent has been obtained.
For women: The study doctor will ask for your 
permission to stay in contact with you 
throughout the length of the pregnancy.
For men: The study doctor will ask for your 
permission and your partner’s to stay in contact 
with your partner throughout the pregnancy.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
133
11.  Updates were made to the Study Specific Materials.
As this is an outsourced study, “Site Investigational Product Binder” is not being used. “Binder” was replaced with “Procedures Manual” for consistency with 
other related Phase 3 studies. Updates were also made for some of the names of the Study Specific Materials that are provided to the investigator.
Sections Affected
Original Content
Amended/New Content
14.4 Preparation, Handling, and 
Storage (paragraphs 3 and 4)
14.5 Drug Accountability (paragraph 
2)
15 Study Specific Materials
Study agent should be administered according to the 
instructions provided in the Site Investigational Product 
Binder.  
Subjects who are able and who have been appropriately 
trained in the self-administration of study agent may self-
administer study agent at home in accordance with 
Section 6.5. Study personnel will instruct subjects on how 
to transport, store and administer medication for at-home 
use as indicated for this protocol. Details will be provided 
in the Site Investigational Product Binder.
Upon termination of the study or at the request of the 
Sponsor or its designee, the investigator must return all 
unused study agent to the Sponsor or its designee or if 
approved by the Sponsor, unused study agent can be 
destroyed directly at the site or locally by an approved 
destruction unit as described in the Site Investigational 
Product Binder.
The investigator will be provided with the following:

Investigator Brochure

Site Investigational Product Binder

Central Laboratory Manual

PRO Questionnaires 

MTX Toxicity Guidelines (Appendix C)

IVRS/IWRS Manual

Electronic Data Capture (eDC) Manual
Study agent should be administered according to the 
instructions provided in the Site Investigational Product 
Binder Procedures Manual.  
Subjects who are able and who have been appropriately 
trained in the self-administration of study agent may self-
administer study agent at home in accordance with 
Section 6.5. Study personnel will instruct subjects on how 
to transport, store and administer medication for at-home 
use as indicated for this protocol. Details will be provided 
in the Site Investigational Product Binder Procedures 
Manual.
Upon termination of the study or at the request of the 
Sponsor or its designee, the investigator must return all 
unused study agent to the Sponsor or its designee or if 
approved by the Sponsor, unused study agent can be 
destroyed directly at the site or locally by an approved 
destruction unit as described in the Site Investigational 
Product Binder Procedures Manual.
The investigator will be provided with the following:

Investigator Brochure

Site Investigational Product Binder Procedures 
Manual

Central Laboratory Manual

PRO Questionnaires 

ePRO Device and Manual

MTX Toxicity Guidelines (Appendix C)

IVRS/IWRS Manual User Guides and Worksheets

Electronic Data Capture (eDC) Manual
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
134
ATTACHMENT 2: ANTICIPATED EVENTS 
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events:

Exacerbations of rheumatoid arthritis (RA)

Worsening joint pain or swelling due to RA

Synovitis
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as 
described in Section 12.3.1, All Adverse Events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to Health 
Authorities. However, if based on an aggregate review, it is determined that an anticipated event is 
possibly related to study drug, the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
135
APPENDIX A
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-g 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.  
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
136
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 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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
137
APPENDIX B
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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
138
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.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
139
APPENDIX C
GUIDELINES FOR MTX DOSE ADJUSTMENTS FOR MTX-
TOXICITY
The following algorithm will be used to make the dose adjustments in the event of MTX-
induced toxicities (see Section 8.1.2):
1.
Mild toxicity 
Labs: liver function test results (AST or ALT) < 2 x upper normal limit (ULN) central 
laboratory, leukocyte count 3.5 x 109 cells per liter
Symptoms: mild nausea, mild abdominal distress, and occasional mild headaches, no rash, 
and no oral ulceration
Adjustment: confirm relevant laboratory findings and continue with the current dosing 
algorithm
2.
Moderate toxicity 
Labs: liver function test results (AST or ALT) 2 x ULN but < 3 x ULN and a leukocyte 
count of 2.0 x 109 cells per liter but < 3.5 x 109 cells per liter  
Symptoms: moderate nausea, moderate abdominal distress, minimal macular 
erythematous rash, and minor oral ulceration
Adjustment: confirm the laboratory findings, decrease the dose of MTX by 50%, and 
repeat the laboratory tests 2 weeks following the dose reduction  
If the liver function tests return to < 2 x ULN, and the leukocyte count returns to values 
between normal and 3.5 x 109 cells per liter, and nausea or headaches improve and rash 
and oral ulceration resolve, the MTX dose may be increased to the baseline dose at the 
investigator’s discretion. 
If the liver function tests remain elevated (2 x ULN and < 3 x ULN) or the leukocyte 
count remains 2.0 x 109 cells per liter but  < 3.5 x 109 cells per liter, or the nausea does 
not improve, the MTX dose should be decreased again by 50%.
3.
Severe toxicity 
Labs: liver function tests results (AST and/or ALT) 3 x ULN, and the leukocyte count 
is < 2.0 x 109 cells per liter
Symptoms: severe nausea and vomiting, severe abdominal pain, severe headaches, and 
diffuse rash or major oral ulceration
Adjustment: confirm the laboratory findings and withhold MTX therapy for 2 weeks, then 
repeat laboratory tests  
If, after 2 weeks, the repeat liver function test results are between ULN and < 3 x ULN, 
the leukocyte count is 2.0 x 109 cells per liter, and nausea or headaches or rash and oral 
ulceration have improved, MTX can be restarted at 50% of the baseline dose, at the 
investigator’s discretion.  
If after 2 weeks, the repeat laboratory tests continue to demonstrate severe toxicity or the 
nausea or headaches, rash, or oral ulceration remain severe, MTX therapy should be 
withheld an additional 2 weeks and the laboratory tests repeated after that time. 
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
140
If the subject improves after an additional 2 weeks off MTX, the MTX should be 
restarted at 50% of baseline dose, at the investigator’s discretion.  
If after an additional 2 weeks off MTX, there has been no improvement in the subject, 
MTX should be discontinued permanently.
NCT01856309


CNTO 136 (sirukumab):  Clinical Protocol CNTO136ARA3004 – Amendment 3
Approved 06 Oct 2016
141
INVESTIGATOR AGREEMENT
NCT01856309

SAP_001.pdf: 
NCT01856309