A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Sirukumab in the Treatment of Patients With Giant Cell Arteritis
Phase: PHASE3
Conditions: Giant Cell Arteritis
Sponsor: GlaxoSmithKline

2015N227575_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
201677
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Study to Evaluate the Efficacy and Safety of 
Sirukumab in the Treatment of Patients with Giant Cell Arteritis
Compound Number:
GSK2973327
Development Phase:
III
Effective Date:
17-NOV-2016
Protocol Amendment Number:  3
Author (s):
 
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

2015N227575_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
201677
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N227575_00
2015-MAY-11
Original
2015N227575_01
2015-OCT-15
Amendment No. 1
The original protocol has been amended to clarify the secondary objectives and endpoints 
of characterization of sustained remission in Parts A and B, collection of patient and 
physician reported outcomes, including correction of the version of the EQ-5D version 
that will be administered and pain assessment using a numeric rating scale. Further 
clarifications have been included in updates to the potential signs and symptoms of GCA, 
prednisone use during screening and taper initiation, subject eligibility for receiving 
open-label sirukumab in Part B and investigator consideration of the individual subject 
benefit-risk of continuing sirukumab in Part B. This amendment includes additional 
information on risk mitigation for GI perforations and serious allergic/hypersensitivity 
events, including adjudication and classification of such events using Sampson criteria. 
The inclusion criteria for GCA diagnostic criteria for temporal artery biopsy and imaging 
and symptoms of active GCA have been updated. The exclusion criteria have been 
updated to include restrictions relating to prolonged use or requirement for continued use 
of systemic corticosteroids and amendment of the time frames for previous use of anti-
TNFtherapies, which are detailed in the prohibited medications section. Additional 
clarifications on circumstances for re-testing of QuantiFERON-TB Gold test results, 
ECG assessment and provision of open-label prednisone to study sites have been 
included. Other changes include removal of restrictions on the use of NSAIDs,
clarification of circumstances requiring discontinuation of study treatment but not study 
withdrawal, and circumstances in which subjects may withdraw from the study. The 
Time and Events table has been updated and corrections included. Other additions 
include guidance to investigators related to treatment of glucocorticoid-induced 
osteoporosis. Study withdrawal is no longer required for events meeting QTc withdrawal 
criteria, liver chemistry stopping criteria and pregnancy. Females using hormonal 
contraception are required to use a secondary method of contraception. Changes to 
statistical considerations include amendment of the sample size sensitivity analysis and 
specification of subjects who discontinue treatment in efficacy and safety analyses. Other 
changes include clarification of protocol-specified exploratory biomarkers and optional 
exploratory biomarkers, updated information on the study number for the exploratory 
imaging sub-study, randomization system and correction of typographical errors.
2015N227575_02
2016-MAR-31
Amendment No. 2
The previous amendment, Protocol Amendment No. 1, has been revised to include the 
assessment of the utility of ultrasound imaging as an indicator of disease activity in an 
exploratory cohort of subjects. Other modifications include updates to the inclusion 
criteria for diagnosis of GCA to allow for diagnosis by ultrasound imaging in sites 
qualified to participate in the ultrasound imaging portion of the study, to further clarify 
features consistent with GCA or PMR flares, and to clarify requirements for the 

2015N227575_03
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prednisone dose at Screening. The inclusion criteria have also been amended to include 
the acceptability of a single view of chest radiographs if consistent with local guidelines. 
Updated information on the pre-filled syringes has been included. Other modifications 
include the clarification that the daily prednisone dose should be taken in a single daily 
administration in the morning. Country-specific requirements have been included for 
Germany, the Netherlands, and Australia and New Zealand. These include a requirement 
to discontinue study drug administration in the event of a serious infection (Germany), a 
requirement for subjects to discontinue the study at the conclusion of Part A after 
completing the 16-week follow up phase (the Netherlands) and a requirement to notify 
investigators when the value of the ESR result is > 40 mm/hr or has increased > 10 
mm/hr from baseline or previous result (Australia and New Zealand). 
2015N227575_03
2016-NOV-17
Amendment No. 3
The previous amendment, Protocol Amendment No. 2, has been revised to include the 
implementation of the Columbia-Suicide Severity Rating Scale to prospectively monitor 
suicidal ideation and behavior. Other modifications include revision of the endpoints for 
the exploratory imaging cohort, further clarifications regarding the initiation of the 
prednisone taper and prednisone sourcing information, and inclusion of malignancies as a 
potential risk of clinical significance. In addition, a requirement for male contraception 
and restrictions on sperm donation, amendment of QTc exclusion and stopping criteria, 
revision of criteria to allow prior anti-IL-6 use if not associated with intolerance or 
inadequate response, and addition of an exclusion criterion related to suicidality are 
included. Pregnancy testing is now required at 4-weekly intervals while subjects are 
receiving study drug during Parts A and B and during the 16-week follow up period after 
drug discontinuation. Additional clarification of reflex testing for hepatitis and 
tuberculosis testing have been included. Updated information regarding database locks 
and unblinding and treatment comparisons has also been included.

PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 201677
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201677......................................................10
2.
INTRODUCTION....................................................................................................18
2.1.
Study Rationale ..........................................................................................18
2.2.
Brief Background ........................................................................................18
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................20
4.
STUDY DESIGN ....................................................................................................25
4.1.
Overall Design ............................................................................................25
4.2.
Treatment Arms and Duration.....................................................................28
4.2.1.
Part A: 52-week double-blind treatment phase ............................28
4.2.2.
Part B: 104-week extension phase...............................................29
4.3.
Type and Number of Subjects.....................................................................30
4.4.
Design Justification.....................................................................................30
4.5.
Dose Justification........................................................................................31
4.6.
Benefit:Risk Assessment ............................................................................31
4.6.1.
Risk Assessment .........................................................................32
4.6.2.
Benefit Assessment.....................................................................36
4.6.3.
Overall Benefit:Risk Conclusion...................................................36
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............36
5.1.
Inclusion Criteria.........................................................................................37
5.2.
Exclusion Criteria........................................................................................39
5.3.
Screening/Baseline/Run-in Failures............................................................41
5.4.
Withdrawal/Stopping Criteria.......................................................................42
5.4.1.
Study Withdrawal.........................................................................42
5.4.2.
Discontinuation of Study Drug......................................................43
5.4.3.
Liver Chemistry Stopping Criteria ................................................44
5.4.3.1.
Study Treatment Restart or Rechallenge....................46
5.4.4.
QTc Stopping Criteria ..................................................................46
5.5.
Subject and Study Completion....................................................................46
6.
STUDY TREATMENT ............................................................................................47
6.1.
Investigational Product and Other Study Treatment....................................47
6.2.
Treatment Assignment................................................................................49
6.3.
Planned Dose Adjustments.........................................................................49
6.4.
Blinding.......................................................................................................51
6.5.
Packaging and Labeling..............................................................................53
6.6.
Preparation/Handling/Storage/Accountability..............................................53
6.7.
Compliance with Study Treatment Administration.......................................53
6.8.
Treatment of Study Treatment Overdose....................................................54
6.9.
Treatment after the End of the Study ..........................................................54
6.10.
Concomitant Medications and Non-Drug Therapies....................................55
6.10.1.
Permitted Medications and Non-Drug Therapies..........................55
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................55
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................56

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7.1.
Time and Events Tables .............................................................................59
7.2.
Screening and Critical Baseline Assessments ............................................71
7.3.
Efficacy.......................................................................................................71
7.3.1.
Patient’s and Physician’s Global Assessment of Disease 
Activity .........................................................................................72
7.4.
Health Outcomes........................................................................................72
7.4.1.
Patient Global Impression of Change (PGIC)...............................72
7.4.2.
Pain Assessment.........................................................................72
7.4.3.
Health Assessment Questionnaire – Disability Index 
(HAQ-DI)......................................................................................72
7.4.4.
Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-Fatigue)...........................................................................73
7.4.5.
Steroid Impact Questionnaire.......................................................73
7.4.6.
36-item Short Form Version 2 Acute (SF-36v2 Acute) .................73
7.4.7.
EuroQoL-5D (EQ-5D) (5L) ...........................................................73
7.5.
Safety .........................................................................................................74
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........74
7.5.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................74
7.5.1.2.
Method of Detecting AEs and SAEs ...........................75
7.5.1.3.
Follow-up of AEs and SAEs........................................75
7.5.1.4.
Cardiovascular and Death Events ..............................76
7.5.1.5.
Other Adverse Events of Special Interest for 
Sirukumab..................................................................76
7.5.1.6.
Events That Occur With Biologics...............................77
7.5.1.7.
Regulatory Reporting Requirements for SAEs............78
7.5.2.
Pregnancy ...................................................................................78
7.5.3.
Physical Exams ...........................................................................78
7.5.4.
Vital Signs....................................................................................79
7.5.5.
Electrocardiogram (ECG).............................................................79
7.5.6.
Clinical Safety Laboratory Assessments ......................................79
7.5.7.
Suicidal Risk Monitoring...............................................................82
7.5.8.
Tuberculosis Evaluation...............................................................83
7.5.9.
Chest Radiograph........................................................................84
7.6.
Pharmacokinetics and Immunogenicity.......................................................84
7.7.
Biomarkers/Pharmacodynamic Markers .....................................................84
7.7.1.
Exploratory Biomarkers................................................................84
7.7.2.
Optional Exploratory Biomarkers .................................................85
7.7.3.
Pharmacodynamic Markers .........................................................85
7.8.
Genetics .....................................................................................................85
7.9.
Exploratory Ultrasound Imaging..................................................................85
7.9.1.
Background and Rationale...........................................................85
7.9.2.
Synopsis......................................................................................86
8.
DATA MANAGEMENT ...........................................................................................86
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................87
9.1.
Hypotheses.................................................................................................87
9.2.
Sample Size Considerations.......................................................................87
9.2.1.
Sample Size Assumptions ...........................................................87
9.2.2.
Sample Size Sensitivity................................................................88
9.2.3.
Sample Size Re-estimation or Adjustment...................................88

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9.3.
Data Analysis Considerations .....................................................................88
9.3.1.
Analysis Populations....................................................................88
9.3.2.
Analysis Datasets ........................................................................89
9.3.3.
Treatment comparisons ...............................................................89
9.3.4.
Interim Analysis ...........................................................................92
9.4.
Key Elements of Analysis Plan ...................................................................92
9.4.1.
Primary Efficacy Analyses ...........................................................92
9.4.2.
Secondary Efficacy Analyses.......................................................93
9.4.3.
Safety Analyses...........................................................................93
9.4.3.1.
Extent of Exposure .....................................................93
9.4.3.2.
Adverse Events ..........................................................93
9.4.3.3.
Laboratory Parameters...............................................94
9.4.3.4.
Other Safety Measures...............................................94
9.4.4.
Health Outcomes Analyses..........................................................94
9.4.5.
Pharmacokinetic and Immunogenicity Analyses ..........................94
9.4.6.
Pharmacodynamic/Exploratory/Biomarker Analyses....................94
9.4.7.
Pharmacogenetic Analyses .........................................................95
10. STUDY GOVERNANCE CONSIDERATIONS........................................................95
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............95
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................95
10.3.
Quality Control (Study Monitoring) ..............................................................96
10.4.
Quality Assurance.......................................................................................97
10.5.
Study and Site Closure ...............................................................................97
10.6.
Records Retention......................................................................................98
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................98
10.8.
Review Committees....................................................................................99
11. REFERENCES.....................................................................................................100
12. APPENDICES......................................................................................................105
12.1.
Appendix 1: Abbreviations and Trademarks..............................................105
12.2.
Appendix 2: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) and 
Collection of Pregnancy Information .........................................................108
12.2.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ............108
12.2.2.
Collection of Pregnancy Information ..........................................109
12.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ............................................................................................110
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................114
12.4.1.
Definition of Adverse Events......................................................114
12.4.2.
Definition of Serious Adverse Events.........................................115
12.4.3.
Definition of Cardiovascular Events ...........................................116
12.4.4.
Recording of AEs and SAEs ......................................................117
12.4.5.
Evaluating AEs and SAEs..........................................................117
12.4.6.
Reporting of SAEs to GSK.........................................................119

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12.5.
Appendix 5: American College of Rheumatology Standard of Care 
Recommendations for the Prevention and Treatment of 
Glucocorticoid-Induced Osteoporosis*......................................................120
12.6.
Appendix 6: Genetic Research .................................................................122
12.7.
Appendix 7 - Country Specific Requirements............................................125
12.8.
Appendix 8: Exploratory US Imaging ........................................................126
12.8.1.
Objectives and Endpoints ..........................................................126
12.8.2.
Type and Number of Subjects....................................................126
12.8.3.
Assessments and Procedures ...................................................127
12.8.3.1.
Sonographer Training...............................................127
12.8.3.2.
Subject Eligibility ......................................................127
12.8.3.3.
Ultrasound Scanning ................................................127
12.8.4.
Blinding......................................................................................128
12.8.5.
Statistical Considerations and Data Analyses ............................128
12.8.5.1.
Hypotheses ..............................................................128
12.8.5.2.
Sample Size Considerations.....................................128
12.8.5.3.
Data Analysis Considerations...................................128
12.8.5.4.
Key Elements of Analysis Plan .................................128
12.9.
Appendix 9: Protocol Changes..................................................................130

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1.
PROTOCOL SYNOPSIS FOR STUDY 201677
Rationale
Multiple lines of evidence support a role for interleukin-6 (IL-6) in the pathophysiology 
of giant cell arteritis (GCA). Sirukumab is a human anti-IL-6 immunoglobulin 
IgG1kappa monoclonal antibody (mAb) with a high affinity and specificity for binding to 
the human IL-6 molecule that may have therapeutic benefit in the treatment of GCA by 
interruption of multiple pathogenic pathways. The purpose of this study is to evaluate the 
efficacy and safety of sirukumab to characterize the benefit-to-risk profile of sirukumab 
in the treatment of active GCA.
Objective(s)/Endpoint(s)
Part A: 52-week double-blind treatment phase
Objectives
Endpoints
Primary
To investigate the efficacy of sirukumab (100 
mg q2w for 12 months) as compared to 
placebo, each administered in addition to a 6-
month prednisone treatment regimen 
Proportion of subjects in 
sustained remission at Week 52, 
defined as having achieved all of 
the following:
1. Remission* by Week 12 and
2. Absence of disease flare**
following remission at Week 
12 through Week 52 and
3. Completion of the assigned 
prednisone taper protocol and
4. No requirement for rescue 
therapy at any time through 
Week 52
*Remission is defined as absence 
of clinical signs and symptoms 
of GCA and normalization of 
ESR [<30mm/hr] and CRP 
[<1mg/dL])
**Flare is defined as recurrence 
of symptoms attributable to 
active GCA, with or without 
elevations in ESR and/or CRP
Secondary
To assess cumulative prednisone doses in 
subjects treated with sirukumab plus 
prednisone as compared to placebo plus 
prednisone
Median and cumulative 
prednisone dose over time
To investigate the efficacy of sirukumab (100 
Proportion of subjects in 

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Objectives
Endpoints
mg q2w for 12 months) administered with a 3-
month prednisone treatment regimen versus 
placebo administered with a 6-month 
prednisone treatment regimen
To investigate the efficacy of sirukumab (100 
mg q2w for 12 months) administered with a 6-
month prednisone treatment regimen as 
compared to placebo administered with a 12-
month prednisone treatment regimen (standard 
of care)
To investigate the efficacy of sirukumab (100 
mg q2w for 12 months) administered with a 3-
month prednisone treatment regimen versus 
placebo administered with a 12-month 
prednisone treatment regimen
To investigate the efficacy of sirukumab (50 
mg q4w for 12 months) as compared to 
placebo, each administered in addition to a 6-
month prednisone treatment regimen
To investigate the efficacy of sirukumab (50 
mg q4w for 12 months) administered with a 6-
month prednisone treatment regimen as 
compared to placebo administered with a 12-
month prednisone treatment regimen
sustained remission at Week 52
To characterize sustained remission over time
Proportion of subjects in 
sustained remission at each time 
point of assessment from Week 
12 to Week 52, where sustained 
remission is defined as having 
achieved all of the following:
1. Remission at Week 12 and
2. Absence of disease flare 
following remission at Week 
12 and
3. Adherence to the assigned 
prednisone taper protocol and
4. No requirement for rescue 
therapy at any time 
To characterize disease flare over time
Time to first GCA flare after 
clinical remission
Number of disease flares per 
patient over time
Proportion of subjects requiring 
hospitalizations for disease flare 
and number of hospitalizations for 
disease flare over time

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Objectives
Endpoints
To evaluate the safety of sirukumab plus 
prednisone treatment compared to placebo plus 
prednisone treatment
To investigate corticosteroid-related toxicities
Incidence of adverse events and 
serious adverse events, incidence 
of corticosteroid-related adverse 
events, changes in vital signs, 
hematology and clinical 
chemistry parameters
To assess the effect of sirukumab treatment on 
health-related quality of life, GCA and steroid-
related symptoms and disability by patient and 
clinician reported outcomes over time
Patient reported outcomes 
including SF-36v2, EQ-5D (5L), 
FACIT-Fatigue, Pain Numeric 
Rating Scale (NRS), Steroid 
Impact PRO, HAQ-DI, Patient 
Global Impression of Change 
(PGIC), Patient Global 
Assessment of disease activity 
(PtGA) 
Clinician reported outcomes 
including Physician Global 
Assessment of disease activity 
(PhGA)
To characterize changes in biomarkers of 
disease activity
Change from baseline in ESR 
over time
Change from baseline in serum 
CRP over time
Pharmacokinetic/Immunogenicity
To investigate the pharmacokinetics of 
subcutaneously administered sirukumab 
Serum concentrations of 
sirukumab
To evaluate immunogenicity of 
subcutaneously administered sirukumab 
Serum anti-sirukumab antibodies 
Pharmacodynamic

To characterize the effect of sirukumab on IL-
6 levels in the blood

Change from baseline in free and 
total IL-6 over time
Exploratory
To explore the effect of sirukumab on 
exploratory biomarkers of Th1 and Th17 cell 
function
Change from baseline in IFN-γ
and IL-17A
To evaluate the effect of sirukumab on 
exploratory biomarkers of bone metabolism 
Change from baseline in serum 
markers of bone 
formation/resorption: 
CTX1/P1NP

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Objectives
Endpoints
To explore the utility of vascular ultrasound 
(US) imaging assessment of inflammation in 
temporal and axillary arteries as an indicator of 
disease activity in a cohort of study subjects
To explore the predictive value of ultrasound 
for clinical efficacy in GCA

Change over time in 
measurements of vascular 
inflammation in temporal and 
axillary arteries 

Correlation of clinical endpoints 
with changes in vascular 
inflammation.

Correlation of changes in 
vascular inflammation on US 
with clinical activity, CRP and 
ESR 

Correlation of changes in 
vascular inflammation on US 
with health-related quality of life 
outcomes
Pharmacogenetic
To potentially explore relationships between 
genetic variants and sirukumab efficacy and 
safety endpoints
Correlation of genetic markers 
with the safety and efficacy 
response to sirukumab
GCA = giant cell arteritis; ESR – erythrocyte sedimentation rate; CRP = C-reactive protein; SF-36 v2 = 36-item short 
form health survey version 2; EQ-5D (3L) = EuroQoL-5 dimensions; FACIT-fatigue = functional assessment of chronic 
illness therapy-fatigue; PRO = patient reported outcomes; HAQ-DI = health assessment questionnaire-disability index; 
PGIC = Patient Global Impression of Change; P1NP = procollagen type 1 N-propeptide; CTX = carboxyterminal cross-
linked telopeptide of bone collagen; IL = interleukin; US=ultrasound.
Part B: 104-week long-term extension phase
Objectives
Endpoints
To evaluate the long-term 
maintenance of disease remission on 
cessation of 12 months of sirukumab 
treatment
Proportion of subjects who remained 
in sustained remission without 
requirement for rescue therapy or 
treatment change at Week 24 of Part B
Proportion of subjects in sustained 
remission over time
Time to first GCA flare for subjects in 
sustained remission at baseline of Part 
B 
Number of disease flares per patient 
over time
Proportion of subjects requiring 
hospitalizations for disease flare and 
number of hospitalizations for disease 

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Objectives
Endpoints
flare over time
Proportion of subjects who remained 
in sustained remission without 
requirement for rescue therapy or 
treatment change 6 months post 
cessation of 12-month sirukumab 
treatment
To assess the effect of sirukumab 
treatment on health-related quality of 
life, GCA and steroid-related 
symptoms and disability by patient 
and clinician reported outcomes over 
time
Patient reported outcomes including 
SF-36v2, EQ-5D (5L), FACIT-
Fatigue, Pain NRS, Steroid Impact 
PRO, HAQ-DI and PtGA
Clinician reported outcomes including 
PhGA
To assess long-term cumulative 
prednisone doses
Median and cumulative prednisone 
dose over time
To assess the long-term safety of 
sirukumab
Incidence of adverse events and 
serious adverse events, changes in 
vital signs, hematology and clinical 
chemistry parameters
To investigate long-term 
corticosteroid-related toxicities
Incidence of corticosteroid-related 
adverse events
To evaluate immunogenicity of 
subcutaneously administered 
sirukumab in subjects receiving open-
label sirukumab
Serum anti-sirukumab antibodies 
GCA = giant cell arteritis; SF-36 v2 = 36-item short form health survey version 2; EQ-5D (3L) = EuroQoL-5 
dimensions; FACIT-fatigue = functional assessment of chronic illness therapy-fatigue; PRO = patient reported 
outcomes; HAQ-DI = health assessment questionnaire-disability index
Overall Design
This is a multi-center, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of 2 doses of sirukumab in the treatment of GCA.  The study will be 
conducted in 2 distinct parts (Part A and Part B) and consists of the following phases:

A screening phase of up to 6 weeks in duration.

Part A: a 52-week double-blind treatment phase to establish the efficacy and 
safety of sirukumab in the treatment of GCA.

Part B: a 104-week long-term extension phase with the option to receive open-
label sirukumab (up to a 52-week duration of open-label treatment) for subjects 
with active disease at the end of Part A, subjects who have not been able to follow 
the prednisone taper during Part A, or those who newly flare during the first 52 
weeks of Part B.

An up to 16-week follow-up phase to ensure that all subjects are evaluated for 
safety at least 16 weeks after receiving the last dose of study drug. This will apply 

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to subjects who are withdrawn prematurely from the study or whose open-label 
treatment with sirukumab in Part B will complete after Week 88. The duration of 
the follow-up may vary depending on the time point when the last dose of study 
drug is taken. Only subjects who complete their sirukumab treatment at Week 104 
will require the full 16-week follow-up period.
The maximum duration of subject participation (including screening) is 178 weeks. 
Completion of Part A is defined as completion of the 52 weeks of double-blind treatment. 
Completion of Part B is defined as completion of the 104 weeks of the extension phase. 
Completion of the study is defined as completion of both Parts A and B of the study 
and/or completion of the 16-week follow-up phase if applicable.
Subjects will be randomized to receive sirukumab 100 mg subcutaneous [SC] every 2 
weeks [q2w] or 50 mg SC every 4 weeks [q4w] or matching placebo. All subjects will 
receive prednisone during the 52-week double-blind treatment period according to a pre-
specified taper regimen.
An Independent Data Monitoring Committee (IDMC) and an independent Clinical Events 
Committee (CEC) will be utilized in this study.
Three primary database locks (DBLs) are planned for reporting of the results:

The first DBL for the primary analysis will occur after all subjects have 
completed the Week 52 visit assessments in Part A or have withdrawn 
prematurely from the study. Treatment-level data will be unblinded to Sponsor 
personnel.

The second DBL for the 6-month follow-up will occur after all subjects have 
completed the Week 24 visit in Part B, or have withdrawn prematurely from the 
study. The data from subjects undergoing the 16-week follow-up assessments at 
the end of Part A will also be included and will potentially comprise a separate 
data set/report if applicable.

The third planned DBL will occur after all subjects have completed the last visit 
in Part B, or have withdrawn prematurely from the study. The Part B DBL will 
include the data from all visits associated with Part B of the study, including the 
16-week follow-up assessments of Part B if applicable.
All subjects and study site personnel will remain blinded to the treatment group 
assignment until all subjects of Part B have completed the Week 24 visit assessments of 
Part B.
Treatment Arms and Duration
In Part A, eligible subjects will be randomized in a ratio of 3:3:2:2:2 to one of the 
following 5 treatment arms:
1.
Treatment Arm A: Sirukumab 100 mg SC q2w for 52 weeks plus a pre-specified 
maximum of 6-month prednisone taper regimen 

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2.
Treatment Arm B: Sirukumab 100 mg SC q2w for 52 weeks plus a pre-specified 
maximum of 3-month prednisone taper regimen 
3.
Treatment Arm C: Sirukumab 50 mg SC q4w for 52-weeks plus a pre-specified 
maximum of 6-month prednisone taper regimen 
4.
Treatment Arm D: Placebo SC q2w for 52 weeks plus a pre-specified maximum of 
6-month prednisone taper regimen
5.
Treatment Arm E: Placebo SC q2w for 52 weeks plus a pre-specified maximum of 
12-month prednisone taper regimen.
The prednisone tapering schedule begins for all subjects upon randomization (Baseline, 
Week 0) as follows:

Subjects will remain on the prednisone dose they are currently receiving at 
Baseline for one week.

At Week 1, the prednisone dose will be decreased in accordance with the pre-
specified prednisone taper schedule. 

The pre-specified maximum tapering schedule to be followed will depend on the 
subject’s treatment group assignment. 

The prednisone taper will be unblinded (open-label) and will consist of identical 
weekly decreases in dose for all subjects until a dose of 20 mg/day is reached, at 
which point the blinded portion of the prednisone tapering regimen will 
commence. 

Subjects who are receiving a prednisone dose of 20 mg/day at Baseline (Week 0) 
should continue taking the open-label 20 mg daily dose for one week. At Week 1, 
these subjects will initiate the blinded taper regimen.
All subjects who complete Part A of the study will be eligible to enter Part B. The two 
populations of subjects expected to enter into Part B are:

Subjects in remission at the primary 52-week endpoint. These subjects will 
discontinue blinded study drug treatment on entry into Part B and will be followed 
for maintenance of response. However, they will have the option to receive open-
label sirukumab 100 mg SC q2w for a maximum of 52 weeks during the first 52 
weeks of Part B in the event of a flare.

Subjects with disease activity at the primary 52-week endpoint or subjects who 
have not been able to follow the prednisone taper during Part A. Upon entry into 
Part B, these subjects will have the option to receive open-label sirukumab 100 
mg SC q2w for a maximum of 52 weeks.

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For subjects who newly flare at any time during the 1st 52 weeks of Part B and require a 
treatment change, open-label sirukumab 100 mg SC q2w can be initiated within the first 
52 weeks of Part B. The duration of treatment will be at the discretion of the investigator 
but must not exceed 52 weeks. Treatment with open-label sirukumab 100 mg SC q2w 
must complete by Week 104 (the end of the extension phase). Corticosteroid use or the 
initiation of methotrexate therapy alone or in addition to sirukumab treatment during Part 
B will be at the discretion of the investigator.
Type and Number of Subjects
Approximately 204 subjects with a diagnosis of GCA based on the Revised GCA 
Diagnosis Criteria will be randomized at Baseline into the 52-week double-blind, placebo 
controlled phase (Part A) of the study.
Subjects are required to have active GCA disease within 6 weeks of baseline where active 
disease is defined as the presence of unequivocal clinical signs and symptoms attributable 
to GCA and increased levels of inflammatory markers [ESR 30 mm/hr and/or CRP 1 
mg/dL (10 mg/L)]. Both new onset (diagnosis within 6 weeks of baseline) and 
relapsing/refractory (established diagnosis greater than 6 weeks prior to baseline with 
disease activity within 6 weeks of baseline) GCA subjects will be eligible.
Relapsing/refractory subjects include those who may have previously been in remission 
with corticosteroid treatment and have recurrence of disease activity (relapsing) or 
subjects who continued to have active disease without remission despite previous or 
ongoing corticosteroid therapy (refractory).
The number of relapsing/refractory subjects will be capped at approximately 50% to 
ensure that a sufficient number of subjects with new onset disease are recruited.
Analysis
The proportion of subjects with sustained remission at Week 52 in the sirukumab 100 mg 
SC q2w plus 6 month prednisone versus placebo plus 6 month prednisone will be 
analyzed using a generalized estimating equations model controlling for stratification
factor of baseline prednisone dose. The model will include treatment, week, treatment-
by-week interaction and subject within week as a random effect. Treatment differences 
will be presented as odds ratios and concluded as statistically significant if P≤0.05.
Since sirukumab is as yet untested in GCA, the study may employ a futility interim 
analysis to enable a decision to stop the study early should there be no or little effect of 
sirukumab.  Depending on the recruitment rate, an interim analysis may be carried out 
when approximately 30% of patients have completed 52 weeks. The study will only be 
stopped for futility (lack of efficacy) if the probability of success of the study (i.e. the 
conditional power based on the observed interim data) is calculated to be very low.

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2.
INTRODUCTION
Sirukumab is a human anti-IL-6 immunoglobulin IgG1kappa mAb with a high affinity 
and specificity for binding to the human IL-6 molecule that is being developed for the 
treatment of giant cell arteritis (GCA).
2.1.
Study Rationale
Multiple lines of evidence support a role for IL-6 in the pathophysiology of GCA
[Emilie, 1994; Roche, 1993].  Sirukumab is a human anti-IL-6 immunoglobulin 
IgG1kappa mAb with a high affinity and specificity for binding to the human IL-6 
molecule that may have therapeutic benefit in the treatment of GCA by interruption of 
multiple pathogenic pathways. The purpose of this study is to evaluate the efficacy and 
safety of sirukumab to characterize the benefit-to-risk profile of sirukumab in the 
treatment of active GCA.
2.2.
Brief Background
GCA is a systemic vasculitis affecting medium-sized and large arteries usually 
accompanied or preceded by systemic inflammation. It is the most common primary form 
of vasculitis in the United States and Europe and occurs predominantly in individuals 
aged 50 years or over with the mean age of onset of approximately 70 years of age 
[Salvarani, 2004]. Women are affected about 3 times as often as men and the most 
common symptoms include headache, visual loss, symptoms of polymyalgia rheumatic 
(PMR) and jaw claudication. Diagnosis is generally confirmed by temporal artery biopsy 
and typically CRP and ESR rate are increased [Nesher, 2014; Waldman, 2013].
Corticosteroids are the treatment of choice starting with an initial high dose of prednisone 
at 40-60 mg/day for most cases followed by a tapered lowering of dose. Despite an often 
rapid improvement of symptoms following initial glucocorticoid treatment, most patients 
develop serious adverse side effects related to use of glucocorticoids. Disease relapse is 
common (50%-80%) during corticosteroid taper [Hachulla, 2001; Weyand, 2000]. While 
the general view is that steroid treatment can be reasonably stopped after 2 years, patients 
usually require steroid therapy for much longer [Hayreh, 2003]. Furthermore, a 
significant proportion (~25%) of patients do not achieve permanent remission [Proven, 
2003].
It is estimated that more than 85% of GCA patients suffer from corticosteroid-related 
side-effects as a result of long-term treatment [Proven, 2003]. Studies with agents, 
including tumor necrosis factor (TNF) inhibitors, to demonstrate disease control and 
corticosteroid sparing properties have not been successful [Hoffman, 2007; Martinez-
Taboada, 2008; Seror, 2013]. Trials with methotrexate have given conflicting results 
[Spies, 2010].  Furthermore, even with control of symptoms with corticosteroid therapy, 
persistent active vascular inflammation can be demonstrated in patients [Achkar, 1994].  
Therefore, a significant unmet need for better therapies remains.
Although the trigger of the disease remains unknown, both adaptive and innate immune 
systems appear to be involved in the pathogenesis of GCA. Histologically, GCA is 

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characterised by a granulomatous infiltrate of T cells and macrophages and both Th1 and 
Th17 cells have been implicated [Weyand, 2013; Weyand, 2011]. IL-6, a cytokine 
produced by T cells, B cells, macrophages, endothelial cells and fibroblasts, is 
upregulated within these inflamed arteries and serum levels of IL-6 correlate with disease 
activity and response to corticosteroid treatment [Emilie, 1994; Roche, 1993]. IL-6 
triggers the synthesis of acute phase reactants, promotes T cell activation, terminal 
differentiation of B cells, survival of plasma cells, differentiation of Th17 cells, and 
induces proinflammatory differentiation of monocyte/macrophages, while inhibiting 
Treg-cell differentiation and function [Rincon, 2012].
This evidence suggests that inhibition of IL-6 activity may be of therapeutic benefit in the 
treatment of GCA by interruption of multiple pathogenic pathways. This potential benefit 
is supported by experience with the open-label use of the IL-6 receptor antagonist, 
tocilizumab, for the treatment GCA patients, when administered with corticosteroids or 
as monotherapy [Besada, 2012; Beyer, 2011; Christidis, 2011; Isik, 2013; Lurati, 2012; 
Salvarani, 2012; Sciascia, 2011; Seitz, 2011; Unizony, 2012; Vinit, 2012]. Based on these 
results, a Phase III randomized, double-blind, placebo-controlled trial of tocilizumab for 
the treatment of GCA has been initiated [Unizony, 2013].
Similar to GCA, patients with rheumatoid arthritis (RA) often have increased levels of 
IL-6 in the synovial fluid and serum, together with TNFα and IL-1 [Gottenberg, 2012; 
Swaak, 1988]. 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 [(Flannery, 2000; Lipsky, 
2006]. Systemically, elevated IL-6 in patients with RA may induce hepatic production of 
acute-phase proteins, increase platelet production, and likely increase hepcidin and the 
development of anemia of chronic inflammation [Nemeth, 2004]. 
Sirukumab is a fully human anti-IL-6 immunoglobulin G1-kappa with a high affinity and 
specificity for binding to the human IL-6 molecule.  It 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. A global Phase III clinical 
program with sirukumab for RA is on-going as a co-development partnership between 
GSK and Janssen-Cilag International.  This program is comprised of four comparative 
Phase III trials in patients with RA who are DMARD- or anti-TNF-inadequate responders 
and a long term extension study for eligible patients. Two Phase II studies have been 
completed. Additional details regarding the RA clinical program are available in the 
Investigator Brochure. 
Based upon the role of IL-6 in the pathogenesis of GCA and the supporting clinical 
evidence with tocilizumab, a randomized, double-blind, placebo-controlled study of 
subjects with active GCA is proposed.  The purpose of this study will be to evaluate the 
efficacy and safety of sirukumab to characterize the benefit-to-risk profile of this agent in 
the treatment of active GCA.

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3.
OBJECTIVE(S) AND ENDPOINT(S)
Part A: 52-week double-blind treatment phase
Objectives
Endpoints
Primary
To investigate the efficacy of 
sirukumab (100 mg q2w for 12 
months) as compared to placebo, each 
administered in addition to a 6-month 
prednisone treatment regimen 
Proportion of subjects in sustained 
remission at Week 52, defined as
having achieved all of the following:
1. Remission* by Week 12 and
2. Absence of disease flare**
following remission at Week 12
through Week 52 and
3. Completion of the assigned 
prednisone taper protocol and
4. No requirement for rescue therapy 
at any time through Week 52
*Remission is defined as absence of 
clinical signs and symptoms of GCA 
and normalization of ESR 
[<30mm/hr] and CRP [<1mg/dL])
**Flare is defined as recurrence of 
symptoms attributable to active GCA, 
with or without elevations in ESR 
and/or CRP
Secondary
To assess cumulative prednisone 
doses in subjects treated with 
sirukumab plus prednisone as
compared to placebo plus prednisone
Median and cumulative prednisone 
dose over time
To investigate the efficacy of 
sirukumab (100 mg q2w for 12 
months) administered with a 3-month
prednisone treatment regimen versus 
placebo administered with a 6-month 
prednisone treatment regimen
To investigate the efficacy of 
sirukumab (100 mg q2w for 12 
months) administered with a 6-month 
prednisone treatment regimen as 
compared to placebo administered 
with a 12-month prednisone treatment
regimen (standard of care)
To investigate the efficacy of 
sirukumab (100 mg q2w for 12 
months) administered with a 3-month 
Proportion of subjects in sustained 
remission at Week 52

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Objectives
Endpoints
prednisone treatment regimen versus 
placebo administered with a 12-month 
prednisone treatment regimen
To investigate the efficacy of 
sirukumab (50 mg q4w for 12 months) 
as compared to placebo, each 
administered in addition to a 6-month 
prednisone treatment regimen
To investigate the efficacy of 
sirukumab (50 mg q4w for 12 months) 
administered with a 6-month 
prednisone treatment regimen as 
compared to placebo administered 
with a 12-month prednisone treatment 
regimen
To characterize sustained remission 
over time
Proportion of subjects in sustained 
remission at each time point of 
assessment from Week 12 to Week 52, 
where sustained remission is defined 
as having achieved all of the 
following:
1. Remission at Week 12 and
2. Absence of disease flare following 
remission at Week 12 and
3. Adherence to the assigned 
prednisone taper protocol and
4. No requirement for rescue therapy 
at any time 
To characterize disease flare over time
Time to first GCA flare after clinical 
remission
Number of disease flares per patient 
over time
Proportion of subjects requiring 
hospitalizations for disease flare and 
number of hospitalizations for disease 
flare over time
To evaluate the safety of sirukumab 
plus prednisone treatment compared to 
placebo plus prednisone treatment
To investigate corticosteroid-related 
toxicities
Incidence of adverse events and 
serious adverse events, incidence of 
corticosteroid-related adverse events, 
changes in vital signs, hematology and 
clinical chemistry parameters
To assess the effect of sirukumab 
treatment on health-related quality of 
life, GCA and steroid-related 
symptoms and disability by patient 
and clinician reported outcomes over 
Patient reported outcomes including 
SF-36v2, EQ-5D (5L), FACIT-
Fatigue, Pain Numeric Rating Scale 
(NRS), Steroid Impact PRO, HAQ-DI, 
Patient Global Impression of Change 

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Objectives
Endpoints
time
(PGIC), Patient Global Assessment of 
disease activity (PtGA) 
Clinician reported outcomes including 
Physician Global Assessment of 
disease activity (PhGA)
To characterize changes in biomarkers 
of disease activity
Change from baseline in ESR over 
time
Change from baseline in serum CRP 
over time
Pharmacokinetic/Immunogenicity
To investigate the pharmacokinetics of 
subcutaneously administered 
sirukumab 
Serum concentrations of sirukumab
To evaluate immunogenicity of 
subcutaneously administered 
sirukumab
Serum anti-sirukumab antibodies 
Pharmacodynamic

To characterize the effect of 
sirukumab on IL-6 levels in the blood

Change from baseline in free and 
total IL-6 over time
Exploratory
To explore the effect of sirukumab on 
exploratory biomarkers of Th1 and 
Th17 cell function
Change from baseline in IFN-γ and 
IL-17A
To evaluate the effect of sirukumab on 
exploratory biomarkers of bone 
metabolism 
Change from baseline in serum 
markers of bone formation/resorption: 
CTX1/P1NP
To explore the utility of vascular 
ultrasound (US) imaging assessment 
of inflammation in temporal and 
axillary arteries as an indicator of 
disease activity in a cohort of study 
subjects

To explore the predictive value of 
ultrasound for clinical efficacy in 
GCA

Change over time in measurements of 
vascular inflammation in temporal 
and axillary arteries 

Correlation of clinical endpoints with
changes in vascular inflammation.

Correlation of changes in vascular 
inflammation on US with clinical 
activity, CRP and ESR 

Correlation of changes in vascular 
inflammation on US with health-
related quality of life outcomes 
Pharmacogenetic
To potentially explore relationships 
between genetic variants and 
sirukumab efficacy and safety 
endpoints
Correlation of genetic markers with 
the safety and efficacy response to 
sirukumab

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GCA = giant cell arteritis; ESR – erythrocyte sedimentation rate; CRP = C-reactive protein; SF-36 v2 = 36-item 
short form health survey version 2; EQ-5D (3L) = EuroQoL-5 dimensions; FACIT-fatigue = functional assessment 
of chronic illness therapy-fatigue; PRO = patient reported outcomes; HAQ-DI = health assessment questionnaire-
disability index; PGIC = Patient Global Impression of Change; P1NP = procollagen type 1 N-propeptide; CTX = 
carboxyterminal cross-linked telopeptide of bone collagen; IL = interleukin; US=ultrasound.

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Part B: 104-week long-term extension phase
Objectives
Endpoints
To evaluate the long-term 
maintenance of disease remission on 
cessation of 12 months of sirukumab 
treatment
Proportion of subjects who remained 
in sustained remission without 
requirement for rescue therapy or 
treatment change at Week 24 of Part B
Proportion of subjects in sustained 
remission over time
Time to first GCA flare for subjects in 
sustained remission at baseline of Part 
B 
Number of disease flares per patient 
over time
Proportion of subjects requiring 
hospitalizations for disease flare and 
number of hospitalizations for disease 
flare over time
Proportion of subjects who remained 
in sustained remission without 
requirement for rescue therapy or 
treatment change 6 months post 
cessation of 12-month sirukumab 
treatment
To assess the effect of sirukumab 
treatment on health-related quality of 
life, GCA and/or steroid-related 
symptoms and disability by patient 
and clinician reported outcomes over 
time
Patient reported outcomes including 
SF-36v2, EQ-5D (5L), FACIT-
Fatigue, Pain NRS, Steroid Impact 
PRO, HAQ-DI and PtGA
Clinician reported outcomes including 
PhGA
To assess long-term cumulative 
prednisone doses
Median and cumulative prednisone 
dose over time
To assess the long-term safety of 
sirukumab
Incidence of adverse events and 
serious adverse events, changes in 
vital signs, hematology and clinical 
chemistry parameters
To investigate long-term 
corticosteroid-related toxicities
Incidence of corticosteroid-related 
adverse events
To evaluate immunogenicity of 
subcutaneously administered 
sirukumab in subjects receiving open-
label sirukumab
Serum anti-sirukumab antibodies 
GCA = giant cell arteritis; SF-36 v2 = 36-item short form health survey version 2; EQ-5D (3L) = EuroQoL-5 
dimensions; FACIT-fatigue = functional assessment of chronic illness therapy-fatigue; PRO = patient reported 
outcomes; HAQ-DI = health assessment questionnaire-disability index

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4.
STUDY DESIGN
4.1.
Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of 2 doses of sirukumab in the treatment of GCA.  The study design is 
summarized in Figure 1.  The study will be conducted in 2 distinct parts (Part A and Part 
B) and consists of the following phases:

A screening phase of up to 6 weeks in duration.

Part A: a 52-week double-blind treatment phase to establish the efficacy and 
safety of sirukumab in the treatment of GCA.

Part B: a 104-week long-term extension phase with the option to receive open-
label sirukumab (up to a 52-week duration of open-label treatment) for subjects 
with active disease at the end of Part A, subjects who have not been able to follow 
the prednisone taper during Part A, or those who newly flare during the first 52 
weeks of Part B.

An up to 16-week follow-up phase to ensure that all subjects are evaluated for 
safety at least 16 weeks after receiving the last dose of study drug. This will apply 
to subjects who are withdrawn prematurely from the study or whose open-label 
treatment with sirukumab in Part B will complete after Week 88. The duration of 
the follow-up may vary depending on the time point when the last dose of study 
drug is taken. Only subjects who complete their sirukumab treatment at Week 104 
will require the full 16-week follow-up period.
The maximum duration of subject participation (including screening) is 178 weeks. 
Completion of Part A is defined as completion of the 52 weeks of double-blind treatment. 
Completion of Part B is defined as completion of the 104 weeks of the extension phase. 
Completion of the study is defined as completion of both Parts A and B of the study 
and/or completion of the up to 16-week follow-up phase if applicable.

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Figure 1
Study Design
Placebo
Placebo
Screening
Double-Blind Randomized Treatment (Part A)
52 Weeks
Extension (Part B)
104 Weeks
Sirukumab 100 mg Q2W
Sirukumab 50 mg Q4W
Prednisone
N=51
N=34
N=34
Remission at 52 weeks
Follow-up off drug
Long-term follow-up 
for flare/relapse
Disease activity or flare
Option for 
open-label 
sirukumab
100mg 
Q2W in 1st
52 weeks 
Corticosteroids or methotrexate **
Prednisone taper according to regimen*
*Rescue corticosteroid permitted, without requirement to withdraw
**Optional as needed (investigator determination)
6 months
12 months
Prednisone
Treatment Arm A
Treatment Arm B
Treatment Arm C
Treatment Arm D
Baseline
Prednisone
Prednisone
Sirukumab 100 mg Q2W
Prednisone
N=34
Total N=204
Treatment Arm E
N=51
Prednisone
This study will be conducted globally in sites selected to reflect the epidemiology of 
GCA.
The study population will be comprised of approximately 204 subjects with a diagnosis 
of GCA based on the Revised GCA Diagnosis Criteria. Both new onset (diagnosis within 
6 weeks of baseline) and relapsing/refractory (established diagnosis greater than 6 weeks 
prior to baseline with disease activity within 6 weeks of baseline) GCA subjects will be 
eligible. 
Eligible subjects will be required to have active disease within 6 weeks prior to the 
Randomization (Baseline) visit. Active disease is defined as the presence of unequivocal 
clinical signs and symptoms attributable to GCA and an ESR ≥30 mm/hr and/or serum 
CRP ≥1 mg/dL (10 mg/L). Signs and symptoms of GCA may include new onset 
headache; jaw claudication (jaw or mouth pain upon chewing); visual signs and 
symptoms including but not limited to amaurosis fugax, transient or episodic blurry 
vision, diplopia, permanent vision loss due to acute ischemic optic neuropathy (AION); 
temporal artery tenderness; scalp tenderness; reduced or absent pulsation in temporal 
artery; cord-like thickening of temporal artery; stroke; scalp necrosis; pain over 
face/scalp arteries; new or worsened extremity claudication; fever of unknown origin; 
PMR symptoms; or other symptoms that in the investigator’s experience are associated 
with GCA.

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All subjects will be receiving background prednisone therapy. Subjects with 
relapsing/refractory GCA will have active disease despite previous or concurrent steroid 
therapy. Prednisone treatment must be initiated at Screening for subjects not currently 
receiving steroid treatment. An increase in prednisone dose may be required for some 
subjects currently receiving therapy to stabilize their disease activity prior to 
randomization. Investigators may consider if higher doses of prednisone are warranted 
for subjects with visual manifestations. The prednisone dose for all subjects at Screening 
will be determined by the Investigator and may be adjusted in an open manner based on 
the subject’s disease status per investigator discretion.  At Baseline (Randomization), 
doses must be within 20-60 mg prednisone for the starting dose when the pre-specified 
prednisone taper is initiated.  Subjects will remain on the prednisone dose they are 
receiving at Baseline for one week and then will decrease the dose at Week 1 as specified 
in the taper regimen.  Subjects will follow the open-label prednisone taper regimen until 
they reach a 20 mg dose of prednisone, when the blinded prednisone taper regimen 
begins. Subjects receiving a 20 mg prednisone dose at Baseline will continue the 20 mg 
dose for one week and at Week 1 will initiate the blinded taper.
Following the Screening period, eligible subjects will be randomized to receive 
sirukumab (100 mg SC q2w or 50 mg SC q4w) or matching placebo. All subjects will 
receive prednisone during the 52-week double-blind treatment period according to a pre-
specified taper regimen. Randomization will be stratified by baseline oral prednisone 
dose (<30 mg/day or ≥ 30 mg/day).  The number of relapsing/refractory subjects will be 
capped at approximately 50% to ensure that a sufficient number of subjects with new 
onset disease are recruited.
An Independent Data Monitoring Committee (IDMC) will be utilized to ensure external 
objective medical and/or statistical review of safety issues in order to protect the ethical 
and safety interests of subjects and to protect the scientific validity of the study. The 
composition, remit, and procedures of the committee are provided in the IDMC charter.
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). The operations, processes, and definitions to be employed by the committee will 
be defined in the CEC charter.
Three primary database locks (DBLs) are planned for reporting of the results:

The first DBL for the primary analysis will occur after all subjects have 
completed the Week 52 visit assessments in Part A or have withdrawn 
prematurely from the study. Treatment-level data will be unblinded to Sponsor 
personnel.

The second DBL for the 6-month follow-up will occur after all subjects have 
completed the Week 24 visit in Part B, or have withdrawn prematurely from the 
study. The data from subjects undergoing the 16-week follow-up assessments at 
the end of Part A will also be included and will potentially comprise a separate 
data set/report if applicable.

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
The third planned DBL will occur after all subjects have completed the last visit 
in Part B, or have withdrawn prematurely from the study. The Part B DBL will 
include the data from all visits associated with Part B of the study, including the 
16-week follow-up assessments of Part B if applicable.
The utility of US in monitoring disease activity in GCA will be explored in a cohort of 
subjects from select centers who have qualified as US imaging centers. Longitudinal 
changes in vascular inflammation of the temporal and axillary arteries will be assessed 
and changes will also be correlated with clinical markers. Additional details on the 
exploratory US imaging cohort are contained in Section 7.9 and Appendix 8.
4.2.
Treatment Arms and Duration
4.2.1.
Part A: 52-week double-blind treatment phase
Following the Screening period, eligible subjects will be randomized at Baseline into Part 
A in a ratio of 3:3:2:2:2 to one of five treatment arms:
1. Treatment Arm A: Sirukumab 100 mg SC q2w for 52 weeks plus a pre-specified 
maximum of 6-month prednisone taper regimen(n=51)
2. Treatment Arm B: Sirukumab 100 mg SC q2w for 52 weeks plus a pre-specified 
maximum of 3-month prednisone taper regimen (n=51)
3. Treatment Arm C: Sirukumab 50 mg SC q4w for 52-weeks plus a pre-specified 
maximum of 6-month prednisone taper regimen (n=34)
4. Treatment Arm D: Placebo SC q2w for 52 weeks plus a pre-specified maximum 
of 6-month prednisone taper regimen (n=34)
5. Treatment Arm E: Placebo SC q2w for 52 weeks plus a pre-specified maximum 
of 12-month prednisone taper regimen (n=34).
All subjects must be receiving prednisone (a minimum dose of 20 mg/day) at the start of 
Screening. Prednisone treatment must be initiated at Screening for subjects not currently 
receiving steroid treatment. The prednisone tapering schedule (summarized in Section 
6.3) will be initiated at randomization for all subjects. Subjects should remain on the 
prednisone dose they are currently receiving at Baseline (randomization) for one week. 
At Week 1, the prednisone dose should be decreased in accordance with the pre-specified 
prednisone taper schedule.  The pre-specified maximum tapering schedule to be 
followed will depend on the subject’s treatment group assignment. The standardized
prednisone taper regimen will be unblinded (open-label) with identical weekly decreases 
in dose according to the starting dose for all subjects, until subjects reach a dose of 20 
mg/day. Thereafter, prednisone dosing will be blinded to allow for the pre-specified 
differences in duration of the prednisone tapering. Subjects who are receiving a 
prednisone dose of open-label 20 mg/day at randomization should continue taking the 20 
mg daily dose for one week. At Week 1, these subjects will initiate the blinded taper 
regimen.

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Subjects unable to follow the prednisone taper due to disease flare, adrenal insufficiency 
or safety reasons will cease the blinded prednisone treatment, and will be offered 
treatment with an investigator-defined open-label corticosteroid rescue regimen in 
combination with double-blind injections of sirukumab or placebo for the full 52 weeks, 
without requirement to withdraw from the study. This study has been designed to allow 
subjects who are unable to follow the prednisone taper to continue in the study and 
follow the assessments at each visit as specified in the protocol.
4.2.2.
Part B: 104-week extension phase
All subjects who complete Part A of the study will be eligible to enter part B. The two 
populations of subjects expected to enter into Part B are:

Subjects in remission at the primary 52-week endpoint. These subjects will 
discontinue blinded study drug treatment on entry into Part B and will be followed 
for maintenance of response. However, in the event of a flare, they will have the 
option to receive, at the discretion of their Investigator, open-label sirukumab 100 
mg SC q2w for a maximum of 52 weeks during the first 52 weeks of Part B. 

Subjects not in remission, at the primary 52-week endpoint or subjects who have 
not been able to taper prednisone during Part A. Upon entry into Part B, these 
subjects will have the option to receive, at the discretion of the Investigator, open-
label sirukumab 100 mg SC q2w for a maximum of 52 weeks.
For subjects who newly flare at any time during the 1st 52 weeks of Part B and require a 
treatment change, open-label sirukumab 100 mg SC q2w can be initiated within the first 
52 weeks of Part B. The duration of treatment will be at the discretion of the investigator 
but must not exceed 52 weeks. Treatment with open-label sirukumab 100 mg SC q2w 
must complete by Week 104 (the end of the extension phase). Corticosteroid use or the 
initiation of methotrexate therapy alone or in addition to sirukumab treatment during Part 
B will be at the discretion of the investigator.
Treatment with open-label sirukumab 100 mg SC q2w must complete by Week 104 (the 
end of the extension phase). Adjustments in corticosteroid dose or the initiation of 
methotrexate therapy alone or in addition to sirukumab treatment during Part B will be at 
the discretion of the investigator. 
Investigators should carefully consider the individual benefit-risk of continuing 
sirukumab in those subjects that continue to experience flares or persistent disease 
activity following the start of open label treatment.
Upon study completion, decisions on treatment options for individual subjects will be at 
the discretion of the investigator.

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4.3.
Type and Number of Subjects
Approximately 204 subjects with a diagnosis of GCA based on the Revised GCA 
Diagnosis Criteria will be randomized at Baseline into the 52-week double-blind, placebo 
controlled phase (Part A) of the study. Eligible subjects will include both GCA patients 
with new onset disease (diagnosis within 6 weeks of baseline) and relapsing/refractory 
(established diagnosis greater than 6 weeks prior to baseline with disease activity within 
6 weeks of baseline). Relapsing/refractory subjects include those who may have 
previously been in remission with corticosteroid treatment and have recurrence of disease 
activity (relapsing) or subjects who continued to have active disease without remission 
despite previous or ongoing corticosteroid therapy. 
The number of relapsing/refractory subjects will be capped at approximately 50% to 
ensure that a sufficient number of subjects with new onset disease are recruited.
4.4.
Design Justification
There have been limited controlled studies conducted to evaluate therapies for GCA and 
no successful regulatory precedent for biologic treatment of GCA. The design of this 
study is similar to the ongoing Phase III study with tocilizumab in GCA subjects 
[Unizony, 2013].
High dose corticosteroid therapy represents the current standard of care in the treatment 
of GCA, providing the justification for the selection of the control arm of placebo plus 
prednisone taper.
Subjects may enter the study on a range of corticosteroid doses (between 20-60 mg daily 
dose prednisone) depending on investigator assessment of the severity of clinical 
symptoms and whether they are new onset or relapsing/refractory subjects (20 – 60 
mg/day). A pre-specified taper will be followed for up to 3, 6 and 12 months. 
Two different prednisone tapering arms (Treatment Arms A/C and B) in combination 
with sirukumab have been included to assess whether a more rapid taper (3 month, 
Treatment Arm B) has the potential to lead to high sustained remission rates in 
combination with sirukumab, even further reducing the adverse effects of corticosteroids. 
Two different placebo arms have been included to provide comparisons for maximum 
standardized tapers of 6 (Treatment Arm D) and 12 months (Treatment Arm E), reflective 
of tapering schedules used in clinical practice.
The 52-week duration of Part A was selected as a time period which would be adequate 
to evaluate sustained remission.
Part B of the study was designed to determine the long-term maintenance of remission 
and safety following cessation of sirukumab treatment, to explore potential requirement 
for additional sirukumab therapy beyond 52 weeks, and to assess the long-term 
corticosteroid use and associated toxicities.

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Since there is not yet robust evidence of efficacy for sirukumab, or other anti-IL-6 
treatments, in GCA, an interim analysis to assess for futility may be included, such that 
the study can be terminated early if there is no evidence of efficacy.
4.5.
Dose Justification
Two doses of sirukumab (100 mg SC q2w and 50 mg SC q4w) were selected based on 
doses which have demonstrated efficacy in a Phase II study of rheumatoid arthritis 
subjects and are presently under investigation in Phase III studies for the treatment of 
moderate to severe rheumatoid arthritis.  The 100 mg SC q2w dose of sirukumab has 
shown numerical superiority at 24 weeks in some efficacy endpoints (ACR20, change in 
disease activity score) over other sirukumab doses tested in the Phase II study, and may 
be more likely to provide a clinically meaningful response in an IL-6 mediated disease 
such as GCA.  The 50 mg q4w dose of sirukumab will also be evaluated to more fully 
characterize the benefit-to-risk profile of sirukumab in GCA.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
sirukumab can be found in the Investigator’s Brochure.  The following section outlines 
the risk assessment and mitigation strategy for this protocol:  

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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [sirukumab]
TB reactivation
Cases of TB reactivation have been reported 
with IL-6 antagonists, such as tocilizumab and 
sirukumab.
Inclusion only of subjects with no evidence of 
active or latent TB infection, negative diagnostic 
TB test at Screening and Screening chest 
radiograph showing no evidence of current or 
previous pulmonary TB (Section 5.1 Bullet 4).
Evaluation of TB throughout the study by use of 
a TB questionnaire and a TB test (Section 7.5.7)
Serious/opportunistic infections
IL-6 deficient mice have been noted to be 
susceptible to infections with Listeria, 
monosytogenes, Toxoplasma gondii, and 
Candida albicans [Dalrymple, 1995; Romani, 
1996; Suzuki, 1997]. Serious, life-threatening 
infections such as septic shock, some of which 
have been fatal, have occurred in subjects 
receiving sirukumab.
Exclusion of subjects with an active current or 
history of recurrent bacterial, viral, fungal, 
mycobacterial, or other infection or those with a 
prior episode of major infection (serious 
infectious event).
Monitoring of serious and opportunistic infections 
by IDMC.
Hypersensitivity
Serious allergic reactions (eg, anaphylaxis) have 
been reported with the administration of mAbs, 
including sirukumab, and may occur during or 
after the administration of the mAbs.
Exclusion of subjects with severe allergic 
reactions to monoclonal antibodies, human 
proteins, or excipients. Subjects will be made 
aware of the potential risk, the signs and 
symptoms of such reactions, and the importance 
of immediately seeking medical attention.
Discontinuation of blinded subcutaneous study 
drug in the event of a severe allergic reaction. 
Monitoring of serious allergic reactions by IDMC; 
adjudication and classification of these events 
using Sampson criteria (Sampson, 2006) by 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
sponsor safety review team will be implemented.
Gastrointestinal perforation
Upper and lower GI tract perforations occurred in 
the anti-IL-6 receptor (tocilizumab) & the anti-IL6 
(sirukumab) Phase III programs. Sirukumab 
binds to IL-6 and prevents binding to IL-6 
receptor (IL-6R). Tocilizumab binds to IL-6 R to 
prevent IL-6 signalling. Potential differences in 
safety between agents that bind to the IL-6 
receptor versus ones that bind to the IL-6 ligand 
(sirukumab) warrants further study.
Exclusion of subjects with a history of 
diverticulitis, inflammatory bowel disease, or 
other symptomatic GI tract condition that might 
predispose to bowel perforation.
Investigators should closely monitor for GI 
perforations with a high degree of suspicion. 
Monitoring of gastrointestinal perforations by 
IDMC.
Cytopenias
Neutropenia  and  thrombocytopenia  have  
occurred  in  sirukumab  studies,  including  
severe thrombocytopenia associated with  
bleeding. Most patients who  developed 
neutropenia while being treated with sirukumab 
did not develop infections, and most
patients who  developed  thrombocytopenia  did  
not  experience  bleeding  events.  
Decreases in platelet counts have also been 
observed.
Exclusion of subjects with absolute neutrophil 
count (ANC) <2x109/L, platelet count 
<140x109/L, WBC count <3.5x109/L, ALC <0.5 
x109/L.
Discontinuation of blinded subcutaneous study 
drug for subjects with 2 confirmed consecutive 
absolute neutrophil counts of <0.5 × 109 cells/L 
or platelet counts <50 x 109 cells/L.
Monitoring of cytopenias by IDMC.
Lipid increases
Increases in blood total cholesterol, LDL, HDL, 
and triglycerides have occurred in sirukumab-
treated subjects. No dose response was 
observed.
Monitor HDL/LDL levels, administer a cholesterol 
lowering agent if indicated.
Liver enzyme increases
Transient asymptomatic increases (1 to 3 x ULN, 
sometimes > 5 x ULN but < 8 x ULN) in blood 
ALT and AST values have been observed in 
subjects in completed and ongoing studies of 
sirukumab. Six subjects have had ALT or AST >3 
x ULN and bilirubin >2 x ULN; all 6 had received 
Exclusion of subjects with AST or ALT >2.0 x 
ULN, or total bilirubin >ULN with the exception of 
Gilbert’s disease. Inclusion of pre-defined liver 
chemistry discontinuation criteria (Section 5.4.3). 
Monitoring of hepatic abnormalities by IDMC.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
sirukumab 100 mg SC q2w. Three subjects had 
concurrent biliary stones/colic, and 1 subject was 
concomitantly taking isoniazid. The hepatobiliary 
laboratory values normalized after surgery or 
discontinuation of isoniazid in these subjects. A 
fifth subject with long-standing methotrexate use, 
who had pre-existing fatty liver disease, 
developed hyperbilirubinemia (>9 x ULN) and 
jaundice, as well as elevations in AST (>5 x 
ULN), after 2 doses of sirukumab 100 mg. A liver 
biopsy revealed active steatohepatitis. After 
discontinuation of methotrexate and sirukumab, 
the hepatobiliary tests improved such that 9 
months later AST was 1-1.5 x ULN, and ALT and 
bilirubin were normal. A sixth subject initially was 
observed to have ALT and AST >5 x ULN which 
both increased 2 weeks later to >20 x ULN with 
bilirubin > 2 x ULN. Notable findings at that time 
were hepatitis E virus IgM positivity and chronic 
liver changes by ultrasound.  Hepatobiliary 
abnormalities had resolved 16 weeks after 
discontinuation of study agent.
Cardiovascular events
No cardiovascular risk with sirukumab has been 
identified in clinical studies to date. Most subjects 
who experienced cardiovascular events in the 
sirukumab RA Phase 3 program had pre-existing 
risk factors as well as active RA. There was no 
association between grade 3 or 4 lipid levels and 
the development of MACE in the majority of 
subjects in the sirukumab Phase 3 RA program. 
Exclusion of subjects with uncontrolled 
cardiovascular disease or marked baseline 
prolongation of QTc interval > 480 msec (QTcB 
or QTcF) or QTc > 500 msec in subjects with 
Bundle Branch Block, history of Torsade de 
Pointes, family history of long QT syndrome, 
history of second or third degree heart block or 
subject with major ischemic event unrelated to 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Overall, the data do not support a direct link 
between sirukumab-induced elevations in lipid 
levels and MACE. However, this study 
population is at high risk for CV disease.
GCA. Inclusion of pre-defined QTc 
discontinuation criteria (Section 5.4.4). 
Monitoring of CV events by CEC and IDMC
Malignancies
The impact of treatment with tocilizumab on the 
development of malignancies is not known, but 
malignancies were observed in clinical studies. 
As an IL-6 inhibitor, sirukumab may have some 
effect on the risk of malignancy by affecting 
immune surveillance. Malignancies have been 
reported with sirukumab in rheumatoid arthritis 
(RA) clinical trials.
Exclusion of subjects with active malignancy or 
history of malignancy within previous 5 years 
(except basal and squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix uteri 
that has been excised and cured). Monitoring of 
malignancies by IDMC.
Study Procedures
Blood draws for safety and biomarker 
assessments
Fainting, mild pain, bruising, irritation or redness 
at the site are associated with blood draws.
Experienced site staff will follow standard 
approaches for managing events related to blood 
draws.
Use of auto-injector
Mild pain, bruising, irritation or redness at the 
injection site may be experienced by some 
patients.
Site staff will be trained and will ensure training 
and oversight of subjects’ capabilities to use the 
auto-injector.
Rapid steroid taper
Steroid withdrawal symptoms and side effects
Inclusion only of subjects with stable disease 
who are able to safely participate in the steroid 
taper. Subjects should have clinically stable 
disease on steroid therapy prior to 
randomization. IDMC will monitor all subjects 
including those in the 3 month taper.

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4.6.2.
Benefit Assessment
The efficacy of sirukumab in subjects with GCA has yet to be established, but available 
evidence suggests that inhibition of IL-6 activity may be of therapeutic benefit in the 
treatment of GCA by interruption of multiple pathogenic pathways. IL-6 inhibition 
results in improvements in patients with active arthritis and biologic agents targeting the 
IL-6 cytokine ligand have been shown to be efficacious in RA. Corticosteroids are the 
treatment of choice but are associated with serious side effects with disease relapse 
common during the prednisone taper. This study, if successful, will deliver a new therapy 
for GCA where there remains a clear and significant unmet medical need.
In addition to receiving treatment with prednisone, subjects may be randomized to active 
treatment with sirukumab that may have clinical utility in the treatment of their GCA. 
Subjects randomized to placebo will still receive the treatment of choice (corticosteroids) 
for their GCA disease.  All subjects will receive a high standard of care throughout the 
study and will benefit from physical examinations with frequent monitoring of vital 
signs, electrocardiograms, and blood tests. A chest radiograph will also be performed at 
Screening. 
4.6.3.
Overall Benefit:Risk Conclusion
Although the efficacy of sirukumab in subjects with GCA has yet to be established, it has 
been shown to be effective in Phase III studies in RA. Furthermore other agents that 
inhibit IL-6 activity have been shown to be efficacious in RA. All subjects will receive 
therapy with corticosteroids and will receive a high standard of care for their disease 
during this study.
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with sirukumab are justified by the 
anticipated benefits that may be afforded to subjects with GCA. If sirukumab is able to 
sustain a corticosteroid free remission this would significantly reduce the burden of 
corticosteroid toxicity that is common in the long term treatment of GCA.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s).
Deviations from 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.

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5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Diagnosis of GCA defined by the following Revised GCA Diagnosis Criteria:

Age ≥50 years.

History of ESR ≥ 50 mm/hour or CRP ≥ 2.45 mg/dL.

Presence of at least one of the following:

Unequivocal cranial symptoms of GCA (new onset localized headache, scalp 
or temporal artery tenderness, ischemia-related vision loss, or otherwise 
unexplained mouth or jaw pain upon mastication).

Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain 
associated with inflammatory stiffness.

Presence of at least one of the following:

Temporal artery abnormality on biopsy revealing features of GCA.

Evidence of large-vessel vasculitis by angiography or cross-sectional 
imaging, including but not limited to magnetic resonance angiography 
(MRA), computed tomography angiography (CTA), ultrasound (US) or 
positron emission tomography-computed tomography (PET-CT).

Evidence of temporal artery vasculitis on US (for US imaging qualified 
centers only).
2. Active GCA within 6 weeks of Randomization (Baseline) where active disease is 
defined by an ESR  30 mm/hr or CRP 1 mg/dL (10 mg/L) AND the presence 
of at least one of the following:

Unequivocal cranial signs and symptoms of GCA (new onset localized headache, 
scalp or temporal artery tenderness, reduced or absent pulsation in temporal 
artery, cord-like thickening of temporal artery, stroke, scalp necrosis, pain over 
face/scalp arteries or otherwise unexplained mouth or jaw pain upon mastication 
[i.e., jaw claudication]).

Visual signs and symptoms associated with GCA, including ischemia-related 
vision loss [permanent vision loss due to AION, amaurosis fugax, episodic blurry 
vision], diplopia, scotoma, nerve palsies, relative afferent papillary defects, central 
retinal artery occlusions. 

Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain 
associated with inflammatory stiffness.

Other features judged by the clinician investigator to be consistent with GCA or 
PMR flares (i.e., new or worsened extremity claudication, unexplained systemic 
symptoms such as fever of unknown origin, weight loss and night sweats). 

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3. At screening, receiving prednisone treatment with a minimum dose of 20 mg /day 
for the treatment of active GCA. Subjects not currently receiving prednisone 
treatment must commence dosing (minimum 20 mg/day of prednisone) at the 
screening visit.
4. Clinically stable GCA disease at baseline such that the subject is able to safely 
participate in the blinded prednisone taper regimen in the opinion of the 
investigator.
5. Practicing acceptable methods of birth control as follows:
Males:
Male subjects with female partners of child bearing potential must comply with 
the following contraception requirements from the time of first dose of study 
medication until 4 months after the last dose of study medication:
a.
Vasectomy with documentation of azoospermia.  
b.
Male condom plus female partner use of one of the GSK Modified List of 
Highly Effective Methods for Avoiding Pregnancy in Females of 
Childbearing potential listed in Appendix 2.
Male subjects should also not donate sperm from the time of first dose of study 
medication until 4 months after the last dose of study medication.
Females:
Female subjects of child-bearing potential must use of one of the GSK Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Childbearing potential listed in Appendix 2.
6. No evidence of active or latent infection with Mycobacterium tuberculosis (TB), 
as defined by all of the following:
a.
No history of active or latent TB infection.
b. A negative diagnostic TB test at Screening defined as a negative 
QuantiFERON Gold test (NB: 2 successive indeterminate QuantiFERON tests 
will be considered as a positive result). In cases where an initial indeterminate 
QuantiFERON test result may be related to sample processing issues, the
second QuantiFERON test may be performed at either the local laboratory or 
the central laboratory at the discretion of the investigator. Re-testing is only 
permitted for indeterminate results. If the re-test also produces an 
indeterminate result, further re-testing to determine study eligibility is not 
permitted either at the local or central laboratory.
c.
Chest radiograph (both posterior-anterior and lateral views unless local 
guidelines recommend only a single view), taken within 12 weeks prior to 
baseline or at Screening, and read locally by a qualified radiologist, with no 
evidence of current active or previous inactive pulmonary tuberculosis.
NB: If there has been recent close contact with persons who have active TB prior to 
study enrolment the subject will be referred to a TB physician to undergo additional 
evaluation.

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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Are pregnant or breastfeeding.
2.
Recent (within the past 12 weeks) or planned major surgery that would impact on 
study procedures or assessments.
3.
Organ transplantation recipients (except corneas within 3 months prior to baseline 
visit).
4.
Had prior treatment with any of the following:

Systemic immunosuppressives, including azathioprine, oral cyclosporine A, 
tacrolimus, mycophenolate mofetil, leflunomide, oral or parenteral gold, and IL-
1ra (anakinra) within 4 weeks of baseline. 

Biologic agents targeted at reducing TNF(including but not limited to 
infliximab, golimumab, certolizumab pegol, etanercept, yisaipu, and adalimumab) 
within 4-8 weeks of baseline, depending on the agent *.

Anti-IL-6 (tocilizumab or any other anti-IL-6 agent) if:

Used within 8 weeks of randomization

Associated with a history of intolerance that precluded further treatment

Associated with an inadequate response to 3 months of therapy

B-cell depleting agents (eg, rituximab) within 12 months prior to baseline or 
longer if B cell counts have not returned to normal range or baseline levels.

Cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or 
other alkylating agents within 4 weeks of baseline.

Abatacept within 8 weeks of baseline.

Tofacitinib within 4 weeks of baseline.

Methotrexate use within 2 weeks of baseline.

Methylprednisolone > 100 mg/day IV (or equivalent) within 8 weeks of baseline.
5.
Regular or continuous systemic corticosteroid use for > 4 years.
6.
Requires continued or repeated use of systemic corticosteroids for conditions other 
than GCA or PMR symptoms associated with GCA.
7.
History of severe allergic reactions to monoclonal antibodies, human proteins, or 
excipients.
8.
Evidence of serious concomitant disease, which in the opinion of the investigator 
makes them unsuitable for participation in the study.
9.
Major ischemic event, unrelated to giant cell arteritis, within 12 weeks of screening.

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10. Marked baseline prolongation of QTc interval > 480 msec (QTcB or QTcF) or QTc 
> 500 msec in subjects with Bundle Branch Block**, history of Torsade de Pointes, 
family history of long QT syndrome, history of second or third degree heart block. 
11. Current liver disease that could interfere with the trial as determined by the physician 
investigator.
12. History of or current active diverticulitis, inflammatory bowel disease, or other 
symptomatic GI tract condition that might predispose to bowel perforation.
13. History of known demyelinating diseases such as multiple sclerosis or optic neuritis.
14. Active infections, or history of recurrent infections or have required management of 
acute or chronic infections, as follows:

Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria,

History or suspicion of chronic infection (e.g joint infection).
OR

Hospitalization for treatment of infection within 60 days of the baseline visit.
OR

Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals, 
or antiparasitic agents) within 60 days of baseline or oral antimicrobials within 30 
days of baseline.
15. Primary or secondary immunodeficiency.
16. HIV infection (positive serology for HIV antibody), hepatitis C (positive serology 
for hepatitis C antibody confirmed positive by hepatitis C RNA PCR which is 
reflexively performed)***.
17. Hepatitis B infection (positive test results for hepatitis B surface antigen or hepatitis 
B core antibody)***.
18. Active malignancy or history of malignancy within previous 5 years (except basal 
and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that 
has been excised and cured).
19. Laboratory abnormalities: 

AST or ALT >2.0 × upper limit of normal (ULN).

Total bilirubin >ULN with the exception of Gilbert’s disease.

Platelet count <140 × 109/L.

Hemoglobin <8.5 g/dL.

WBC count <3.5 × 109/L.

ANC <2 × 109/L.

ALC <0.5 × 109/L.

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
Serum creatinine ≥ 2.0 mg/dL (SI: positive ≥ 177 µmol/L).
20. Has received, or is expected to receive, any live virus or bacterial vaccination within 
3 months before the first administration of study drug, during the study, or within 4 
months after the last administration of study drug.
21. Any other autoimmune disease (such as SLE, RA, inflammatory arthritis, other 
vasculitides, scleroderma, polymyositis, dermatomyositis or other similar systemic 
connective tissue diseases).
22. Uncontrolled psychiatric or emotional disorder, drug abuse, alcohol abuse within 
past 3 years.
23. Current history of suicidal ideation or past history of suicide attempt.
*Please refer to Section 6.10.2 Prohibited Medications and Non-Drug Therapies for 
additional guidance.
**The QTc should be based on averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5-10 minute) recording period.
*** If seropositive, referral of the subject for consultation with a physician with expertise 
in the treatment of HIV or hepatitis B or C virus infection is recommended.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events.
Re-testing
If a subject has signed the Informed Consent Form (ICF) and failed to meet at least one 
entry criterion, the site may retest laboratory values or repeat a study entry procedure 
once only during the screening period. Laboratory parameters can only be re-tested once. 
If a different laboratory parameter is found to be out of range in the re-test, no further 
testing is allowed. Re-testing may be performed to determine eligibility within the 
screening window. Subjects that have laboratory values that do not meet the entry criteria 
following the re-test are to be deemed a screen failure. Exceptions to re-testing are chest 
radiograph and a positive result for the QuantiFERON-TB Gold test; these screening tests 
may not be repeated to meet eligibility criteria. An indeterminate result for the 
QuantiFERON-TB Gold test may be re-tested and subjects will be eligible upon a 
negative re-test result). In cases where an initial indeterminate QuantiFERON test result 
may be related to sample processing issues, the second QuantiFERON test may be 
performed at either the local laboratory or the central laboratory at the discretion of the 
investigator. Re-testing is only permitted for indeterminate results. If the re-test also 

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produces an indeterminate result, further re-testing to determine study eligibility is not 
permitted either at the local or central laboratory.
Re-screening
If a subject is a screen failure but at some point in the future is expected to meet the 
subject eligibility criteria, the subject may be re-screened on only one occasion and only 
after consultation with the Sponsor or Sponsor designee. Subjects who are re-screened
will be assigned a new subject number, undergo the informed consent process, and then 
restart a new screening phase.
5.4.
Withdrawal/Stopping Criteria
5.4.1.
Study Withdrawal
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. Subjects may also be withdrawn from the study for any of the following 
reasons:

Investigator discretion

Sponsor request

Use of a new investigational drug

Protocol violation

Subject lost to follow-up

Subject withdraws consent
It should be noted that there is no requirement to withdraw a subject from the study for 
lack of efficacy. This study is designed to follow subjects over the long-term, irrespective 
of requirement for rescue treatment or withdrawal of study drug. The investigator should 
make every reasonable attempt to enable the subject to continue participation in the study 
and present for visits as scheduled. The investigator should offer treatment with an 
investigator-defined open-label corticosteroid rescue regimen in combination with 
double-blind injections of study drug (sirukumab or placebo) for the remainder of the 52 
week double-blind treatment period. Methotrexate treatment may also be initiated as part 
of the rescue regimen at the discretion of the investigator.
The reason for a subject not completing the study will be recorded in the Early 
Withdrawal Case Report Form (CRF). In the event that a subject withdraws consent to 
participate further in the study, the investigator must make every reasonable attempt to 
document the reason for withdrawal of consent in the CRF.

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The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
Subjects who are withdrawn prematurely from the study should attend the Early 
Withdrawal visit and should also undergo a 16-week Follow-up period for the evaluation 
of safety. The assessments to be performed at the Early Withdrawal and Follow-up visits 
are detailed in Section 7.1, Time and Events Tables.
Subjects withdrawn prematurely from the study will not be replaced.
5.4.2.
Discontinuation of Study Drug
Permanent discontinuation of study drug will not require the subject to be withdrawn 
from the study. Subjects should continue where possible to be followed and disease status 
assessed. Upon permanent discontinuation of subcutaneously-administered blinded
sirukumab or matching placebo, corticosteroid dose and treatment will be at the 
discretion of the investigator.
Study drug (subcutaneously-administered blinded sirukumab or matching placebo) must
be permanently discontinued for any of the following:
1.
The investigator (in consultation with the medical monitor) believes that for safety 
reasons (e.g., adverse event) it is in the best interest of the subject to stop treatment.
2.
Severe allergic reaction or anaphylactic reaction resulting in bronchospasm with 
wheezing, or dyspnea requiring ventilatory support, or symptomatic hypotension 
with a > 40 mmHg decrease in systolic blood pressure that occurs following study 
drug administration.
3.
Reaction suggestive of serum sickness occurring 1-14 days after study drug
administration.  These may be manifested by symptoms of myalgias, arthralgias, 
fever, rash, pruritus, facial, hand, or lip edema, dysphagia, urticaria, sore throat, 
and/or headache.

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4.
Adverse events (AEs) or laboratory abnormalities indicative of safety concerns 
which are significant enough to discontinue study drug in the opinion of the 
investigator.
5.
Pregnancy.
6.
Liver function abnormalities as specified in Section 5.4.3.
7.
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).
8.
Active or latent TB.
9.
Malignancy, excluding nonmelanoma skin cancer.
10. Demyelination, either central or peripheral.
11. Two confirmed consecutive absolute neutrophil counts of <0.5 × 109 cells/L.
12. Two confirmed consecutive platelet counts <50 x 109 cells/L.
13. Acute diverticulitis requiring antibiotic treatment.
14. Gastrointestinal perforation.
Subjects must not receive blinded subcutaneous sirukumab or matching placebo during 
the course of a serious infection. Subjects who temporarily discontinue blinded 
sirukumab or matching placebo due to an infection or other reasons should continue to 
follow the prednisone taper schedule.
Discontinuation of blinded subcutaneous sirukumab or matching placebo must be 
strongly considered for subjects who develop a serious infection such as sepsis or 
meningoencephalitis, and considered for subjects who have serious infections requiring 
hospitalization or IV antibiotic therapy.
Discontinuation of blinded subcutaneous sirukumab or matching placebo should also be 
considered for severe injection-site reactions.
5.4.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Subjects meeting the liver chemistry stopping and increased monitoring criteria may be 
required to temporarily or permanently discontinue study treatment.

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Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 3
Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

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Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 3
5.4.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed. 
5.4.4.
QTc Stopping Criteria
An ECG is required only at screening. If an additional ECG is performed during study 
participation outside of study requirements and any of the bulleted criteria below are met, 
study treatment should be discontinued and the Medical Monitor should be contacted. 
There is no requirement for the subject to be withdrawn from the study.
QTc Stopping Criteria:

QTc 530 msec (all subjects)
OR

Change from baseline of QTc > 60 msec.
The same QT correction formula must be used for each individual subject to determine 
eligibility for and discontinuation from the study.  This formula may not be changed or 
substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception.  

The QTc should be based on averaged QTc values of triplicate ECGs obtained 
over a brief (e.g., 5-10 minute) recording period.
5.5.
Subject and Study Completion
A completed subject is one who has completed both Part A and Part B (and the maximum 
of a 16-week follow-up upon completion of Part B, if applicable) of the study. As 
discussed in Section 4.1, the up to 16-week follow-up visit is only for subjects who are 
withdrawn prematurely from the study or for those subjects in Part B of the study who 
complete open-label treatment with sirukumab 100 mg SC q2w after Week 88.
The end of the study is defined as the last subject’s last visit.

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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments. Study treatment specifically related to sirukumab and matching placebo is 
distinguished by the use of the terminology “subcutaneously-administered blinded study 
drug or treatment (sirukumab and matching placebo)”. 
Sirukumab and matching placebo will be supplied by the Sponsor. Both sirukumab and 
matching placebo will be administered subcutaneously using an autoinjector device. The 
sirukumab drug product provided for this study is supplied in a 1 mL Pre-filled Syringe
(PFS) fitted with a spring-powered, disposable autoinjector device for single use SC 
administration of liquid biologic drug products (SmartJect Autoinjector) that is 
permanently assembled on the syringe.  The sirukumab PFS is aseptically filled to deliver 
a dose of either 100 mg/1.0 mL or 50 mg/1.0 mL of sirukumab in a Becton-Dickinson 
(BD) Hypak, 1 mL glass SCF (presiliconized) syringe barrel with a 26 gauge (G) ½ inch 
fixed needle, an elastomeric needle shield, and a fluoropolymer coated elastomeric 
plunger stopper. Placebo for sirukumab PFS provided for this study is supplied in a 
matching presentation.
However, as a contingency, sirukumab may also be supplied as a single-use prefilled 
syringe-Ultrasafe (PFS-U), which is a ready to use liquid filled 1-mL-long syringe 
product supplied with a passive safety needle guard (UltraSafe Passive Delivery System, 
Safety Syringes, Inc.) for SC administration. Placebo for sirukumab PFS-U will also be 
supplied as appropriate.
The needle shield on the PFS (either assembled into UltraSafe needle guard or 
autoinjector/prefilled pen) is made with a derivative of natural rubber latex, which may cause 
allergic reactions in individuals sensitive to latex.
Prednisone for the pre-specified standard blinded taper will be provided by the Sponsor. 
The prednisone used in the blinded taper of this study is manufactured by Jubilant 
Cadista (Salisbury, MD) and supplied to the Sponsor by Myoderm (Norristown, PA).
Prednisone for the unblinded (open-label) taper will be provided by the sites or by the 
Sponsor in certain countries in order to comply with local regulations. Use of standard 
release prednisone is required for the open-label taper. Prednisone doses between 60 and 
20 mg will be administered during the unblinded (open label) taper. Subjects who reach 
20 mg will receive the blinded prednisone from that visit. Prednisone doses below 20 mg 
and/or matching placebo will be provided in blister packs for blinded administration.
Subjects should take their prednisone daily dose in one single daily administration in the 
morning.

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Study Treatment
Product name:
Sirukumab
Placebo
Prednisone/
prednisone 
placebo
Dosage form:
1.0 mL Pre-filled syringe
1.0 mL Pre-filled 
syringe
Tablets
Unit dose 
strength(s)/Dosage 
level(s):
100 mg/mL or
50 mg/mL
--
Up to-60 
mg/day
Route of Administration
SC
SC
Oral
Dosing instructions:
SC q2w (treatment arms A & B) 
SC q4w (treatment arm C)
SC q2w 
(treatment arms 
D & E)
20-60 mg/day 
open-label then 
0-18 mg/day 
taper (blinded)
Note subjects randomized to treatment arm C will alternate between sirukumab 50 mg SC and matching placebo SC 
injections in order to maintain the blind (see Section 6.4).
Instructions for use of the SmartJect autoinjector will be provided to subjects and to the 
sites. Each step in the instructions is essential to ensure a successful delivery of study 
drug. It is important that the autoinjector is held against the skin at the injection site with 
sufficient force to disengage the safety interlock and make the push button actuatable, the 
actuation button is pressed to begin the injection cycle, and the autoinjector remains in 
place until the complete dose is delivered (second audible click or 15 seconds).
The investigator and designated site staff will be trained in the use of the SmartJect 
autoinjector for the SC administration of study drug. The trained site staff will be 
responsible for training each individual subject in the proper use of the SmartJect 
autoinjector.  The study drug will be administered by the trained site staff during site 
visits until the subject is trained and confident in the use of the SmartJect auto-injector to 
self-administer study drug at home. If necessary a family member or carer will be trained 
in the use of the SmartJect autoinjector in order to administer the injection to the subject.
Study drug will be administered by the trained site staff at the Baseline and Week 2 
visits. At the Week 4 visit, subjects will self-administer study drug at the site under the 
supervision of the trained site staff unless they are unable or unwilling to do so. In this 
case, study drug will be administered by the trained site staff.
At the relevant site visits, study drug must be withheld until all patient reported outcomes 
(PROs) questionnaires have been completed and blood samples taken for 
pharmacokinetic (PK) analysis of sirukumab serum concentrations (in order to collect a 
pre-dose sample). The visits scheduled for PRO and PK analyses are provided in Section 
7.1, Time and Events Tables.
Once these assessments are completed, subjects will self-administer study drug at the site 
or may have study drug administered by the trained site staff. Subjects will self-
administer study drug at home in between site visits. Subjects unable or unwilling to self-
administer study drug at home may be able to attend the clinic between scheduled visits 
for study drug administration. 

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Subjects who self-administer study drug at home, should be instructed to take the study 
drug q2w but no more than 4 days from the scheduled dosing day. Administrations of 
study drug must be at least 7 days apart. Subjects will be instructed to contact the 
investigator promptly in the event of any signs of an allergic reaction, infection or 
bleeding. 
6.2.
Treatment Assignment
Central randomization will be implemented in this study.  Subjects will be assigned to 1 
of 5 treatment arms in accordance with the computer-generated randomization schedule 
generated prior to the start of the study, using validated software.  Randomization will be 
performed by an Interactive Response Technology System (IRT).  Randomization will be 
stratified by baseline oral prednisone dose (<30 mg/day or 30 mg/day. Subjects will be 
randomized in a ratio of 3:3:2:2:2 to 1 of 5 treatment arms:
1.
Treatment Arm A: Sirukumab 100 mg SC q2w for 52 weeks plus a pre-specified 
maximum of 6-month prednisone taper regimen(n=51)
2.
Treatment Arm B: Sirukumab 100 mg SC q2w for 52 weeks plus a pre-specified 
maximum of 3-month prednisone taper regimen (n=51)
3.
Treatment Arm C: Sirukumab 50 mg SC q4w for 52-weeks plus a pre-specified 
maximum of 6-month prednisone taper regimen (n=34)
4.
Treatment Arm D: Placebo SC q2w for 52 weeks plus a pre-specified maximum of 
6-month prednisone taper regimen (n=34)
5.
Treatment Arm E: Placebo SC q2w for 52 weeks plus a pre-specified maximum of 
12-month prednisone taper regimen (n=34).
Once a randomization number has been assigned to a subject, it will not be re-assigned.
6.3.
Planned Dose Adjustments
No dose adjustment of sirukumab will be allowed in this study.
All subjects must be receiving prednisone (a minimum dose of 20 mg/day) at the start of 
Screening. Prednisone treatment must be initiated at Screening for subjects not currently 
receiving steroid treatment. A pre-specified prednisone tapering schedule outlined in 
Table 1 begins for all subjects upon randomization at Baseline, (Week 0). The 
standardized prednisone taper regimen will be open-label with identical weekly decreases 
in dose according to the starting dose for all subjects, until subjects reach a dose of 20 
mg/day. Thereafter, prednisone dosing will be blinded to allow the pre-specified 
differences in tapering. 
Requirements for the prednisone taper are as follows:

Subjects will remain on the prednisone dose they are currently receiving at 
Baseline (Week 0) for one week. 

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
At Week 1, the prednisone dose will be decreased in accordance with the pre-
specified prednisone taper schedule (Table 1). 

The pre-specified maximum tapering schedule to be followed will depend on the 
subject’s treatment group assignment. 

The prednisone taper will be unblinded (open-label) and will consist of identical 
weekly decreases in dose for all subjects until a dose of 20 mg/day is reached, at 
which point the blinded portion of the prednisone tapering regimen will 
commence. 

Subjects who are receiving a prednisone dose of 20 mg/day at Baseline (Week 0) 
should continue taking the open-label 20 mg daily dose for one week. At Week 1, 
these subjects will initiate the blinded taper regimen.
Subjects unable to follow the prednisone taper due to disease flare, adrenal insufficiency 
or safety reasons will cease the blinded prednisone treatment, and will be offered 
treatment with an investigator-defined open-label corticosteroid rescue regimen in 
combination with double-blind injections of sirukumab q2w or placebo q2w for the full 
52 weeks. Subjects should continue to be followed per the protocol-specified assessments 
while receiving rescue treatment. There is no requirement for these subjects to be 
withdrawn from the study. When considering use of rescue prednisone, investigators 
should carefully assess whether the symptoms are related to an inflammatory GCA flare 
which would signify failure of tapering or is more likely due to non-inflammatory 
symptoms which could represent adrenal insufficiency or other co-morbidities.
Table 1
Prednisone Taper
3 Month
6 Month
12 Month
Open-Label Taper
60
60
60
50
50
50
40
40
40
35
35
35
30
30
30
25
25
25
20
20
20
Blinded Taper
15
15
18
10
13
17
5
12
15
3
10
15
1
9
13
0
8
10
0
7
10
0
6
10
0
6
10
0
5
9

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3 Month
6 Month
12 Month
0
5
9
0
4
9
0
4
9
0
3
8
0
3
8
0
2
8
0
2
8
0
1
7
0
1
7
0
0
7
0
0
7
0
0
6
0
0
6
0
0
6
0
0
6
0
0
5
0
0
5
0
0
5
0
0
5
0
0
4
0
0
4
0
0
4
0
0
4
0
0
3
0
0
3
0
0
3
0
0
3
0
0
2
0
0
2
0
0
2
0
0
2
0
0
1
0
0
1
0
0
1
0
0
1
*Individual subjects will be receiving differing doses of prednisone at specified time points. Therefore, the tapering 
schedule indicates the required decrease in prednisone dose on a weekly basis, with the specific week varying by 
individual subject.
6.4.
Blinding
Blinding will be maintained during the 52-week double blind treatment phase of this 
study by the provision of sirukumab and matching placebo for sirukumab in pre-filled 
syringes in a matching presentation.  Blinding to the prednisone dose during the taper 
will be maintained by providing prednisone dosages below 20 mg in numbered blister 

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packs. Depending on the subject’s assignment to either the 3, 6 or 12 month taper, the 
over-encapsulated dose may or may not contain prednisone. The blister packs contain a 
combination of over-encapsulated 10 mg, 5 mg and/or 1 mg prednisone tablets with 
cellulose filler to prevent rattling and/or placebo capsules containing only the filler. Each 
patient, regardless of treatment arm, will be provided the same number of capsules per 
day for a given week to maintain the blind.
Blinding during the q4w dosing regimen will be maintained by the provision of placebo 
for sirukumab such that subjects randomized to this arm will follow a q2w dosing 
regimen but alternate between active (starting at baseline) and placebo treatments for the 
duration of the 52 week double-blind phase.
Investigators and the Sponsor/study team will remain blinded to the results of the fasting 
lipids, CRP and ESR laboratory tests after the start of treatment. Investigators and the 
study team will have access to Screening and Baseline values, and will thereafter remain 
blinded to these results until the end of Part A.  Alerts will be provided by the central 
laboratory for abnormal, clinically significant findings to enable investigators to manage 
subject safety.  Since the ESR is measured at the site, an unblinded assessor at the local 
laboratory will report the ESR results. The investigator will be notified of the value of the 
ESR result when an ESR value is > 40 mm/hr in order to determine if a treatment change 
is warranted. Investigators are advised to consider these notifications of an elevated ESR 
which has reached the alert value as an additional element in the determination of 
whether a subject is experiencing GCA disease flare. An elevated ESR in isolation should 
not be the sole basis for investigator assessment of disease flare, particularly in the 
absence of clinical symptoms (e.g., cranial or PMR) suggestive of disease activity.
An IDMC may carry out a futility assessment when approximately 30% of subjects have 
completed 52 weeks, dependent upon the recruitment rates. This committee will consist 
of clinicians and statisticians who are external to GSK in order to maintain the integrity 
of the blind during the 52-week double-blind treatment phase of the study.
The CEC, an independent committee composed of external specialists will be blinded to 
treatment assignment and will therefore not affect the integrity of the blind.
This will be a double-blind study and the following will apply:

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the GSK
Medical Monitor or appropriate GSK study personnel to discuss options before 
unblinding the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 

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treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the CRF.
A subject may continue in the study if that subject’s treatment assignment is unblinded 
but this must be discussed with the Medical Monitor.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
Sirukumab and matching placebo should be stored at 2-8C and protected from light. Do 
not remove from the outer carton until ready to use. The storage temperature should be 
monitored and any excursions noted. 
Prior to use the SmartJect autoinjector should be removed from the outer carton and 
allowed to sit at ambient temperature for 30 minutes with the cap in place. 

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SPM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.
Compliance with Study Treatment Administration
Subjects will be provided with a worksheet to record the dates when they self-administer 
study treatments at home. Compliance with sirukumab or matched placebo and 
prednisone and matched placebo will be assessed through querying the subject’s 
worksheet during the site visits and will be documented in the source documents and 
CRF.  A record of the number of sirukumab or placebo pre-filled syringes and 
prednisone/placebo tablets dispensed to and taken by each subject must be maintained 

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and reconciled with study treatment and compliance records.  Treatment start and stop 
dates, including dates for treatment delays will also be recorded in the CRF.
A record of study treatments administered during site visits will be documented in the 
source documents and CRF.
6.8.
Treatment of Study Treatment Overdose
Subjects in clinical studies with sirukumab have received up to 10 mg/kg sirukumab IV 
q2w and no dose-limiting toxicity has been observed. No clinical information is available 
for sirukumab doses greater than 10 mg/kg.
For this study, any dose of sirukumab >100 mg within a 7 day period will be considered 
an overdose.
GSK does not recommend specific treatment for an overdose of sirukumab (see Section 
5.22 on overdose in the sirukumab IB). 
The investigator should refer to the approved product label for advice on an overdose of 
prednisone.
In the event of an overdose the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the subject for AEs/serious adverse events (SAEs) and laboratory 
abnormalities until sirukumab can no longer be detected systemically (at least 70 
days for sirukumab).
3.
Obtain a plasma sample for PK analysis within 70 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study.  Upon study completion, decisions on treatment options for individual subjects will 
be at the discretion of the investigator.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.

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6.10.
Concomitant Medications and Non-Drug Therapies
All concomitant medications taken during the study will be recorded in the concomitant 
medications CRF.
6.10.1.
Permitted Medications and Non-Drug Therapies
The following drugs are permitted during the study:

The use of statins for the treatment of hyperlipidemia is permitted in this study. 
However, some statins such as simvastatin, atorvastatin, cerivastatin, and 
lovastatin are metabolized by cytochrome P450 enzymes and caution should be 
exercised when sirukumab is co-administered with these CYP3A4 substrate drugs.

Inflammatory cytokines, including IL-6, are known to down regulate activity and 
expression of multiple cytochrome P450 (CYP) 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.  Caution should also be exercised when 
sirukumab is coadministered with CYP3A4 substrate drugs such as oral 
contraceptives, and certain statin medications mentioned above.

Analgesics, paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), 
including aspirin, at the usual marketed doses approved in the country in which 
the study is being conducted. 

The use of topical analgesics including capsaicin and diclofenac.

Stable doses of inhaled and topical corticosteroids.
6.10.2.
Prohibited Medications and Non-Drug Therapies
The following drugs and vaccines are prohibited within the specified time frames and 
with concomitant SC administration of study drug:

Systemic immunosuppressives such as azathioprine, oral cyclosporine A, 
tacrolimus, mycophenolate mofetil, leflunomide, oral or parenteral gold, and IL-
1ra (anakinra) within 4 weeks of baseline.

Biologic agents targeted at reducing TNF(including but not limited to 
infliximab, golimumab, certolizumab pegol, etanercept, yisaipu, and adalimumab
and/or biosimilar or generic versions of these agents) within the specified time 
frames.

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Anti-TNFTherapy
Treatment Prior to First Study Agent 
Administration (Baseline)
Infliximab, infliximab 
biosimilar, golimumab IV
8 Weeks
Golimumab SC, adalimumab, 
certolizumab pegol
6 Weeks
Etanercept, yisaipu
4 Weeks

Prior anti-IL-6 (tocilizumab or any other anti-IL-6 agent) if:

Used within 8 weeks of randomization

Associated with a history of intolerance that precluded further treatment

Associated with an inadequate response to 3 months of therapy

B-cell depleting agents (eg, rituximab) within 12 months prior to baseline or 
longer if  B cell counts have not returned to the normal range or baseline levels. 

Cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or 
other alkylating agents within 4 weeks of baseline.

Abatacept within 8 weeks of baseline.

Tofacitinib within 4 weeks of baseline.

Methotrexate within 2 weeks of baseline in Part A of the study only. Methotrexate 
use in Part B of the study is at the discretion of the investigator and may be used 
concurrently with open-label sirukumab in Part B.

Systemic corticosteroids for conditions other than GCA within 8 weeks of 
baseline or a reasonable possibility of requiring systemic corticosteroids during 
Part A.

Use of investigational agents within 12 weeks of baseline.

Receipt of any live virus or bacterial vaccination within 3 months before the first 
administration of study drug, during the study, or within 4 months after the last 
administration of study drug.
7.
STUDY ASSESSMENTS AND PROCEDURES
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 Tables, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment. It 
should be noted that for those subjects with disease flare at any visit, the assessments to 

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be performed are those specified in the Early Withdrawal or Flare visit in all of the 
following Time and Events Tables.
The assessments for Part A of the study are provided in Time and Events Table 2 in 
Section 7.1. 
Part B assessments are included in separate Time and Events Tables (Table 3, Table 4
and Table 5).  It should be noted that the Week 52 visit of Part A also serves as the Week 
0 visit of Part B of the study.
Part B Time and Events Tables should be followed as described below:
Time and Events Table 3:  Assessments for subjects who will not receive open-label 
treatment with sirukumab during Part B. Dispensing of investigational product is not 
required. Hematology and clinical chemistry assessments and pregnancy testing from the 
Week 16 visit onwards are also not required as subjects will have completed the 16-week 
post-drug follow up assessments.
Time and Events Table 4: Assessments for subjects who initiate open-label sirukumab 
treatment at the baseline visit of Part B (those with disease activity or flare at the Week 
52 visit of Part A).
Time and Events Table 5: Assessments for subjects who initiate open-label sirukumab 
treatment after the baseline visit and anytime up to the Week 52 visit of Part B (those 
who flare during Part B). These subjects will initially be following the assessments in 
Time and Events Table 3 and will undergo the assessments scheduled for that visit and
will include initiation of open-label sirukumab treatment at that same visit.
Subsequent visits will follow the assessments from Time and Events Table 5 starting 
from the visit labelled ‘plus 2 weeks’ onwards. It is important that upon initiation of 
open-label sirukumab therapy, the next visit should occur 2 weeks after treatment start.
For these subjects, the last visit in Part B should be scheduled for when they have been in 
Part B for 104 weeks or upon completion of the 16-week follow-up if applicable.
At the clinic visits where blood samples for lipid analysis are collected, the subjects 
should be instructed to fast for at least 9 hours (water is permitted) prior to the visit; this 
will be an overnight fast from the time of going to bed and missing breakfast until after 
the blood draws in the clinic. It may be preferable to schedule clinic visits in the morning 
to minimize inconvenience to the subject. Fasting is not required for visits where there is 
no requirement for lipid analysis.
PRO questionnaires should be completed by subjects before any other assessments and 
before the administration of study drug. PRO questionnaires should be completed before 
the completion of the physician reported questionnaires. PRO questionnaires should be 
completed by the subject in the following order:
1. Patient Global Assessment of disease activity (PtGA).
2. Patient Global Impression of Change (PGIC).

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3. Pain Numeric Rating Scale (NRS).
4. HAQ-DI (for subgroup of subjects with PMR).
5. FACIT-fatigue.
6. Steroid Impact PRO.
7. SF-36v2 acute.
8. EQ-5D (5L)
9. Columbia-Suicide Severity Rating Scale (C-SSRS).
Clinician-reported outcome questionnaires include the Physician Global Assessment of 
disease activity (PhGA), which should be completed after the PRO questionnaires have 
first been completed by subjects.

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7.1.
Time and Events Tables
Table 2
Time and Events Table for Part A of the Study (52-week Double-blind Treatment Phase)
Screening (~Wk -6+ 3d)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal 
Follow  Up
Written Informed Consent1
x
Subject Demography
x
Medical and disease history
x
Inclusion/Exclusion Criteria
x
x
Randomization
x
Autoinjector training2
x
x
x
Dispense Investigational Product
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x3
Assess Invest. Product compliance
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
Prior Medications
x
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
PGIC4
x
x
x
x
x
Pain NRS4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
HAQ-DI4
x
x
x
x
x
x
x
FACIT-Fatigue4
x
x
x
x
x
x
x
Steroid Impact4
x
x
x
x
x
x
x
SF-36v2 (acute)4
x
x
x
x
x
x
x
EQ-5D (5L)4
x
x
x
x
x
x
x

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Screening (~Wk -6+ 3d)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal 
Follow  Up
Safety Assessments
Physical Examination5
x
x
x
x
x
x
Vital Signs6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
12-lead ECG7
x
Chest radiograph
x
TB evaluation8
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
QuantiFERON-TB Gold Test9
x
Height and weight
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
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
Hemoglobin A1c
x
x
x
x
x
x
x
x
Pregnancy Test10
S
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
HIV, HBsAg, HBcAb, Hepatitis C11
x
PK12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Immunogenicity12
x
x
x
x
x
x
x

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Screening (~Wk -6+ 3d)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal 
Follow  Up
Exploratory Lab Assessments
IL-6 measurements
x
x
x
x
Blood Biomarkers & exploratory 
markers
x
x
x
x
x
x
x
Blood and Urine Markers, 
Transcriptomics (optional)13
x
x
x
x
x
x
x
Pharmacogenetics sample14
x
Exploratory US Imaging
Ultrasound imaging15
x16
x
x
x
x

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1.
Including consent for pharmacogenetics.
2.
Assuming placebo will also be administered using autoinjector. Additional training may be provided when required.
3.
Only for those subjects who initiate open-label sirukumab treatment at the start of Part B.
4.
PROs to be completed by subjects before other clinically evaluated assessments or blood draws and before the administration of study drug. At visits where subject is 
fasting for blood draws, the option exists to perform blood draws prior to completing PROs as necessary to end the fast.  HAQ-DI administered only to sub-set of subjects 
with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of questionnaires and after conducting patient assessments).
5.
Complete physical exam at Screening and brief physical exam at other time points.
6.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
7.
And when any suspected cardiac abnormality. Average of triplicate recordings.
8.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
9.
Chest radiograph taken up to 3 months prior to Week 0 may be used to qualify at screening.
10. Pregnancy test: urine = U, serum = S. Premenopausal women only.
11. If hepatitis C antibody positive, a hepatitis C RNA PCR assay should be reflexively performed on a fresh sample to confirm the result.
12. On study drug administration days, Pharm serum samples must be collected prior to study drug 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.
13. To be collected only for those subjects consenting to provide samples for the biobank for future exploration of GCA disease biology.
14. Sample should be collected at the baseline visit but may be collected at any visit post-baseline if not collected at the  baseline visit.
15. Selected sites participating in the exploratory US imaging portion only; restricted to subjects with new onset disease
16. Optimally (but not required), to be performed prior to or within 3 days of the start of prednisone.

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Table 3
Time and Events Table for Part B of the Study (104-week Extension): Subjects NOT Receiving Open-label 
Sirukumab During Part B
Wk 0/(Wk 52 of Part A)
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
Concomitant Medications
x
x
x
x
x
x
x
x
x
x
x
x
Assess Invest. Product compliance1
x
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)2
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain NRS2
x
x
x
x
x
x
x
x
x
x
HAQ-DI2
x
x
x
x
x
x
x
x
FACIT-Fatigue2
x
x
x
x
x
x
x
x
Steroid Impact2
x
x
x
x
x
x
x
x
SF-36v2 (acute) 2
x
x
x
x
x
x
x
x
EQ-5D (5L) 2
x
x
x
x
x
x
x
x
Safety Assessments
Physical Examination3
x
x
x
x
x
Vital Signs4
x
x
x
x
x
x
x
x
x
x
x
x
TB evaluation5
x
x
x
x
x
x6
Height and weight
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS2
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x6
x6
Serum chemistry
x
x
x
x
x
x6
x6
CRP
x
x
x
x
x
x
x
x
x
x
x
x

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Wk 0/(Wk 52 of Part A)
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
ESR
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x6
x6
Hemoglobin A1c
x
x
x
x6
x6
Pregnancy Test7
U
U
U
U
U
U6
Exploratory Lab Assessments
IL-6 measurements
x
Blood Biomarkers & exploratory 
markers
x
Blood and Urine Markers, 
Transcriptomics (optional)
x
Exploratory US Imaging
Ultrasound imaging8
x
1.
Assessment from Week 52 visit of Part A
2.
PROs to be completed by subjects before other clinically evaluated assessments or blood draws and before the administration of study drug. At visits where subject 
is fasting for blood draws, the option exists to perform blood draws prior to completing PROs as necessary to end the fast. HAQ-DI administered only to sub-set of 
subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of questionnaires and after conducting patient 
assessments). 
3.
Brief physical exam.
4.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
5.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
6.
To be performed only if Early Withdrawal visit or flare occurs on or before Week 16 visit.
7.
Pregnancy test: urine = U, serum = S. Premenopausal women only.
8.
For subjects participating in the exploratory US imaging cohort. Ultrasound scans to be performed only in the event of disease flare or relapse in Part B. Part B scans 
will conclude when the last subject in the US imaging cohort completes Part A.

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Table 4
Time and Events Table for Part B (104-week Extension) of the Study: Subjects Receiving Open-label Sirukumab 
Immediately Upon Entry into Part B
Wk 0/(Wk 52 of Part A)
Wk25d
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 485d1
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
Follow  Up
Dispense Investigational Product
x
x
x
x
x
x
x
x
x
Assess Invest. Product compliance
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
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)2
x
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain NRS2
x
x
x
x
x
x
x
x
x
x
x
HAQ-DI2
x
x
x
x
x
x
x
x
FACIT-Fatigue2
x
x
x
x
x
x
x
x
Steroid Impact2
x
x
x
x
x
x
x
x
SF-36v2 (acute) 2
x
x
x
x
x
x
x
x
EQ-5D (5L) 2
x
x
x
x
x
x
x
x
Safety Assessments
Physical Examination3
x
x
x
x
x
x
Vital Signs4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
TB evaluation5
x
x
x
x
x
x
x
x
x
x
x
x
Height and weight
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
x

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Wk 0/(Wk 52 of Part A)
Wk25d
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 485d1
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
Follow  Up
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x
x
x
x
x
x
x
Hemoglobin A1c
x
x
x
x
x
x
x
x
x
x
Pregnancy Test6
U
U
U
U
U
U
U
U
U
U
U
U
U
PK7
x
x
x
x
x
x
x
Immunogenicity7
x
x
x
x
x
x
x
Exploratory Lab Assessments
IL-6 measurements
x
Blood Biomarkers & exploratory 
markers
x
Blood and Urine Markers, 
Transcriptomics (optional)
x
Exploratory US Imaging
Ultrasound imaging8
x

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1.
Visit only to dispense IP; no assessments are required.
2.
PROs to be completed by subjects before other clinically evaluated assessments or blood draws and before the administration of study drug. At visits where 
subject is fasting for blood draws, the option exists to perform blood draws prior to completing PROs as necessary to end the fast. HAQ-DI administered only 
to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of questionnaires and after conducting 
patient assessments). 
3.
Brief physical exam.
4.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
5.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test (or if not approved at the site, a tuberculin skin test) should be performed at any time 
during the study if TB is suspected.
6.
Pregnancy test: urine = U, serum = S. Premenopausal women only. A urine pregnancy test should be performed every 4 weeks while taking open-label 
sirukumab and for 16 weeks post discontinuation of sirukumab treatment. Subjects should perform a urine pregnancy test at home when there is no study visit 
corresponding to the 4-weekly interval. Pregnancy test kits will be provided by the central laboratory for subject use at home. 
7.
On study drug administration days, Pharm serum samples must be collected prior to study drug 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.. 
8.
For subjects participating in the exploratory US imaging cohort. Ultrasound scans to be performed only in the event of disease flare or relapse in Part B. Part B 
scans will conclude when the last subject in the US imaging cohort completes Part A.

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Table 5
Time and Events Table for Part B (104-week Extension) of the Study: Subjects Receiving Open-label Sirukumab 
at Any Time AFTER (but NOT immediately Upon) Entry into Part B
Start of open-label 
sirukumab  1
PLUS 2 Wks5d
PLUS 4 Wks5d
PLUS 8 Wks5d
PLUS 12 Wks5d
PLUS 16 Wks5d
PLUS 24 Wks5d
PLUS 36 Wks5d
PLUS 48 Wks5d2
PLUS 52 Wks5d
PLUS 76 WKS5d
PLUS 104 Wks5d 3
Flare
Early Withdrawal 
Follow  Up
Dispense Investigational Product
x
x
x
x
x
x
x
x
Assess Invest. Product compliance
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
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)4
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain NRS4
x
x
x
x
x
x
x
x
x
x
HAQ-DI4
x
x
x
x
x
x
x
FACIT-Fatigue4
x
x
x
x
x
x
x
Steroid Impact4
x
x
x
x
x
x
x
SF-36v2 (acute)4
x
x
x
x
x
x
x
EQ-5D (5L)4
x
x
x
x
x
x
x
Safety Assessments
Physical Examination5
x
x
x
x
x
Vital Signs6
x
x
x
x
x
x
x
x
x
x
x
x
x
TB evaluation7
x
x
x
x
x
x
x
x
x
x
x
Height and weight
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x

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Start of open-label 
sirukumab  1
PLUS 2 Wks5d
PLUS 4 Wks5d
PLUS 8 Wks5d
PLUS 12 Wks5d
PLUS 16 Wks5d
PLUS 24 Wks5d
PLUS 36 Wks5d
PLUS 48 Wks5d2
PLUS 52 Wks5d
PLUS 76 WKS5d
PLUS 104 Wks5d 3
Flare
Early Withdrawal 
Follow  Up
CRP
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x
x
x
x
x
x
Hemoglobin A1c
x
x
x
x
x
x
x
x
x
Pregnancy Test8
U
U
U
U
U
U
U
U
U
U
U
U
PK9
x
x
x
x
x
x
Immunogenicity9
x
x
x
x
x
x
Exploratory US Imaging
Ultrasound imaging10
x

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1.
Upon the initiation of open-label sirukumab, perform the assessments from Time and Events Table 3 at the visit the subject was scheduled to undergo 
when study drug is started.
2.
Visit only to dispense IP; no assessments are required.
3.
Although this visit is labelled as 104 weeks since the start of open-label sirukumab, it does not take into account the exact start time, since this will be 
different for each subject depending upon when in the first 52 weeks of Part B open-label sirukumab was started. The important point to note, is that this 
last visit should be scheduled when each of these subjects will complete 104 weeks in Part B.
4.
PROs to be completed by subjects before other clinically evaluated assessments or blood draws and before the administration of study drug. At visits 
where subject is fasting for blood draws, the option exists to perform blood draws prior to completing PROs as necessary to end the fast. HAQ-DI 
administered only to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of 
questionnaires and after conducting patient assessments). .  
5.
Brief physical exam. 
6.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
7.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
8.
Pregnancy test: urine = U, serum = S. Premenopausal women only. A urine pregnancy test should be performed every 4 weeks while taking open-label 
sirukumab and for 16 weeks post discontinuation of sirukumab treatment. Subjects should perform a urine pregnancy test at home when there is no study 
visit corresponding to the 4-weekly interval. Pregnancy test kits will be provided by the central laboratory for subject use at home. 
9.
On study drug administration days, Pharm serum samples must be collected prior to study drug 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.. 
10. For subjects participating in the exploratory US imaging cohort. Ultrasound scans to be performed only in the event of disease flare or relapse in Part B. 
Part B scans will conclude when the last subject in the US imaging cohort completes Part A.

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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
Screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
Procedures conducted as part of the subject’s routine clinical management (e.g. chest 
radiograph taken up to 3 months prior to baseline) and obtained prior to signing of 
informed consent may be utilized for Screening or baseline purposes provided the 
procedure meets the protocol-defined criteria and has been performed in the timeframe of 
the study.
All subjects should be receiving prednisone treatment at Screening. Prednisone treatment 
must be initiated at Screening for subjects not currently receiving steroid treatment. 
Subjects should be reminded to discontinue any other prednisone or corticosteroid 
treatment and take only the prednisone study treatment. The prednisone dose for all 
subjects at Screening will be determined by the Investigator and may be adjusted based 
on the subject’s disease status per investigator discretion.  An increase in prednisone dose 
may be required for some subjects currently receiving therapy to stabilize their disease 
activity prior to randomization. Investigators may consider if higher doses of prednisone 
are warranted for subjects with visual manifestations. Subjects are required to have 
clinically stable GCA disease at baseline and able to participate in the blinded prednisone 
taper regimen in the opinion of the investigator. At Baseline (Randomization), doses must 
be within 20-60 mg prednisone for the starting dose when the pre-specified prednisone 
taper is initiated.
7.3.
Efficacy
Efficacy of sirukumab in GCA will be assessed from the presence of GCA activity 
including investigator assessment of signs and symptoms of GCA (new onset localized 
headache, scalp or temporal artery tenderness, reduced or absent pulsation in temporal 
artery, cord-like thickening of temporal artery, stroke, scalp necrosis, pain over face/scalp 
arteries, or otherwise unexplained mouth or jaw pain upon mastication [i.e., jaw 
claudication]); visual signs and symptoms (including but not limited to transient or 
episodic blurry vision, diplopia, scotoma, ischemia-related vision loss [permanent vision 
loss due to AION], amaurosis fugax); PMR symptoms [shoulder and/or hip girdle pain 
associated with inflammatory stiffness]; other features associated with GCA such as new 
or worsened extremity claudication and fever of unknown origin; and laboratory results 
for serum ESR and CRP levels (blinded to investigator).

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7.3.1.
Patient’s and Physician’s Global Assessment of Disease Activity
The Patient’s and Physician’s Global Assessments of Disease Activity 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 GCA activity” to
“extremely active GCA”.  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.
7.4.
Health Outcomes
In addition to the Patient’s and Physician’s Global Assessment of Disease Activity, other 
health outcome measures used in this study are PGIC, pain assessment using an 11-point 
numeric rating scale, HAQ-DI, FACIT-fatigue, Steroid Impact questionnaire, SF-36 v2 
Acute health survey questionnaire, and EQ5D (5L). These questionnaires should be 
completed in the order specified in Section 7.
7.4.1.
Patient Global Impression of Change (PGIC)
Patient-reported response to treatment will be assessed using the Patient Global 
Impression of Change (PGIC) measure, a single item completed by subjects to provide a 
clinically meaningful summary of an individual’s response to treatment. The assessment 
provides an estimate of the magnitude of treatment response at different time points 
during the study. Additionally, the subject rating of change will be used to support the 
estimation of a minimum clinically meaningful change score for the Steroid Impact PRO. 
Responses include: Much Better, Better, Slightly Better, No Change, Slightly Worse, 
Worse, Much Worse.
7.4.2.
Pain Assessment
Subjects will be asked to rate the severity of  their average pain now on an 11-point  
numeric rating scale  with anchors ranging from 0, “no pain” to 10, “the worst pain 
imaginable”.
7.4.3.
Health Assessment Questionnaire – Disability Index (HAQ-DI)
The functional status of the subgroup of subjects with PMR will be assessed using the 
HAQ-DI [Fries, 1980]. This 20-question instrument assesses the degree of difficulty 
encountered in accomplishing tasks in 8 functional areas (dressing, arising, eating, 
walking, hygiene, reaching, gripping, and activities of daily living). Responses are scored 
from 0 (no difficulty) to 3 (inability to perform a task in that area).

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7.4.4.
Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-Fatigue)
The FACIT-Fatigue is a questionnaire that assesses self-reported tiredness, weakness, and 
difficulty conducting usual activities due to fatigue [Cella, 2002; Yellen, 1997]. The total 
FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue.
7.4.5.
Steroid Impact Questionnaire
The benefits, side effects and impact of steroids on GCA symptoms and subjects will be 
assessed using a GCA disease specific patient reported questionnaire, the Steroid Impact 
Questionnaire. The Steroid Impact Questionnaire contains 50 items assessing steroid 
dose/duration (4 items), general impact (baseline burden; 19 items), benefits (7 items), 
work/productivity (3 items), side effects (10 items), emotions (6 items), and overall 
satisfaction (1 item).
7.4.6.
36-item Short Form Version 2 Acute (SF-36v2 Acute)
The Medical Outcome Study health measure entitled the 36-item Short-Form Version 2 
acute (SF-36v2 acute) 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 [Ware, 1994].  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 [Ware, 1992].
7.4.7.
EuroQoL-5D (EQ-5D) (5L)
The EQ-5D is a standardized measure of health status developed by the EuroQoL Group 
to provide a simple, generic measure of health for clinical and economic appraisal 
(EuroQol Group, 1990). The EQ-5D is applicable to a wide range of health conditions 

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and treatments.  EQ-5D essentially consists of 2 elements:  The EQ-5D descriptive 
system and the EQ visual analogue scale (EQ VAS).  The EQ-5D descriptive system 
comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, unable to do. The respondent is asked to 
indicate his/her health state by ticking (or placing a cross) in the box against the most 
appropriate statement in each of the 5 dimensions.  This decision results in a 1-digit 
number expressing the level selected for that dimension.  The digits for 5 dimensions can 
be combined in a 5-digit number describing the respondent’s health state which can be 
converted into a single summary index (EQ-5D index) by applying a formula that 
attaches values (also called weights) to each of the levels in each dimension.  The EQ 
VAS records the respondent’s self-rated health on a vertical line, VAS where the 
endpoints are ‘Best imaginable health state’ and ‘Worst imaginable health state’.  The EQ 
VAS can be used as a quantitative measure of health outcome as judged by the individual 
respondents.
7.5.
Safety
Safety will be assessed from the documentation of adverse events and review of vital 
signs and laboratory assessments including complete blood counts, serum chemistry 
profiles, fasting serum lipids, HbA1c, hepatitis B and C serologies, and markers of bone 
turnover.  The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to 
prospectively monitor suicidal ideation and behavior (Section 7.5.7). Adverse events 
(including serious and opportunistic infections, cardiovascular events, gastrointestinal 
perforations, hepatic laboratory abnormalities, and cytopenias) will be monitored on a 
regular and/or event-driven basis by an IDMC throughout the study.
Planned time points for all safety assessments are listed in the Time and Events Tables
(Section 7.1).
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.5.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the 
follow-up contact (see Section 7.5.1.3), at the time points specified in the Time 
and Events Tables (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

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
Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in. 
7.5.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.5.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 4.
Other AEs of special interest not defined in Section 4.6.1 are injection site reactions, total 
or partial blindness, limb claudication, and scalp or tongue necrosis. In addition, severe 
disease flares, including hospitalizations will be monitored.
Other AEs of special interest for sirukumab are hematologic laboratory abnormalities 
(decreases in neutrophils and platelets), hepatobiliary laboratory abnormalities, lipid 
parameter abnormalities, serious CV events, infections, malignancies, and gastrointestinal 
perforations. 
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 

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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.
Corticosteroid-related AEs such as diabetes mellitus, osteoporosis, fractures, infection, 
glaucoma, and cataracts among others will be evaluated in relation to steroid exposure 
and baseline risk. Since subjects participating in this study may be receiving high doses 
of prednisone for a prolonged period, investigators should consider implementation of the 
American College of Rheumatology recommendations for the prevention and treatment 
of glucocorticoid-induced osteoporosis (Grossman, 2010). A summary of these 
recommendations is included in Section 12.5, Appendix 5. Investigators should also 
consider whether their subjects may benefit from other approaches for minimizing 
corticosteroid-related AEs, such as the prophylactic use of proton pump inhibitors for 
gastroprotection.
7.5.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding CV (including 
sudden cardiac death) and non-CV death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
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 
special 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. This will allow external review of cases and determination of diagnosis prior 
to analysis.
7.5.1.5.
Other Adverse Events of Special Interest for Sirukumab
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 

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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.
Other Events of Interest
Sirukumab, by its mechanism of action as an IL-6 inhibitor, would be expected to have 
some properties of immunosuppression. Increased susceptibility to infections is an 
identified risk of sirukumab. Serious, life-threatening infections such as septic shock, 
some of which have been fatal,  have occurred in subjects receiving sirukumab. IL-6 
deficient mice have been found to be susceptible to infections with Listeria 
monocytogenes, Toxoplasma gondii, and Candida albicans. [Dalrymple, 1995; Romani, 
1996; Suzuki, 1997].  In addition, as an IL-6 inhibitor, sirukumab may have some effect 
on the risk of malignancy by affecting immune surveillance. Further, gastrointestinal 
perforations have been reported with another anti-IL-6 agent [ACTEMRA Prescribing 
Information, 2011] and with sirukumab. Please refer to Table 4.6.1 and the Investigator 
Brochure for additional information.
7.5.1.6.
Events That Occur With Biologics
Injection Site Reactions
An injection site reaction is any unfavorable or unintended sign that occurs at the study 
drug injection site. All subjects must be carefully observed for symptoms of an injection 
site reaction. Prior to and including through Week 4, subjects will be observed for at least 
30 minutes after the SC injection of study drug for symptoms of an injection site reaction. 
After Week 4, subjects do not need to be observed for 30 minutes for the post-
administration injection-site evaluation if they are self-administering at home. However, 
subjects should promptly notify the site if they experience a reaction at the site of 
injection. 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.
Allergic/Hypersensitivity Reactions
All subjects will be observed carefully for symptoms of allergic reactions for at least 30 
minutes after the SC injection of study drug when administered at the study site. If mild 
or moderate allergic reaction is observed, acetaminophen 650 mg per mouth (PO) or 
NSAIDS and diphenhydramine 25 mg orally or intravenously may be administered. If the 
reaction is not severe, subsequent injections at the appropriate treatment intervals may be 
undertaken with caution.
Subjects with severe reactions following an injection such as bronchospasm with 
wheezing and/or dyspnea requiring ventilator support, or symptomatic hypotension with 
a decrease in systolic blood pressure greater than 40 mmHg will not be permitted to 
receive any additional study drug injections. In the case of such reactions, appropriate 
medical treatment should be administered.

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In cases of serious allergic/hypersensitivity reactions, additional details on the case will 
be collected via a targeted follow-up questionnaire. An internal safety review team will 
adjudicate these events to determine if the events meet the Sampson criteria (Sampson, 
2006).
7.5.1.7.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.5.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects
will be collected after the start of dosing and until the Follow-up visit.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 2.

Female subjects who become pregnant during the study must have study drug 
discontinued immediately. These subjects should continue to follow the protocol-
specified visit schedule.
7.5.3.
Physical Exams

A complete physical examination will be conducted at screening and will include, 
at a minimum, assessment of the Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. Height and weight will also be measured and recorded.

A brief physical examination will be conducted at all other time points and 
include, at a minimum assessments of the skin, lungs, CV system, and abdomen 
(liver and spleen).

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
Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.5.4.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure and pulse rate.
7.5.5.
Electrocardiogram (ECG)
Triplicate 12-lead ECGs will be obtained at the Screening visit using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  The screening ECG will ensure that a comparative ECG is available prior to 
study drug administration in order to detect any changes should a subject require an ECG 
for any reason during the study. Refer to Section 5.4.4 for QTc discontinuation criteria 
and additional QTc readings that may be necessary.
In the event of a suspected cardiac abnormality, the investigator should make every 
reasonable attempt to obtain the results of the ECG performed in the emergency hospital 
facility.
7.5.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 6, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedules. 
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
Pregnancy testing (where applicable) should be conducted every 4 weeks while subjects 
are receiving study drug and during the 16-week follow-up period. Pregnancy tests may 
be performed by the subject at home using the test kits provided by the central laboratory 
when there is no study visit associated with the testing time point. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Hematology, clinical chemistry, and additional parameters to be tested are listed in Table 
6.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 112 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 

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return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) will be used to grade laboratory abnormalities as appropriate.
The investigators and the Sponsor/study team will remain blinded to the results of the 
ESR (performed locally), CRP and fasting lipid analyses (see Section 6.4) after the start 
of treatment during Part A of the study. The central laboratory will send an alert to the 
investigator for LDL values >160 mg/dL (SI units 4.1 mmol/L) or triglycerides >500 
mg/dL (SI units 5.6 mmol/L).

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Table 6
Laboratory Parameters
Hematology
Hemoglobin
Hematocrit
Red blood cell (RBC) count
White blood cell (WBC) count 
with differential
Neutrophils, absolute
Neutrophils, segs (%)
Neutrophils, bands (%)
Basophils (%)
Eosinophils (%)
Eosinophils, absolute
Lymphocytes (%)
Monocytes (%)
Platelet count
Serum Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Blood urea nitrogen (BUN)
Creatinine
Glucose
Aspartate transaminase
Alanine transaminase
Alkaline phosphatase
Calcium
Phosphate
Albumin
Total protein
Bilirubin, direct, indirect and 
total
Fasting lipids
Total cholesterol
Low density lipoprotein (LDL)
High density lipoprotein (HDL)
Triglycerides
Serum and urine pregnancy test for premenopausal women only
Serology for HIV, hepatitis B surface antigen, hepatitis B core antibody and hepatitis C antibody 1
Other tests
Hemoglobin A1c
C-reactive protein (CRP) 2,3
Erythrocyte sedimentation rate 
(ESR) 2, 3
QuantiFERON-TB Gold Test
1.
If hepatitis C antibody positive, a hepatitis C RNA PCR assay should be reflexively performed on a fresh sample 
to confirm the result
2.
Investigators will remain blinded to the results of the ESR, CRP and fasting lipids after the start of treatment
during Part A of the study (see Section 6.4). ESR will be analyzed at the local laboratory.
3.
Required for the evaluation of efficacy.
Values for liver transaminase levels (AST, ALT), absolute neutrophil count (ANC), and 
platelet count that require study drug interruption and/or permanent discontinuation of 
study drug administration are listed below in Table 7.

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Table 7
Values for Liver Transaminase Levels, Absolute Neutrophil Count, 
and Platelet Count That Require Study Drug Interruption and/or
Permanent Discontinuation of Study Drug
ALT or AST increased
ALT or AST
Action
≥3xULN) for laboratory reference range.
Interrupt study drug administration, assess for 
symptoms, and repeat ALT/AST test as soon as 
possible* (see Section 5.4.3).
May resume study drug when <3x ULN
Criteria for drug-induced liver injury
Permanent discontinuation of study drug
Low Absolute Neutrophil Count (ANC)
Neutrophil count 
Action
0.5 to ≤1.0 x 103/L
(SI: 0.5 to ≤1.0 x 109 cells/L)
Interrupt study drug administration, repeat ANC 
test as soon as possible*
May resume study drug when >1.0 x 103/μL
<0.5 x 103/L
(SI: <0.5 x 109 cells/L)
Interrupt study drug administration, repeat ANC 
test as soon as possible*
If confirmed to be <0.5 x 103/μL, discontinue 
study drug permanently (see Section 5.4.2)
Low Platelet Count
Platelet count 
Action
50,000 to ≤100,000/L
(SI: 50 to ≤100 x 109 cells/L)
Interrupt study drug administration, repeat 
platelet count test as soon as possible*
May resume study drug when platelet count 
>100,000/L
<50,000/L
(SI: <50 x 109 cells/L)
Interrupt study drug administration, repeat 
platelet count test as soon as possible*
If confirmed to be <50,000/μL, discontinue study 
drug permanently (see Section 5.4.2)
* Retesting should be performed by Central laboratory
Note: A WBC evaluation may include any abnormal cells, which will then be reported by 
the laboratory. Any RBC evaluation may include abnormalities in the RBC count and/or 
RBC parameters and/or RBC morphology, which will then be reported by the laboratory. 
In addition, any other abnormal cells in a blood smear will also be reported.
Any abnormalities in MCH, MCHC and MCV will be reported by the laboratory.
7.5.7.
Suicidal Risk Monitoring
Sirukumab is considered to potentially be a CNS-active drug. There has been some 
concern that some CNS-active drugs may be associated with an increased risk of suicidal 
thinking or behaviour when given to some patients with certain conditions. Although this 
drug or other similar drugs in this class have not been shown to be associated with an 
increased risk of suicidal thinking or behaviour when given to this patient population, 

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GSK considers it important to monitor for such events before or during clinical studies 
with compounds such as this.
Subjects being treated with sirukumab should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Consideration should 
be given to discontinuing sirukumab in subjects who experience signs of suicidal ideation 
or behaviour.
Suicidal ideation and behaviour will be assessed at baseline and at the time points 
indicated in Time and Events Table 2 and in Time and Events Table 3 using the patient-
reported outcome version of the C-SSRS [Mundt, 2010].
7.5.8.
Tuberculosis Evaluation
A QuantiFERON-TB Gold Test will be performed at Screening. This test can be 
performed at any time during the study if TB is suspected.
A TB questionnaire will be completed at the times specified in Section 7.1, Time and 
Events Tables. This questionnaire will evaluate signs and symptoms of active TB in order 
to aid in the early detection of TB reactivation or new TB infection during the study. The 
following series of questions is suggested for use during the TB 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 drug 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 active TB 
must immediately discontinue study drug and be referred to a physician specializing in 
TB 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 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. 

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Study drug administration should be interrupted during the investigation. A positive 
QuantiFERON-TB Gold test result should be considered detection of latent TB. If the 
result is indeterminate, the test should be repeated. If recommended, treatment for latent 
TB must be initiated prior to the administration of further study drug. Subjects who 
discontinue treatment for latent TB prematurely or who are noncompliant with therapy 
must immediately discontinue further administration of study drug and should return for 
all subsequent scheduled study visits.
7.5.9.
Chest Radiograph
A chest radiograph will be performed at the Screening visit only for the detection of TB. 
A chest radiograph taken up to 3 months prior to Week 0 may be used to qualify as the 
screening radiograph.
7.6.
Pharmacokinetics and Immunogenicity
Blood samples for PK analysis of sirukumab serum concentrations and for analyses of 
antibodies to sirukumab will be collected at the time points specified in Section 7.1, Time 
and Events Tables. The actual date and time of each blood sample collection will be 
recorded. Blood samples for PK analyses of sirukumab serum concentrations must be 
drawn prior to the administration of study drug.
At visits where sirukumab serum concentrations and antibodies to sirukumab will be 
evaluated, one blood draw of sufficient volume will be used to divide the sample into 3 
aliquots, one each for sirukumab serum concentrations and antibodies to sirukumab plus 
a back-up.
PK analyses of sirukumab serum concentrations and anti-sirukumab antibodies will be 
performed using validated bioanalytical assays by Janssen Research and Development 
under the control of PTS-DMPK/Scinovo, GlaxoSmithKline, the details of which will be 
included in the SPM.
Processing, storage and shipping procedures are provided in the SPM.
7.7.
Biomarkers/Pharmacodynamic Markers
7.7.1.
Exploratory Biomarkers
Blood samples will be taken at the times indicated in Time and Events Table 2, Section 
7.1 for assessment of changes in the biomarkers of bone formation or resorption, CTX1
and P1NP, and for changes in biomarkers indicative of Th1 and Th17 cell function, IFN-γ
and IL-17A. An additional sample should be taken at the time of onset of disease flare 
when applicable for assessment of IFN-γ and IL-17A.

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7.7.2.
Optional Exploratory Biomarkers
Subjects will also have the option to provide blood and urine samples for future 
evaluation of biomarkers related to GCA disease activity and transcriptomic analyses to 
further elucidate the biology of the disease. These samples will be stored in a biobank for 
a period of up to 5 years. Provision of these samples is optional and is not required for 
participation in the study.
7.7.3.
Pharmacodynamic Markers
Blood samples will be taken at the times indicated in Time and Events Table 2, Section 
7.1 for assessment of changes in free and total IL-6 as a pharmacodynamic marker of 
sirukumab activity. Analyses of serum IL-6 levels will be performed using validated 
assays by Janssen Research and Development
7.8.
Genetics
A blood sample for genetic research will be collected from consenting subjects at the 
baseline visit. Refusal to participate in the genetic research will not preclude the subject 
from participating in the study.
7.9.
Exploratory Ultrasound Imaging
7.9.1.
Background and Rationale
The results of three recent meta-analyses have provided evidence to support the utility of 
US imaging in the diagnosis of GCA [Ball, 2010; Arrida, 2010; Karassa, 2005]. 
Additional data from a multicenter study, TABUL (Temporal Artery Biopsy versus 
ULtrasound), conducted at centers trained in US imaging techniques, also support the 
diagnostic utility of US in GCA [Luqmani, 2015]. However, the role of US imaging in 
the assessment of GCA disease activity remains unclear. Available evidence consists of 
results from a study which found persistent abnormalities suggestive of an association 
with relapse when GCA patients were assessed by ultrasound imaging every 2-4 weeks 
[De Miguel, 2012]. Permanent visual loss is also associated with the presence of 
abnormal sonographic features of cranial and extra-cranial arteries [Schmidt, 2008; 
Schmidt, 2009; Czihal, 2012]. A recent prospective observational study has demonstrated 
that ultrasound can be informative in distinguishing potential flares from exacerbations of 
unrelated headache in patients with diagnosis of GCA [Ponte, 2015]. Taken together, 
these findings suggest that ultrasound imaging may provide a useful diagnostic and 
biomarker approach for assessing and monitoring disease activity in GCA.
Currently, no valid biomarkers exist to assess response to therapy and to predict relapse. 
Changes in the conventional inflammatory markers (CRP and ESR) do not consistently 
reflect disease activity [Tse, 1998]. Therefore, the utility of US in monitoring disease 
activity in GCA will be explored in a cohort of study subjects from select participating 
centers by sonographers trained and/or qualified as proficient in US imaging.  

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Longitudinal changes in vascular inflammation of the temporal and axillary arteries and 
the predictive value of US for disease activity will be assessed. 
7.9.2.
Synopsis
A cohort of subjects with new onset GCA from participating imaging centers who have 
consented to participate in the US imaging portion of this study will be evaluated. These 
subjects will undergo US scans of their temporal and axillary arteries at the specified time 
points for assessment of changes in vascular inflammation. 
Only subjects with newly diagnosed GCA are eligible to participate. Due to the 
exploratory nature of this portion of the study, there is no pre-specified sample size for 
this cohort.  However, it is estimated that up to 50 subjects may participate.
Subjects will have an initial baseline scan at Screening and assessments at Baseline 
(Week 0), Weeks 12 and 52. Additional US scans should also be conducted in the event 
of relapses or flares, including flares/relapses that occur during Part B of the study. US 
scanning for flares/relapses in Part B of the study will conclude when the last subject in 
the US imaging cohort completes Part A of the study. Thereafter, no additional scans will 
be taken.
Subjects may also be asked to provide retrospective consent for assessment of their 
diagnostic US scan. Efforts should be made to conduct the baseline US scan within 3 
days of initiating prednisone therapy. However, inability to comply with this time frame 
does not exclude subjects from participation. Data will be analyzed according to the time 
frame between prednisone dose and US scan. Detailed information on US imaging in this 
cohort of study subjects is included in Appendix 8.
8.
DATA MANAGEMENT

For this study (eDM) subject data will be entered into GSK defined CRFs, 
transmitted electronically to GSK or designee and combined with data provided 
from other sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.

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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary null hypothesis (H0) for this study is that there is no difference between 
sirukumab 100mg SC q2w plus 6 month prednisone (Treatment Arm A) and placebo plus 
6 month prednisone (Treatment Arm D) in the proportions of subjects with sustained 
disease remission at 52 weeks.
The alternative hypothesis (H1) for this study is that there is a difference in the 
proportions of subjects with sustained disease remission at 52 weeks. 
The hypothesis to be tested for the proportion of subjects in sustained disease remission 
at 52 weeks using a 2-sided test at α=0.05 will therefore be:
H0:  Sirukumab 100mg SC q2w + 6 month prednisone = placebo + 6 month 
prednisone  
Vs. 
H1: Sirukumab 100mg SC q2w + 6 month prednisone ≠ placebo + 6 month 
prednisone
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size has been calculated assuming a 30% sustained remission rate on the 
placebo plus 6 month prednisone arm, versus a 70% rate on the sirukumab plus 6 month 
prednisone arms at 52 weeks.  To be able to detect that difference using a 5% 
significance level, the sample size of N=51 on sirukumab 100mg SC q2w, N=34 on 
sirukumab 50 mg SC q4w and N=34 on placebo when used in combination with a 6 
month prednisone taper has > 91% power.
The study is also powered to detect a statistically significant difference between 
sirukumab 100 mg SC q2w plus 3 month prednisone (Treatment Arm B) and placebo 
plus 6 month prednisone (Treatment Arm D) only if the assumptions for 6 month 
prednisone taper apply to the 3 month prednisone taper (i.e. 70% sustained remission rate 
at week 52). 
Subjects will be assigned to study treatment arms using an allocation ratio of 3:3:2:2:2, 
see Section 6.2 for more details. The randomisation will be stratified by baseline oral 
prednisone dose (<30 mg/day or ≥ 30 mg/day).   

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9.2.2.
Sample Size Sensitivity
A sample size sensitivity analysis was performed to assess the effect on power if the 
sirukumab plus 6 month prednisone response rate was lower than expected at 65%, 60% 
or 55%.
Response Rate
Sirukumab 100 mg
+ 6m Pred
Difference
Active-Placebo
N
Placebo +6m Pred
N
Sirukumab 
100mg + 6m 
Pred
Power
70%
40%
34
51
96%
65%
35%
34
51
89%
60%
30%
34
51
79%
55%
25%
34
51
64%
Assuming a placebo response rate of 30%, the target sample size of 34 for placebo plus 6 
month prednisone and 51 for sirukumab 100 mg SC q2w plus 6 month prednisone, a 
treatment difference larger than 21% will achieve statistical significance at the 
alpha=0.05 level.
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
For statistical analysis, all tests will be two-sided with significance interpreted at the 
α=0.05 significance level.
9.3.1.
Analysis Populations
The analysis populations will include:
Intent to Treat (ITT) population: The ITT population is defined as all subjects who 
were randomised to treatment and who received at least one dose of study medication. 
This population will be the primary population for statistical comparisons for efficacy. 
Safety population: This population will consist of all randomised subjects who received 
at least one or a partial dose of study medication. Subjects will be assessed according to 
the treatment they receive. This population will be used for assessing safety.
Further details of these and any other are included in the Reporting and Analysis Plan 
(RAP).

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9.3.2.
Analysis Datasets
Observed: Observed data is the data collected or observed for the subject with no 
imputation for missing data.
Further details are included in the RAP.
9.3.3.
Treatment comparisons
Primary comparison of interest is the comparison between sirukumab 100 mg SC q2w 
plus 6 month prednisone (Treatment Arm A) and placebo plus 6 month prednisone 
(Treatment Arm D) for the proportion of subjects in sustained disease remission at Week 
52 in the ITT population at the 0.05 significance level. The analysis will be adjusted for 
the stratification factor applied at randomization.
If the test of the primary endpoint for the primary comparison is statistically significant at 
α=0.05 (2-sided), the cumulative prednisone dose at week 52 (key secondary endpoint) 
for the primary comparison (arm A vs arm D) will be tested at a significance level of 0.05 
(2-sided). If the statistical significance for the primary endpoint is not met, then the key 
secondary endpoint in the sequence cannot be deemed statistically significant, although 
nominal p-values may be reported and considered descriptive but should not be 
interpreted inferentially.
For the 2 endpoints outlined above the following treatment comparisons will also be 
evaluated following the same sequential approach provided that the primary endpoint for 
the primary comparison achieves significance:

Sirukumab 100mg SC q2w plus 3 month prednisone versus placebo plus 6 month 
prednisone (Arm B vs. Arm D)

Sirukumab 100mg SC q2w plus 6 month prednisone versus placebo plus 12 month 
prednisone (Arm A vs. Arm E)

Sirukumab 100mg SC q2w plus 3 month prednisone versus placebo plus 12 month 
prednisone (Arm B vs. Arm E) 
Comparisons with Sirukumab 50mg SC q4w (Arm C) will be similarly evaluated. 
An overview of the multiplicity control is provided in Figure 2.
An alternative testing hierarchy, used to address regional differences in the regulatory 
requirements for controlling type 1 error, will be specified in the RAP.

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Analyses of other efficacy endpoints will not be subject to any multiple comparison 
procedure. All statistical tests will be 2-sided and performed at an overall significance 
level of 0.05.
Further details are included in the RAP.

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Figure 2
Overview of the Multiplicity control

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9.3.4.
Interim Analysis
Since sirukumab is as yet untested in GCA, the study may employ a futility interim 
analysis to enable a decision to stop the study early should there be no or little effect of 
sirukumab.  Dependent on the recruitment rate, the interim analysis may be carried out 
when approximately 30% of subjects have completed 52 weeks. The study will only be 
stopped for futility (lack of efficacy) if the probability of success of the study (i.e. the 
conditional power based on the observed interim data) is calculated to be very low. The 
futility assessment will be carried out by an IDMC, composed of clinicians and 
statisticians who are external to GSK, such that GSK remains fully blinded to all data and 
results.  
The study will not be stopped early for efficacy to ensure no increase in the risk of a false 
positive result.  
Full details of the process and decision criteria for this interim analysis for futility are
included in the RAP.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Efficacy Analyses
The primary endpoint is a proportion of subjects in sustained remission at Week 52, 
defined as having:
5.
Achieved remission (absence of clinical signs and symptoms of GCA and 
normalization of ESR [<30 mm/hr] and CRP [<1 mg/dL]), by Week 12
6.
Absence of disease flare (recurrence of symptoms attributable to active GCA, with or 
without elevations in ESR and/or CRP) following remission at Week 12 through 
Week 52
7.
Completed the assigned prednisone taper protocol
8.
No requirement for rescue therapy at any time through Week 52.
Subjects who do not achieve remission within 12 weeks, require rescue therapy, 
discontinue treatment during the study or withdraw early from the study for any reason or 
do not follow the assigned prednisone taper will be recorded as non-responders in the 
analysis of the primary endpoint.
The proportion of subjects with sustained remission at week 52 in the sirukumab 100 mg 
SC q2w plus 6 month prednisone (Arm A) versus placebo plus 6 month prednisone (Arm 
D) will be analysed using a logistic regression model controlling for the stratification 
factor of baseline prednisone dose. The model will also include the treatment arms. Odds 
ratios and 95% confidence intervals will be produced.
If however a non-parametric approach is more appropriate then the Cochran-Mantel-
Haenszel will be used.

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As a supportive of the primary endpoint, the percentage of subjects meeting each of the 
components of the primary endpoint at Week 52 will be presented and the treatment 
effect on those components will be evaluated.
Further details of the analysis are included in the RAP. 
9.4.2.
Secondary Efficacy Analyses
For the analysis of secondary endpoints, all major continuous endpoints such as 
cumulative prednisone dose in Part A and Part B will be analysed using repeated 
measures mixed effects model. The analysis will be adjusted for the stratification factors 
applied at randomisation, as well as the baseline value for the parameter being tested. 
The proportion of subjects in sustained remission over time (Part A and Part B) will be 
analysed using the logistic regression as described for the primary endpoint.
The major secondary endpoints for each comparison of interest will be tested using a step 
down sequential testing procedure to control the type 1 error.
Further details of the analysis are included in the RAP. 
9.4.3.
Safety Analyses
Safety in Part A and Part B will be evaluated by adverse events, and changes in 
laboratory parameters. All safety analyses will be performed on the safety population. 
Complete details of the safety analyses are provided in the RAP.
9.4.3.1.
Extent of Exposure
The number of day’s exposure to study drug will be summarized by treatment group.
9.4.3.2.
Adverse Events
The proportion of subjects reporting AEs will be tabulated for each treatment group. The 
following summaries of AEs will be provided:

All AEs

Treatment-related AEs

AEs leading to withdrawal

AEs leading to discontinuation of study drug

Serious AEs

Serious CV events adjudicated by the CEC.

AEs of special interest, including corticosteroid-related AEs.

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9.4.3.3.
Laboratory Parameters
Laboratory data (absolute values and changes from baseline) will be summarized by visit 
and treatment group. In addition, the number and percent of subjects with values of 
clinical concern will be summarized by treatment group.
9.4.3.4.
Other Safety Measures
Reason for withdrawal/treatment discontinuation will be summarized. Summary statistics 
for vital signs evaluations at each visit will be presented by treatment group. In addition, 
summary statistics for change from baseline for vital signs evaluations will be presented 
by treatment group.
ECG findings will be summarized by treatment group.
Further details are provided in the RAP.
9.4.4.
Health Outcomes Analyses
All continuous endpoints such as SF-36 will be analysed using repeated measures mixed 
effects model. The analysis will be adjusted for the stratification factors applied at 
randomisation, as well as the baseline value for the parameter being tested. 
Health outcomes endpoints will also be summarised appropriately.
Further details are provided in the RAP.
9.4.5.
Pharmacokinetic and Immunogenicity Analyses
Serum concentrations of sirukumab in Part A will be summarized descriptively by time 
and treatment group. All data will be listed.
Possible relationships between serum concentrations and efficacy or safety endpoints 
may be investigated in an exploratory manner, if appropriate.
Immunogenicity (serum anti-sirukumab antibodies) in Part A and Part B if applicable will 
be summarized descriptively by time and treatment group.
All data will be listed.
Further details are included in the RAP.
9.4.6.
Pharmacodynamic/Exploratory/Biomarker Analyses
Pharmacodynamic and biomarker data in Part A will be presented in graphical and/or 
tabular form and will be summarised descriptively. As appropriate, exploratory statistical 
analyses may be conducted where the distribution of biomarker data will be investigated. 

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Possible relationships between biomarker data and efficacy endpoints may be 
investigated in an exploratory manner, if appropriate. 
Further details are included in the RAP.
9.4.7.
Pharmacogenetic Analyses
Any PGx analyses will be described separately from the main clinical study report. GSK 
may summarize the PGx research results in the clinical study report, or separately, or may 
publish the results in scientific journal.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

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
Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK (or designee) monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK (or designee) will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents

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10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
(or designee) may conduct a quality assurance assessment and/or audit of the site 
records, and the regulatory agencies may conduct a regulatory inspection at any 
time during or after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK (or 
designee) monitor will conduct site closure activities with the investigator or site 
staff, as appropriate, in accordance with applicable regulations including GCP, 
and GSK Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK (or designee) will discuss the 
reasons for taking such action with the investigator or the head of the medical 
institution (where applicable).  When feasible, GSK (or designee) will provide 
advance notification to the investigator or the head of the medical institution, 
where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK (or 
designee) will promptly inform all investigators, heads of the medical institutions
(where applicable) and/or institution(s) conducting the study. GSK (or designee) 
will also promptly inform the relevant regulatory authorities of the suspension or 
premature discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.

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10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK [or designee] audit or regulatory inspection) and must be 
available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK (or designee) will inform the investigator of the time period for retaining 
these records to comply with all applicable regulatory requirements.  The 
minimum retention time will meet the strictest standard applicable to that site for 
the study, as dictated by any institutional requirements or local laws or 
regulations, GSK standards/procedures, and/or institutional requirements. 

The investigator must notify GSK (or designee) of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  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 a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.

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The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter which is available upon request.
An independent CEC will be established for this study to review case information on 
serious 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.

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11.
REFERENCES
Achkar, A.A., Lie, J.T., Hunder, G.G., O’Fallon, W.M., and Gabriel, S.E. (1994). How 
does previous corticosteroid treatment affect the biopsy findings in giant cell (temporal) 
arteritis? Annals of Internal Medicine 120, 987-992.
ACTEMRA [prescribing information]. South San Francisco, CA: Genentech, Inc; 2011.
Arrida, A., Kyprianou, M., Kanakis, M., and Sfikakis, P.P. (2010). The diagnostic value 
of ultrasonography-derived edema of the temporal artery wall in giant cell arteritis: a 
second meta-analysis. BMC Musculoskeletal Disorders 11, 44.
Ball, E.L., Walsh, S.R., Tang, T.Y., Gohil, R., and Clarke, J.M. (2010). Role of 
ultrasonography in the diagnosis of temporal arteritis. The British Journal of Surgery 97, 
1765-1771.
Besada, E., and Nossent, J.C. (2012). Ultrasonographic resolution of the vessel wall 
oedema with modest clinical improvement in a large-vessel vasculitis patient treated with 
tocilizumab. Clinical Rheumatology 31, 1263-1265.
Beyer, C., Axmann, R., Sahinbegovic, E., Distler, J.H., Manger, B., Schett, G., and 
Zwerina, J. (2011). Anti-interleukin 6 receptor therapy as rescue treatment for giant cell 
arteritis. Annals of the Rheumatic Diseases 70, 1874-1875.
Cella D, Lai J, Chang C, et al.  Fatigue in cancer patients compared with fatigue in the
general United States population.  Cancer.  2002:94(2):528-538.
Christidis, D., Jain, S., and Das Gupta, B. (2011). Successful use of tocilizumab in 
polymyalgic onset biopsy positive GCA with large vessel involvement. BMJ case reports
2011.
Czihal, M., Zanker, S., Rademacher, A., Tato, T.Y., Kuhlencordt, P.J., Schulze-Koops, 
H., and Hoffman, U. (2012). Sonographic and clinical pattern of extracranial and cranial 
giant cell arteritis. Scandinavian Journal of Rheumatology 41:231-236.
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.
De Miguel, E., Roxo, A., Castillo, C., Peiteado, D., Villalba, A., and Martin-Mola, E. 
(2012). The utility and sensitivity of colour Doppler ultrasound in monitoring changes in 
giant cell arteritis. Clinical and Experimental Rheumatology 30, S34-38.
Emilie, D., Liozon, E., Crevon, M.C., Lavignac, C., Portier, A., Liozon, F., and 
Galanaud, P. (1994). Production of interleukin 6 by granulomas of giant cell arteritis. 
Human Immunology 39, 17-24.
EuroQol Group.  EuroQol – a new facility for the measurement of health-related quality 
of life.  Health Policy.  1990;16:199-208

2015N227575_03
CONFIDENTIAL
201677
101
Flannery, C.R., Little, C.B., Hughes, C.E., Curtis, C.L., Caterson, B., and Jones, S.A. 
(2000). IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan 
catabolism in articular cartilage. Matrix biology : Journal of the International Society for 
Matrix Biology 19, 549-553.
Fries JF, Spitz P, Kraines RG, Holman HR.  Measurement of patient outcomes in 
arthritis.  Arthritis Rheum. 1980;23:137-145.
Gottenberg, J.E., Dayer, J.M., Lukas, C., Ducot, B., Chiocchia, G., Cantagrel, A., Saraux, 
A., Roux-Lombard, P., and Mariette, X. (2012). Serum IL-6 and IL-21 are associated 
with markers of B cell activation and structural progression in early rheumatoid arthritis: 
results from the ESPOIR cohort. Annals of the Rheumatic Diseases 71, 1243-1248.
Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, Curtis JR, Furst
DE, McMahon M, Patkar NM, Volkmann E, Saag KG. (2010). American College of 
Rheumatology 2010 Recommendations for the Prevention and Treatment of 
Glucocorticoid-Induced Osteoporosis. Arthritis Care and Research, 62(11), 1515-1526.
Hachulla, E., Boivin, V., Pasturel-Michon, U., Fauchais, A.L., Bouroz-Joly, J., Perez-
Cousin, M., Hatron, P.Y., and Devulder, B. (2001). Prognostic factors and long-term 
evolution in a cohort of 133 patients with giant cell arteritis. Clinical and Experimental 
Rheumatology 19, 171-176.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.
Hayreh, S.S., and Zimmerman, B. (2003). Management of giant cell arteritis. Our 27-year 
clinical study: new light on old controversies. Ophthalmologica. Journal International 
d’Ophtalmologie. International Journal of Ophthalmology. Zeitschrift fur 
Augenheilkunde 217, 239-259.
Hoffman, G.S., Cid, M.C., Rendt-Zagar, K.E., Merkel, P.A., Weyand, C.M., Stone, J.H., 
Salvarani, C., Xu, W., Visvanathan, S., Rahman, M.U., and Infliximab, G.C.A.S.G. 
(2007). Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell 
arteritis: a randomized trial. Annals of Internal Medicine 146, 621-630.
ICH Topic M 3 (R2) Guidance on Non-Clinical Safety Studies for the Conduct of Human 
Clinical Trials and Marketing Authorization for Pharmaceuticals. Note 5. 2009. 
CPMP/ICH/286/95.”
Isik, M., Kilic, L., Dogan, I., and Calguneri, M. (2013). Tocilizumab for giant cell 
arteritis: an amazing result. Rheumatology International 33, 2961-2962.

2015N227575_03
CONFIDENTIAL
201677
102
Karassa, F.B., Matsagas, M.I., Schmidt, W.A., and Ioannidis, J.P. (2005). Meta-analysis: 
test performance of ultrasonography for giant-cell arteritis. Annals of Internal Medicine 
142, 359-369.
Lipsky, P.E. (2006). Interleukin-6 and rheumatic diseases. Arthritis Research & Therapy
8 Suppl 2, S4.
Luqmani R, Lee E, Singh S, Gillett M, Schmidt WA, Bradburn M, Dasgupta B, 
Diamantopoulos AP, Forrester-Barker W, Hamilton W, Masters S, McDonald B, 
McNally E, Pease CT, Piper J, Salmon J, Wailoo A, Wolfe K, Hutchings A. Inter-Rater 
Analysis of Ultrasound and Histological Findings in Patients with Suspected Giant Cell 
Arteritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10).
Lurati, A., Bertani, L., Re, K.A., Marrazza, M., Bompane, D., and Scarpellini, M. (2012). 
Successful treatment of a patient with giant cell vasculitis (Rheuma arteritis) with 
tocilizumab a humanized anti-interleukin-6 receptor antibody. Case Reports in 
Rheumatology 2012, 639612.
Martinez-Taboada VM, Rodriguez-Valverde V, Carreno  L, et al (2008). A double-blind 
placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid 
side effects. Annals of the Rheumatic Diseases 67, 625-630.
Mundt JC, Greist JH, Gelenberg AJ, Katzelnick DJ, Jefferson JW, Modell JG. Feasibility 
and validation of a computer-automated Columbia-Suicide Severity Rating Scale using 
interactive voice response technology. J Psychiat Res. 2010; 44(16):1224-1228.
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B.K., and Ganz, 
T. (2004). IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the 
iron regulatory hormone hepcidin. The Journal of Clinical Investigation 113, 1271-1276.
Nesher, G. (2014). The diagnosis and classification of giant cell arteritis. Journal of 
Autoimmunity 48-49, 73-75.
Ponte C, Vaggers S, Sznajd J, O'Neill L, Piper J, Gunn J, Mankia K, Luqmani R. How 
Can We Use Ultrasound in the Diagnosis and Management of Patients with Giant Cell 
Arteritis? [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10).
Proven, A., Gabriel, S.E., Orces, C., O’Fallon, W.M., and Hunder, G.G. (2003). 
Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis 
and Rheumatism 49, 703-708.
Rincon, M. (2012). Interleukin-6: from an inflammatory marker to a target for 
inflammatory diseases. Trends in Immunology 33, 571-577.
Roche, N.E., Fulbright, J.W., Wagner, A.D., Hunder, G.G., Goronzy, J.J., and Weyand, 
C.M. (1993). Correlation of interleukin-6 production and disease activity in polymyalgia 
rheumatica and giant cell arteritis. Arthritis and Rheumatism 36, 1286-1294.

2015N227575_03
CONFIDENTIAL
201677
103
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.
Salvarani, C., Crowson, C.S., O’Fallon, W.M., Hunder, G.G., and Gabriel, S.E. (2004). 
Reappraisal of the epidemiology of giant cell arteritis in Olmsted County, Minnesota, 
over a fifty-year period. Arthritis and Rheumatism 51, 264-268.
Salvarani, C., Magnani, L., Catanoso, M., Pipitone, N., Versari, A., Dardani, L., 
Pulsatelli, L., Meliconi, R., and Boiardi, L. (2012). Tocilizumab: a novel therapy for 
patients with large-vessel vasculitis. Rheumatology (Oxford, England) 51, 151-156.
Sampson HA, Munoz-Furlong A, Campbell RL, et.al. (2006). Second symposium on the
definition and management of anaphylaxis: Summary report-Second National Institute of
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J
Allergy Clin Immunol.117, 391-397.
Schmidt WA, Krause E, Schicke B, Kuchenbecker J, Gromnica-Ihle E. Do temporal 
artery duplex ultrasound findings correlate with ophtalmic complications in giant cell 
arteritis? Rheumatology (Oxford). 2009 Apr; 48(4):383-5.
Schmidt WA, Moll A, Seifert A, Schicke B, Gromnica-Ihle E, Krause A. Prognosis of 
large-vessel giant cell arteritis. Rheumatology (Oxford). 2008 Sep;47(9):1406-8.
Sciascia, S., Rossi, D., and Roccatello, D. (2011). Interleukin 6 blockade as steroid-
sparing treatment for 2 patients with giant cell arteritis. The Journal of Rheumatology 38, 
2080-2081.
Seitz, M., Reichenbach, S., Bonel, H.M., Adler, S., Wermelinger, F., and Villiger, P.M. 
(2011). Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case 
series. Swiss Medical Weekly 141, w13156.
Seror, R., Baron, G., Hachulla, E., Debandt, M., Larroche, C., Puechal, X., Maurier, F., 
de Wazieres, B., Quemeneur, T., Ravaud, P., and Mariette, X. (2013). Adalimumab for 
steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised 
controlled trial. Annals of the Rheumatic Diseases.
Spies, C.M., Burmester, G.R., and Buttgereit, F. (2010). Methotrexate treatment in large 
vessel vasculitis and polymyalgia rheumatic. Clinical and Experimental Rheumatology
28, S172-177.
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.
Swaak, A.J., van Rooyen, A., Nieuwenhuis, E., and Aarden, L.A. (1988). Interleukin-6 
(IL-6) in synovial fluid and serum of patients with rheumatic diseases. Scandinavian 
Journal of Rheumatology 17, 469-474.

2015N227575_03
CONFIDENTIAL
201677
104
Tse, W.Y., Cockwell, P., and Savage, C.O. (1998). Assessment of disease activity in 
systemic vasculitis. Postgraduate Medical Journal 74, 1-6.
Unizony, S., Arias-Urdaneta, L., Miloslavsky, E., Arvikar, S., Khosroshahi, A., Keroack, 
B., Stone, J.R., and Stone, J.H. (2012). Tocilizumab for the treatment of large-vessel 
vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis 
Care & Research 64, 1720-1729.
Unizony, S.H., Dasgupta, B., Fisheleva, E., Rowell, L., Schett, G., Spiera, R., Zwerina, 
J., Harari, O., and Stone, J.H. (2013). Design of the tocilizumab in giant cell arteritis trial. 
International Journal of Rheumatology 2013, 912562.
Vinit, J., Bielefeld, P., Muller, G., and Besancenot, J.F. (2012). Efficacy of tocilizumab in 
refractory giant cell arteritis. Joint, Bone, Spine : Revue du Rhumatisme 79, 317-318.
Waldman, C.W., Waldman, S.D., and Waldman, R.A. (2013). Giant cell arteritis. The 
Medical Clinics of North America 97, 329-335.
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.
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.
Weyand, C.M., and Goronzy, J.J. (2013). Immune mechanisms in medium and large-
vessel vasculitis. Nature Reviews. Rheumatology 9, 731-740.
Weyand, C.M., Fulbright, J.W., Hunder, G.G., Evans, J.M., and Goronzy, J.J. (2000). 
Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. 
Arthritis and Rheumatism 43, 1041-1048.
Weyand, C.M., Younge, B.R., and Goronzy, J.J. (2011). IFN-gamma and IL-17: the two 
faces of T-cell pathology in giant cell arteritis. Current Opinion in Rheumatology 23, 43-
49.
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E.  Measuring fatigue sand other 
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system.  J Pain Sympt Manage. 1997;13;63-74.  

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACR
American College of Rheumatology
AE
Adverse Event
AION
Acute Ischemic Optic Neuropathy
ALT
Alanine Transaminase
ANC
Absolute Neutrophil Count
AST
Aspartate Transaminase
BCG
Bacille Calmette-Guérin
BD
Becton-Dickinson
bili
Bilirubin
CEC
Clinical Events Committee 
CONSORT
Consolidated Standards of Reporting Trials
COX-2
Cyclooxygenase-2
CRF
Case Report Form
CRP
C-reactive Protein
C-SSRS
Columbia-Suicide Severity Rating Scale
CTA
Computed Tomography Angiography
CTX
Carboxyterminal Cross-linked Telopeptide of Bone 
Collagen
CV
Cardiovascular
DBL
Database lock
dL
Deciliter
DMARD
Disease Modifying Antirheumatic Drugs
ECG
Electrocardiogram
eDM
Electronic Data Management
EQ VAS
EuroQoL Visual Analogue Scale
EQ-5D
EuroQoL-5 Dimensions
ESR
Erythrocyte Sedimentation Rate
EudraCT
European Clinical Trials Database
FACIT-Fatigue
Functional assessment of Chronic Illness Therapy-Fatigue
FDA
Food and Drug Administration
G
gauge
GCA
Giant Cell Arteritis
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
gr
Gram
GSK
GlaxoSmithKline
HAQ-DI
Health Assessment Questionnaire-Disability Index
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen

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HIV
Human Immunodeficiency Virus
hr
Hour
IB
Investigator’s Brochure
ICF
Informed Consent Form
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IgG1
Immunoglobulin G1
IL-1
Interleukin-1
IL-1ra
Anakinra
IL-6
Interleukin-6
IL-17A
Interleukin-17A
IRB
Institutional Review Board
IV
Intravenous
IRT
Interactive Response Technology
LOCF
Last Observation Carried Forward
LTBI
Latent Tuberculosis Infection
mAb
Monoclonal Antibody
MedDRA
Medical Dictionary for Regulatory Activities
mol
Micromoles
mg
Milligrams
Mm
Millimeters
MMF
Mycophenolate Mofetil
MRA
Magnetic Resonance Angiography
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTX
Methotrexate
NCI-CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NRS
Numeric Rating Scale
NSAID
Nonsteroidal anti-inflammatory drug
PGIC
Patient Global Impression of Change
PhGA
Physician Global Assessment
P1NP
Procollagen Type 1 N-propeptide
PET-CT
Positron Emission Tomography-computed Tomography
PFS
Pre-filled Syringe
PFS-U
Prefilled Syringe-Ultrasafe
PK
Pharmacokinetic
PMR
Polymyalgia Rheumatic
po
Per os (by mouth)
PRO
Patient Reported Outcomes
PtGA
Patient Global Assessment
q2w
Every 2 Weeks
q4w
Every 4 Weeks
RA
Rheumatoid Arthritis
RAP
Reporting and Analysis Plan

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SAE
Serious Adverse Event
SC
Subcutaneous
SF-36v2
36-item Short Form Health Survey Version 2
SI
International System of Units
SLE
Systemic Lupus Erythematosus
SPM
Study Procedures Manual 
TIA
Transient Ischemic Attack
TST
Tuberculin Skin Test
TB
Tuberculosis
TNF
Tumor Necrosis Factor
ULN
Upper Limit of Normal
US
Ultrasound
VAS
Visual Analogue Scale
vs
Versus
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
ACTEMRA
Hypak
QuantiFERON
RIBA
SCF
SmartJect (Autoinjector)
UltraSafe Passive

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12.2.
Appendix 2: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
(FRP) and Collection of Pregnancy Information
12.2.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 

Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007a].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Oral Contraceptive, either combined or progestogen alone [Hatcher, 
2007a] Injectable progestogen [Hatcher, 2007a]
o
Contraceptive vaginal ring [Hatcher, 2007a]
o
Percutaneous contraceptive patches [Hatcher, 2007a]
If using hormonal contraceptives, including oral, injections and patches, a secondary 
method of contraception must be used.
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and,
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g. male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009]. 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.

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12.2.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject or female 
partner of male study subject who becomes pregnant while participating in or while 
partner is participating in this study.

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating in this study will 
discontinue study drug. There is no requirement to be withdrawn from the study.

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12.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2 
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen)
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for PK analysis, obtained 
within 24 hours after last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

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
Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted

If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography)
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2. All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 

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studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5. If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6. PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 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. Instructions for sample handling and shipping are in 
the SPM.
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.

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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.

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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 

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condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
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 medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF.

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 

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and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 

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or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data.

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the SAE 
coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.5.
Appendix 5: American College of Rheumatology Standard of 
Care Recommendations for the Prevention and Treatment of 
Glucocorticoid-Induced Osteoporosis*
Recommended Monitoring for Patients Receiving Prevalent Glucocorticoid Therapy 
for a Duration >3 Months

Consider serial bone mineral density testing

Consider annual serum 25-hydroxyvitamin D measurement

Annual height measurement 

Assessment of incident fragility fracture 

Assessment of osteoporosis medication compliance
Pharmacologic Recommendations for Postmenopausal Women and Men age >50 
Years Starting Glucocorticoid Therapy with an Anticipated Duration of >3 Months, 
or Prevalent Glucocorticoid Therapy of a Duration of at Least 3 months 
Low-risk patient
Alendronate for _7.5 mg/day prednisone 
OR
Risedronate for _7.5 mg/day prednisone 
OR
Zoledronic acid for _7.5 mg/day prednisone
Medium-risk patient
Alendronate for any dose of glucocorticoids 
OR
Risedronate for any dose of glucocorticoids 
OR
Zoledronic acid for _7.5 mg/day prednisone
High-risk patient
Alendronate 
OR
Risedronate 
OR
Zoledronic acid
OR
Teriparatide

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* Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, Curtis JR, Furst 
DE, McMahon M, Patkar NM, Volkmann E, Saag KG. (2010). American College of 
Rheumatology 2010 Recommendations for the Prevention and Treatment of 
Glucocorticoid-Induced Osteoporosis. Arthritis Care and Research, 62(11), 1515-1526.

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12.6.
Appendix 6: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including sirukumab, prednisone or any concomitant 
medicines;

GCA susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 

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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 

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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.

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12.7.
Appendix 7 - Country Specific Requirements
In Germany, subcutaneous administration of sirukumab or matching placebo must be 
discontinued for subjects with a clinically important, active infection. This treatment 
must be withheld until serious and/or severe infections have been completely resolved. 
This includes all opportunistic infections, sepsis or meningoencephalitis.
In the Netherlands, no subject will be enrolled in the extension phase (Part B) of the 
study. Subjects will discontinue the study upon completion Part A and the 16-week 
follow-up phase.
In Australia and New Zealand, the investigator will be notified of the value of the ESR 
result when an ESR value is > 40 mm/hr or in the event of a increase from baseline or 
previous visit of  > 10 mm/hr in order to determine if a treatment change is warranted.

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12.8.
Appendix 8: Exploratory US Imaging
The utility of US in monitoring disease activity in GCA will be investigated in a cohort of 
subjects with new onset GCA. Longitudinal changes in vascular inflammation of the 
temporal and axillary arteries will be characterized. Only subjects with new onset GCA 
will participate in order to optimize the ability to detect inflammatory changes on US, 
based on the potential likelihood that these subjects would not have been receiving 
corticosteroids prior to diagnosis.
12.8.1.
Objectives and Endpoints
The objectives and endpoints of this exploratory US imaging cohort are as follows:
Objectives
Endpoints
To explore the utility of vascular 
ultrasound (US) imaging assessment 
of inflammation in temporal and 
axillary arteries as an indicator of 
disease activity in a cohort of study 
subjects

To explore the predictive value of 
ultrasound for clinical efficacy in 
GCA

Change over time in measurements of 
vascular inflammation in temporal 
and axillary arteries 

Correlation of clinical endpoints with 
changes in vascular inflammation.

Correlation of changes in vascular 
inflammation on US with clinical 
activity, CRP and ESR 

Correlation of changes in vascular 
inflammation on US with health-
related quality of life outcomes.
12.8.2.
Type and Number of Subjects
Only subjects with new onset GCA are eligible to participate in the exploratory imaging 
portion of this study. These subjects will have a diagnosis of GCA based on the Revised 
GCA Diagnosis Criteria, and present with new onset GCA disease, defined as having a 
diagnosis within 6 weeks of baseline. Subjects should have either initiated prednisone 
treatment upon entry into Screening and after their Screening US scan has been 
performed or corticosteroid therapy should have only been recently initiated, optimally 
within 3 days of the Screening scan. However, inability to comply with this time frame 
does not exclude subjects from participation.

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As this is an exploratory study, there is no pre-specified sample size. However it is 
estimated that up to 50 subjects may participate. 
12.8.3.
Assessments and Procedures
12.8.3.1.
Sonographer Training
All sonographers participating in this study must have undergone training with 
documented approval to qualify as a participating site. Sites previously trained for 
participation in the TABUL study will not be required to participate in the training 
sessions, but may certify through a separate process. Processes and procedures for 
training and qualification are outlined in the Imaging Acquisition Guidelines.  
Sonographers participating in the training course will US scan a requisite number of 
healthy volunteers/non-GCA subjects and at least one patient volunteer with active GCA 
as per the protocol definition for qualification. All volunteers recruited to participate in 
the sonographer training will be required to provide consent prior to participation. GCA 
patients who participate in the sonographer training may be eligible to enroll in Study 
201677, but they are excluded from participating in the imaging cohort portion of the 
study. Detailed information on the sonographer training process is contained in the 
training manual.
12.8.3.2.
Subject Eligibility
Study subjects consenting to participate in the exploratory US imaging cohort are eligible 
only if they have newly diagnosed GCA (within 6 weeks of baseline), based on the 
Revised GCA Diagnosis Criteria as described in Section 5.1. At Baseline, subjects must 
have fulfilled all of the eligibility criteria for Study 201677 and be randomized into the 
study to continue participation in the exploratory imaging cohort. Screen failures for 
Study 201677 will not be eligible to participate in this cohort.
Optimally, the study baseline scan (Screening) would be performed prior to the initiation 
of prednisone treatment. If this is not possible, then efforts should be made to perform the 
US scan within 3 days of initiating prednisone treatment. However, the inability to 
comply with this time frame is not exclusionary. The number of days between initiation 
of prednisone treatment and the US scan will be recorded. 
12.8.3.3.
Ultrasound Scanning
Participating subjects will undergo US scans at the following time points:
1. Screening, or after consent has been provided to participate in the imaging cohort. 
Optimally (but not required), this scan would be performed within 3 days of 
initiating corticosteroid therapy for GCA disease activity: 
2. Week 0 (Randomization)
3. Week 12

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4. Week 52
5. Any time point of disease relapse/flare during Part A or Part B of the study, with 
every effort made to conduct the US scan within 3 days of rescue prednisone 
administration. The number of days between the US scan and rescue prednisone 
administration will be recorded. Scanning in the event of relapse/flare during Part 
B will conclude when the last subject in the exploratory US imaging cohort 
completes Part A. No additional Part B scans will be taken after this time point.
The timings of the US assessments are included in Section 7.1, Time and Events Tables, 
Table 2, Table 3, Table 4 and Table 5.  
The scans will be sent for independent review by a central reader. Full details on the US 
scanning process, training requirements, image transfer and de-identification, 
assessments and data collection are provided in the Imaging Acquisition Guidelines. 
12.8.4.
Blinding
The central reader will remain blinded to the subject’s treatment group. Investigators and 
sponsor will remain blinded to the central US results. No clinical findings will be 
communicated by the central reader to investigators. Scans may be reviewed at the site 
according to local policy.
12.8.5.
Statistical Considerations and Data Analyses
12.8.5.1.
Hypotheses
The objectives of the evaluations in the US imaging cohort are exploratory and 
observational. There are no formal statistical hypotheses planned.
Exploratory comparisons will be made between the sirukumab and placebo arms, if 
appropriate.
12.8.5.2.
Sample Size Considerations
There are no formal calculations of power or sample size for this cohort. There is no pre-
specified upper or lower limit for subject enrolment in this cohort.  Therefore, no sample 
size sensitivity was performed and there are no plans for sample size re-estimation .
12.8.5.3.
Data Analysis Considerations
No formal analyses are planned for this cohort.
12.8.5.4.
Key Elements of Analysis Plan
Data from the US imaging cohort may be reported separately from the main 201677 
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Data will be analyzed according to the timeframe between prednisone dose and US scan.
Graphics and/or descriptive statistics will be used to describe the time course and 
magnitude of changes in key markers (e.g. halo). If data permits, analyses assessing the 
associations between these key markers and some disease activity and health outcomes 
indicators (e.g. GCA disease activity, ESR, CRP, fatigue and pain) will be carried out 
using descriptive statistics and graphics.
Full details of the approaches will be described separately from the main clinical study 
report.

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12.9.
Appendix 9: Protocol Changes
Amendment 01  15 October 2015
1. Clarification of the secondary objective and endpoint relating to characterization 
of disease remission. Characterization of disease flare over time has been 
delineated as a separate secondary objective.
Rationale: Sustained remission will be assessed at various time points throughout 
the 52-week treatment period and will not include subjects who are in remission 
but have not been able to follow the protocol taper and/or received rescue therapy. 
Section 1 and Section 3: Objective(s)/Endpoint(s)
Part A: 52-week double-blind treatment phase
To characterize remission sustained
remission and disease flare over time
Proportion of subjects in sustained 
remission over at each time point of 
assessment from Week 12 to Week 
52, where sustained remission is 
defined as having achieved all of the 
following:

Remission at Week 12 and

Absence of disease flare 
following remission at Week 12 
and

Adherence to the assigned 
prednisone taper protocol and

No requirement for rescue 
therapy at any time
To characterize disease flare over 
time
Time to first GCA flare after clinical 
remission
Number of disease flares per patient 
over time
Proportion of subjects requiring 
hospitalizations for disease flare and 
number of hospitalizations for disease 
flare over time
2. Clarification of the objectives and endpoints related to patient and physician 
reported health outcomes.
Rationale: To provide additional details for clarification and correction of errors 
in the original protocol.
Section 1 and Section 3: Objective(s)/Endpoint(s)

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Part A: 52-week double-blind treatment phase
To assess the effect of sirukumab 
treatment on health-related quality of 
life, GCA and/or steroid-related 
symptoms and disability by patient 
and clinician reported outcomes over
time
Patient reported outcomes including 
SF-36v2, EQ-5D (35L), FACIT-
Fatigue, Pain VASNumeric Rating 
Scale (NRS), Steroid Impact PRO, 
HAQ-DI, Patient Global Impression 
of Change (PGIC), Patient Global 
Assessment of disease activity 
(PtGA)
Clinician reported outcomes 
including Physician Global 
Assessment of disease activity 
(PhGA)
3. Amendment of the endpoints for evaluation of maintenance of disease remission 
and patient and physician reported outcomes in Part B. 
Rationale: Clarification that the key secondary endpoint in Part B is proportion of 
subjects who had achieved sustained remission at the end of Part A and remained 
in sustained remission without a treatment change at Week 24 of Part B.  Subjects 
who received 12 months of sirukumab treatment during Part B will also be 
evaluated for sustained remission 6 months post cessation of treatment. It is also 
clarified that hospitalizations over time will be assessed. Additional details on 
objectives and assessment of patient and physician reported outcomes have been 
included for clarification purposes and for correction of errors in the original 
protocol.
Section 1 and Section 3: Objective(s)/Endpoint(s)
Part B: 104-week long-term extension phase
Objectives
Endpoints
To evaluate the long-term 
maintenance of disease remission on 
cessation of 12 months of sirukumab 
treatment
Proportion of subjects who remained 
in sustained remission 6 months post 
cessation of 12-month sirukumab 
treatment without requirement for 
rescue therapy or treatment change 
at Week 24 of Part B
Proportion of subjects in sustained
remission over time
Time to first GCA flare for subjects in 
sustained remission at baseline of Part 
B 
Number of disease flares per patient 

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Objectives
Endpoints
over time
Proportion of subjects requiring 
hospitalizations for disease flare and 
number of hospitalizations for disease 
flare over time
Proportion of subjects who 
remained in sustained remission 
without requirement for rescue 
therapy or treatment change 6 
months post cessation of 12-month 
sirukumab treatment
To assess the effect of sirukumab 
treatment on health-related quality of 
life, GCA and/or steroid-related 
symptoms and disability by patient 
and clinician reported outcomes over 
time
Patient reported outcomes including 
SF-36v2, EQ-5D (35L), FACIT-
Fatigue, Pain VASNRS, Steroid 
Impact PRO, HAQ-DI and PtGA
Clinician reported outcomes 
including PhGA
4. Clarification of the signs and symptoms of GCA.
Rationale: To provide additional detail and clarifications for investigator guidance 
and consideration.
Section 4.1 Overall Design
Signs and symptoms of GCA may include PMR symptoms,  new onset headache; jaw 
claudication (jaw or mouth pain upon chewing); visual signs and symptoms including 
but not limited to amaurosis fugax, transient or episodic blurry vision, diplopia, 
permanent vision loss due to acute ischemic optic neuropathy (AION); temporal artery 
tenderness; scalp tenderness; reduced or absent pulsation in temporal artery; cord-
like thickening of temporal artery; stroke; scalp necrosis; pain over face/scalp 
arteries; new or worsened extremity claudication; fever of unknown origin; PMR 
symptoms; or other symptoms that in the investigator’s experience are associated with 
GCA.
5. Clarification and correction of wording around prednisone during Screening and 
initiation of the open-label and blinded prednisone taper.
Rationale: Prednisone dose during Screening should be determined by 
investigator to ensure disease activity is stable at Randomization when prednisone 
taper is initiated. It is clarified that the first decrease in prednisone dose per the 
taper regimen occurs at Week 1.
Section 4.1 Overall Design

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The prednisone dose for all subjects at Screening will be determined by the Investigator 
and starting doses must be within 20-60 mg prednisone at Baseline (Randomization).may 
be adjusted in an open manner based on the subject’s disease status per investigator 
discretion.  At Baseline (Randomization), doses must be within 20-60 mg prednisone 
for the starting dose when the pre-specified prednisone taper is initiated. Subjects 
will remain on the prednisone dose they are receiving at Baseline for one week and 
then will decrease the dose at Week 1, as specified in the taper regimen.  Subjects 
will follow the open-label prednisone taper regimen until they reach a 20 mg dose of 
prednisone when the blinded prednisone taper regimen begins. Subjects receiving a 
20 mg prednisone dose at Baseline will continue the 20 mg dose for one week and at 
Week 1 will initiate the blinded taper.
6. Addition of details regarding the imaging sub-study.
Rationale: To add the study number and clarify that it will be conducted at select 
centers.
Section 4.1 Overall Design
A separate exploratory sub-study (Study 205028) will be conducted at selected centers
to assess the utility of imaging assessment of inflammation as an indicator of disease 
activity in a cohort of study subjects. The details of this exploratory sub-study will be 
provided in a separate protocol.
7. Clarifications of circumstances for receiving open-label sirukumab in Part B.
Rationale: To clarify that open-label sirukumab and corticosteroid use and 
corticosteroid dose adjustments are determined by the investigator based on their 
assessment of the subject’s disease activity. Guidance is provided to investigators 
to consider appropriate use of sirukumab in subjects with continued disease 
activity or with persistent flares to help ensure that sirukumab therapy is 
discontinued in individual circumstances where it is ineffective.
Section 4.2.2 Part B: 104-week extension phase
All subjects who complete Part A of the study will be eligible to enter part B. The two 
populations of subjects expected to enter into Part B are:

Subjects in remission at the primary 52-week endpoint. These subjects will 
discontinue blinded study drug treatment on entry into Part B and will be followed 
for maintenance of response. However, in the event of a flare. they will have the 
option to receive, at the discretion of their Investigator, open-label sirukumab 
100 mg SC q2w for a maximum of 52 weeks during the first 52 weeks of Part B in 
the event of a flare. 

Subjects with disease activity not in remission at the primary 52-week endpoint 
or subjects who have not been able to follow the prednisone taper taper 
prednisone during Part A. Upon entry into Part B, these subjects will have the 

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option to receive, at the discretion of the Investigator, open-label sirukumab 
100 mg SC q2w for a maximum of 52 weeks.
For subjects who newly flare at any time during the 1st 52 weeks of Part B and require a 
treatment change, open-label sirukumab 100 mg SC q2w can be initiated within the first 
52 weeks of Part B. The duration of treatment will be at the discretion of the investigator 
but must not exceed 52 weeks. Treatment with open-label sirukumab 100 mg SC q2w 
must complete by Week 104 (the end of the extension phase). Corticosteroid use
Adjustments in corticosteroid dose or the initiation of methotrexate therapy alone or in 
addition to sirukumab treatment during Part B will be at the discretion of the investigator.
Investigators should carefully consider the individual benefit-risk of continuing 
sirukumab in those subjects that continue to experience flares or persistent disease 
activity following the start of open label treatment.
8. Clarification of the risk mitigation strategies for hypersensitivity and GI 
perforations, including the addition of information regarding sponsor classification 
of hypersensitivity reactions using the Sampson criteria. Amendment of the 
wording to clarify that subjects with hypersensitivity reactions, cytopenias, liver 
enzyme increases and cardiovascular events should discontinue study treatment 
without requirement to withdraw from the study. Clarification of wording on 
disease stability for initiating the prednisone taper. 
Rationale: To help ensure subject safety, additional wording has been added 
around subject awareness of the nature and risks of hypersensitivity reactions and 
investigator vigilance in monitoring for signs of GI perforations due to the 
potential for these to be masked by prednisone use. Sponsor adjudication of 
hypersensitivity reactions using the Sampson criteria will be implemented to 
further characterize any such events. Risk mitigation strategies include 
discontinuation of study drug but not subject withdrawal from the study.
Section 4.6.1 Risk Assessment
Hypersensitivity
Serious allergic reactions (eg, 
anaphylaxis) have been 
reported with the 
administration of mAbs, 
including sirukumab, and may 
occur during or after the 
administration of the mAbs.
Exclusion of subjects with 
severe allergic reactions to 
monoclonal antibodies, human 
proteins, or excipients. 
Withdrawal of study drug in the 
event of a severe allergic 
reaction. Subjects will be 
made aware of the potential 
risk, the signs and 
symptoms of such reactions, 
and the importance of 
immediately seeking medical 
attention.
Discontinuation of blinded 
subcutaneous study drug in 
the event of a severe allergic 

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reaction. 
Monitoring of serious 
allergic reactions by IDMC; 
adjudication and 
classification of these events 
using Sampson criteria 
(Sampson, 2006) by sponsor 
safety review team will be 
implemented.
Gastrointestinal perforation
Upper and lower GI tract 
perforations occurred in the 
anti-IL-6 receptor (tocilizumab) 
Phase III program. Sirukumab 
binds to IL-6 and prevents 
binding to IL-6 receptor (IL-
6R). Tocilizumab binds to IL-6 
R to prevent IL-6 signalling. 
Potential differences in safety 
between agents that bind to 
the IL-6 receptor versus ones 
that bind to the IL-6 ligand 
(sirukumab) warrants further 
study.
Exclusion of subjects with a 
history of diverticulitis, 
inflammatory bowel disease, or 
other symptomatic GI tract 
condition that might predispose 
to bowel perforation.
Investigators should closely 
monitor for GI perforations 
with a high degree of 
suspicion. Monitoring of 
gastrointestinal perforations by 
IDMC.
Cytopenias
Neutropenia and 
thrombocytopenia have 
occurred in sirukumab studies, 
including severe 
thrombocytopenia associated 
with bleeding. Decreases in 
platelet counts have also been 
observed.
Exclusion of subjects with 
absolute neutrophil count 
(ANC) <2x109/L, platelet count 
<140x109/L, WBC count
<3.5x109/L, ALC <0.5 x109/L.
Withdrawal of Discontinuation 
of blinded subcutaneous 
study drug for subjects with 2
confirmed consecutive 
absolute neutrophil counts of 
<0.5 × 109 cells/L or platelet 
counts <50 x 109 cells/L.
Monitoring of cytopenias by 
IDMC.
Liver enzyme increases
Transient asymptomatic 
increases (1 to 3 x ULN, 
sometimes > 5 x ULN but < 8 x 
ULN) in blood ALT and AST 
values have been observed in 
subjects in completed and 
ongoing studies of sirukumab. 
These changes were not 
associated with an increase in 
bilirubin.
Exclusion of subjects with AST 
or ALT >2.0 x ULN, or total 
bilirubin >ULN with the 
exception of Gilbert’s disease. 
Inclusion of pre-defined liver 
chemistry withdrawal 
discontinuation criteria 
(Section 5.4.3). Monitoring of 
hepatic abnormalities by IDMC.

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Cardiovascular events
No cardiovascular risk with 
sirukumab has been identified 
in clinical studies to date. 
However, the study population 
is at high risk for CV disease.
Exclusion of subjects with 
uncontrolled cardiovascular 
disease or marked baseline 
prolongation of QTc interval ≥ 
450 msec (QTcB or QTcF), 
history of Torsade de Pointes, 
family history of long QT 
syndrome, history of second or 
third degree heart block or 
subject with major ischemic 
event unrelated to GCA. 
Inclusion of pre-defined QTc 
withdrawal discontinuation
criteria (Section 5.4.4). 
Monitoring of CV events by 
CEC and IDMC
Rapid steroid taper
Steroid withdrawal symptoms 
and side effects
Inclusion only of subjects with 
stable disease who are able to 
safely participate in the steroid 
taper. Subjects should be 
stabilized have clinically 
stable disease on steroid 
therapy prior to randomization. 
IDMC will monitor all subjects 
including those in the 3 month 
taper.
9. Clarification of the wording describing the mechanism of IL-6 inhibition.
Rationale: Sirukumab does not target the IL-6 receptor but inhibits IL-6 activity 
by binding to the molecule itself.
Section 4.6.3 Overall Benefit:Risk Conclusion
Although the efficacy of sirukumab in subjects with GCA has yet to be 
established, it has been shown to be effective in Phase II studies in RA. 
Furthermore other agents that target the IL-6 receptor inhibit IL-6 activity have 
been shown to be efficacious in RA.
10. Clarification of inclusion criteria related to diagnosis of GCA and signs and 
symptoms of active GCA.
Rationale: To provide additional guidance to investigators regarding 
qualifications for a diagnosis of GCA on biopsy and imaging and for signs and 
symptoms of GCA to ensure inclusion of appropriate patients in the study.
Section 5.1 Inclusion Criteria

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1. Diagnosis of GCA defined by the following Revised GCA Diagnosis Criteria:

Presence of at least one of the following:

Temporal artery abnormality on biopsy revealing features of GCA.

Evidence of large-vessel vasculitis by angiography or cross-sectional 
imaging, including but not limited to magnetic resonance angiography 
(MRA), computed tomography angiography (CTA), ultrasound (US) or
positron emission tomography-computed tomography (PET-CT) or evidence 
of large-vessel or temporal artery vasculitis by ultrasound (US).
2. Active GCA within 6 weeks of Randomization (Baseline) where active disease is 
defined by an ESR  30 mm/hr or CRP 1 mg/dL AND the presence of at least 
one of the following:

Unequivocal cranial signs and symptoms of GCA (new onset localized headache, 
scalp or temporal artery tenderness, ischemia-related vision loss [permanent 
vision loss due to AION, amaurosis fugax, episodic blurry vision], diplopia, or
reduced or absent pulsation in temporal artery, cord-like thickening of 
temporal artery, stroke, scalp necrosis, pain over face/scalp arteries or 
otherwise unexplained mouth or jaw pain upon mastication [i.e., jaw 
claudication]).

Visual signs and symptoms associated with GCA, including ischemia-related 
vision loss [permanent vision loss due to AION, amaurosis fugax, episodic 
blurry vision], diplopia, scotoma, nerve palsies, relative afferent papillary 
defects, central retinal artery occlusions. 
11. Amendment of inclusion criteria for TB testing.  
Rationale: All sites are capable of conducting the QuantiFERON Gold test. To 
ensure consistency of testing across the study for TB, the options for T spot and 
skin testing have been removed.          
6.   No evidence of active or latent infection with Mycobacterium tuberculosis (TB),        
as defined by all of the following:
a. No history of active or latent TB infection.
b. A negative diagnostic TB test at Screening defined as: a negative 
QuantiFERON Gold test (NB: 2 successie indeterminate QuantiFERON tests 
will be considered as a positive result).
OR

If QuantiFERON gold or T-spot test is not approved or registered in country 
of participation, then a negative tuberculin skin test (TST) reaction as per 
local guidelines is required (it is strongly recommended that patients with a 
history of BCG vaccination be tested with QuantiFERON gold test).

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12. Correction of time frames for biologic use and reference to section for additional 
guidance.
Rationale: Based on the pharmacokinetic profile of anti-TNFtherapies, a 
minimum of a 4 week wash out period is required. 
Section 5.2 Exclusion Criteria
4. Had prior treatment with any of the following:

Biologic agents targeted at reducing TNF(including but not limited to 
infliximab, golimumab, certolizumab pegol, etanercept, yisaipu, and 
adalimumab) within 24-8 weeks of baseline, depending on the agent *.
Please refer to the Study Procedures Manual (SPM) for guidance Section 6.10.2 
Prohibited Medications and Non-Drug Therapies for additional guidance.
13. Addition of exclusion criteria related to prolonged use or requirement for 
continued use of systemic corticosteroids.
Rationale: Patients who have used systemic corticosteroids for more than 4 years 
represent a refractory population who are unlikely to tolerate a steroid taper, such 
as that included in this trial. Patients who require continued use of systemic 
corticosteroids for conditions other than GCA are not suitable candidates for a 
steroid taper. 
Section 5.2 Exclusion Criteria
5. Regular or continuous systemic corticosteroid use for > 4 years.
6. Requires continued or repeated use of systemic corticosteroids for conditions 
other than GCA.
14. Clarification of requirements for eligibility based on results of the QuantiFERON-
TB Gold test and for re-screening.
Rationale: A single indeterminate result is not sufficient to exclude patients who 
may benefit from this study due to the relatively high rate of occurrence in 
patients who may not carry a risk of tuberculosis. An indeterminate result 
followed by a negative re-test result is sufficient to exclude patients with a risk of 
tuberculosis. 
Section 5.3 Screening/Baseline/Run-in Failures
Re-testing
Exceptions to re-testing are chest radiograph, ECG, and a positive result for the
QuantiFERON-TB Gold test; these screening tests may not be repeated to meet eligibility 

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criteria. An indeterminate result for the QuantiFERON-TB Gold test may be re-
tested and subjects will be eligible upon a negative re-test result.
Re-screening
If a subject is a screen failure but at some point in the future is expected to meet the 
subject eligibility criteria, the subject may be re-screened on only one occasion and only 
after consultation with the Sponsor or Sponsor designee. Subjects who are re-screened 
will be assigned a new subject number, undergo the informed consent process, and then 
restart a new screening phase
15. Clarification of circumstances related to withdrawal from the study and 
discontinuation of study drug.
Rationale: This study is designed to collect information on disease status even 
when study drug has been discontinued. To ensure subject safety, events which
require withdrawal of study drug are described, but it is clarified that study 
withdrawal is not required and subjects should continue to be followed. 
Section 5.4 Withdrawal/Stopping Criteria 
5.4.1 Study Withdrawal
A subject may withdraw from study treatment the study at any time at his/her own 
request, or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral or administrative reasons. If a subject withdraws from the study, he/she may 
request destruction of any samples taken, and the investigator must document this in the 
site study records. Subjects may also be withdrawn from the study for any of the 
following reasons:

Investigator discretion

Sponsor request

Adverse events (AEs) or laboratory abnormalities indicative of safety concerns

Pregnancy

Use of a new investigational drug

Protocol violation

Subject lost to follow-up

Subject withdraws consent
5.4.12 WithdrawalDiscontinuation of Study Drug
Permanent withdrawaldiscontinuation of study drug will not require the subject to be 
withdrawn from the study.

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2. Severe allergic reaction or aAnaphylactic reaction resulting in bronchospasm 
with wheezing, or dyspnea requiring ventilatory support, or symptomatic 
hypotension with a > 40 mmHg decrease in systolic blood pressure that occurs 
following study drug administration.
4. Adverse events (AEs) or laboratory abnormalities indicative of safety 
concerns which are significant enough to discontinue study drug in the 
opinion of the investigator.
5. Pregnancy.
6. Liver function abnormalities as specified in Section 5.4.3. 
8. Active or subject with latent TB who discontinues treatment for latent TB 
prematurely or is not compliant with treatment for latent TB.
16. Clarification of requirements for subjects meeting liver chemistry stopping and 
monitoring criteria. 
Rationale: Subjects may be required to discontinue study treatment for safety 
reasons, but are not required to withdraw from the study.
Section 5.4.3 Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Subjects meeting the liver chemistry stopping and increased monitoring criteria 
may be required to temporarily or permanently discontinue study treatment.
17. Clarification of ECG criteria.
Rationale: To clarify that QTC stopping criteria requiring discontinuation of study 
drug are applicable only when ECGs are performed outside of study requirements, 
as only a screening ECG is required. 
Section 5.4.4 QTc Stopping Criteria
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:An ECG is required only at screening. If an additional ECG is performed 
during study participation outside of study requirements and any of the bulleted 
criteria below are met, study treatment should be discontinued and the Medical 
Monitor should be contacted. There is no requirement for the subject to be 
withdrawn from the study.

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18. Clarification that sponsor may supply the open-label prednisone is some countries.
Rationale: Compliance with local regulations.
Section 6.1 Investigational Product and Other Study Treatment
Prednisone for the pre-specified standard blinded taper will be provided by the Sponsor.  
Prednisone for the unblinded (open-label) taper will be provided by the sites or by the 
Sponsor in certain countries in order to comply with local regulations. Use of 
standard release prednisone is required for the open-label taper.
19. Clarification of method for randomization.
Rationale: Provide appropriate terminology for randomization system.
Section 6.2 Treatment Assignment
Randomization will be performed by an Interactive Voice Recognition System
(IVRS)Interactive Response Technology System (IRT).
20. Provision of guidance to investigators for situations in which a small increase in 
prednisone dose is warranted. 
Rationale: Changes in prednisone dose should be considered only in situations 
representative of a GCA flare. 
Section 6.3 Planned Dose Adjustments
Subjects unable to follow the prednisone taper due to disease flare, adrenal insufficiency 
or safety reasons will cease the blinded prednisone treatment, and will be offered 
treatment with an investigator-defined open-label corticosteroid rescue regimen in 
combination with double-blind injections of sirukumab q2w or placebo q2w for the full 
52 weeks. Subjects should continue to be followed per the protocol-specified assessments 
while receiving rescue treatment. There is no requirement for these subjects to be 
withdrawn from the study. When considering use of rescue prednisone, investigators 
should carefully assess whether the symptoms are related to an inflammatory GCA 
flare which would signify failure of tapering or is more likely due to non-
inflammatory symptoms which could represent adrenal insufficiency or other co-
morbidities.
21. Clarification of notifications of ESR results.
Rationale: ESR alert values may be needed for investigators to make informed 
decisions regarding the clinical management of subjects experiencing a GCA 
disease flare and should be considered in the context of the presenting clinical 
symptoms.
Section 6.4 Blinding

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Investigators will remain blinded to the results of the fasting lipids, CRP and ESR 
laboratory tests. Alerts will be provided by the central laboratory for abnormal, clinically 
significant findings to enable investigators to manage subject safety.  Since the ESR is 
measured at the site, an unblinded assessor at the local laboratory will report the ESR 
results. The investigator will be notified of the value of the ESR result when an ESR 
result value is > 40 mm/hr in order to determine if a treatment change is warranted. 
Investigators are advised to consider these notifications of an elevated ESR which 
has reached the alert value as an additional element in the determination of whether 
a subject is experiencing GCA disease flare. An elevated ESR in isolation should not 
be the sole basis for investigator assessment of disease flare, particularly in the 
absence of clinical symptoms (e.g., cranial or PMR) suggestive of disease activity.
22. Clarification of permitted NSAID use.
Rationale: There is no basis for restrictions on NSAID use.
Section 6.10.1 Permitted Medications and Non-Drug Therapies

Subjects treated with NSAIDs, including aspirin and selective COX-2 inhibitors, 
and other analgesics should receive the usual marketed doses approved in the 
country in which the study is being conducted. Prescriptions of NSAIDs and other 
analgesics generally should not be adjusted for at least 4 weeks prior to the first 
administration of the study drug to Week 52 if possible. The dose and the type of 
NSAIDs or other analgesics may be changed (reduced or temporally discontinued) 
at the discretion of the investigator if the subject develops unacceptable side 
effects or a contraindication to their use. When the reason to reduce or temporarily 
discontinue the NSAID or analgesic has ceased, the dose should be adjusted back 
to the approved level. Acetaminophen/paracetamol dosed no more than 3.0 
gm/day and/or an opioid not exceeding the potency equivalent of 30 mg of orally 
administered morphine are allowable as rescue medication for no more than 10 
consecutive days. Analgesics, paracetamol and nonsteroidal anti-
inflammatory drugs (NSAIDs), including aspirin, at the usual marketed 
doses approved in the country in which the study is being conducted. 
23. Clarification of wash out periods for prior use of anti-TNFtherapies. 
Rationale: Biologics have long drug half-lives. Details on the wash out period for 
specific anti-TNFtherapies are provided based on their pharmacokinetic profile. 
Section 6.10.2 Prohibited Medications and Non-Drug Therapies

Biologic agents targeted at reducing TNF(including but not limited to 
infliximab, golimumab, certolizumab pegol, etanercept, yisaipu, and adalimumab)
within the specified time frames.

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Anti-TNFTherapy
Treatment Prior to First Study Agent 
Administration (Baseline)
Infliximab, infliximab biosimilar, 
golimumab IV
8 Weeks
Golimumab SC, adalimumab, 
certolizumab pegol
6 Weeks
Etanercept, yisaipu
4 Weeks
24. Addition of restrictions for systemic corticosteroid use.
Rationale: Subjects who require systemic corticosteroid use for conditions other 
than GCA may be negatively impacted by the prednisone requirements for this 
trial.
Section 6.10.2 Prohibited Medications and Non-Drug Therapies

Systemic corticosteroids for conditions other than GCA within 8 weeks of 
baseline or a reasonable possibility of requiring systemic corticosteroids 
during Part A.
25. Clarification of requirements for laboratory assessments and pregnancy testing for 
subjects not receiving open-label sirukumab in Part B.
Rationale: Less stringent safety monitoring is acceptable for subjects not 
receiving open-label sirukumab in Part B. 
Section 7: Study Assessments and Procedures
Time and Events Table 3:  Assessments for subjects who will not receive open-label 
treatment with sirukumab during Part B. Dispensing of investigational product is and 
hematology, and clinical chemistry assessments from the Week 76 visit onwards are not 
required. Hematology and clinical chemistry assessments and pregnancy testing from 
the Week 16 visit onwards are also not required as subjects will have completed the 
16-week post-drug follow up assessments.
26. Clarification and correction of PRO questionnaires.
Rationale: To provide additional details on the questionnaires.
Section 7: Study Assessments and Procedures

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PRO questionnaires should be completed by subjects before any other assessments and 
before the administration of study drug. PRO questionnaires should be completed before 
the completion of the physician reported questionnaires. PRO questionnaires should be 
completed by the subject in the following order:
1.
Patient Global Assessment of disease activity (PtGA).
2.
Patient Global Impression of Change (PGIC).
3.
Pain VASNumeric Rating Scale (NRS).
4.
HAQ-DI (for subgroup of subjects with PMR).
5.
FACIT-fatigue.
6.
Steroid Impact PRO.
7.
SF-36v2 acute.
8.
EQ-5D (35L).
Clinician-reported outcome questionnaires include the Physician Global Assessment 
of disease activity (PhGA), which should be completed after the PRO questionnaires 
have first been completed by subjects.
27. Changes in Time and Events Tables and correction of typographical errors. 
Rationale: Consistency with the protocol specifications and requirements.
Section 7.1 Time and Events Tables

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Table 2 Time and Events Table for Part A of the Study (52-week Double-blind Treatment Phase)
Screening (~Wk -6)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal  or Flare
Follow  Up
Written Informed Consent1
x
Subject Demography
x
Medical and disease history
x
Inclusion/Exclusion Criteria
x
x
Randomization
x
Autoinjector training2
x
x
x
x
Dispense Investigational Product
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x3
Assess Invest. Product compliance
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
Prior Medications
x
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient4, physician)4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
PGIC4
x
x
x
x
x
Pain VASNRS4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
HAQ-DI4
x
x
x
x
x
x
x
FACIT-Fatigue4
x
x
x
x
x
x
x
Steroid Impact4
x
x
x
x
x
x
x
SF-36v2 (acute)4
x
x
x
x
x
x
x
EQ-5D (35L)4
x
x
x
x
x
x
x
Safety Assessments
Physical Examination5
x
x
x
x
x
x
Vital Signs6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

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Screening (~Wk -6)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal  or Flare
Follow  Up
12-lead ECG7
x
Chest radiograph
x
TB evaluation8
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
QuantiFERON-TB Gold Test9
x
Height and weight
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
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
Hemoglobin A1c
x
x
x
x
x
x
x
x
Pregnancy Test10
S
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
HIV, HBsAg, HBcAb, Hepatitis C11
x
PK12
x
x
x
x
x
x
x
x
x
x
Immunogenicity12
x
x
x
x
x
x
x
Exploratory Lab Assessments
IL-6 measurements
x
x
Blood Biomarkers & exploratory 
markers
x
x
x
x
x
x
x
Blood and Urine Markers, 
Transcriptomics (optional)13
x
x
x
x
x
x
x
Pharmacogenetics sample14
x

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1.
Including consent for pharmacogenetics.
2.
Assuming placebo will also be administered using autoinjector. Additional training may be provided when required.
3.
Only for those subjects who initiate open-label sirukumab treatment at the start of Part B.
4.
To be completed by subjects before any other assessments and before the administration of study drug. HAQ-DI administered only to sub-set of subjects with PMR.
PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of questionnaires). 
5.
Complete physical exam at Screening and brief physical exam at other time points.
6.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
7.
And when suspected heart attack.
8.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
9.
If a QuantiFERON-TB Gold Test is not approved at a site, a tuberculin skin test should be performed. In addition, to be performed at any time during the study if TB is 
suspected. Chest radiograph taken up to 3 months prior to Week 0 may be used to qualify at screening.
10. Pregnancy test: urine = U, serum = S. Premenopausal women only.
11. If hepatitis C antibody positive, a hepatitis C RNA PCR assay should be reflexively performed on a fresh sample to confirm the result.
12. On study drug administration days, Pharm serum samples must be collected prior to study drug 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.
13. To be collected only for those subjects consenting to provide samples for the biobank for future exploration of GCA disease biology.
14. Sample should be collected at the baseline visit but may be collected at any visit post-baseline if not collected at the  baseline visit

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Table 3 Time and Events Table for Part B of the Study (104-week Extension): Subjects NOT Receiving Open-label Sirukumab During 
Part B
Wk 0/(Wk 52 of Part A)
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal or Flare
Concomitant Medications
x
x
x
x
x
x
x
x
x
x
x
x
Assess Invest. Product compliance1
x
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)2
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain VASNRS2
x
x
x
x
x
x
x
x
x
x
HAQ-DI2
x
x
x
x
x
x
x
x
FACIT-Fatigue2
x
x
x
x
x
x
x
x
Steroid Impact2
x
x
x
x
x
x
x
x
SF-36v2 (acute) 2
x
X
x
x
x
x
x
x
EQ-5D (35L) 2
x
x
x
x
x
x
x
x
Safety Assessments
Physical Examination13
x
x
x
x
x
Vital Signs24
x
x
x
x
x
x
x
x
x
x
x
x
TB evaluation35
x
x
x
x
x
x
x
x
x
x
x6
Height and weight
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x6
x6
Serum chemistry
x
x
x
x
x
x6
x6
CRP
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x

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Wk 0/(Wk 52 of Part A)
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal or Flare
Lipid panel (fasting)
x
x
x
x
x
x
x
x
x6
x6
Hemoglobin A1c
x
x
x
x
x
x
x
x
x6
x6
Pregnancy Test7
U
U
U
U
U
U
U
U
U6
Immunogenicity
x
x
x
x
x
Exploratory Lab Assessments
Blood Biomarkers & exploratory 
markers
x
Blood and Urine Markers, 
Transcriptomics (optional)
x
1.
Complete physical exam at Screening and brief physical exam at other time points. Assessment from Week 52 visit of Part A.
2.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.To be completed by subjects before any other 
assessments. HAQ-DI administered only to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subjects 
complete their questionnaires).
3.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test (or if not approved at the site, a tuberculin skin test) should be performed at any time during 
the study if TB is suspectedBrief physical exam.
4.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
5.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test (or if not approved at the site, a tuberculin skin test) should be performed at any time during 
the study if TB is suspected.
6.
To be performed only if Early Withdrawal visit or flare occurs on or before Week 16 visit.
7.
Pregnancy test: urine = U, serum = S. Premenopausal women only.

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Table 4 Time and Events Table for Part B (104-week Extension) of the Study: Subjects Receiving Open-label Sirukumab Immediately 
Upon Entry into Part B
Wk 0/(Wk 52 of Part A)
Wk25d
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d1
wk 485d1
wk 525d
wk 7865d
wk 1045d
Flare
Early Withdrawal  or Flare
Follow  Up
Dispense Investigational Product
x
x
x
x
x
x
x
x
x
x
x
x
Assess Invest.Product compliance
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
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA1 (patient, physician)2
x
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain VASNRS2
x
x
x
x
x
x
x
x
x
x
x
HAQ-DI2
x
x
x
x
x
x
x
x
FACIT-Fatigue2
x
x
x
x
x
x
x
x
Steroid Impact2
x
x
x
x
x
x
x
x
SF-36v2 (acute) 2
x
x
x
x
x
x
x
x
EQ-5D (35L) 2
x
x
x
x
x
x
x
x
Safety Assessments
Physical Examination3
x
x
x
x
x
x
Vital Signs4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Chest radiograph
TB evaluation5
x
x
x
x
x
x
x
x
x
x
x
x
x
Height and weight
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
x

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Wk 0/(Wk 52 of Part A)
Wk25d
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d1
wk 485d1
wk 525d
wk 7865d
wk 1045d
Flare
Early Withdrawal  or Flare
Follow  Up
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x
x
x
x
x
x
x
U
Hemoglobin A1c
x
x
x
x
x
x
x
x
x
x
x
Pregnancy Test6
U
U
U
U
U
U
U
U
U
U
Immunogenicity7
x
x
x
x
x
x
x
Exploratory Lab Assessments
Blood Biomarkers & exploratory 
markers
x
Blood and Urine Markers, 
Transcriptomics (optional)
x
1.
Additional visits will be scheduled at Wk 48, Wk 66, and Wk 90 to dispense open-label sirukumab as appropriate..Visit only to dispense IP; no assessments 
are required.
2.
To be completed by subjects before any other assessments and before the administration of open-label sirukumab as applicable. HAQ-DI administered only 
to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subjects complete their questionnaires))
3.
Complete Brief physical exam at Screening and brief physical exam at other time points
4.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
5.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test (or if not approved at the site, a tuberculin skin test) should be performed at any time 
during the study if TB is suspected.
6.
Pregnancy test: urine = U, serum = S. Premenopausal women only.
7.
On study drug administration days, serum samples to measure antibodies to sirukumab must be collected prior to study drug administration. 

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Table 5 Time and Events Table for Part B (104-week Extension) of the Study: Subjects Receiving Open-label Sirukumab at Any Time 
AFTER (but NOT immediately Upon) Entry into Part B
Start of open-label 
sirukumab  1
PLUS 2 Wks5d
PLUS 4 Wks5d
PLUS 8 Wks5d
PLUS 12 Wks5d
PLUS 16 Wks5d
PLUS 24 Wks5d
PLUS 36 Wks5d2
PLUS 48 Wks5d2
PLUS 52 Wks5d
PLUS 786 WKS5d
PLUS 104 Wks5d 3
Flare
Early Withdrawal  or Flare
Follow  Up
Dispense Investigational Product
x
x
x
x
x
x
x
x
x
x
Assess Invest. Product compliance
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
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient4, physician)4
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain VASNRS4
x
x
x
x
x
x
x
x
x
x
HAQ-DI4
x
x
x
x
x
x
x
FACIT-Fatigue4
x
x
x
x
x
x
x
Steroid Impact4
x
x
x
x
x
x
x
SF-36v2 (acute)4
x
x
x
x
x
x
x
EQ-5D (35L)4
x
x
x
x
x
x
x
Safety Assessments
Physical Examination5
x
x
x
x
x
Vital Signs6
x
x
x
x
x
x
x
x
x
x
x
x
x
Chest radiograph
TB evaluation7
x
x
x
x
x
x
x
x
x
x
x
Height and weight
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x

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Start of open-label 
sirukumab  1
PLUS 2 Wks5d
PLUS 4 Wks5d
PLUS 8 Wks5d
PLUS 12 Wks5d
PLUS 16 Wks5d
PLUS 24 Wks5d
PLUS 36 Wks5d2
PLUS 48 Wks5d2
PLUS 52 Wks5d
PLUS 786 WKS5d
PLUS 104 Wks5d 3
Flare
Early Withdrawal  or Flare
Follow  Up
CRP
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x
x
x
x
x
x
Hemoglobin A1c
x
x
x
x
x
x
x
x
x
Pregnancy Test8
U
U
U
U
U
U
U
U
U
Immunogenicity9
x
x
x
x
x
x
1.
Upon the initiation of open-label sirukumab, perform the assessments from Time and Events Table 3 at the visit the subject was scheduled to undergo 
when study drug is started.
2.
Additional visits will be scheduled at Wk 48, Wk 66, and Wk 90 to dispense open-label sirukumab as appropriate..Visit only to dispense IP; no 
assessments are required.
3.
Although this visit is labelled as 104 weeks since the start of open-label sirukumab, it does not take into account the exact start time, since this will be 
different for each subject depending upon when in the first 52 weeks of Part B open-label sirukumab was started. The important point to note, is that this 
last visit should be scheduled when each of these subjects will complete 104 weeks in Part B.
4.
To be completed by subjects before any other assessments and before the administration of open-label sirukumab as applicable. HAQ-DI administered 
only to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subjects complete their 
questionnaires).
5.
Complete Brief physical exam at Screening and brief physical exam at other time points. 
6.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
7.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test (or if not approved at the site, a tuberculin skin test) should be performed at any 
time during the study if TB is suspected.
8.
Pregnancy test: urine = U, serum = S. Premenopausal women only.
9.
On study drug administration days, serum samples to measure antibodies to sirukumab must be collected prior to study drug administration.

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28. Clarification of requirements for prednisone starting dose at Screening and 
Baseline.
Rationale: To clarify that the investigator should determine the prednisone dose 
during screening and adjust accordingly so that subject is receiving a dose 
consistent with protocol requirements at Baseline. 
Section 7.2 Screening and Critical Baseline Assessments
Prednisone treatment must be initiated at Screening for subjects not currently receiving 
steroid treatment. Subjects should be reminded to discontinue any other prednisone 
or corticosteroid treatment and take only the prednisone study treatment. The 
prednisone dose for all subjects at Screening will be determined by the Investigator 
and may be adjusted based on the subject’s disease status per investigator 
discretion. An increase in prednisone dose may be required for some subjects currently 
receiving therapy to stabilize their disease activity prior to randomization. Investigators 
may consider if higher doses of prednisone are warranted for subjects with visual 
manifestations. Subjects are required to have clinically stable GCA disease at baseline
and able to participate in the blinded prednisone taper regimen in the opinion of the 
investigator. At Baseline (Randomization), doses must be within 20-60 mg 
prednisone for the starting dose when the pre-specified prednisone taper is initiated.
29. Provision of details on GCA signs and symptoms
Rationale: Investigator guidance for consideration when assessing GCA activity.
Section 7.3 Efficacy
Efficacy of sirukumab in GCA will be assessed from the presence of GCA activity 
including investigator assessment of signs and symptoms of GCA (new onset localized 
headache, scalp or temporal artery tenderness, ischemia-related vision loss [permanent 
vision loss due to AION, amaurosis fugax, episodic blurry vision], diplopia, reduced or 
absent pulsation in temporal artery, cord-like thickening of temporal artery, stroke, 
scalp necrosis, pain over face/scalp arteries, or otherwise unexplained mouth or jaw 
pain upon mastication [i.e., jaw claudication]); visual signs and symptoms (including 
but not limited to transient or episodic blurry vision, diplopia, scotoma, ischemia-
related vision loss [permanent vision loss due to AION], amaurosis fugax); PMR 
symptoms [shoulder and/or hip girdle pain associated with inflammatory stiffness]; and 
other features associated with GCA such as new or worsened extremity claudication and 
fever of unknown origin); and laboratory results for serum ESR and CRP levels (blinded 
to investigator).
30. Corrections, clarifications and additional details of PRO instruments. 
Rationale: A numeric rating scale for pain assessment is a more sensitive scale. 
Section 7.4 Health Outcomes

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In addition to the Patient’s and Physician’s Global Assessment of Disease Activity, other 
health outcome measures used in this study are PGIC, pain assessment using a VAS an 
11-point numeric rating scale, HAQ-DI, FACIT-fatigue, Steroid Impact questionnaire, 
SF-36 v2 Acute health survey questionnaire, and EQ5D (35L). These questionnaires 
should be completed in the order specified in Section 7.
Section 7.4.2 Pain Assessment
Subjects will be asked to assess rate the severity of  their average pain now on a visual 
analogue scale (VAS) ranging from “no pain” to “the worst possible pain an 11-point  
numeric rating scale  with anchors ranging from 0, “no pain” to 10, “the worst pain 
imaginable”.
Section 7.4.5 Steroid Impact Questionnaire
The benefits, side effects and impact of steroids on GCA symptoms and subjects will be 
assessed using a GCA disease specific patient reported questionnaire, the Steroid Impact 
Questionnaire. The Steroid Impact Questionnaire contains 50 items assessing steroid 
dose/duration (4 items), general impact (baseline burden; 19 items), benefits (7 
items), work/productivity (3 items), side effects (10 items), emotions (6 items), and 
overall satisfaction (1 item).
Section 7.4.7 EuroQoL-5D (EQ-5D) (35L)
The EQ-5D descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 
no problems, some problems, extreme problems. 5 levels: no problems, slight 
problems, moderate problems, severe problems, unable to do.
31. Addition of the American College of Rheumatology recommendations for 
prevention and treatment of osteoporosis and guidance for investigators to 
consider prophylactic use of proton pump inhibitors.
Rationale: Since study subjects may be on high doses of prednisone, investigator 
guidance is provided for management of corticosteroid-induced osteoporosis and 
gastroprotection.
Section 7.5.1.3 Follow-up of AEs and SAEs
Corticosteroid-related AEs such as diabetes mellitus, osteoporosis, fractures, infection, 
glaucoma, and cataracts among others will be evaluated in relation to steroid exposure 
and baseline risk. Further information on assessment of specific events will be available 
in the SPM. Since subjects participating in this study may be receiving high doses of 
prednisone for a prolonged period, investigators should consider implementation of 
the American College of Rheumatology recommendations for the prevention and 
treatment of glucocorticoid-induced osteoporosis (Grossman, 2010). A summary of 
these recommendations is included in Section 12.5, Appendix 5. Investigators should 
also consider whether their subjects may benefit from other approaches for 

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minimizing corticosteroid-related AEs, such as the prophylactic use of proton pump 
inhibitors for gastroprotection.
32. Addition of wording to specify requirement to collect additional details on cases of 
serious allergic/hypersensitivity reactions.
Rationale: Cases will be adjudicated by the Sponsor and classified according to 
the Sampson criteria.
Section 7.5.1.6 Allergic/Hypersensitivity Reactions
All subjects will be observed carefully for symptoms of allergic reactions for at least 30 
minutes after the SC injection of study drug when administered at the study site. If mild 
or moderate allergic reaction is observed, acetaminophen 650 mg per mouth (PO) or 
NSAIDS and diphenhydramine 25 mg orally or intravenously may be administered. If the 
reaction is not severe, subsequent injections at the appropriate treatment intervals may be 
undertaken with caution.
Subjects with severe reactions following an injection such as bronchospasm with 
wheezing and/or dyspnea requiring ventilator support, or symptomatic hypotension with 
a decrease in systolic blood pressure greater than 40 mmHg will not be permitted to 
receive any additional study drug injections. In the case of such reactions, appropriate 
medical treatment should be administered.
In cases of serious allergic/hypersensitivity reactions, additional details on the case 
will be collected via a targeted follow-up questionnaire. An internal safety review 
team will adjudicate these events to determine if the events meet the Sampson 
criteria (Sampson, 2006).
33. Amendment of requirement to withdraw from study in the event of pregnancy.
Rationale: The study is designed to collect information on disease status after 
discontinuing therapy. This is applicable even in cases of pregnancy.
Section 7.5.2 Pregnancy

Female subjects who become pregnant during the study must have study drug 
withdrawn discontinued immediately and be withdrawn from the study. 
Complete the assessments for the Early Withdrawal visit at the time of withdrawal 
and the Follow-up visit 16 weeks later (see Section 5.4).  These subjects should 
continue to follow the protocol-specified visit schedule.
34. Amendment of QTC withdrawal criteria to discontinuation criteria.
Rationale: To provide clarification on requirement to discontinue study drug 
versus study withdrawal.

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Section 7.5.5 Electrocardiogram (ECG)
Triplicate 12-lead ECGs will be obtained at the Screening visit using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  The screening ECG will ensure that a comparative ECG is available prior to 
study drug administration in order to detect any changes should a subject require an ECG 
for any reason during the study. Refer to Section 5.4.4 for QTc withdrawal 
discontinuation criteria and additional QTc readings that may be necessary.
35. Amendment of clinical laboratory assessment withdrawal criteria to 
discontinuation criteria.
Rationale: To provide clarification on requirement to discontinue study drug 
versus study withdrawal.
Section 7.5.6 Clinical Safety Laboratory Assessments
Values for liver transaminase levels (AST, ALT), absolute neutrophil count (ANC), and 
platelet count that require study drug interruption and/or permanent withdrawal
discontinuation of study drug administration are listed below in Table 7.
Table 7 Values for Liver Transaminase Levels, Absolute Neutrophil Count, and Platelet 
Count That Require Study Drug Interruption and/or Permanent Withdrawal
Discontinuation of Study Drug
36. Amendment of the requirements for TB testing to allow only testing using 
QuantiFERON-TB Gold Test.
Rationale: QuantiFERON-TB Gold Test is available in all countries and should be 
used at all sites to ensure consistency of testing.
Section 7.5.7 Tuberculosis Evaluation
A QuantiFERON-TB Gold Test will be performed at Screening. If a QuantiFERON-TB 
Gold Test is not approved at a site, a PPD skin test should be performed instead. These
This tests can be performed at any time during the study if TB is suspected.
Subjects who experience close contact with an individual with active TB during the 
conduct of the study must have a repeat chest radiograph, a repeat QuantiFERON-TB 
Gold test, a repeat tuberculin skin test in countries in which the QuantiFERON-TB Gold 
test is not approved/registered, and, if possible, referral to a physician specializing in TB 
to determine the subject’s risk of developing active TB and whether treatment for latent 
TB is warranted. Study drug administration should be interrupted during the 
investigation. A positive QuantiFERON-TB Gold (or tuberculin skin) test result should 
be considered detection of latent TB.

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37. Clarification of protocol-specified exploratory biomarkers and optional 
exploratory biomarkers.
Rationale: To provide additional clarifications on the two approaches for 
biomarker assessment.
Section 7.7 Biomarker(s)
Section 7.7.1 Optional Exploratory Biomarkers
Subjects will also have the option to provide blood and urine samples for future 
evaluation of biomarkers related to GCA disease activity and transcriptomic analyses to 
further elucidate the biology of the disease.
38. Amendment of the sample size sensitivity analysis.
Rationale: The sensitivity analysis was carried out for the response rate for 
sirukumab and not for the placebo arm as there is more uncertainty around the 
response rate for sirukumab than for placebo.
Section 9.2.2 Sample Size Sensitivity
A sample size sensitivity analysis was performed to assess the effect on power if the 
placebo sirukumab plus 6 month prednisone response rate was higher lower than 
expected at35 65%, 4060% or 4555%.
39. Addition of subjects who discontinue study treatment as non-responders in the 
primary endpoint analysis and update of the approach for analysis of primary and 
secondary endpoints.
Rationale: Subjects who discontinue treatment will not fulfil the requirements for 
a responder. Logistic regression model is preferred approach for analysis.
Section 9.4.1 Primary Efficacy Analyses
Subjects who do not achieve remission within 12 weeks, require rescue therapy, 
discontinue treatment during the study or withdraw early from the study for any 
reason or do not follow the assigned prednisone taper will be recorded as non-responders 
in the analysis of the primary endpoint.
The proportion of subjects with sustained remission at week 52 in the sirukumab 100 mg 
SC q2w plus 6 month prednisone (Arm A) versus placebo plus 6 month prednisone (Arm 
D) will be analysed using a generalised estimating equations logistic regression model 
controlling for the stratification factor of baseline prednisone dose. The model will also
include the treatment, week, and treatment-by-week interaction and subject within week 
as a random effect arms. Odds ratios and 95% confidence intervals will be produced.
If however a non-parametric approach is more appropriate then the Cochran-
Mantel-Haenszel will be used.

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Section 9.4.2 Secondary Efficacy Analyses
The proportion of subjects in sustained remission over time (Part A and Part B) will be 
analysed using the generalised estimating equations logistic regression as described for 
the primary endpoint.
40. Addition of AEs leading to discontinuation of study drug and summaries of 
reasons for treatment discontinuation.
Rationale: To further characterize the safety profile of sirukumab as treatment 
discontinuation may be frequently based on an adverse event.
Section 9.4.3.2 Adverse Events
The proportion of subjects reporting AEs will be tabulated for each treatment group. The 
following summaries of AEs will be provided:

All AEs

Treatment-related AEs

AEs leading to withdrawal 

AEs leading to discontinuation of study drug
Section 9.4.3.4 Other Safety Measures
Reason for withdrawal/treatment discontinuation will be summarized.
41. Addition of requirement for a secondary method of contraception for females 
using hormonal contraception.
Rationale: There is a hypothetical risk for sirukumab to decrease the effectiveness 
of oral contraceptives. Therefore, additional precautions should be taken.
Appendix 2, Section 12.2.1 Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP)
If using hormonal contraceptives, including oral, injections and patches, a 
secondary method of contraception must be used.
42. Clarification that pregnancy does not require withdrawal from the study.
Rationale: The study is designed to collect information on disease status after 
discontinuing therapy. This is applicable even in cases of pregnancy.

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Appendix 2, Section 12.2.2 Collection of Pregnancy Information
Any female subject who becomes pregnant while participating in this study will 
discontinue study drug and be withdrawn from the study. There is no requirement 
to be withdrawn from the study.
43. Addition of details on the American College of Rheumatology Standard of Care 
Recommendations for the Prevention and Treatment of Glucocorticoid-Induced 
Osteoporosis
Rationale: For investigator guidance as subjects may be on high doses of 
prednisone for prolonged periods.
Section 12.5, Appendix 5 American College of Rheumatology Standard of Care 
Recommendations for the Prevention and Treatment of Glucocorticoid-Induced 
Osteoporosis*
Recommended Monitoring for Patients Receiving Prevalent Glucocorticoid Therapy 
for a Duration >3 Months

Consider serial bone mineral density testing

Consider annual serum 25-hydroxyvitamin D measurement

Annual height measurement 

Assessment of incident fragility fracture 

Assessment of osteoporosis medication compliance
Pharmacologic Recommendations for Postmenopausal Women and Men age >50 
Years Starting Glucocorticoid Therapy with an Anticipated Duration of >3 Months, 
or Prevalent Glucocorticoid Therapy of a Duration of at Least 3 months 
Low-risk patient
Alendronate for _7.5 mg/day prednisone
OR
Risedronate for _7.5 mg/day prednisone 
OR
Zoledronic acid for _7.5 mg/day prednisone
Medium-risk patient
Alendronate for any dose of glucocorticoids 
OR
Risedronate for any dose of glucocorticoids 
OR
Zoledronic acid for _7.5 mg/day prednisone
High-risk patient
Alendronate 

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OR
Risedronate 
OR
Zoledronic acid
OR
Teriparatide
* Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, Curtis JR, 
Furst DE, McMahon M, Patkar NM, Volkmann E, Saag KG. (2010). American 
College of Rheumatology 2010 Recommendations for the Prevention and Treatment 
of Glucocorticoid-Induced Osteoporosis. Arthritis Care and Research, 62(11), 1515-
1526.
44. Correction of typographical errors and administrative changes related to 
amendment of protocol.
Title Page
Updated author list
Author (s):
 
 
Medical Monitor/Sponsor Information Page
Regulatory Agency Identifying Number(s): EudraCT number 2015-001758-14, IND 
101073
Updated Table of Contents 
Section 1, Protocol Synopsis for Study 201677, Overall Design
Subjects will be randomized to receive sirukumab (100 mg subcutaneous [SC] every 2 
weeks [q2w] or 50 mg SC every 4 weeks [q4w] or matching placebo.
Type and Number of Subjects
Subjects are required to have active GCA disease within 6 weeks of baseline where active 
disease is defined as the presence of unequivocal clinical signs and symptoms attributable 
to GCA and increased levels of inflammatory markers (ESR 30 mm/hr and/or CRP 1 
mg/dL).
Section 9.3.4 Interim Analysis
Full details of the process and decision criteria for this interim analysis for futility are
included in the IDMC charterRAP. 
PPD

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Addition of new protocol references
Section 11 References
Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, Curtis JR,
Furst DE, McMahon M, Patkar NM, Volkmann E, Saag KG. (2010). American 
College of Rheumatology 2010 Recommendations for the Prevention and Treatment 
of Glucocorticoid-Induced Osteoporosis. Arthritis Care and Research, 62(11), 1515-
1526.
Sampson HA, Munoz-Furlong A, Campbell RL, et.al. (2006). Second symposium on 
the definition and management of anaphylaxis: Summary report-Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol.117, 391-397.
Updates to Appendix 1, Abbreviations and Trademarks
IVRS
Interactive Voice Recognition System
IRT
Interactive Response Technology
NRS
Numeric Rating Scale
NSAID
Nonsteroidal anti-inflammatory drug
PhGA
Physician Global Assessment
PtGA
Patient Global Assessment
Addition of Appendix 5 and Appendix 8, Protocol Changes and re-numbering of 
subsequent appendices.

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Amendment 02  31 March 2016
1. Inclusion of the pharmacodynamic measurement enabling evaluation of sirukumab 
effects on blood IL-6 levels. 
Rationale: IL-6 is a pharmacodynamic marker directly related to the mechanism of action 
of sirukumab. Assay development has progressed to enable the assessment of total and 
free IL-6, thus enabling a more robust and accurate measurement of the 
pharmacodynamic effect of sirukumab on IL-6 levels.
Section 1 and Section 3: Objective(s)/Endpoint(s)
Objectives
Endpoints
Pharmacodynamic

To characterize the effect of 
sirukumab on IL-6 levels in the 
blood

Change from baseline in free and 
total IL-6 over time
Section 7.7.Biomarkers/Pharmacodynamic Markers
Section 7.7.3 Pharmacodynamic Markers
Blood samples will be taken at the times indicated in Time and Events Table 2, 
Section 7.1 for assessment of changes in free and total IL-6 as a pharmacodynamic 
marker of sirukumab activity.. Analyses of serum IL-6 levels will be performed 
using validated assays by Janssen Research and Development.
Section 9.4.6  Pharmacodynamic/Exploratory/Biomarker Analyses
Pharmacodynamic and Bbiomarker data in Part A will be presented in graphical and/or 
tabular form and will be summarised descriptively.
2. Inclusion of the information and relevant details regarding the new exploratory US 
imaging cohort. 
Rationale: Protocol has been amended to include the exploratory US imaging sub-study 
as a cohort of Study 201677 rather than conducting as a separate sub-study. 

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Section 1 and Section 3: Objective(s)/Endpoint(s)
Objectives
Endpoints
Exploratory
To explore the utility of vascular 
ultrasound (US) imaging assessment 
of inflammation in temporal and 
axillary arteries as an indicator of 
disease activity in a cohort of study 
subjects

To explore the predictive value of 
ultrasound for clinical efficacy in 
GCA

Change over time of the following 
measurements of vascular 
inflammation in temporal and 
axillary arteries:   
- Presence/absence of occlusion
- Presence/absence and 
maximum diameter of halo
- Presence/absence of stenosis
  

Correlation of clinical endpoints 
with changes in vascular 
inflammation.

Correlation of changes in vascular 
inflammation on US with clinical 
markers such as GCA disease 
activity, CRP and ESR 

Correlation of changes in vascular 
inflammation on US with health-
related quality of life outcomes
Section 4.1 Overall Design
A separate exploratory sub-study (Study 205028) will be conducted at selected centers to 
assess the utility of imaging assessment of inflammation as an indicator of disease 
activity in a cohort of study subjects. The details of this exploratory sub-study will be 
provided in a separate protocol.
The utility of US in monitoring disease activity in GCA will be explored in a cohort 
of subjects from select centers who have qualified as US imaging centers. 
Longitudinal changes in vascular inflammation of the temporal and axillary arteries 
will be assessed and changes will also be correlated with clinical markers. 
Additional details on the exploratory US imaging cohort are contained in Section 7.9 
and Appendix 8.
Section 7.9 Exploratory Ultrasound Imaging
7.9   Exploratory Ultrasound Imaging 
7.9.1 Background and Rationale
The results of three recent meta-analyses have provided evidence to support the 
utility of US imaging in the diagnosis of GCA [Ball, 2010; Arida, 2010; Karassa, 

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2005]. Additional data from a multicenter study, TABUL (Temporal Artery Biopsy 
versus ULtrasound), conducted at centers trained in US imaging techniques, also 
support the diagnostic utility of US in GCA [Luqmani, 2015]. However, the role of 
US imaging in the assessment of GCA disease activity remains unclear. Available 
evidence consists of results from a study which found persistent abnormalities 
suggestive of an association with relapse when GCA patients were assessed by 
ultrasound imaging every 2-4 weeks [de Miguel, 2012]. Permanent visual loss is also 
associated with the presence of abnormal sonographic features of cranial and extra-
cranial arteries [Schmidt, 2008; Schmidt, 2009; Czihal, 2012]. A recent prospective 
observational study has demonstrated that ultrasound can be informative in 
distinguishing potential flares from exacerbations of unrelated headache in patients 
with diagnosis of GCA [Ponte, 2015]. Taken together, these findings suggest that 
ultrasound imaging may provide a useful diagnostic and biomarker approach for 
assessing and monitoring disease activity in GCA.
Currently, no valid biomarkers exist to assess response to therapy and to predict 
relapse. Changes in the conventional inflammatory markers (CRP and ESR) do not 
consistently reflect disease activity [Tse, 1998]. Therefore, the utility of US in 
monitoring disease activity in GCA will be explored in a cohort of study subjects 
from select participating centers by sonographers trained and/or qualified as 
proficient in US imaging.  Longitudinal changes in vascular inflammation of the 
temporal and axillary arteries and the predictive value of US for disease activity will 
be assessed. 
7.9.2 Synopsis
A cohort of subjects with new onset GCA from participating imaging centers who 
have consented to participate in the US imaging portion of this study will be 
evaluated. These subjects will undergo US scans of their temporal and axillary 
arteries at the specified time points for assessment of changes in vascular 
inflammation. 
Only subjects with newly diagnosed GCA are eligible to participate. Due to the 
exploratory nature of this portion of the study, there is no pre-specified sample size 
for this cohort.  However, it is estimated that up to 50 subjects may participate.
Subjects will have an initial baseline scan at Screening and assessments at Weeks 12 
and 52. Additional US scans should also be conducted in the event of relapses or 
flares, including flares/relapses that occur during Part B of the study. Subjects may 
also be asked to provide retrospective consent for assessment of their diagnostic US 
scan. Efforts should be made to conduct the baseline US scan within 3 days of 
initiating prednisone therapy. However, inability to comply with this time frame 
does not exclude subjects from participation. Data will be analyzed according to the 
time frame between prednisone dose and US scan. Detailed information on US 
imaging in this cohort of study subjects is included in Appendix 8.

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Appendix 8
12.8  Appendix 8: Exploratory US Imaging
The utility of US in monitoring disease activity in GCA will be investigated in a 
cohort of subjects with new onset GCA. Longitudinal changes in vascular 
inflammation of the temporal and axillary arteries will be characterized. Only 
subjects with new onset GCA will participate in order to optimize the ability to 
detect inflammatory changes on US, based on the potential likelihood that these 
subjects would not have been receiving corticosteroids prior to diagnosis.
12.8.1 Objectives and Endpoints
The objectives and endpoints of this exploratory US imaging cohort are as follows:
Objectives
Endpoints
To explore the utility of vascular 
ultrasound (US) imaging assessment 
of inflammation in temporal and 
axillary arteries as an indicator of 
disease activity in a cohort of study 
subjects

To explore the predictive value of 
ultrasound for clinical efficacy in 
GCA

Change over time of the following 
measurements of vascular 
inflammation in temporal and 
axillary arteries:   
- Presence/absence of occlusion
- Presence/absence and 
maximum diameter of halo
- Presence/absence of stenosis
  

Correlation of clinical endpoints 
with changes in vascular 
inflammation.

Correlation of changes in vascular 
inflammation on US with clinical 
markers such as GCA disease 
activity, CRP and ESR 

Correlation of changes in vascular 
inflammation on US with health-
related quality of life outcomes
12.8.2   Type and Number of Subjects
Only subjects with new onset GCA are eligible to participate in the exploratory 
imaging portion of this study. These subjects will have a diagnosis of GCA based on 
the Revised GCA Diagnosis Criteria, and present with new onset GCA disease, 
defined as having a diagnosis within 6 weeks of baseline. Subjects should have either 
initiated prednisone treatment upon entry into Screening and after their Screening 
US scan has been performed or corticosteroid therapy should have only been 
recently initiated, optimally within 3 days of the Screening scan. However, inability 
to comply with this time frame does not exclude subjects from participation.

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As this is an exploratory study, there is no pre-specified sample size. However it is 
estimated that up to 50 subjects may participate. 
12.8.3   Assessments and Procedures
12.8.3.1  Sonographer Training
All sonographers participating in this study must have undergone training with 
documented approval to qualify as a participating site. Sites previously trained for 
participation in the TABUL study will not be required to participate in the training 
sessions, but may certify through a separate process. Processes and procedures for 
training and qualification are outlined in the Imaging Acquisition Guidelines.  
Sonographers participating in the training course will US scan a requisite number 
of healthy volunteers/non-GCA subjects and at least one patient volunteer with 
active GCA as per the protocol definition for qualification. All volunteers recruited 
to participate in the sonographer training will be required to provide consent prior 
to participation. GCA patients who participate in the sonographer training may be 
eligible to enroll in Study 201677, but they are excluded from participating in the 
imaging cohort portion of the study. Detailed information on the sonographer 
training process is contained in the training manual.
12.8.3.2  Subject Eligibility
Study subjects consenting to participate in the exploratory US imaging cohort are 
eligible only if they have newly diagnosed GCA (within 6 weeks of baseline), based 
on the Revised GCA Diagnosis Criteria as described in Section 5.1. At Baseline, 
subjects must have fulfilled all of the eligibility criteria for Study 201677 and be 
randomized into the study to continue participation in the exploratory imaging 
cohort. Screen failures for Study 201677 will not be eligible to participate in this 
cohort.
Optimally, the study baseline scan (Screening) would be performed prior to the 
initiation of prednisone treatment. If this is not possible, then efforts should be made 
to perform the US scan within 3 days of initiating prednisone treatment. However, 
the inability to comply with this time frame is not exclusionary. The number of days 
between initiation of prednisone treatment and the US scan will be recorded. 
12.8.3.3   Ultrasound Scanning
Participating subjects will undergo US scans at the following time points:
1. Screening, or after consent has been provided to participate in the imaging 
cohort. Optimally (but not required), this scan would be performed within 3 
days of initiating corticosteroid therapy for GCA disease activity: 
2. Week 0 (Randomization)
3. Week 12

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4. Week 52
5. Any time point of disease relapse/flare during Part A or Part B of the study, 
with every effort made to conduct the US scan within 3 days of rescue 
prednisone administration. The number of days between the US scan and 
rescue prednisone administration will be recorded. 
The timings of the US assessments are included in Section 7.1, Time and Events 
Tables, Table 2, Table 3, Table 4 and Table 5.  
The scans will be sent for independent review by a central reader. Full details on the 
US scanning process, training requirements, image transfer and de-identification, 
assessments and data collection are provided in the Imaging Acquisition Guidelines.
12.8.4    Blinding
The central reader will remain blinded to the subject’s treatment group. 
Investigators and sponsor will remain blinded to the central US results. No clinical 
findings will be communicated by the central reader to investigators. Scans may be 
reviewed at the site according to local policy.
12.8.5   Statistical Considerations and Data Analyses
12.8.5.1 Hypotheses
The objectives of the US imaging cohort are exploratory and observational. There 
are no formal statistical hypotheses planned.
Exploratory comparisons will be made between the sirukumab and placebo arms, if 
appropriate.
12.8.5.2   Sample Size Considerations
There are no formal calculations of power or sample size for this cohort. There is no 
pre-specified upper or lower limit for subject enrolment in this cohort.  Therefore, 
no sample size sensitivity was performed and there are no plans for sample size re-
estimation .
12.8.5.3  Data Analysis Considerations
No formal analyses are planned for this cohort.
12.8.5.4   Key Elements of Analysis Plan
Data from the US imaging cohort may be reported separately from the main 201677 
clinical study report. 

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Data will be analyzed according to the timeframe between prednisone dose and US 
scan.
Graphics and/or descriptive statistics will be used to describe the time course and 
magnitude of changes in key markers (e.g. halo and stenosis sizes, presence of 
occlusions). If data permits, analyses assessing the associations between these key 
markers and some disease activity and health outcomes indicators (e.g. GCA disease 
activity, ESR, CRP, fatigue and pain) will be carried out using descriptive statistics 
and graphics.
Full details of the approaches will be described separately from the main clinical 
study report.
3. Updated inclusion criteria to allow for diagnosis of GCA by US imaging in centers 
who are participating in the exploratory US imaging portion of the study.
Rationale: US imaging has been shown to be an accurate technique for diagnosis of GCA 
for sonographers trained in the TABUL method. Therefore, trained and qualified centers 
participating in the exploratory US portion of the study may also qualify subjects for this 
study by confirming a diagnosis of GCA by US imaging.
Section 5.1 Inclusion Criteria #1

Presence of at least one of the following:

Temporal artery abnormality on biopsy revealing features of GCA.

Evidence of large-vessel vasculitis by angiography or cross-sectional 
imaging, including but not limited to magnetic resonance angiography 
(MRA), computed tomography angiography (CTA), ultrasound (US) or 
positron emission tomography-computed tomography (PET-CT).

Evidence of temporal artery vasculitis on US (for US imaging qualified 
centers only).
4. Further clarification of the inclusion criteria for active GCA by including 
additional details on features associated with GCA.
Rationale: To provide additional guidance to investigators on features of GCA that may 
present clinically as systemic symptoms.
Section 5.1 Inclusion Criteria #2

Other features judged by the clinician investigator to be consistent with GCA or 
PMR flares (i.e., new or worsened extremity claudication, unexplained systemic 
symptoms such as fever of unknown origin, weight loss and night sweats).

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5. Additional clarification of the prednisone dose at screening.
Rationale: The prednisone dose at screening must be a minimum of 20 mg/day but there 
is no requirement to limit the dose to 60 mg/day during the screening period.
Section 5.1 Inclusion Criteria #3
At screening, receiving or able to receive initiate prednisone 20-60mg/day treatment 
with a minimum dose of 20 mg /day for the treatment of active GCA.
6. Addition of wording to clarify requirements for chest radiographs to exclude 
infection with TB.
Rationale: Single views of chest radiographs are acceptable according to local guidance 
in some countries, such as Germany. The protocol has been amended to clarify the 
acceptability of local practices/guidance.
Section 5.1 Inclusion Criteria #6
c. Chest radiograph (both posterior-anterior and lateral views unless local guidelines 
recommend only a single view), taken within 12 weeks prior to baseline or at Screening, 
and read locally by a qualified radiologist, with no evidence of current active or previous 
inactive pulmonary tuberculosis.
7. Addition of details to clarify that physicians with hepatitis B expertise should be 
consulted in the event of positive results for hepatitis B testing.
Rationale: To include guidance to investigators for clinical follow up in the event of 
positive findings for hepatitis B testing.
Section 5.2 Exclusion Criteria # 16
Hepatitis B infection (positive test results for hepatitis B surface antigen or hepatitis B 
core antibody)**.
** If seropositive, consultation with a physician with expertise in the treatment of HIV or 
hepatitis B or C virus infection is recommended.
8. Amendment of wording describing the needle shield for the sirukumab PFS.
Rationale: To correct the description for the needle shield for consistency with the 
updated IB, including the information on the potential risk of allergic reaction in latex-
sensitive individuals.
Section 6.1 Investigational Product and Other Study Treatment
The sirukumab PFS is aseptically filled to deliver a dose of either 100 mg/1.0 mL or 50 
mg/1.0 mL of sirukumab in a Becton-Dickinson (BD) Hypak, 1 mL glass SCF 

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(presiliconized) syringe barrel with a 26 gauge (G) ½ inch fixed needle, a non-latex-
based an elastomeric needle shield, and a fluoropolymer coated elastomeric plunger 
stopper.
The needle shield on the PFS (either assembled into UltraSafe needle guard or 
autoinjector/prefilled pen) is made with a derivative of natural rubber latex, which may 
cause allergic reactions in individuals sensitive to latex.
9. Addition of wording to clarify that the prednisone dose should be taken as a single 
daily administration in the morning.
Rationale: To ensure consistency of prednisone dosing in the study to minimize any variation 
in prednisone pharmacokinetics.
Section 6.1 Investigational Product and Other Study Treatment
Prednisone doses below 20 mg and/or matching placebo will be provided in blister packs 
for blinded administration. Subjects should take their prednisone daily dose in one 
single daily administration in the morning.
10. Update the Time and Events Tables to include additional time points for PK 
assessments and additional samples for IL-6 measurements, to include the 
assessments for the exploratory US imaging cohort, and to amend the footnote 
wording for requirement for ECG .
Rationale: For consistency with protocol changes.
Section 7.1 Time and Events Tables

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Table 2 Time and Events Table for Part A of the Study (52-week Double-blind Treatment Phase)
Screening (~Wk -6)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal 
Follow  Up
Laboratory Assessments 
PK12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Immunogenicity12
x
x
x
x
x
x
x
Exploratory Lab Assessments
IL-6 measurements
x
x
x
x
Blood Biomarkers & exploratory 
markers
x
x
x
x
x
x
x
Blood and Urine Markers, 
Transcriptomics (optional)13
x
x
x
x
x
x
x
Pharmacogenetics sample14
x
Exploratory US Imaging
x
Ultrasound imaging15
x16
x
x
x
1.
Including consent for pharmacogenetics.
2.
Assuming placebo will also be administered using autoinjector. Additional training may be provided when required.
3.
Only for those subjects who initiate open-label sirukumab treatment at the start of Part B.
4.
To be completed by subjects before any other assessments and before the administration of study drug. HAQ-DI administered only to sub-set of subjects with PMR. PGA 
assessed using PtGA (subjects) and PhGA (physicians, after subject completion of questionnaires). 
5.
Complete physical exam at Screening and brief physical exam at other time points.
6.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
7.
And when suspected heart attack cardiac abnormality.
8.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
9.
Chest radiograph taken up to 3 months prior to Week 0 may be used to qualify at screening.
10. Pregnancy test: urine = U, serum = S. Premenopausal women only.
11. If hepatitis C antibody positive, a hepatitis C RNA PCR assay should be reflexively performed on a fresh sample to confirm the result.

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12. On study drug administration days, Pharm serum samples must be collected prior to study drug 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.
13. To be collected only for those subjects consenting to provide samples for the biobank for future exploration of GCA disease biology.
14. Sample should be collected at the baseline visit but may be collected at any visit post-baseline if not collected at the baseline visit.
15. Selected sites participating in the exploratory US imaging portion only; restricted to subjects with new onset disease
16. Optimally (but not required), to be performed prior to or within 3 days of the start of prednisone.

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Table 3 Time and Events Table for Part B (104-week Extension) of the Study: Subjects NOT receiving Open-label Sirukumab During Part 
B 
Wk 0/(Wk 52 of Part A)
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
Exploratory Lab Assessments
IL-6 measurements
x
Blood Biomarkers & exploratory 
markers
x
Blood and Urine Markers, 
Transcriptomics (optional)
x
Exploratory US Imaging
Ultrasound imaging8
x
1.
Assessment from Week 52 visit of Part A
2.
To be completed by subjects before any other assessments. HAQ-DI administered only to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) 
and PhGA (physicians, after subjects complete their questionnaires). 
3.
Brief physical exam.
4.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
5.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
6.
To be performed only if Early Withdrawal visit or flare occurs on or before Week 16 visit.
7.
Pregnancy test: urine = U, serum = S. Premenopausal women only.
8.
Ultrasound scan to be performed only in the event of disease flare or relapse in Part B for subjects participating in the exploratory US imaging cohort.

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Table 4 Time and Events Table for Part B (104-week Extension) of the Study: Subjects receiving Open-label Sirukumab Immediately 
Upon Entry into Part B 
Wk 0/(Wk 52 of Part A)
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
Laboratory Assessments
PK7
x
x
x
x
Immunogenicity7
x
x
x
x
Exploratory Lab Assessments
IL-6 measurements
x
Blood Biomarkers & exploratory 
markers
x
Blood and Urine Markers, 
Transcriptomics (optional)
x
Exploratory US Imaging
Ultrasound imaging8
x
1.
Visit only to dispense IP; no assessments are required.
2.
To be completed by subjects before any other assessments and before the administration of open-label sirukumab as applicable. HAQ-DI administered only to sub-set of 
subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subjects complete their questionnaires))
3.
Brief physical exam.
4.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
5.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test (or if not approved at the site, a tuberculin skin test) should be performed at any time during the 
study if TB is suspected.
6.
Pregnancy test: urine = U, serum = S. Premenopausal women only.
7.
On study drug administration days, Pharm serum samples must be collected prior to study drug 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.. 
8.
Ultrasound scan to be performed only in the event of disease flare or relapse in Part B for subjects participating in the exploratory US imaging cohort.

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Table 5 Time and Events Table for Part B (104-week Extension) of the Study: Subjects Receiving Open-label Sirukumab at Any Time 
AFTER (but NOT immediately Upon) Entry into Part B
Start of open-label 
sirukumab  1
PLUS 2 Wks5d
PLUS 4 Wks5d
PLUS 8 Wks5d
PLUS 12 Wks5d
PLUS 16 Wks5d
PLUS 24 Wks5d
PLUS 36 Wks5d
PLUS 48 Wks5d2
PLUS 52 Wks5d
PLUS 76 WKS5d
PLUS 104 Wks5d 3
Flare
Early Withdrawal 
Follow  Up
Laboratory Assessments
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x
x
x
x
x
x
Hemoglobin A1c
x
x
x
x
x
x
x
x
x
Pregnancy Test8
U
U
U
U
U
U
U
U
U
PK9
x
x
x
x
x
x
Immunogenicity9
x
x
x
x
x
x
Exploratory US Imaging
Ultrasound imaging10
x
1.
Upon the initiation of open-label sirukumab, perform the assessments from Time and Events Table 3 at the visit the subject was scheduled to undergo when study drug is 
started.
2.
Visit only to dispense IP; no assessments are required.
3.
Although this visit is labelled as 104 weeks since the start of open-label sirukumab, it does not take into account the exact start time, since this will be different for each 
subject depending upon when in the first 52 weeks of Part B open-label sirukumab was started. The important point to note, is that this last visit should be scheduled when 
each of these subjects will complete 104 weeks in Part B.
4.
To be completed by subjects before any other assessments and before the administration of open-label sirukumab as applicable. HAQ-DI administered only to sub-set of 
subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subjects complete their questionnaires).
5.
Brief physical exam. 
6.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
7.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.

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8.
Pregnancy test: urine = U, serum = S. Premenopausal women only.
9.
On study drug administration days, Pharm serum samples must be collected prior to study drug 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.
10. Ultrasound scan to be performed only in the event of disease flare or relapse in Part B for subjects participating in the exploratory US imaging cohort. 

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11. Modify the wording related to when the results of an ECG should be obtained.
Rationale: The results of an ECG performed for any suspected cardiac abnormality 
should be obtained.
Section 7.5.5 Electrocardiogram (ECG)
In the event of a suspected myocardial infarction cardiac abnormality, the investigator 
should make every reasonable attempt to obtain the results of the ECG performed in the 
emergency hospital facility. at the time of the suspected myocardial infarction.
12. Correct typographical error in time frame for assessment of cumulative 
prednisone dose.
Section 9.3 Data Analysis Considerations, Section 9.3.3 Treatment comparisons
3. Cumulative prednisone dose over 786 week period
13. Include additional references for the exploratory US imaging portion of the study.
Section 11
Arrida, A., Kyprianou, M., Kanakis, M., and Sfikakis, P.P. (2010). The diagnostic 
value of ultrasonography-derived edema of the temporal artery wall in giant cell 
arteritis: a second meta-analysis. BMC Musculoskeletal Disorders 11, 44.
Ball, E.L., Walsh, S.R., Tang, T.Y., Gohil, R., and Clarke, J.M. (2010). Role of 
ultrasonography in the diagnosis of temporal arteritis. The British Journal of 
Surgery 97, 1765-1771.
Czihal, M., Zanker, S., Rademacher, A., Tato, T.Y., Kuhlencordt, P.J., Schulze-
Koops, H., and Hoffman, U. (2012). Sonographic and clinical pattern of extracranial 
and cranial giant cell arteritis. Scandinavian Journal of Rheumatology 41:231-236.
De Miguel, E., Roxo, A., Castillo, C., Peiteado, D., Villalba, A., and Martin-Mola, E. 
(2012). The utility and sensitivity of colour Doppler ultrasound in monitoring 
changes in giant cell arteritis. Clinical and Experimental Rheumatology 30, S34-38.
Karassa, F.B., Matsagas, M.I., Schmidt, W.A., and Ioannidis, J.P. (2005). Meta-
analysis: test performance of ultrasonography for giant-cell arteritis. Annals of 
Internal Medicine 142, 359-369.
Luqmani R, Lee E, Singh S, Gillett M, Schmidt WA, Bradburn M, Dasgupta B, 
Diamantopoulos AP, Forrester-Barker W, Hamilton W, Masters S, McDonald B, 
McNally E, Pease CT, Piper J, Salmon J, Wailoo A, Wolfe K, Hutchings A. Inter-

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Rater Analysis of Ultrasound and Histological Findings in Patients with Suspected 
Giant Cell Arteritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10).
Ponte C, Vaggers S, Sznajd J, O'Neill L, Piper J, Gunn J, Mankia K, Luqmani R. 
How Can We Use Ultrasound in the Diagnosis and Management of Patients with 
Giant Cell Arteritis? [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). 
Schmidt WA, Moll A, Seifert A, Schicke B, Gromnica-Ihle E, Krause A. Prognosis 
of large-vessel giant cell arteritis. Rheumatology (Oxford). 2008 Sep;47(9):1406-8.
Schmidt WA, Krause E, Schicke B, Kuchenbecker J, Gromnica-Ihle E. Do temporal 
artery duplex ultrasound findings correlate with ophtalmic complications in giant 
cell arteritis? Rheumatology (Oxford). 2009 Apr; 48(4):383-5.
14. Inclusion of information in Appendix 7 for Country Specific Amendments
Rationale: To reflect changes requested by central ethics committees in Germany and the 
Netherlands to include additional measures regarding subject safety and for consistency 
with local guidelines with respect to chest radiographs.
Section 12.7 Appendix 7 Country Specific Requirements
In Germany, subcutaneous administration of sirukumab or matching placebo must 
be discontinued for subjects with a clinically important, active infection. This 
treatment must be withheld until serious and/or severe infections have been 
completely resolved. This includes all opportunistic infections, sepsis or 
meningoencephalitis.
In the Netherlands, no subject will be enrolled in the extension phase (Part B) of the 
study. Subjects will discontinue the study upon completion Part A and the 16-week 
follow-up phase.
In Australia and New Zealand, the investigator will be notified of the value of the 
ESR result when an ESR value is > 40 mm/hr or in the event of a increase from 
baseline or previous visit of  > 10 mm/hr in order to determine if a treatment change 
is warranted.
15. Administrative changes
Updated author list, Table of Contents, name and contact information for GSK medical 
monitor and correction of typographical error in Abbreviations. 

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Amendment 03 17 November 2016
1. Clarification of the endpoints for the ultrasound imaging cohort. 
Rationale: Occlusion and stenosis will not be assessed by sonographers. Since this is an 
exploratory cohort of the study, the analyses related to changes in vascular information 
will be detailed in a separate RAP. 
Section 1 Protocol Synopsis for Study 201677, Objective(s)/Endpoint(s)
Section 3 Objectives and Endpoints
Section 12.8 Appendix 8: Exploratory US Imaging, Section 12.8.1 Objectives and 
Endpoints
Objectives
Endpoints
To explore the utility of vascular 
ultrasound (US) imaging assessment 
of inflammation in temporal and 
axillary arteries as an indicator of 
disease activity in a cohort of study 
subjects

To explore the predictive value of 
ultrasound for clinical efficacy in 
GCA

Change over time of the following in
measurements of vascular 
inflammation in temporal and 
axillary arteries:   
- Presence/absence of occlusion
- Presence/absence and maximum 
diameter of halo
- Presence/absence of stenosis
  

Correlation of clinical endpoints with 
changes in vascular inflammation

Correlation of changes in vascular 
inflammation on US with clinical 
markers such as GCA disease
activity, CRP and ESR 

Correlation of changes in vascular 
inflammation on US with health-
related quality of life outcomes
GCA = giant cell arteritis; ESR – erythrocyte sedimentation rate; CRP = C-reactive protein; SF-36 v2 = 36-item short 
form health survey version 2; EQ-5D (3L) = EuroQoL-5 dimensions; FACIT-fatigue = functional assessment of chronic 
illness therapy-fatigue; PRO = patient reported outcomes; HAQ-DI = health assessment questionnaire-disability index; 
PGIC = Patient Global Impression of Change; P1NP = procollagen type 1 N-propeptide; CTX = carboxyterminal cross-
linked telopeptide of bone collagen; IL = interleukin; US=ultrasound.
2. Inclusion on information on the 3 time points when the database will be locked 
and the data to be included.
Rationale: The results from Parts A and B will be analyzed separately. The results of 
Part A will be analyzed when the last subject completes Week 52 of treatment and the 
data reported. The data for the 1st 6 months of Part B will also comprise a separate 
data set and report.

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Section 1 Protocol Synopsis for Study 201677, Overall Design
Section 4 Study Design, Section 4.1 Overall Design
Three primary database locks (DBLs) are planned for reporting of the results:

The first DBL for the primary analysis will occur after all subjects have 
completed the Week 52 visit assessments in Part A or have withdrawn 
prematurely from the study. Treatment-level data will be unblinded to 
Sponsor personnel.

The second DBL for the 6-month follow-up will occur after all subjects have 
completed the Week 24 visit in Part B, or have withdrawn prematurely from 
the study. The data from subjects undergoing the 16-week follow-up 
assessments at the end of Part A will also be included and will potentially 
comprise a separate data set/report if applicable.

The third planned DBL will occur after all subjects have completed the last 
visit in Part B, or have withdrawn prematurely from the study. The Part B 
DBL will include the data from all visits associated with Part B of the study, 
including the 16-week follow-up assessments of Part B if applicable.
All subjects and study site personnel will remain blinded to the treatment group 
assignment until all subjects of Part B have completed the Week 24 visit assessments 
of Part B.
3. Additional clarification regarding requirements for implementation of the 
prednisone taper.
Rationale: To include additional details for investigator understanding of how to 
implement the prednisone taper for their study subjects.
Section 1 Protocol Synopsis for Study 201677, Treatment Arms and Duration
The prednisone tapering schedule begins for all subjects upon randomization 
(Baseline, Week 0) as follows:

Subjects will remain on the prednisone dose they are currently receiving at 
Baseline for one week. 

At Week 1, the prednisone dose will be decreased in accordance with the pre-
specified prednisone taper schedule. 

The pre-specified maximum tapering schedule to be followed will depend on 
the subject’s treatment group assignment. 

The prednisone taper will be unblinded (open-label) and will consist of 
identical weekly decreases in dose for all subjects until a dose of 20 mg/day is 
reached, at which point the blinded portion of the prednisone tapering 
regimen will commence. 

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
Subjects who are receiving a prednisone dose of 20 mg/day at Baseline (Week 
0) should continue taking the open-label 20 mg daily dose for one week. At 
Week 1, these subjects will initiate the blinded taper regimen.
Section 4 Study Design, Section 4.2 Treatment Arms and Duration, Section 4.2.1 Part A: 
52-week, double-blind treatment phase
All subjects must be receiving prednisone (a minimum dose of 20 mg/day) at the 
start of Screening. Prednisone treatment must be initiated at Screening for subjects 
not currently receiving steroid treatment. The prednisone tapering schedule 
(summarized in Section 6.3) will be initiated at randomization for all subjects. Subjects 
should remain on the prednisone dose they are currently receiving at Baseline 
(randomization) for one week. At Week 1, the prednisone dose should be decreased 
in accordance with the pre-specified prednisone taper schedule.   The pre-specified 
maximum tapering schedule to be followed will depend on the subject’s treatment group 
assignment. The standardized prednisone taper regimen will be unblinded (open-label)
with identical weekly decreases in dose according to the starting dose for all subjects, 
until subjects reach a dose of 20 mg/day. Thereafter, prednisone dosing will be blinded to 
allow for the pre-specified differences in duration of the prednisone tapering. Subjects 
who are receiving a prednisone dose of open-label 20 mg/day at randomization 
should continue taking the 20 mg daily dose for one week. At Week 1, these subjects 
will initiate the blinded taper regimen.
Section 6 Study Treatment, Section 6.3 Planned Dose Adjustments
No dose adjustment of sirukumab will be allowed in this study.
All subjects must be receiving prednisone (a minimum dose of 20 mg/day) at the 
start of Screening. Prednisone treatment must be initiated at Screening for subjects 
not currently receiving steroid treatment. A pre-specified prednisone tapering 
schedule outlined in Table 1 will be initiated at randomization, depending on the 
subject’s treatment group assignment begins for all subjects upon randomization at 
Baseline, (Week 0). The standardized prednisone taper regimen will be open-label with 
identical weekly decreases in dose according to the starting dose for all subjects, until 
subjects reach a dose of 20 mg/day. Thereafter, prednisone dosing will be blinded to 
allow the pre-specified differences in tapering.
Requirements for the prednisone taper are as follows:

Subjects will remain on the prednisone dose they are currently receiving at 
Baseline (Week 0) for one week. 

At Week 1, the prednisone dose will be decreased in accordance with the pre-
specified prednisone taper schedule (Table 1). 

The pre-specified maximum tapering schedule to be followed will depend on 
the subject’s treatment group assignment. 

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
The prednisone taper will be unblinded (open-label) and will consist of 
identical weekly decreases in dose for all subjects until a dose of 20 mg/day is 
reached, at which point the blinded portion of the prednisone tapering 
regimen will commence. 

Subjects who are receiving a prednisone dose of 20 mg/day at Baseline (Week 
0) should continue taking the open-label 20 mg daily dose for one week. At 
Week 1, these subjects will initiate the blinded taper regimen.
Section 7 Study Assessments and Procedures, Section 7.2 Screening and Critical Baseline 
Assessments
All subjects should be receiving prednisone treatment at Screening. Prednisone 
treatment must be initiated at Screening for subjects not currently receiving steroid 
treatment.
4. Addition of values for CRP units in mg/L.
Rationale: To specify the unit in mg/L for consistency with results from the central 
laboratory.
Section 1 Protocol Synopsis for Study 201677, Type and Number of Subjects
Section 4 Study Design, Section 4.1 Overall Design
Subjects are required to have active GCA disease within 6 weeks of baseline where 
active disease is defined as the presence of unequivocal clinical signs and symptoms 
attributable to GCA and increased levels of inflammatory markers ([ESR 30 mm/hr 
and/or CRP 1 mg/dL (10 mg/L)].
Section 4 Study Design, Section 4.1 Overall Design
Eligible subjects will be required to have active disease within 6 weeks prior to the 
Randomization (Baseline) visit. Active disease is defined as the presence of 
unequivocal clinical signs and symptoms attributable to GCA and an ESR ≥30 mm/hr 
and/or serum CRP ≥1 mg/dL (10 mg/L).
Section 5 Selection of Study Population and Withdrawa Criteria, Section 5.1 Inclusion 
Criteria
1. Diagnosis of GCA defined by the following Revised GCA Diagnosis 
Criteria:

Age ≥50 years.

History of ESR ≥ 50 mm/hour or CRP ≥ 2.45 mg/dL (≥ 24.5 mg/L)
2. Active GCA within 6 weeks of Randomization (Baseline) where active 
disease is defined by an ESR  30 mm/hr or CRP 1 mg/dL (10 mg/L)
AND the presence of at least one of the following:

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5. Update of study schematic to clarify that prednisone should be taken during 
Screening.
Rationale: To specify that prednisone should be taken during Screening.
Section 4 Study Design, Section 4.1 Overall Design
6. Update of risk assessment table and modification of events of special interest for 
sirukumab.
Rationale: To incorporate the findings from the Phase III sirukumab study in 
rheumatoid arthritis and for consistency with the updated investigator brochure
Section 4: Study Design, Section 4.6 Benefit:Risk Assessment, Section 4.6.1 Risk 
Assessment

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [sirukumab]
TB reactivation
Cases of TB reactivation have been reported 
with other IL-6 antagonists, such as tocilizumab
and sirukumab.
Inclusion only of subjects with no evidence of 
active or latent TB infection, negative diagnostic 
TB test at Screening and Screening chest 
radiograph showing no evidence of current or 
previous pulmonary TB (Section 5.1 Bullet 4).
Evaluation of TB throughout the study by use of 
a TB questionnaire and a TB test (Section 7.5.7)
Serious/opportunistic infections
IL-6 deficient mice have been noted to be 
susceptible to infections with Listeria, 
monosytogenes, Toxoplasma gondii, and 
Candida albicans [Dalrymple, 1995; Romani, 
1996; Suzuki, 1997]. Serious, life-threatening 
infections such as septic shock, some of which 
have been fatal, have occurred in subjects 
receiving sirukumab.
Exclusion of subjects with an active current or 
history of recurrent bacterial, viral, fungal, 
mycobacterial, or other infection or those with a 
prior episode of major infection (serious 
infectious event).
Monitoring of serious and opportunistic infections 
by IDMC.
Hypersensitivity
Serious allergic reactions (eg, anaphylaxis) have 
been reported with the administration of mAbs, 
including sirukumab, and may occur during or 
after the administration of the mAbs.
Exclusion of subjects with severe allergic 
reactions to monoclonal antibodies, human 
proteins, or excipients. Subjects will be made 
aware of the potential risk, the signs and 
symptoms of such reactions, and the importance 
of immediately seeking medical attention.
Discontinuation of blinded subcutaneous study 
drug in the event of a severe allergic reaction. 
Monitoring of serious allergic reactions by IDMC; 
adjudication and classification of these events 
using Sampson criteria (Sampson, 2006) by 
sponsor safety review team will be implemented.
Gastrointestinal perforation
Upper and lower GI tract perforations occurred in 
Exclusion of subjects with a history of 

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the anti-IL-6 receptor (tocilizumab) & the anti-
IL6 (sirukumab) Phase III programs. Sirukumab 
binds to IL-6 and prevents binding to IL-6 
receptor (IL-6R). Tocilizumab binds to IL-6 R to 
prevent IL-6 signalling. Potential differences in 
safety between agents that bind to the IL-6 
receptor versus ones that bind to the IL-6 ligand 
(sirukumab) warrants further study.
diverticulitis, inflammatory bowel disease, or 
other symptomatic GI tract condition that might 
predispose to bowel perforation.
Investigators should closely monitor for GI 
perforations with a high degree of suspicion. 
Monitoring of gastrointestinal perforations by 
IDMC.
Cytopenias
Neutropenia and thrombocytopenia have 
occurred in sirukumab studies, including severe 
thrombocytopenia associated with bleeding. 
Decreases in platelet counts have also been 
observed.
Most patients who  developed neutropenia 
while being treated with sirukumab did not 
develop infections, and most
patients who  developed  thrombocytopenia  
did  not  experience  bleeding  events.
Exclusion of subjects with absolute neutrophil 
count (ANC) <2x109/L, platelet count 
<140x109/L, WBC count <3.5x109/L, ALC <0.5 
x109/L.
Discontinuation of blinded subcutaneous study 
drug for subjects with 2 confirmed consecutive 
absolute neutrophil counts of <0.5 × 109 cells/L 
or platelet counts <50 x 109 cells/L.
Monitoring of cytopenias by IDMC.
Lipid increases
Increases in blood total cholesterol, LDL, HDL, 
and triglycerides have occurred in sirukumab-
treated subjects. No dose response was 
observed.
Monitor HDL/LDL levels, administer a cholesterol 
lowering agent if indicated.
Liver enzyme increases
Transient asymptomatic increases (1 to 3 x ULN, 
sometimes > 5 x ULN but < 8 x ULN) in blood 
ALT and AST values have been observed in 
subjects in completed and ongoing studies of 
sirukumab. These changes were not associated 
with an increase in bilirubin. Six subjects have 
had ALT or AST >3 x ULN and bilirubin >2 x 
ULN; all 6 had received sirukumab 100 mg SC 
Exclusion of subjects with AST or ALT >2.0 x 
ULN, or total bilirubin >ULN with the exception of 
Gilbert’s disease. Inclusion of pre-defined liver 
chemistry discontinuation criteria (Section 5.4.3). 
Monitoring of hepatic abnormalities by IDMC.

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q2w. Three subjects had concurrent biliary 
stones/colic, and 1 subject was 
concomitantly taking isoniazid. The 
hepatobiliary laboratory values normalized 
after surgery or discontinuation of isoniazid 
in these subjects. A fifth subject with long-
standing methotrexate use, who had pre-
existing fatty liver disease, developed 
hyperbilirubinemia (>9 x ULN) and jaundice, 
as well as elevations in AST (>5 x ULN), after 
2 doses of sirukumab 100 mg. A liver biopsy 
revealed active steatohepatitis. After 
discontinuation of methotrexate and 
sirukumab, the hepatobiliary tests improved 
such that 9 months later AST was 1-1.5 x 
ULN, and ALT and bilirubin were normal. A 
sixth subject initially was observed to have 
ALT and AST >5 x ULN which both increased 
2 weeks later to >20 x ULN with bilirubin > 2 x 
ULN. Notable findings at that time were 
hepatitis E virus IgM positivity and chronic 
liver changes by ultrasound.  Hepatobiliary 
abnormalities had resolved 16 weeks after 
discontinuation of study agent.
Cardiovascular events
No cardiovascular risk with sirukumab has been 
identified in clinical studies to date. Most 
subjects who experienced cardiovascular 
events in the sirukumab RA Phase 3 program 
had pre-existing risk factors as well as active 
RA. There was no association between grade 
Exclusion of subjects with uncontrolled 
cardiovascular disease or marked baseline 
prolongation of QTc interval ≥ 450 msec (QTcB 
or QTcF), history of Torsade de Pointes, family 
history of long QT syndrome, history of second 
or third degree heart block or subject with major 

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3 or 4 lipid levels and the development of 
MACE in the majority of subjects in the 
sirukumab Phase 3 RA program. Overall, the 
data do not support a direct link between 
sirukumab-induced elevations in lipid levels 
and MACE. However, the study population is at 
high risk for CV disease.
ischemic event unrelated to GCA. Inclusion of 
pre-defined QTc discontinuation criteria 
(Section 5.4.4). Monitoring of CV events by CEC 
and IDMC
Malignancies
The impact of treatment with tocilizumab on 
the development of malignancies is not 
known, but malignancies were observed in 
clinical studies. 
As an IL-6 inhibitor, sirukumab may have 
some effect on the risk of malignancy by 
affecting immune surveillance. Malignancies 
have been reported with sirukumab in 
rheumatoid arthritis (RA) clinical trials.
Exclusion of subjects with active malignancy 
or history of malignancy within previous 5 
years (except basal and squamous cell 
carcinoma of the skin or carcinoma in situ of 
the cervix uteri that has been excised and 
cured). Monitoring of malignancies by IDMC.
Study Procedures
Blood draws for safety and biomarker 
assessments
Fainting, mild pain, bruising, irritation or redness 
at the site are associated with blood draws.
Experienced site staff will follow standard 
approaches for managing events related to blood 
draws.
Use of auto-injector
Mild pain, bruising, irritation or redness at the
injection site may be experienced by some 
patients.
Site staff will be trained and will ensure training 
and oversight of subjects’ capabilities to use the 
auto-injector.
Rapid steroid taper
Steroid withdrawal symptoms and side effects
Inclusion only of subjects with stable disease 
who are able to safely participate in the steroid 
taper. Subjects should have clinically stable 
disease on steroid therapy prior to 

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randomization. IDMC will monitor all subjects 
including those in the 3 month taper.

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Section 7 Study Assessments and Procedures, Section 7.5 Safety, Section 7.5.1 Adverse 
Events (AE) and Serious Adverse Events (SAEs), Section 7.5.1.5 Other Adverse Events 
of Special Interest for Sirukumab
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. . Increased susceptibility to infections is an identified risk 
of sirukumab. Serious, life-threatening infections such as septic shock, some of 
which have been fatal,  have occurred in subjects receiving sirukumab. IL-6 deficient 
mice have been found to be susceptible to infections with Listeria monocytogenes, 
Toxoplasma gondii, and Candida albicans. [Dalrymple, 1995; Romani, 1996; Suzuki, 
1997].  In addition, as an IL-6 inhibitor, sirukumab may have some effect on the risk of 
malignancy by affecting immune surveillance. Further, gastrointestinal perforations have 
been reported with another anti-IL-6 agent [ACTEMRA Prescribing Information, 2011] 
and with sirukumab. Please refer to Table 4.6.1 and the Investigator Brochure for 
additional information.

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7. To update the benefit:risk conclusion.
Rationale: To clarify that the efficacy has been demonstrated in Phase III trials in RA.
Section 4.6 Benefit:Risk Assessment, Section 4.6.3 Overall Benefit:Risk Conclusion
Although the efficacy of sirukumab in subjects with GCA has yet to be established, it has 
been shown to be effective in Phase II III studies in RA.
8. To update the Inclusion Criteria to clarify prednisone requirements at Screening.
Rationale: To clarify that subjects should be receiving prednisone at the start of 
Screening.
Section 5 Selection of Study Population and Withdrawa Criteria, Section 5.1 Inclusion 
Criteria
3.  At screening, receiving or able to initiate prednisone treatment with a minimum 
dose of 20 mg /day for the treatment of active GCA. Subjects not currently receiving 
prednisone treatment must commence dosing (minimum 20 mg/day of prednisone) 
at the screening visit.
9. To include information on requirements for contraception and sperm donation.
Rationale: Use of male contraception and restrictions on sperm donation have been 
included for consistency with Janssen’s requirements for safety monitoring
Section 5 Selection of Study Population and Withdrawa Criteria, Section 5.1 Inclusion 
Criteria
5. Practicing acceptable methods of birth control Acceptable methods of birth 
control are provided in Appendix 2.as follows:
Males:
Male subjects with female partners of child bearing potential must comply 
with the following contraception requirements from the time of first dose of 
study medication until 4 months after the last dose of study medication:
h.
Vasectomy with documentation of azoospermia.  
i.
Male condom plus female partner use of one of the GSK Modified List of 
Highly Effective Methods for Avoiding Pregnancy in Females of 
Childbearing potential listed in Appendix 2.
Male subjects should also not donate sperm from the time of first dose of 
study medication until 4 months after the last dose of study medication.
Females:

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Female subjects of child-bearing potential must use of one of the GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Childbearing potential listed in Appendix 2.
10. To modify the requirements for QuantiFERON Gold TB testing.
Rationale: An indeterminate result may be a consequence of issues with sample 
processing; therefore, allowance for local laboratory testing after an initial indeterminate 
result from the central laboratory is permissible.
Section 5 Selection of Study Population and Withdrawa Criteria, Section 5.1 Inclusion 
Criteria
6. No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as 
defined by all of the following:
a.
No history of active or latent TB infection.
b. A negative diagnostic TB test at Screening defined as a negative 
QuantiFERON Gold test (NB: 2 successive indeterminate QuantiFERON 
tests will be considered as a positive result). In cases where an initial 
indeterminate QuantiFERON test result may be related to sample 
processing issues, the second QuantiFERON test may be performed at 
either the local laboratory or the central laboratory at the discretion of 
the investigator. Re-testing is only permitted for indeterminate results. 
If the re-test also produces an indeterminate result, further re-testing to 
determine study eligibility is not permitted either at the local or central 
laboratory.
c.
Chest radiograph (both posterior-anterior and lateral views unless local 
guidelines recommend only a single view), taken within 12 weeks prior to 
baseline or at Screening, and read locally by a qualified radiologist, with no 
evidence of current active or previous inactive pulmonary tuberculosis.
11. To modify the Exclusion Criteria and Prohibited Medications sections regarding 
prior use of anti-IL-6 agents.
Rationale: Sirukumab efficacy can reasonably be evaluated in study subjects who 
previously used an anti-IL-6 agent without evidence of an inadequate response or 
intolerance to the agent used.
Section 5 Selection of Study Population and Withdrawal Criteria, Section 5.2 Exclusion 
Criteria
4.
Had prior treatment with any of the following:

Any prior use of tocilizumab or other anti-IL-6 agents.

Anti-IL-6 (tocilizumab or any other anti-IL-6 agent) if:

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
Used within 8 weeks of randomization

Associated with a history of intolerance that precluded further 
treatment

Associated with an inadequate response to 3 months of therapy
Section 6.10 Concomitant Medications and Non-Drug Therapies, Section 6.10.2
Prohibited Medications and Non-Drug Therapies
The following drugs and vaccines are prohibited within the specified time frames and 
with concomitant SC administration of study drug:

Any prior use of tocilizumab or other anti-IL-6 agents.

Anti-IL-6 (tocilizumab or any other anti-IL-6 agent) if:

Used within 8 weeks of randomization

Associated with a history of intolerance that precluded further 
treatment

Associated with an inadequate response to 3 months of therapy
12. To modify the requirements for ECG test results for study eligibility and stopping 
criteria and to clarify ECG testing requirements.
Rationale: Sirukumab use is not associated with a QTc liability. The elderly patient 
population in this study is more likely to have excursions outside of the previous 
requirements in the absence of increased risk; therefore, the QTc requirements for 
eligibility were amended to be less restrictive. 
Section 5 Selection of Study Population and Withdrawa Criteria, Section 5.2 Exclusion 
Criteria
10. Marked baseline prolongation of QTc interval ≥ 450  > 480 msec (QTcB or 
QTcF) or QTc > 500 msec in subjects with Bundle Branch Block**, history of 
Torsade de Pointes, family history of long QT syndrome, history of second or 
third degree heart block.
**The QTc should be based on averaged QTc values of triplicate ECGs obtained 
over a brief (e.g., 5-10 minute) recording period.
Section 5.4 Withdrawal/Stopping Criteria, 5.4.4 QTc Stopping Criteria
QTc Stopping Criteria:

QTc > 500 530 msec OR Uncorrected QT > 600 msec (all subjects)
OR

Change from baseline of QTc > 60 msec.

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For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
13. To clarify testing procedures for hepatitis C.
Rationale: To ensure that subject eligibility is based on a confirmed positive result for 
hepatitis C.
Section 5: Selection of Study Population and Withdrawal Criteria, Section 5.2 Exclusion 
Criteria
16. HIV infection (positive serology for HIV antibody), hepatitis C (positive serology 
for hepatitis C antibody confirmed positive by hepatitis C RNA PCR which is 
reflexively performed)***.
*** If seropositive, referral of the subject for consultation with a physician with 
expertise in the treatment of HIV or hepatitis B or C virus infection is recommended.
14. To include wording to clarify exclusion requirements for continued or repeated use 
of corticosteroids.
Rationale: To clarify that subjects receiving corticosteroid treatment for symptoms of 
PMR are eligible.
Section 5: Selection of Study Population and Withdrawal Criteria, Section 5.2 Exclusion 
Criteria
6. Requires continued or repeated use of systemic corticosteroids for conditions other 
than GCA or PMR symptoms associated with GCA.
15. To include behaviors related to suicidality as an exclusion.
Rationale: Per GSK policy, prospective monitoring of suicidal ideation and behavior is 
implemented in clinical trials for investigational agents with potential activity on the 
central nervous system, including sirukumab. This exclusion has been included to 
decrease the likelihood of enrolment of patients at risk of suicidal behaviors.
Section 5: Selection of Study Population and Withdrawa Criteria, Section 5.2 Exclusion 
Criteria

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23. Current history of suicidal ideation or past history of suicide attempt.
16. To clarify requirements for re-testing for ECG assessment and QuantiFERON-TB 
Gold test.
Section 5.3 Screening/Baseline/Run-in Failures
Re-testing
If a subject has signed the Informed Consent Form (ICF) and failed to meet at least one 
entry criterion, the site may retest laboratory values or repeat a study entry procedure 
once only during the screening period. Laboratory parameters can only be re-tested once. 
If a different laboratory parameter is found to be out of range in the re-test, no further 
testing is allowed. Re-testing may be performed to determine eligibility within the 
screening window. Subjects that have laboratory values that do not meet the entry criteria 
following the re-test are to be deemed a screen failure. Exceptions to re-testing are chest 
radiograph, ECG, and a positive result for the QuantiFERON-TB Gold test; these 
screening tests may not be repeated to meet eligibility criteria. An indeterminate result for 
the QuantiFERON-TB Gold test may be re-tested and subjects will be eligible upon a 
negative re-test result). In cases where an initial indeterminate QuantiFERON test 
result may be related to sample processing issues, the second QuantiFERON test
may be performed at either the local laboratory or the central laboratory at the 
discretion of the investigator. Re-testing is only permitted for indeterminate results. 
If the re-test also produces an indeterminate result, further re-testing to determine 
study eligibility is not permitted either at the local or central laboratory.
17. To clarify methotrexate use as a rescue therapy.
Rationale: Investigators may use either corticosteroids and/or methotrexate in the event 
of a flare.
Section 5.4 Withdrawal/Stopping Criteria, Section 5.4.1 Study Withdrawal
It should be noted that there is no requirement to withdraw a subject from the study for 
lack of efficacy. This study is designed to follow subjects over the long-term, irrespective 
of requirement for rescue treatment or withdrawal of study drug. The investigator should 
make every reasonable attempt to enable the subject to continue participation in the study 
and present for visits as scheduled. The investigator should offer treatment with an 
investigator-defined open-label corticosteroid rescue regimen in combination with 
double-blind injections of study drug (sirukumab or placebo) for the remainder of the 52 
week double-blind treatment period. Methotrexate treatment may also be initiated as 
part of the rescue regimen at the discretion of the investigator.

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18. To clarify requirements for discontinuation of study drug.
Rationale: To provide guidance to the investigator on management of corticosteroid 
treatment in the event of discontinuation of blinded sirukumab or matching placebo and 
to clarify the requirements for study drug discontinuation (blinded sirukumab or 
matching placebo only) in the event of infection.
Section 5.4 Withdrawal/Stopping Criteria, Section 5.4.2 Discontinuation of Study Drug
Permanent discontinuation of study drug will not require the subject to be withdrawn 
from the study. Subjects should continue where possible to be followed and disease status 
assessed. Upon permanent discontinuation of subcutaneously-administered blinded 
sirukumab or matching placebo, corticosteroid dose and treatment will be at the 
discretion of the investigator.
Study drug (subcutaneously-administered blinded sirukumab or matching placebo)
must be permanently discontinued for any of the following:
Subjects must not receive study drug blinded subcutaneous sirukumab or matching 
placebo during the course of a serious infection. Subjects who temporarily discontinue 
blinded sirukumab or matching placebo due to an infection or other reasons should 
continue to follow the prednisone taper schedule.
Discontinuation of study drug blinded subcutaneous sirukumab or matching placebo
must be strongly considered for subjects who develop a serious infection such as sepsis or 
meningoencephalitis, and considered for subjects who have serious infections requiring 
hospitalization or IV antibiotic therapy.
Discontinuation of study drug blinded subcutaneous sirukumab or matching placebo
should also be considered for severe injection-site reactions.
19. To clarify terminology for study treatment.
Rationale: Since both blinded sirukumab or matching placebo and prednisone may be 
considered study treatment, the terminology has been clarified to distinguish them.
Section 6 Study Treatment, Section 6.1 Investigational Product and Other Study 
Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments. Study treatment specifically related to sirukumab and matching placebo 
is distinguished by the use of the terminology “subcutaneously-administered blinded 
study drug or treatment (sirukumab and matching placebo)”. 

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20. To clarify administration of sirukumab and matching placebo. 
Rationale: To clarify that blinded sirukumab or matching placebo will be administered 
using an autoinjector device.
Section 6 Study Treatment, Section 6.1 Investigational Product and Other Study 
Treatment
Sirukumab and matching placebo will be supplied by the Sponsor. Both sirukumab and 
matching placebo will be administered subcutaneously using an autoinjector device.
21. To include information on the sourcing of the blinded prednisone.
Rationale: As the Sponsor provides the blinded prednisone, the manufacturer was 
included for informational purposes.
Section 6 Study Treatment, Section 6.1 Investigational Product and Other Study 
Treatment
Prednisone for the pre-specified standard blinded taper will be provided by the Sponsor. 
The prednisone used in the blinded taper of this study is manufactured by Jubilant 
Cadista (Salisbury, MD) and supplied to the Sponsor by Myoderm (Norristown, 
PA). 
22. To clarify the method of blinding of prednisone and laboratory values for CRP and 
ESR.
Rationale: To provide additional information on how the study blind is maintained for the 
prednisone taper, and to clarify that CRP and ESR values prior to the start of study 
treatment are not blinded to the investigator nor the Sponsor/study team as there is no 
impact on the integrity of the study blind prior to the start of sirukumab treatment.
Section 6: Study Treatment, Section 6.4 Blinding
Blinding will be maintained during the 52-week double blind treatment phase of this 
study by the provision of sirukumab and matching placebo for sirukumab in pre-filled 
syringes in a matching presentation.  Blinding to the prednisone dose during the taper 
will be maintained by providing prednisone dosages below 20 mg in numbered blister 
packs. Depending on the subject’s assignment to either the 3, 6 or 12 month taper, the 
over-encapsulated dose may or may not contain prednisone. The blister packs contain a 
combination of over-encapsulated 10 mg, 5 mg and/or 1 mg prednisone tablets with 
cellulose filler to prevent rattling and/or placebo capsules containing only the filler. 
Each patient, regardless of treatment arm, will be provided the same number of 
capsules per day for a given week to maintain the blind.
Blinding during the q4w dosing regimen will be maintained by the provision of placebo 
for sirukumab such that subjects randomized to this arm will follow a q2w dosing 

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regimen but alternate between active (starting at baseline) and placebo treatments for the 
duration of the 52 week double-blind phase.
Investigators and the Sponsor/study team will remain blinded to the results of the 
fasting lipids, CRP and ESR laboratory tests after the start of treatment.  Investigators 
and the study team will have access to Screening and Baseline values, and will 
thereafter remain blinded to these results until the end of Part A.  Alerts will be 
provided by the central laboratory for abnormal, clinically significant findings to enable 
investigators to manage subject safety.
Section 7 Study Assessments and Procedures, Section 7.5 Safety, Section 7.5.6 Clinical 
Safety Laboratory Assessments
The investigators and the Sponsor/study team will remain blinded to the results of the 
ESR (performed locally), CRP and fasting lipid analyses (see Section 6.4) after the 
start of treatment during Part A of the study.
23. To include biosimilar/generic versions of biologics in prohibited medications.
Rationale: Biosimilar/generic versions of anti-TNF agents may be available for use with 
similar restrictions to other marketed agents.
Section 6.10 Concomitant Medications and Non-Drug Therapies, Section 6.10.2 
Prohibited Medications and Non-Drug Therapies
Biologic agents targeted at reducing TNF(including but not limited to infliximab, 
golimumab, certolizumab pegol, etanercept, yisaipu, and adalimumab and/or biosimilar 
or generic versions of these agents) within the specified time frames.
24. Addition of the assessment of the C-SSRS
Rationale: Per GSK policy, prospective monitoring of suicidal ideation and behavior is 
implemented in clinical trials for investigational agents with potential activity on the 
central nervous system, including sirukumab. 
Section 7: Study Assessments and Procedures
1. Patient Global Assessment of disease activity (PtGA).
2. Patient Global Impression of Change (PGIC).
3. Pain Numeric Rating Scale (NRS).
4. HAQ-DI (for subgroup of subjects with PMR).
5. FACIT-fatigue.
6. Steroid Impact PRO.
7. SF-36v2 acute.
8. EQ-5D (5L)

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9. Columbia-Suicide Severity Rating Scale (C-SSRS).
Section 7 Study Assessments and Procedures, Section 7.5 Safety
Safety will be assessed from the documentation of adverse events and review of vital 
signs and laboratory assessments including complete blood counts, serum chemistry 
profiles, fasting serum lipids, HbA1c, hepatitis B and C serologies, and markers of bone 
turnover.  The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to 
prospectively monitor suicidal ideation and behavior (Section 7.5.7).
Section 7: Study Assessments and Procedures, Section 7.5 Safety, Section 7.5.7 Suicidal 
Risk Monitoring
Sirukumab is considered to potentially be a CNS-active drug. There has been some 
concern that some CNS-active drugs may be associated with an increased risk of 
suicidal thinking or behaviour when given to some patients with certain conditions. 
Although this drug or other similar drugs in this class have not been shown to be 
associated with an increased risk of suicidal thinking or behaviour when given to 
this patient population, GSK considers it important to monitor for such events 
before or during clinical studies with compounds such as this.
Subjects being treated with sirukumab should be monitored appropriately for 
suicidal ideation and behaviour or any other unusual changes in behaviour. 
Consideration should be given to discontinuing sirukumab in subjects who 
experience signs of suicidal ideation or behaviour.
Suicidal ideation and behaviour will be assessed at baseline and at the time points 
indicated in Time and Events Table 2 and in Time and Events Table 3 using the 
patient-reported outcome version of the C-SSRS [Mundt, 2010].
25. To clarify requirements for assessment of subjects for injection site reactions.
Rationale: Assessments may only be conducted when subjects receive injections at the 
study center.
Section 7 Study Assessments and Procedures, Section 7.5 Safety, Section 7.5.1 Adverse 
Events (AE) and Serious Adverse Events (SAEs), Section 7.5.1.6 Events that Occur with 
Biologics
Injection Site Reactions
An injection site reaction is any unfavorable or unintended sign that occurs at the study 
drug injection site. All subjects must be carefully observed for symptoms of an injection 
site reaction. Prior to and including through Week 4, subjects will be observed for at least 
30 minutes after the SC injection of study drug for symptoms of an injection site reaction. 
After Week 4, subjects do not need to be observed for 30 minutes for the post-

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administration injection-site evaluation if they are self-administering at home. 
However, subjects should promptly notify the site if they experience a reaction at 
the site of injection. 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.
26. To update the requirements for collection of pregnancy information.
Rationale: To clarify that pregnancy details of female partners of male study subjects will 
be collected.
Section 7 Study Assessments and Procedures, Section 7.5 Safety, Section 7.5.2 
Pregnancy

Details of all pregnancies in female subjects and female partners of male 
subjects will be collected after the start of dosing and until the Follow-up visit.
Section 12 Appendices, Section 12.2 Appendix 2: Modified List of Highly Effective 
Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) and 
Collection of Pregnancy Information, Section 12.2.2 Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject or female 
partner of male study subject who becomes pregnant while participating in or 
while partner is participating in this study.
27. To include the requirement for pregnancy testing at additional time points during 
the study.
Rationale: Pregnancy testing (when applicable) should be conducted every 4 weeks while 
receiving study treatment.
Section 7 Study Assessments and Procedures, Section 7.5 Safety, Section 7.5.6 Clinical 
Safety Laboratory Assessments
Pregnancy testing (where applicable) should be conducted every 4 weeks while 
subjects are receiving study drug and during the 16-week follow-up period. 
Pregnancy tests may be performed by the subject at home using the test kits 
provided by the central laboratory when there is no study visit associated with the 
testing time point.
28. Clarification of ultrasound scanning in the event of flare for Part B of the study.
Rationale: For logistical purposes, scanning in the event of flare in Part B will conclude 
when the last subject in the exploratory imaging cohort completes Part A of the study.

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Section 7.9 Exploratory Ultrasound Imaging, 7.9.2 Synopsis
Subjects will have an initial baseline scan at Screening and assessments at Baseline 
(Week 0), Weeks 12 and 52. Additional US scans should also be conducted in the event 
of relapses or flares, including flares/relapses that occur during Part B of the study. US 
scanning for flares/relapses in Part B of the study will conclude when the last 
subject in the US imaging cohort completes Part A of the study. Thereafter, no 
additional scans will be taken. 
Section 12.8 Appendix 8, Section 12.8.3 Assessments and Procedures, Section 12.8.3 
Ultrasound Scanning
5. Any time point of disease relapse/flare during Part A or Part B of the study, with 
every effort made to conduct the US scan within 3 days of rescue prednisone 
administration. The number of days between the US scan and rescue prednisone 
administration will be recorded. Scanning in the event of relapse/flare during 
Part B will conclude when the last subject in the exploratory US imaging 
cohort completes Part A. No additional Part B scans will be taken after this 
time point.
29. To include updated information on the statistical plans. for treatment comparisons 
and an overview of the multiplicity control.
Rationale: To provide additional details on the statistical plans for treatment comparisons 
and an overview of the multiplicity control.
Section 9 Statistical Considerations and Data Analysis, Section 9.3 Data Analysis  
Considerations, Section 9.3.3 Treatment comparisons
Primary comparison of interest is the comparison between sirukumab 100 mg SC q2w 
plus 6 month prednisone (Treatment Arm A) and placebo plus 6 month prednisone 
(Treatment Arm D) for the proportion of subjects with in sustained disease remission at 
52 weeks Week 52 in the ITT population at the 0.05 significance level. The observed 
dataset will be used for this comparison. The analysis will be adjusted for the 
stratification factor applied at randomization. as well as the baseline value for the 
parameter being tested.
If the test of the primary endpoint for the primary comparison is statistically significant 
at α=0.05, the following major secondary endpoints for the primary comparison will be 
tested in the sequential order: (2-sided), the cumulative prednisone dose at week 52 
(key secondary endpoint) for the primary comparison (arm A vs arm D) will be 
tested at a significance level of 0.05 (2-sided). If the statistical significance for the 
primary endpoint is not met, then the key secondary endpoint in the sequence 
cannot be deemed statistically significant, although nominal p-values may be 
reported and considered descriptive but should not be interpreted inferentially.

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
Cumulative prednisone dose over 52 week period

Proportions of subjects with sustained disease remission at 6 months post cessation of 
12-month sirukumab treatment 

Cumulative prednisone dose over 76 week period
For the 2 endpoints outlined above, the following treatment comparisons will also be 
evaluated following the same sequential approach provided that the primary endpoint for 
the primary comparison achieves significance:

Sirukumab 100mg SC q2w plus 3 month prednisone versus placebo plus 6 month 
prednisone (Arm B vs. Arm D)

Sirukumab 100mg SC q2w plus 6 month prednisone versus placebo plus 12 month 
prednisone (Arm A vs. Arm E)

Sirukumab 100mg SC q2w plus 3 month prednisone versus placebo plus 12 month 
prednisone (Arm B vs. Arm E) 
Comparisons with Sirukumab 50mg SC q4w (Arm C) will be similarly evaluated. 
Comparisons of interest for other secondary efficacy endpoints will also be assessed. 
An overview of the multiplicity control is provided in Figure 2.
An alternative testing hierarchy, used to address regional differences in the 
regulatory requirements for controlling type 1 error, will be specified in the RAP.
Analyses of other efficacy endpoints will not be subject to any multiple comparison 
procedure. All statistical tests will be 2-sided and performed at an overall 
significance level of 0.05.
Further details are included in the RAP.

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Figure 1: Overview of the Multiplicity control

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30. To update the Time and Events Tables to incorporate and reflect the changes in the protocol amendment.
Section 7 Study Assessments, Section 7.1 Time and Events Tables
Table 2 Time and Events Table for Part A of the Study (52-week Double-blind Treatment Phase)
Screening (~Wk -6+ 3d)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal 
Follow  Up
Written Informed Consent1
x
Subject Demography
x
Medical and disease history
x
Inclusion/Exclusion Criteria
x
x
Randomization
x
Autoinjector training2
x
x
x
Dispense Investigational Product
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x3
Assess Invest. Product compliance
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
Prior Medications
x
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
PGIC4
x
x
x
x
x
Pain NRS4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
HAQ-DI4
x
x
x
x
x
x
x
FACIT-Fatigue4
x
x
x
x
x
x
x
Steroid Impact4
x
x
x
x
x
x
x
SF-36v2 (acute)4
x
x
x
x
x
x
x

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Screening (~Wk -6+ 3d)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal 
Follow  Up
EQ-5D (5L)4
x
x
x
x
x
x
x
Safety Assessments
Physical Examination5
x
x
x
x
x
x
Vital Signs6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
12-lead ECG7
x
Chest radiograph
x
TB evaluation8
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
QuantiFERON-TB Gold Test9
x
Height and weight
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
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
Hemoglobin A1c
x
x
x
x
x
x
x
x
Pregnancy Test10
S
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
HIV, HBsAg, HBcAb, Hepatitis C11
x
PK12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Immunogenicity12
x
x
x
x
x
x
x

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Screening (~Wk -6+ 3d)
Baseline (Wk 0)
wk 23d
wk 43d
wk 83d
wk 123d
wk 163d
wk 203d
wk 243d
wk 283d
wk 323d
wk 363d
wk 403d
wk 443d
wk 483d
wk 523d
Flare
Early Withdrawal 
Follow  Up
Exploratory Lab Assessments
IL-6 measurements
x
x
x
x
Blood Biomarkers & exploratory 
markers
x
x
x
x
x
x
x
Blood and Urine Markers, 
Transcriptomics (optional)13
x
x
x
x
x
x
x
Pharmacogenetics sample14
x
Exploratory US Imaging
Ultrasound imaging15
x16
x
x
x
x

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1.
Including consent for pharmacogenetics.
2.
Assuming placebo will also be administered using autoinjector. Additional training may be provided when required.
3.
Only for those subjects who initiate open-label sirukumab treatment at the start of Part B.
4.
PROs Tto be completed by subjects before any other clinically evaluated assessments or blood draws and before the administration of study drug. At visits where 
subject is fasting for blood draws, the option exists to perform blood draws prior to completing PROs as necessary to end the fast.  HAQ-DI administered only to 
sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of questionnaires and after conducting patient 
assessments).
5.
Complete physical exam at Screening and brief physical exam at other time points.
6.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
7.
And when any suspected cardiac abnormality. Average of triplicate recordings.
8.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
9.
Chest radiograph taken up to 3 months prior to Week 0 may be used to qualify at screening.
10. Pregnancy test: urine = U, serum = S. Premenopausal women only.
11. If hepatitis C antibody positive, a hepatitis C RNA PCR assay should be reflexively performed on a fresh sample to confirm the result.
12. On study drug administration days, Pharm serum samples must be collected prior to study drug 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.
13. To be collected only for those subjects consenting to provide samples for the biobank for future exploration of GCA disease biology.
14. Sample should be collected at the baseline visit but may be collected at any visit post-baseline if not collected at the  baseline visit.
15. Selected sites participating in the exploratory US imaging portion only; restricted to subjects with new onset disease
16. Optimally (but not required), to be performed prior to or within 3 days of the start of prednisone.

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Table 3 Time and Events Table for Part B (104-week Extension) of the Study: Subjects NOT receiving Open-label Sirukumab During Part 
B 
Wk 0/(Wk 52 of Part A)
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
Concomitant Medications
x
x
x
x
x
x
x
x
x
x
x
x
Assess Invest. Product compliance1
x
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)2
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain NRS2
x
x
x
x
x
x
x
x
x
x
HAQ-DI2
x
x
x
x
x
x
x
x
FACIT-Fatigue2
x
x
x
x
x
x
x
x
Steroid Impact2
x
x
x
x
x
x
x
x
SF-36v2 (acute) 2
x
x
x
x
x
x
x
x
EQ-5D (5L) 2
x
x
x
x
x
x
x
x
Safety Assessments
Physical Examination3
x
x
x
x
x
Vital Signs4
x
x
x
x
x
x
x
x
x
x
x
x
TB evaluation5
x
x
x
x
x
x6
Height and weight
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS2
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x6
x6
Serum chemistry
x
x
x
x
x
x6
x6
CRP
x
x
x
x
x
x
x
x
x
x
x
x

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Wk 0/(Wk 52 of Part A)
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
ESR
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x6
x6
Hemoglobin A1c
x
x
x
x6
x6
Pregnancy Test7
U
U
U
U
U
U6
Exploratory Lab Assessments
IL-6 measurements
x
Blood Biomarkers & exploratory 
markers
x
Blood and Urine Markers, 
Transcriptomics (optional)
x
Exploratory US Imaging
Ultrasound imaging8
x
1.
Assessment from Week 52 visit of Part A
2.
PROs Tto be completed by subjects before any other clinically evaluated assessments or blood draws and before the administration of study drug. At visits 
where subject is fasting for blood draws, the option exists to perform blood draws prior to completing PROs as necessary to end the fast. HAQ-DI 
administered only to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of questionnaires and after
conducting patient assessments).
3.
Brief physical exam
4.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
5.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
6.
To be performed only if Early Withdrawal visit or flare occurs on or before Week 16 visit.
7.
Pregnancy test: urine = U, serum = S. Premenopausal women only.
8.
For subjects participating in the exploratory US imaging cohort. Ultrasound scan to be performed only in the event of disease flare or relapse in Part B for 
subjects participating in the exploratory US imaging cohort Part B scans will conclude when the last subject in the US imaging cohort completes Part A.

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Table 4 Time and Events Table for Part B (104-week Extension) of the Study: Subjects receiving Open-label Sirukumab Immediately 
Upon Entry into Part B 
Wk 0/(Wk 52 of Part A)
Wk25d
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 485d1
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
Follow  Up
Dispense Investigational Product
x
x
x
x
x
x
x
x
x
Assess Invest. Product compliance
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
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)2
x
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain NRS2
x
x
x
x
x
x
x
x
x
x
x
HAQ-DI2
x
x
x
x
x
x
x
x
FACIT-Fatigue2
x
x
x
x
x
x
x
x
Steroid Impact2
x
x
x
x
x
x
x
x
SF-36v2 (acute) 2
x
x
x
x
x
x
x
x
EQ-5D (5L) 2
x
x
x
x
x
x
x
x
Safety Assessments
Physical Examination3
x
x
x
x
x
x
Vital Signs4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
TB evaluation5
x
x
x
x
x
x
x
x
x
x
x
x
Height and weight
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
x

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Wk 0/(Wk 52 of Part A)
Wk25d
wk 45d
wk 85d
wk 125d
wk 165d
wk 245d
wk 365d
wk 485d1
wk 525d
wk 765d
wk 1045d
Flare
Early Withdrawal 
Follow  Up
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x
x
x
x
x
x
x
Hemoglobin A1c
x
x
x
x
x
x
x
x
x
x
Pregnancy Test6
U
U
U
U
U
U
U
U
U
U
U
U
U
PK7
x
x
x
x
x
x
x
Immunogenicity7
x
x
x
x
x
x
x
Exploratory Lab Assessments
IL-6 measurements
x
Blood Biomarkers & exploratory 
markers
x
Blood and Urine Markers, 
Transcriptomics (optional)
x
Exploratory US Imaging
Ultrasound imaging8
x

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1.
Visit only to dispense IP; no assessments are required.
2.
PROs Tto be completed by subjects before any other clinically evaluated assessments or blood draws and before the administration of study drug. At 
visits where subject is fasting for blood draws, the option exists to perform blood draws prior to completing PROs as necessary to end the fast.
HAQ-DI administered only to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of 
questionnaires and after conducting patient assessments). 
3.
Brief physical exam.
4.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
5.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test (or if not approved at the site, a tuberculin skin test) should be performed at any time 
during the study if TB is suspected.
6.
Pregnancy test: urine = U, serum = S. Premenopausal women only. A urine pregnancy test should be performed every 4 weeks while taking open-label 
sirukumab and for 16 weeks post discontinuation of sirukumab treatment. Subjects should perform a urine pregnancy test at home when there is 
no study visit corresponding to the 4-weekly interval. Pregnancy test kits will be provided by the central laboratory for subject use at home. 
7.
On study drug administration days, Pharm serum samples must be collected prior to study drug 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.. 
8.
For subjects participating in the exploratory US imaging cohort. Ultrasound scan to be performed only in the event of disease flare or relapse in Part B for 
subjects participating in the exploratory US imaging cohort Part B scans will conclude when the last subject in the US imaging cohort completes Part A.

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Table 5 Time and Events Table for Part B (104-week Extension) of the Study: Subjects Receiving Open-label Sirukumab at Any Time 
AFTER (but NOT immediately Upon) Entry into Part B
Start of open-label 
sirukumab  1
PLUS 2 Wks5d
PLUS 4 Wks5d
PLUS 8 Wks5d
PLUS 12 Wks5d
PLUS 16 Wks5d
PLUS 24 Wks5d
PLUS 36 Wks5d
PLUS 48 Wks5d2
PLUS 52 Wks5d
PLUS 76 WKS5d
PLUS 104 Wks5d 3
Flare
Early Withdrawal 
Follow  Up
Dispense Investigational Product
x
x
x
x
x
x
x
x
Assess Invest. Product compliance
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
Efficacy Assessments
GCA disease activity
x
x
x
x
x
x
x
x
x
x
x
x
x
PGA (patient, physician)4
x
x
x
x
x
x
x
x
x
x
x
x
Health Outcomes
Pain NRS4
x
x
x
x
x
x
x
x
x
x
HAQ-DI4
x
x
x
x
x
x
x
FACIT-Fatigue4
x
x
x
x
x
x
x
Steroid Impact4
x
x
x
x
x
x
x
SF-36v2 (acute)4
x
x
x
x
x
x
x
EQ-5D (5L)4
x
x
x
x
x
x
x
Safety Assessments
Physical Examination5
x
x
x
x
x
Vital Signs6
x
x
x
x
x
x
x
x
x
x
x
x
x
TB evaluation7
x
x
x
x
x
x
x
x
x
x
x
Height and weight
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 

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Start of open-label 
sirukumab  1
PLUS 2 Wks5d
PLUS 4 Wks5d
PLUS 8 Wks5d
PLUS 12 Wks5d
PLUS 16 Wks5d
PLUS 24 Wks5d
PLUS 36 Wks5d
PLUS 48 Wks5d2
PLUS 52 Wks5d
PLUS 76 WKS5d
PLUS 104 Wks5d 3
Flare
Early Withdrawal 
Follow  Up
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x
Lipid panel (fasting)
x
x
x
x
x
x
x
x
x
Hemoglobin A1c
x
x
x
x
x
x
x
x
x
Pregnancy Test8
U
U
U
U
U
U
U
U
U
U
U
U
PK9
x
x
x
x
x
x
Immunogenicity9
x
x
x
x
x
x
Exploratory US Imaging
Ultrasound imaging10
x

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1.
Upon the initiation of open-label sirukumab, perform the assessments from Time and Events Table 3 at the visit the subject was scheduled to undergo 
when study drug is started.
2.
Visit only to dispense IP; no assessments are required.
3.
Although this visit is labelled as 104 weeks since the start of open-label sirukumab, it does not take into account the exact start time, since this will be 
different for each subject depending upon when in the first 52 weeks of Part B open-label sirukumab was started. The important point to note, is that this 
last visit should be scheduled when each of these subjects will complete 104 weeks in Part B.
4.
PROs Tto be completed by subjects before any other clinically evaluated assessments or blood draws and before the administration of study drug. At 
visits where subject is fasting for blood draws, the option exists to perform blood draws prior to completing PROs as necessary to end the 
fast. HAQ-DI administered only to sub-set of subjects with PMR. PGA assessed using PtGA (subjects) and PhGA (physicians, after subject completion of 
questionnaires and after conducting patient assessments). 
5.
Brief physical exam. 
6.
Measure in a semi-supine position after 5 minutes rest; includes blood pressure, temperature and heart rate.
7.
Suggested questions (see Section 7.5.7). A QuantiFERON-TB Gold Test should be performed at any time during the study if TB is suspected.
8.
Pregnancy test: urine = U, serum = S. Premenopausal women only. A urine pregnancy test should be performed every 4 weeks while taking open-
label sirukumab and for 16 weeks post discontinuation of sirukumab treatment. Subjects should perform a urine pregnancy test at home when 
there is no study visit corresponding to the 4-weekly interval. Pregnancy test kits will be provided by the central laboratory for subject use at 
home. 
9.
On study drug administration days, Pharm serum samples must be collected prior to study drug 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.. 
10. For subjects participating in the exploratory US imaging cohort. Ultrasound scan to be performed only in the event of disease flare or relapse in Part 
B for subjects participating in the exploratory US imaging cohort Part B scans will conclude when the last subject in the US imaging cohort 
completes Part A.

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31. To include corrections and clarifications to Table 6 Laboratory Parameters 
consistent with the amended protocol.
Section 7, Study Assessments, Section 7.5 Safety, Section 7.5.6 Clinical Safety 
Laboratory Assessments
Table 6 Laboratory Parameters
Hematology
Hemoglobin
Hematocrit
Red blood cell (RBC) count
White blood cell (WBC) count 
with differential
Neutrophils, absolute
Neutrophils, segs (%)
Neutrophils, bands (%)
Basophils (%)
Eosinophils (%)
Eosinophils, absolute
Lymphocytes (%)
Monocytes (%)
Platelet count
Serum Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Blood urea nitrogen (BUN)
Creatinine
Glucose
Aspartate transaminase
Alanine transaminase
Alkaline phosphatase
Calcium
Phosphate
Albumin
Total protein
Bilirubin, direct, indirect and 
total
Fasting lipids
Total cholesterol
Low density lipoprotein (LDL)
High density lipoprotein (HDL)
Triglycerides
Serum and urine pregnancy test for premenopausal women only
Serology for HIV, hepatitis B surface antigen, hepatitis B core antibody and hepatitis C antibody 1
Other tests
Hemoglobin A1c
C-reactive protein (CRP) 2,3
Erythrocyte sedimentation rate 
(ESR) 2, 3
QuantiFERON-TB Gold Test Test (or PPD skin test at sites where QuantiFERON-TB Gold Test is 
not approved)
4.
If hepatitis C antibody positive, a hepatitis C RNA PCR assay should be reflexively performed on the same a 
fresh sample to confirm the result
5.
Investigators will remain blinded to the results of the ESR, CRP and fasting lipids after the start of treatment 
during Part A of the study (see Section 6.4). ESR will be analyzed at the local laboratory.
6.
Required for the evaluation of efficacy.
32. To update references to include reference for C-SSRS.
Section 11 References
Mundt JC, Greist JH, Gelenberg AJ, Katzelnick DJ, Jefferson JW, Modell JG. 
Feasibility and validation of a computer-automated Columbia-Suicide Severity 

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Rating Scale using interactive voice response technology. J Psychiat Res. 2010; 
44(16):1224-1228.
33. Update Abbreviations table to include protocol changes.
Section 12 Appendices, Section 12.1 Appendix 1:  Abbreviations and Trademarks
CRP
C-reactive Protein
C-SSRS
Columbia-Suicide Severity Rating Scale
CTA
Computed Tomography Angiography
CV
Cardiovascular
DBL
Database lock
dL
Deciliter
Administrative changes
Updated author list and Table of Contents