Clinical trial NCT02573012
Conditions: Rheumatoid Arthritis
Sponsor: Hoffmann-La Roche
Start date: 2016-03-29; Completion date: 2018-02-09
Enrollment: 314 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase IIIb/IV, two-arm, randomized, double-blind, placebo-controlled, parallel-group, international, multicenter trial compares the change in disease activity (as assessed by Disease Activity Score in 28 joints \[DAS28\] erythrocyte sedimentation rate \[ESR\]) from randomization to Week 24 post-randomization, in participants with stable low disease activity \[LDA\] (DAS28 ESR score less than or equal to \[\<=\] 3.2) who receive tocilizumab, and have been randomized to either continue or taper prednisone in a double-blinded fashion.

Detailed description:

Arms: arm 1: Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks. arm 2: Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.
Interventions: intervention 1: Placebo matched to prednisone intervention 2: Prednisone intervention 3: Tocilizumab
Intervention descriptions: intervention 1: Participants will receive placebo matched to prednisone orally for 24 weeks. intervention 2: Participants will receive prednisone either at a constant dose of 5 mg/day, or 5 mg/day with 1 mg decrements every 4 weeks orally for 24 weeks. intervention 3: Participants will receive tocilizumab at a dose of 162 mg once a week subcutaneously for 24 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title:  
Prospective, multicentre, placebo-controlled, double-blind interventional 
study to compare the efficacy of maintenance treatment with Tocilizumab 
with or without Glucocorticoid discontinuation in rheumatoid arthritis 
patients 
 
NCT Number:   
NCT02573012 
 
Document Dates:  
Protocol Amendment/Version 3: 22-Jun-16 


 
Title
22-Jun-2016 14:27:28
Date and Time (UTC)
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Tocilizumab—F. Hoffmann-La Roche Ltd 
Protocol MA29585, Version 3.0                                                                                                                              
 
PROTOCOL 
TITLE: 
PROSPECTIVE, MULTICENTRE, PLACEBO-
CONTROLLED, DOUBLE-BLIND STUDY TO COMPARE 
THE EFFICACY OF MAINTENANCE TREATMENT WITH 
TOCILIZUMAB WITH OR WITHOUT GLUCOCORTICOID 
DISCONTINUATION IN RHEUMATOID ARTHRITIS 
PATIENTS 
PROTOCOL NUMBER: MA29585 
VERSION NUMBER: 
3.0 
EUDRACT NUMBER: 
2014-004673-16 
TEST PRODUCT: 
Tocilizumab, prednisone 
MEDICAL MONITOR: 
 
 M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1.0: 30-Mar-2015 
DATE AMENDED: 
Version 2.0: 05-Jun-2015 
Version 2.1: 22-Jun-2015 
Version 3.0: See electronic date stamp below 


 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
LIST OF TABLES ............................................................................................................ 7 
LIST OF FIGURES .......................................................................................................... 8 
PROTOCOL ACCEPTANCE FORM ................................................................................ 9 
PROTOCOL SYNOPSIS ............................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 25 
1. 
BACKGROUND ..................................................................................................... 29 
1.1 
Background on Rheumatoid Arthritis .......................................................... 29 
1.1.1 
Current Treatment Options ............................................................... 29 
1.1.2 
Treatment Recommendations ........................................................... 30 
1.2 
Glucocorticoids in the Treatment of RA ...................................................... 30 
1.3 
Tocilizumab in the Treatment of RA ........................................................... 33 
1.4 
Study Rationale and Benefit-Risk Assessment .......................................... 37 
2. 
OBJECTIVES ........................................................................................................ 39 
2.1 
Efficacy Objectives..................................................................................... 39 
2.2 
Safety Objectives ....................................................................................... 39 
2.3 
Patient-Reported Outcome Objectives ....................................................... 40 
2.4 
Exploratory Objectives ............................................................................... 40 
3. 
STUDY DESIGN ................................................................................................... 40 
3.1 
Description of Study ................................................................................... 40 
3.1.1 
Steering Committee .......................................................................... 50 
3.1.2 
Independent Data Monitoring Committee.......................................... 50 
3.2 
End of Study .............................................................................................. 50 
3.3 
Rationale for the Study Design .................................................................. 50 
3.3.1 
Rationale for the Study Drug Dose and Schedule ............................. 51 
3.3.1.1 
Tocilizumab ..................................................................... 51 
3.3.1.2 
Prednisone ...................................................................... 51 
3.3.2 
Rationale for Patient Population ....................................................... 51 
3.3.3 
Rationale for Control Group .............................................................. 52 
3.3.4 
Rationale for the Study Endpoints..................................................... 52 
3.3.4.1 
28-Joint Disease Activity Score (DAS28) ......................... 52 
3.3.4.2 
CDAI and SDAI ............................................................... 52 
3.3.4.3 
ACR Core Set and Response Criteria ............................. 53 
3.3.4.4 
HAQ-DI ........................................................................... 53 


 
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3.3.4.5 
Rheumatoid Arthritis Impact of Disease (RAID) 
Questionnaire .................................................................. 54 
3.3.4.6 
Work Productivity and Activity Impairment 
Questionnaire: Rheumatoid Arthritis (WPAI:RA) .............. 54 
3.3.5 
Rationale for Biomarker Assessments .............................................. 54 
3.4 
Outcome Measures.................................................................................... 55 
3.4.1 
Efficacy Outcome Measures ............................................................. 55 
3.4.2 
Safety Outcome Measures ............................................................... 55 
3.4.3 
Patient-Reported Outcome Measures ............................................... 56 
3.4.4 
Exploratory Outcome Measures ....................................................... 56 
4. 
MATERIALS AND METHODS ............................................................................... 57 
4.1 
Patients ...................................................................................................... 57 
4.1.1 
Management of Enrolment to Achieve the Randomization 
Target ............................................................................................... 57 
4.1.2 
Inclusion Criteria ............................................................................... 57 
4.1.3 
Exclusion Criteria .............................................................................. 58 
4.2 
Method of Treatment Assignment and Blinding .......................................... 61 
4.3 
Study Treatment ........................................................................................ 61 
4.3.1 
Formulation, Packaging, and Handling ............................................. 62 
4.3.1.1 
Tocilizumab ..................................................................... 62 
4.3.1.2 
Prednisone ...................................................................... 62 
4.3.2 
Dosage, Administration, and Compliance ......................................... 64 
4.3.2.1 
Tocilizumab ..................................................................... 64 
4.3.2.2 
Prednisone and other Systemic Glucocorticoids .............. 66 
4.3.3 
Investigational Medicinal Product Accountability ............................... 68 
4.3.4 
Post-Trial Access to Tocilizumab SC or IV ........................................ 69 
4.4 
Concomitant Therapy ................................................................................. 69 
4.4.1 
Permitted Therapy ............................................................................ 69 
4.4.1.1 
Open-label csDMARDs .................................................... 69 
4.4.1.2 
Analgesics and Anti-inflammatories ................................. 69 
4.4.1.3 
Proton Pump Inhibitors .................................................... 70 
4.4.1.4 
Glucocorticoid-Induced Osteopenia/Osteoporosis 
Therapy ........................................................................... 70 
4.4.1.5 
Lipid-lowering Therapy .................................................... 70 
4.4.1.6 
Open-label Systemic Glucocorticoids .............................. 70 
4.4.1.7 
Drug Interactions Guidance for Permitted Therapy .......... 70 
4.4.2 
Prohibited Therapy ........................................................................... 71 
4.5 
Study Assessments ................................................................................... 71 
4.5.1 
Informed Consent Forms and Screening Log ................................... 72 
4.5.2 
Demographic Data and Medical History ............................................ 72 
4.5.3 
Physical Examinations ...................................................................... 72 


 
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4.5.4 
Vital Signs, Height, Weight and Body Mass Index ............................ 72 
4.5.5 
Concomitant Therapy ....................................................................... 73 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples ...................... 73 
4.5.7 
Homeostasis Model Assessment ...................................................... 75 
4.5.8 
Evaluations of Rheumatoid Arthritis .................................................. 75 
4.5.8.1 
Swollen Joint Count and Tender Joint Count.................... 75 
4.5.8.2 
Physician’s Global Assessment of Disease Activity 
VAS ................................................................................. 76 
4.5.8.3 
DAS28 ESR .................................................................... 76 
4.5.8.4 
Morning Stiffness............................................................. 76 
4.5.8.5 
Assessments not conducted at the site ........................... 76 
4.5.9 
Patient-Reported Outcomes ............................................................. 77 
4.5.9.1 
Health Assessment Questionnaire - Disability Index 
(HAQ-DI) ......................................................................... 77 
4.5.9.2 
Rheumatoid Arthritis Impact of Disease (RAID) 
Questionnaire .................................................................. 77 
4.5.9.3 
Work Productivity and Activity Impairment 
Questionnaire: Rheumatoid Arthritis V2.0 or V2.1 
(WPAI:RA)....................................................................... 77 
4.5.9.4 
Patient’s Global Assessment of Disease Activity 
VAS ................................................................................. 77 
4.5.10 Randomization Criteria ..................................................................... 77 
4.5.11 RA Flare Assessment  and Treatment (24 Week Tapering 
Phase) 
78 
4.5.12 Samples for Research Biosample Repository ................................... 79 
4.5.12.1 
Overview of the Research Biosample Repository ............ 79 
4.5.12.2 
Approval by the Institutional Review Board or 
Ethics Committee ............................................................ 79 
4.5.12.3 
Sample Collection ........................................................... 79 
4.5.12.4 
Confidentiality .................................................................. 80 
4.5.12.5 
Consent to Participate in the Research Biosample 
Repository ....................................................................... 81 
4.5.12.6 
Withdrawal from the Research Biosample 
Repository ....................................................................... 81 
4.5.12.7 
Monitoring and Oversight ................................................ 81 
4.6 
Patient, Treatment, Study, and Site Discontinuation .................................. 81 
4.6.1 
Patient Discontinuation from the Study ............................................. 81 
4.6.2 
Study Treatment Discontinuation ...................................................... 82 
4.6.3 
Study and Site Discontinuation ......................................................... 83 
5. 
ASSESSMENT OF SAFETY ................................................................................. 83 
5.1 
Safety Plan ................................................................................................ 83 
5.1.1 
Precautions Related to Treatment with Tocilizumab ......................... 83 


 
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5.1.1.1 
Hypersensitivity reactions ................................................ 83 
5.1.1.2 
Infection and Serious Infections ....................................... 84 
5.1.1.3 
Tuberculosis .................................................................... 84 
5.1.1.4 
Gastrointestinal Perforation ............................................. 84 
5.1.1.5 
Demyelinating Disorders ................................................. 84 
5.1.1.6 
Viral Reactivation ............................................................ 84 
5.1.1.7 
Active Hepatic Disease, Hepatic Impairment, 
Hepatic transaminase elevations ..................................... 84 
5.1.1.8 
Haematological Abnormalities ......................................... 85 
5.1.1.9 
Elevated Lipid Parameters .............................................. 86 
5.1.1.10 
Other Potential Risks ....................................................... 87 
5.1.2 
Precautions Related to Glucocorticoid Use ....................................... 87 
5.1.3 
Management of Specific Adverse Events .......................................... 88 
5.1.3.1 
Management of Adrenal Insufficiency .............................. 88 
5.2 
Safety Parameters and Definitions ............................................................. 88 
5.2.1 
Adverse Events ................................................................................ 88 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ........................................................................................... 89 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) ..................................................................................... 90 
5.2.4 
Selected Adverse Events .................................................................. 91 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ..................................................................................... 91 
5.3.1 
Adverse Event Reporting Period ....................................................... 91 
5.3.2 
Eliciting Adverse Event Information .................................................. 91 
5.3.3 
Assessment of Severity of Adverse Events ....................................... 91 
5.3.4 
Assessment of Causality of Adverse Events ..................................... 92 
5.3.5 
Procedures for Recording Adverse Events ....................................... 93 
5.3.5.1 
Injection Site Reactions and Infusion Reactions .............. 93 
5.3.5.2 
Diagnosis versus Signs and Symptoms ........................... 93 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events ............................................................................. 93 
5.3.5.4 
Persistent or Recurrent Adverse Events .......................... 94 
5.3.5.5 
Abnormal Laboratory Values ........................................... 94 
5.3.5.6 
Abnormal Vital Sign Values ............................................. 95 
5.3.5.7 
Abnormal Liver Function Tests ........................................ 95 
5.3.5.8 
Deaths ............................................................................. 96 
5.3.5.9 
Pre-existing Medical Conditions ...................................... 96 
5.3.5.10 
Lack of Efficacy or Worsening of Rheumatoid 
Arthritis ............................................................................ 96 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .................... 96 


 
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5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ............................................ 97 
5.3.5.13 
Patient-Reported Outcome Data ..................................... 97 
5.4 
Immediate Reporting Requirements from Investigator to Sponsor ............. 97 
5.4.1 
Emergency Medical Contacts ........................................................... 98 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ................................................... 98 
5.4.2.1 
Events That Occur Prior to Initiation of Treatment ........... 98 
5.4.2.2 
Events That Occur after Initiation of Treatment ............... 98 
5.4.3 
Reporting Requirements for Pregnancies ......................................... 99 
5.4.3.1 
Pregnancies in Female Patients ...................................... 99 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ........... 99 
5.4.3.3 
Abortions ......................................................................... 99 
5.4.3.4 
Congenital Anomalies/Birth Defects ................................ 99 
5.5 
Follow-Up of Patients after Adverse Events ............................................. 100 
5.5.1 
Investigator Follow-Up .................................................................... 100 
5.5.2 
Sponsor Follow-Up ......................................................................... 100 
5.6 
Post-Study Adverse Events ..................................................................... 100 
5.7 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Ethics Committees .................................................. 100 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................ 101 
6.1 
Determination of Sample Size .................................................................. 101 
6.2 
Summaries of Conduct of Study............................................................... 102 
6.3 
Summaries of Treatment Group Comparability ........................................ 102 
6.4 
Efficacy Analyses ..................................................................................... 102 
6.4.1 
Primary Efficacy Endpoint ............................................................... 102 
6.4.2 
Secondary Efficacy Endpoints ........................................................ 103 
6.5 
Safety Analyses ....................................................................................... 103 
6.6 
Patient-Reported Outcome Analyses ....................................................... 103 
6.7 
Exploratory Analyses ............................................................................... 103 
6.8 
Interim Analyses ...................................................................................... 103 
6.8.1 
Planned Interim Analyses ............................................................... 103 
7. 
DATA COLLECTION AND MANAGEMENT ........................................................ 103 
7.1 
Data Quality Assurance ........................................................................... 103 
7.2 
Electronic Case Report Forms ................................................................. 104 
7.3 
Source Data Documentation .................................................................... 104 
7.4 
Use of Computerized Systems ................................................................. 105 
7.5 
Retention of Records ............................................................................... 105 
8. 
ETHICAL CONSIDERATIONS ............................................................................ 105 


 
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8.1 
Compliance with Laws and Regulations ................................................... 105 
8.2 
Informed Consent .................................................................................... 105 
8.3 
Institutional Review Board or Ethics Committee ....................................... 106 
8.4 
Confidentiality .......................................................................................... 107 
8.5 
Financial Disclosure ................................................................................. 107 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION .............. 107 
9.1 
Study Documentation ............................................................................... 107 
9.2 
Protocol Deviations .................................................................................. 107 
9.3 
Site Inspections ....................................................................................... 108 
9.4 
Administrative Structure ........................................................................... 108 
9.5 
Publication of Data and Protection of Trade Secrets ................................ 108 
9.6 
Protocol Amendments .............................................................................. 109 
10. REFERENCES .................................................................................................... 110 
11. APPENDICES ..................................................................................................... 119 
APPENDIX 1: Schedule of Assessments - Screening (All Patients) & Lead-
in Phase (Track TCZ-Naïve) .................................................................... 120 
APPENDIX 2: Schedule of Assessments - 24 Week Tapering Phase (All 
Patients) .................................................................................................. 127 
APPENDIX 3:   Schedule of Assessments - Early Treatment 
Discontinuations ...................................................................................... 131 
APPENDIX 4:   Health Assessment Questionnaire (HAQ-DI) .............................. 134 
APPENDIX 5:   Rheumatoid Arthritis Impact of Disease (RAID) 
QuestionNaire .......................................................................................... 136 
APPENDIX 6:   Work Productivity and Activity Impairment Questionnaire 
Rheumatoid Arthritis English-US v2.0 (WPAI:RA) .................................... 138 
APPENDIX 7:   ACR Revised Criteria for the Classification of Functional 
Capacity in Rheumatoid Arthritis .............................................................. 140 
APPENDIX 8:   Joints to be Assessed for Swelling and Tenderness ................... 141 
APPENDIX 9:   Tuberculosis Evaluation During Screening ................................. 142 
APPENDIX 10:   Global Assessment of Disease Activity VAS ............................. 145 
APPENDIX 11:   Recommendations for Management of Adrenal 
Insufficiency ............................................................................................. 146 
APPENDIX 12:   Suggested Glucocorticoid Conversion Table ............................ 149 
 
LIST OF TABLES 
Table 1:  
Summary of Key Adverse Events Associated with GC Use in 
Patients with RA ..................................................................................... 31 
Table 2: 
Treatment Modifications in Case of Elevations in ALT & AST ................. 84 
Table 3: 
Treatment Modifications in Case of Decreases in Neutrophil Count ....... 86 


 
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Table 4: 
Treatment Modifications in Case of Decreases in Platelet Count ............ 86 
Table 5: 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE .............................................................................. 92 
 
LIST OF FIGURES 
Figure 1: 
Study Design .......................................................................................... 16 
Figure 2: 
Track TCZ-experienced patients (pre-randomization) ............................. 42 
Figure 3: 
Track TCZ-naïve patients (pre-randomization) ....................................... 45 
Figure 4: 
All patients: Randomized Tapering Phase, Post-Study Treatment, 
and Safety Follow-up .............................................................................. 49 
Figure 5: 
Daily Prednisone Doses for patients continuing 5 mg/day of 
prednisone ............................................................................................. 63 
Figure 6: 
Daily Prednisone Doses for patients on tapering prednisone .................. 63 
 
 
 


 
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PROTOCOL ACCEPTANCE FORM 
TITLE: 
PROSPECTIVE, MULTICENTRE, PLACEBO-
CONTROLLED, DOUBLE-BLIND STUDY TO COMPARE 
THE EFFICACY OF MAINTENANCE TREATMENT WITH 
TOCILIZUMAB WITH OR WITHOUT GLUCOCORTICOID 
DISCONTINUATION IN RHEUMATOID ARTHRITIS 
PATIENTS 
PROTOCOL NUMBER: 
MA29585 
VERSION NUMBER: 
3.0 
EUDRACT NUMBER: 
2014-004673-16 
TEST PRODUCT: 
Tocilizumab, prednisone 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local Study Monitor.   


 
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PROTOCOL SYNOPSIS 
TITLE: 
PROSPECTIVE, 
MULTICENTRE, 
PLACEBO-CONTROLLED, 
DOUBLE-BLIND STUDY TO COMPARE THE EFFICACY OF 
MAINTENANCE TREATMENT WITH TOCILIZUMAB WITH OR 
WITHOUT 
GLUCOCORTICOID 
DISCONTINUATION 
IN 
RHEUMATOID ARTHRITIS PATIENTS 
PROTOCOL NUMBER: 
MA29585 
VERSION NUMBER: 
3.0 
EUDRACT NUMBER: 
2014-004673-16 
TEST PRODUCT: 
Tocilizumab, prednisone 
PHASE: 
IIIb/IV 
INDICATION: 
Rheumatoid Arthritis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
 
I. Objectives 
Efficacy Objectives 
 
To compare the impact on disease activity of continued vs. tapered prednisone in RA 
patients with stable low disease activity (LDA; defined as a Disease Activity Score [DAS28]-
erythrocyte sedimentation rate [ESR] score ≤ 3.2), as assessed by the change in DAS28 
ESR score between randomization and Week 24 post-randomization. 
The key secondary efficacy objective for this study is as follows: 
 
To compare the proportion of patients who continue vs. taper prednisone with LDA (DAS28 
ESR score ≤ 3.2) at Week 24 post-randomization, who have not suffered a flare due to 
rheumatoid arthritis (RA) and who showed no confirmed adrenal insufficiency requiring 
replacement therapy. 
Other secondary efficacy objectives for this study are as follows: 
 
To compare, between patients who continue vs. taper prednisone: 
o 
changes in disease activity measures, such as clinical disease activity index (CDAI) and 
simplified disease activity index (SDAI) from randomization to Week 24 post-
randomization  
o 
the proportion of patients with ≥ 1 RA flare, the time to first RA flare and the number of 
RA flares 
o 
the proportion of patients with ≥ 1 administration of RA flare rescue medication, the time 
to first administration, and the number of administrations of RA flare rescue medication 


 
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o 
cumulative prednisone exposure (dose) between randomization and Week 24 post-
randomization 
o 
the proportion of patients who maintain LDA (DAS28 ESR score ≤ 3.2) and the proportion 
of patients who maintain the baseline disease activity level at Week 24 post-
randomization  
o 
proportion of patients who permanently discontinue study treatment due to insufficient RA 
flare control 
o 
changes in the ACR core set from randomization to post-randomization Week 24 
o 
to identify predictors of successful prednisone dose-tapering at Week 24 post-
randomization.  
Safety Objectives 
The safety objectives for this study are as follows: 
 
To evaluate the safety and tolerability of tocilizumab (TCZ) during the randomized phase of 
the study, based on an assessment of adverse events (AEs), vital signs, physical 
examination and clinical laboratory tests, including immunogenicity, in patients with 
rheumatoid arthritis who continue vs taper prednisone.   
 
To describe the safety of the proposed prednisone-tapering scheme. 
For further details on study objectives, refer to Section 2.3 (Patient-reported outcome objectives), 
and Section 2.4 (Exploratory objectives). 
 
II. Study Design 
Description of Study 
This is a Phase IIIb/IV, two-arm, randomized, double-blind, placebo-controlled, parallel-group, 
international, multicentre trial.  The primary study objective is to compare the change in disease 
activity (as assessed by DAS28 ESR) from randomization to Week 24 post-randomization, in 
patients with stable LDA (DAS28 ESR score ≤ 3.2) who have been randomized to either continue 
or taper prednisone in a double-blinded fashion. Patients can enter and be randomized into this 
study via two tracks. In order to reach the randomization target of 226 patients, between 240 and 
450 patients are planned to be recruited via both tracks in parallel over an approximately 1-year 
period. Given that the randomization ratio will differ between the two tracks, recruitment of 
patients into the two tracks will be steered to achieve the randomization target without exceeding 
the total number of 450 recruited patients. A Steering Committee will oversee the general conduct 
of the study. An independent Data Monitoring Committee (iDMC) will share responsibility for 
evaluating the safety of the patients participating in the trial at regular intervals throughout the 
study.   
See Figure 1 for an overview of the study design. 
Track TCZ-experienced patients 
This track consists of patients who received TCZ for at least 24 weeks prior to randomization, 
either subcutaneously (SC), at a dose of 162 mg once a week (QW) or intravenously (IV), at a 
dose of 8 mg/kg every 4 weeks (Q4W), not exceeding 800 mg/dose.   
Furthermore, eligible patients must have received 5 – 15 mg/day oral prednisone (or 
glucocorticoid [GC] equivalent) for at least 20 weeks prior to the Screening Visit, and they must 


 
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be on 5 mg/day oral prednisone (or GC equivalent) at the Screening Visit.  Eligible patients must 
also have a DAS28 ESR score ≤ 3.2 at the Screening Visit; see below for a complete list of 
eligibility criteria. 
The Screening Visit for TCZ-experienced patients occurs up to 6 weeks prior to randomization. 
TCZ-experienced patients will be switched to Sponsor-provided open-label prednisone 5 mg/day 
after signed informed consent, and as per Section 4.3.2.2.   
Patients on conventional synthetic disease modifying anti-rheumatic drug (csDMARD) therapy at 
the Screening Visit should be maintained on this therapy until the end of the study, and no new 
csDMARD may be initiated after the patient has signed the informed consent. Modification of 
stable csDMARD therapy is restricted, as per Section 4.4.1.1.  
Oral and other systemic glucocorticoids not provided by the Sponsor are forbidden after signed 
informed consent.  Intra-articular or parenteral glucocorticoids are forbidden within 6 weeks prior 
to randomization (within 12 weeks prior to randomization for intra-articular triamcinolone); see 
Section 4.3.2.2 for specific instructions.   
During the Screening Period, other analgesics and anti-inflammatory drugs (e.g. non-steroidal 
anti-inflammatory drugs [NSAIDs], acetaminophen) are allowed. If clinically feasible and safe, 
investigators should encourage patients to withhold these drugs for 12-24 hours prior to the 
randomization visit at which the baseline efficacy assessments are conducted; see Section 
4.4.1.2 for specific instructions. 
TCZ-experienced patients will be randomized if they meet all randomization criteria as per 
Section 4.5.10. 
See Figure 2 for a graphical representation of the study design, emphasizing the pre-
randomization period for Track TCZ-experienced patients. 
Track TCZ-naïve patients 
This track consists of patients who have not received any prior treatment with TCZ, or whose 
previous TCZ treatment occurred > 12 months prior to screening, and TCZ was not discontinued 
due to lack of efficacy, side effects, or any other safety concerns. At the Screening Visit, eligible 
patients must have active RA defined as DAS28 ESR > 3.2, must be considered by the 
investigator as inadequate responders to csDMARDs or biological disease-modifying 
antirheumatic drugs (bDMARDs), and must be receiving oral prednisone 5 to 15 mg/day (or GC 
equivalent).  Patients fulfilling all eligibility criteria will be enrolled in the 24-week Lead-in Phase, 
during which time they will receive open-label TCZ SC at a dose of 162 mg QW or open-label 
TCZ IV at a dose of 8 mg/kg Q4W, not exceeding 800 mg/dose. The choice between TCZ SC or 
TCZ IV will be made by the investigator, depending on the local availability and individual patient 
acceptance and tolerability of the SC formulation.  
During the open-label Lead-in Phase, the dose of prednisone (or GC equivalent) will be tapered 
down to prednisone 5 mg/day (if clinically feasible) according to a scheme determined by the 
investigator.   
All patients who are not on prednisone 5 mg/day (or GC equivalent) at the open-label Lead-
in Week 20 Visit will be withdrawn from the study.   
Patients who are on prednisone 5 mg/day (or GC equivalent) at the open-label Lead-in Week 20 
Visit will be treated the following way:  
 
Patients with a DAS28 ESR ≤ 3.2 at the Lead-in Week 20 Visit will be switched to 
Sponsor-provided open-label prednisone 5 mg/day for an additional 4 weeks. Patients on 


 
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csDMARD therapy at the Lead-in Week 20 Visit should be maintained on this therapy 
until the end of the study, and no new csDMARD may be initiated after this visit.  
Modification of stable csDMARD therapy is restricted, as per Section 4.4.1.1. 
 
Patients with a DAS28 ESR > 3.2 at the Lead-in Week 20 Visit will be withdrawn from 
the study, unless they have improved considerably, defined as a DAS28 ESR score < 4.4 
and a change in DAS28 ESR score ≥ 1.2 compared to baseline. Considerably 
improved patients at Lead-in Week 20 (DAS28 ESR score > 3.2 and < 4.4 and a 
change in DAS28 ESR score ≥ 1.2 compared to baseline) may continue TCZ SC and 
prednisone 5 mg/day (or GC equivalent) treatment for an additional 4 weeks. At the 
Lead-in Week 24 Visit, patients will be switched to Sponsor-provided open-label 
prednisone 5 mg/day for an additional 4 weeks if: 
1. They are receiving prednisone 5 mg/day (or GC equivalent), and  
2. DAS28 ESR ≤ 3.2.  
Patients not meeting these two criteria will be withdrawn.   
Patients on csDMARD therapy at the Lead-in Week 24 Visit should be maintained on this 
therapy until the end of the study, and no new csDMARD may be initiated after this visit.  
Modification of stable csDMARD therapy is restricted, as per Section 4.4.1.1. 
Oral and other systemic glucocorticoids not provided by the Sponsor are forbidden during 4 
weeks prior to randomization, but otherwise permitted during the open-label Lead-in Phase. Intra-
articular or parenteral glucocorticoids are forbidden within 6 weeks prior to randomization (within 
12 weeks prior to randomization for intra-articular triamcinolone); see Section 4.3.2.2 for specific 
instructions.   
During the Lead-in Phase, other analgesics and anti-inflammatory drugs (e.g. NSAIDs, 
acetaminophen) are allowed. If clinically feasible and safe, investigators should encourage 
patients to withhold these drugs for 12-24 hours prior to visits at which efficacy assessments are 
conducted.  See Section 4.4.1.2 for specific instructions. 
RA flares are treated according to standard clinical practice during the Screening and open-label 
Lead-in Phase. 
See Figure 3 for a graphical representation of the study design, emphasizing the pre-
randomization period (including the open-label Lead-in Phase) for Track TCZ-naïve patients. 
Track TCZ-naïve patients will be randomized if they meet all randomization criteria as per Section 
4.5.10. 
Patients who do not meet the randomization criteria will attend a Study Treatment Discontinuation 
Visit, followed in 4 weeks by a Safety Monitoring Visit (see Appendix 3). These patients will be 
subsequently treated outside of the study, according to local clinical practice, at the discretion of 
the investigator.  
Randomization numbers will be generated by Roche or its designee and provided to the 
Interactive Response System (IxRS).  Prior to entering the 24-week double-blind Tapering Phase, 
patients will be randomly assigned (1:1) to one of two treatment groups, either continuing 
5 mg/day of prednisone or tapering prednisone in a double-blinded fashion.  It is predicted that 
approximately 95% of patients entering from Track TCZ-experienced patients and 50% of 
patients entering from Track TCZ-naïve patients will be randomized, resulting in approximately 
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24-week Double-blind Tapering Phase (all patients randomized from the TCZ-experienced and -
naïve tracks) 
During the 24-week Tapering Phase, randomized patients will receive double-blinded treatment 
with either blinded study prednisone 5 mg/day or a blinded study tapering regimen consisting of 1 
mg decrements of study prednisone every 4 weeks. Study prednisone will be replaced with 
increasing amounts of placebo during the tapering. All randomized patients will be treated with 
open-label TCZ SC (162 mg QW) or TCZ IV (8 mg/kg Q4W, not exceeding 800 mg/dose).   
Initiation of new csDMARD is forbidden for all patients. Patients must have their existing 
csDMARD therapy maintained stable throughout the Tapering phase (see Section 4.4.1.1 for 
specific instructions): 
 
csDMARD dose may not be increased; 
 
csDMARD dose reductions or discontinuation are allowed for safety reasons. 
The use of systemic GCs which are not provided by the Sponsor are generally prohibited during 
the 24-week double-blind Tapering Phase, with the exception of treating or preventing serious 
illness, particularly serious infections or adrenal insufficiency or crisis (see Section 4.3.2.2 for 
specific 
instructions). 
Other 
analgesics 
and 
anti-inflammatory 
drugs 
(e.g. 
NSAIDs, 
acetaminophen) are allowed. If clinically feasible and safe, investigators should encourage 
patients to withhold these drugs for 12-24 hours prior to visits at which efficacy assessments are 
conducted (see Section 4.4.1.2 for specific instructions). 
Patients who successfully complete the Tapering Phase will attend a Study Treatment 
Discontinuation visit at Week 24, and a Safety Follow-up Visit at Week 28 (see Appendix 2). 
Patients who prematurely withdraw from treatment during the Tapering Phase will attend a Study 
Treatment Discontinuation Visit followed in 4 weeks by a Safety Monitoring Visit. These patients 
will be treated thereafter according to the investigator’s discretion and encouraged to attend a 
study visit at Week 24; see Schedule of Assessments (Appendix 3). Patients who prematurely 
discontinue study medication will not be replaced. 
See Figure 4 for a graphical representation of the study design emphasizing the post-
randomization period applicable to all randomized patients from both tracks. 
RA Flare Assessment and Treatment during the 24-week Double-blind Tapering Phase 
During the 24-week Tapering Phase, an RA flare may be detected at any scheduled or 
unscheduled visit, and is defined as: 
 
a current DAS28 ESR score > 3.2, and 
 
an increase in DAS28 ESR score > 0.6 from the randomization visit value. 
RA flare assessment and treatment must be conducted according to the instructions in Section 
4.5.11. 
For a patient experiencing an RA flare, TCZ and study prednisone will continue to be dispensed 
as planned and the blind maintained. The patient will also receive a 2-week course of RA flare 
rescue medication, consisting of 5 mg/day of Sponsor-provided open-label prednisone. Dose 
increases to existing csDMARDs or addition of new csDMARDs or any other RA therapy is 
prohibited (as per Sections 4.4.1 and 4.4.2). 
Patients will need to be followed up with a Flare Assessment at the end of the 2-week RA flare 
rescue medication course.  Patients will be determined to have either a resolved RA flare or a 
second RA flare, according to criteria defined in Section 4.5.11. Patients with persisting RA flares 


 
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after treatment of the second flare, will be withdrawn from the study treatment, and followed up 
and treated as per Appendix 3. 
Safety Follow-up Phase 
Patients completing the 24-week Tapering Phase will undergo a Safety Follow-up Visit 4 weeks 
after the completion of the Tapering Phase (i.e. at Week 28 post-randomization).   
Post-study Treatment 
Management of patients completing the 24-week Tapering Phase, including treatment of any 
potential RA flares following completion of study treatment, will be according to local standard 
clinical practice, at the discretion of the investigator. However, to ensure the scientific integrity of 
the study and to maintain the blind until database lock, it is recommended that patients 
completing the 24-week Tapering Phase be treated with open-label 3 mg/day of prednisone and 
continue TCZ (SC or IV). Higher doses of prednisone, e.g. 5 mg/day may be required in patients 
who were receiving RA flare rescue medication at Week 24 post-randomization.  
The end of the trial is defined as the date of the last visit of the last participating patient in this 
study. Study unblinding will occur after data base lock, and patients will be subsequently informed 
as to their previously assigned treatment groups.  
A Schedule of Assessments is provided in Appendix 1, Appendix 2, and Appendix 3. 
 
 
 
 


 
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Figure 1: Study Design 
 
 
bDMARD: biologic disease-
modifying anti-rheumatic 
drug 
csDMARD: conventional 
synthetic DMARD 
DAS: Disease Activity Scale 
ESR: erythrocyte 
sedimentation rate 
GC: glucocorticoid 
IV: intravenous(ly) 
LI: Lead-in 
PRED: prednisone 
QW: once every week 
Q4W: once every 4 weeks 
RAND: randomization 
SC: subcutaneous(ly) 
SPOL: Sponsor Provided 
Open-Label 
SPOL5: Sponsor Provided 
Open-Label PRED 5mg/d 
Rand: randomization 
TCZ: tocilizumab 
Wk(s) = week(s) 
* TCZ SC 162 mg QW or 
TCZ IV 8mg/kg Q4W 
Δ add, drop or dose change 
† percentage of screened 
(†) percentage of enrolled 


 
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III. Number of Patients 
Up to 450 patients are expected to be recruited into the study via both tracks in parallel in order to 
reach 226 randomized patients.  About 50% of patients entering from Track TCZ-naïve patients 
are expected to be randomized vs about 95% from Track TCZ-experienced patients. 
Target Population 
There are two target populations for this study: 
 
Track TCZ-experienced patients: Patients with a DAS28 ESR score ≤ 3.2 who are currently 
receiving TCZ (SC or IV) and 5 mg/day of prednisone (or GC equivalent). Eligibility criteria 
are evaluated during Screening, which starts up to 6 weeks prior to randomization. 
 
Track TCZ-naïve patients: Patients with moderate to severe active RA with an inadequate 
response to current csDMARD or bDMARD therapy, and who require current treatment with 5 
to 15 mg/day of prednisone (or GC equivalent). Following treatment with TCZ and GC taper 
(if clinically feasible) during the 24-week Lead-Phase, these patients are eligible for 
randomization if they maintain a DAS28 ESR score ≤ 3.2 and stable prednisone dose of 
5 mg/day for 4 weeks prior to randomization. Eligibility criteria are evaluated during Screening, 
which starts up to 4 weeks prior to enrolment in the Lead-in Phase. 
 
IV. Eligibility Criteria 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Track TCZ-experienced patients (study entry is enrolment following randomization): 
1. Able and willing to give written informed consent and comply with the requirements of the 
study protocol (including treatment on an outpatient basis). 
2. Age ≥ 18 years. 
3. RA of ≥ 6 months duration diagnosed according to the revised 1987 American College of 
Rheumatology (ACR, formerly the American Rheumatism Association) criteria or 2010 ACR / 
EULAR (European League Against Rheumatism) criteria. 
4. Have received TCZ either SC (162 mg QW) or IV (8 mg/kg Q4W, not exceeding 800 mg/dose) 
for the treatment of RA for at least 24 weeks prior to randomization. 
5. Have received 5 - 15 mg/day of prednisone (or GC equivalent) for the treatment of RA for at 
least 20 weeks prior to screening. 
6. Currently receiving 5 mg/day of oral prednisone (or GC equivalent) at the Screening Visit. 
7. Have a DAS28 ESR score ≤ 3.2 assessed 4 to 6 weeks prior to randomization (assessed at 
the Screening Visit or a visit prior to the Screening Visit). 
Track TCZ-naïve patients (study entry is enrolment into the lead-in phase): 
1. Able and willing to give written informed consent and comply with the requirements of the 
study protocol (including treatment on an outpatient basis). 
2. Age ≥ 18 years. 
3. RA of ≥ 6 months duration diagnosed according to the revised 1987 ACR criteria or 2010 
ACR / EULAR (European League Against Rheumatism) criteria. 
4. Have active RA (defined as DAS28 ESR score > 3.2). 


 
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5. Are considered by the investigator as inadequate responders to csDMARDs or bDMARDs.  
Are TCZ treatment naïve or last TCZ treatment was > 12 months prior to screening and TCZ 
was not discontinued due to lack of efficacy, side effects, or any other safety reasons. 
6. Are receiving 5 - 15 mg/day prednisone (or GC equivalent) for the treatment of RA. 
 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 
General 
1. Major surgery (including joint surgery) within 8 weeks prior to screening, or planned major 
surgery during the study and up to 6 months after randomization. 
2. Pregnant women or nursing (breastfeeding) mothers. 
3. In females of childbearing potential, a positive serum pregnancy test at screening. 
4. Females of childbearing potential unwilling or unable to use a reliable means of contraception 
(e.g., physical barrier [patient or partner], contraceptive pill or patch, spermicide and barrier, 
or intrauterine device) during study treatment and for a minimum of 3 months after the last 
dose of TCZ.  
5. Body weight of ≥ 150 kg. 
6. Lack of peripheral venous access. 
Disease-related 
7. RA of functional class IV, as defined by the ACR Classification of Functional Status in 
Rheumatoid Arthritis (see Appendix 7). 
8. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus, 
mixed connective tissue disease, scleroderma, polymyositis, or significant systemic 
involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, or Felty syndrome).  
Secondary Sjögren syndrome with RA may be allowed per the discretion of the investigator. 
9. Diagnosed with juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16 
years. 
10. Prior or current inflammatory joint disease other than RA (e.g., gout, Lyme disease, sero-
negative spondyloarthropathy, including reactive arthritis, psoriatic arthritis, arthropathy of 
inflammatory bowel disease), or prior or current joint infections. 
11. Previous history of primary or secondary adrenal insufficiency.  
Previous or Concomitant Prohibited Therapy 
12. Treatment with any investigational agent (tocilizumab excepted) within 4 weeks (or 5 half-
lives of the investigational drug, whichever is longer) of screening. Treatment with 
csDMARDs, other DMARDS, and/or biologics for RA which is permanently discontinued 
within 5 half-lives prior to randomization. 
13. Previous treatment with any cell-depleting therapies, including investigational agents or 
approved therapies (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD20). 
14. Treatment with IV gamma globulin, plasmapheresis or Prosorba column within 6 months of 
screening. 
15. Intraarticular (IA) or parenteral GCs within 6 weeks prior to randomization (within 12 weeks 
prior to randomization for intra-articular triamcinolone). 


 
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16. Previous treatment with oral or parenteral GCs for conditions other than RA, at any dose 
used continuously for > 1 week, during the last 1 year prior to screening. Current treatment 
with topical GC exceeding 20% of body surface area.  
17. Immunization with a live/attenuated vaccine within 30 days prior to screening. Patients must 
agree not to take live attenuated vaccines (including seasonal nasal flu vaccine, varicella 
vaccine for shingles or chickenpox, vaccines for measles, mumps or rubella without or with 
varicella [MMR or MMRV], oral polio vaccine and vaccines for yellow fever), within 30 days 
before the Screening Visit, throughout the duration of the trial and for 60 days following the 
last dose of study drug. 
18. Any previous treatment with alkylating agents such as chlorambucil or with total lymphoid 
irradiation. 
Laboratory Exclusion Criteria 
19. Inadequate haematological function indicated by any of the following: 
 
White blood cells (WBCs) < 3.0 x 109/L (3,000/mm3). 
 
Platelet count < 100 x 109/L (100,000/mm3). 
 
Haemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L). 
 
Absolute neutrophil count (ANC) < 2.0 x 109/L (2,000/mm3). 
 
Absolute lymphocyte count < 0.5 x 109/L (500/mm3). 
20. Inadequate renal function indicated by serum creatinine > 1.4 mg/dL (> 124 µmol/L) in female 
patients and > 1.6 mg/dL (> 141 µmol/L) in male patients 
21. Inadequate liver function indicated by any of the following: 
 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times the 
upper limit of normal (ULN). 
 
Total bilirubin > ULN. 
22. Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCV Ab). 
Previous or Concomitant Conditions 
23. History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies. 
24. Evidence 
of 
current 
serious 
uncontrolled 
cardiovascular 
(including 
uncontrolled 
hyperlipidemia), nervous system, pulmonary (including obstructive pulmonary disease), renal, 
hepatic, endocrine (including uncontrolled diabetes mellitus) or gastrointestinal (GI) disease. 
25. Current liver disease as determined by the investigator. 
26. History of diverticulitis, peptic ulcer disease, diverticulosis requiring antibiotic treatment, or 
chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis, or other 
symptomatic lower GI conditions that might predispose to perforations. 
27. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other 
opportunistic infections (including, but not limited to, tuberculosis [TB] and atypical 
mycobacterial disease, hepatitis B and C, Epstein-Barr virus, cytomegalovirus and herpes 
zoster, but excluding fungal infections of nail beds) on the day of enrolment. Track TCZ-
experienced patients are exempt if they have an active mild infection which does not warrant 
a treatment interruption as per protocol Section 5.1.1.2 or local standard of care. 
28. Neuropathies and/or other conditions that might interfere with pain evaluation (e.g. 
fibromyalgia) and/or are typically treated with systemic GCs, unless related to primary 
disease under investigation. 


 
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29. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 
4 weeks of screening or oral antibiotics within 2 weeks prior to screening  
30. Active TB requiring treatment within the previous 3 years (patients previously treated for TB 
with no recurrence within 3 years are permitted). Patients failing to complete the TB 
evaluation (as per Appendix 9) by the end of screening are excluded.  
31. History of or currently active, primary or secondary immunodeficiency. 
32. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years 
(including haematological malignancies and solid tumours, except basal and squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix uteri that was excised and cured), or 
breast cancer diagnosed within the previous 20 years. 
33. History of alcohol, drug or chemical abuse within 1 year prior to screening. 
34. Pre-existing central nervous system (CNS) demyelination or seizure disorders. 
35. Any medical or psychological condition that in the opinion of the principal investigator would 
interfere with safe completion of the trial. 
 
V. Length of Study 
The recruitment phase is expected to last approximately one year.  A 24-week Lead-in Phase is 
required for TCZ-naïve patients. This may be prolonged to 28 weeks in certain cases as defined 
in the study design section. Patients who are already receiving TCZ will undergo a 4 to 6-week- 
screening.  Both inclusion tracks will last 28 weeks after randomization. 
VI. End of Study 
The end of the trial is defined as the date of the last visit of the last participating patient in this 
study.  This is expected to occur 28 weeks after the last patient has been randomized into the 
study.  
VII. Outcome Measures 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
 
Change in DAS28 ESR between randomization and Week 24 post-randomization. DAS28 
ESR is a composite score based on tender and swollen 28-joint count, patient’s assessment 
of global status and ESR. 
The key secondary efficacy outcome measure for this study is as follows: 
 
The proportion of patients with LDA (DAS28 ESR score ≤ 3.2) at Week 24 post-
randomization, who have not suffered a flare due to RA and who showed no confirmed 
adrenal insufficiency that required replacement therapy. 
Other secondary efficacy outcome measures for this study are as follows: 
 
Change in CDAI / SDAI between randomization and Week 24 post-randomization.  The CDAI 
is composite score based on tender and swollen joint count, and the patient’s and physician’s 
assessment of global status. The SDAI includes the components of CDAI as well as C-
reactive protein (CRP).  
 
The proportion or patients with ≥ 1 RA flare, the time to first RA flare and the number of RA 
flares. 


 
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 
The proportion of patients with ≥ 1 administration of RA flare rescue medication, the time to 
first administration, and the number of administrations of RA flare rescue medication. 
 
Cumulative prednisone exposure (dose) between randomization and Week 24 post-
randomization. 
 
The proportion of patients who maintain LDA (DAS28 ESR score ≤ 3.2) and the proportion of 
patients who maintain the baseline disease activity level at Week 24 post-randomization. 
 
The proportion of patients who permanently discontinue study treatment due to insufficient 
RA flare control. 
 
Changes in the ACR core set from randomization to post-randomization Week 24, including: 
swollen and tender joint counts; patient’s assessment of pain and global status; physician’s 
assessment of global status; Health Assessment Questionnaire – Disability Index (HAQ-DI); 
and acute phase  reactants  (high  sensitivity  C-reactive protein [hsCRP] and erythrocyte 
sedimentation rate [ESR]). 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 
Nature, frequency and severity of AEs (graded according to CTCAE v4.0) including non-
serious and serious adverse events (SAEs), and AEs of special interest. 
 
Changes in vital signs, physical findings, and clinical laboratory results during and following 
TCZ administration. 
 
Assessment of immunogenicity: Immunogenicity sampling will be “event-driven”; for patients 
who experience a hypersensitivity reaction (including anaphylaxis), additional samples will 
be taken and tested for anti-TCZ antibodies, plasma TCZ levels (PK) and sIL-6R (PD) at 
time of event and 8 weeks after the event, as part of the standard immunogenicity sampling 
protocol. No immunogenicity sampling is required in case of injection site reactions. 
 
Proportion of patients with confirmed adrenal insufficiency that required replacement therapy. 
Patient-Reported Outcome Measures 
The PRO outcome measures for this study include the following: 
 
RAID score (measured at enrolment (Track TCZ-naïve patients only), randomization and at 
Week 24 post-randomization). 
 
HAQ-DI score (assessed at baseline, randomization and at Week 24 post-randomization). 
 
Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis (WPAI:RA) 
score (assessed at enrolment (Track TCZ-naïve patients only), randomization and at Week 
24 post-randomization). 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 
Levels of biomarkers, including but not limited to bone turnover biomarkers, at relevant time 
points; see Section 3.4.7 for details. 
 
Measure of non-inherited biomarkers associated with RA biology and TCZ biology; see 
Section 3.4.7 for details. 


 
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 
Change in the modified Homeostasis Model Assessment (HOMA1) from the beginning to the 
end of the Lead-in Phase (Track TCZ-naïve patients only).  
 
Change in HOMA1 from randomization to the end of the study (Week 24; both tracks). 
 
VIII. Investigational Medicinal Products 
Tocilizumab  
 
Track TCZ-experienced patients must have received TCZ (162 mg QW SC or 8 mg/kg Q4W 
IV, not exceeding 800 mg/dose) for at least 24 weeks prior to randomization. The 
Randomization Visit should coincide with the date of the next scheduled TCZ dose. 
 
Track TCZ-naïve patients will enter a 24-week Lead-in Phase, during which time they will 
receive open-label TCZ SC at a dose of 162 mg QW or open-label TCZ IV at a dose of 8 
mg/kg Q4W (not exceeding 800 mg/dose) at the investigator’s discretion. (Patients eligible 
for a 4-week extension of the Lead-in Phase, as per Section 3.1, will receive 28 weeks of 
open-label TCZ). Patients transitioning from a previous bDMARD to TCZ (SC or IV) should 
receive their first TCZ dose at Lead-in Visit 1, and this visit should coincide with the date of 
the next scheduled administration of the previous bDMARD. TCZ SC initiation should be 
performed under the supervision of a qualified healthcare professional.  
 
24-week Tapering Phase: randomized patients will receive open-label TCZ SC (162 mg QW) 
or TCZ IV (8 mg/kg Q4W, not exceeding 800 mg/dose). 
 
Post-study Treatment will be according to local clinical practice, at the discretion of the 
investigator. It is recommended that patients completing the 24-week Tapering Phase 
continue treatment with TCZ (SC or IV).  
Prednisone and Other Systemic Glucocorticoids 
 Screening: Track TCZ-experienced patients: Prednisone or GC administered during Screening 
is non-IMP. Patients are switched to Sponsor-provided open-label 5 mg/day prednisone at the 
Screening Visit (after signing informed consent, and only if they are currently on oral 
prednisone 5 mg/day or GC equivalent), and will continue taking Sponsor-provided open-label 
5 mg/day prednisone for the duration of the screening period.  Patients not on prednisone 5 
mg/day (or GC equivalent) at the Screening Visit will have failed screening. 
 Screening and Lead-in Phase: Track TCZ-naïve patients: Prednisone or GC administered 
during the Screening or Lead-in phase is non-IMP. Eligible patients must be receiving 5 to 
15 mg/day of prednisone (or GC equivalent).  Patients will enter a 24-week Lead-in Phase, 
during which time they will continue their open-label prednisone (or GC equivalent). During the 
Lead-in Phase, the dose of prednisone will be tapered down to 5 mg/day (if clinically feasible) 
according to a scheme determined by the investigator. All patients who are not on prednisone 
5 mg/day (or GC equivalent) at Lead-in Week 20 are discontinued from the study. Patients on 
5 mg/day of prednisone (or GC equivalent) and with a DAS28 ESR score ≤ 3.2 at Lead-in 
Week 20 must be switched to Sponsor-provided open-label 5 mg/day prednisone for the 
remainder of the Lead-in period (until Lead-in Week 24 / Randomization Visit). Patients who 
are on 5 mg/day of prednisone (or GC equivalent) and with a DAS28 ESR score > 3.2 at 
Lead-in Week 20 are discontinued from the study unless they have improved considerably 
(DAS28 ESR score < 4.4 and a change in DAS28 ESR score ≥1.2 compared to baseline).  
Considerably improved patients may continue in the Lead-in Phase and are re-assessed at 
Lead-in Week 24.  If these patients are on 5 mg/day of prednisone (or GC equivalent) and 
have a DAS28 ESR score ≤ 3.2 at Lead-in Week 24, they must be switched to Sponsor 


 
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provided open-label 5 mg/day prednisone for the remainder of the Lead-in period (until Lead-
in Week 28 / Randomization Visit). 
 24-week Tapering Phase (Double-blind) - All randomized patients: Study Prednisone: Study 
prednisone (defined as active prednisone ± placebo) is IMP. Track TCZ-experienced and 
Track TCZ-naïve patients randomized to tapered prednisone will receive 4 over-encapsulated 
tablets throughout the 24 weeks of Tapering Phase, consisting of a tapering dose of study 
prednisone, starting with 4 mg/day, with decrements of 1 mg every 4 weeks. Patients 
randomized to continuing prednisone will receive 5 mg/day of study prednisone as 4 over-
encapsulated tablets throughout the 24 weeks of Tapering Phase. Study prednisone should 
be taken in the morning. 
 24-week Tapering Phase - All randomized patients: Flare Rescue Medication: Prednisone 
administered as a RA flare rescue medication is non-IMP. Patients experiencing an RA flare 
during the 24-week Tapering Phase must be treated with Sponsor-provided flare rescue 
prednisone according to Section 4.5.11. (Note: patients experiencing an RA flare during the 
Lead-in Phase are treated as per local practice).  
 
Non-Sponsor Systemic Glucocorticoid Administration – All Study Phases:  
 
Non-Sponsor systemic GC (i.e. oral prednisone and other systemic GC compounds and 
formulations not provided by the Sponsor) administration is highly restricted: 
o 
All patients: Intra-articular or parenteral GCs are prohibited within 6 weeks prior to 
randomization (within 12 weeks prior to randomization for intra-articular 
triamcinolone); see Exclusion Criteria (Section 4.1.3).   
o 
Track TCZ-naïve patients: Non-Sponsor systemic GC (any route of administration) 
for any purpose (including RA) must not be used after 4 weeks prior to 
randomization and throughout the 24-week double-blind Tapering Phase.  Only 
Sponsor-provided Study prednisone or RA flare rescue prednisone (see above) 
may be used; see Randomization Criteria (Section 4.5.10). 
o 
Track TCZ-experienced patients: Non-Sponsor systemic GC (any route of 
administration) for any purpose (including RA) must not be used after signed 
informed consent and throughout the 24-week double-blind Tapering Phase.  Only 
Sponsor-provided Study prednisone or RA flare rescue prednisone (see above) 
may be used. 
 
Short-term non-Sponsor systemic GC is permitted after randomization when deemed 
necessary for treatment or prevention of serious illness, in particular serious infections 
and adrenal insufficiency or adrenal crisis (see Appendix 11).  This administration will be 
made according to the medical judgment of the investigator, and should be documented 
in the eCRFs. This non-Sponsor systemic GC treatment or prevention should be stopped 
as soon as clinically safe. 
 
Post-study Treatment will be according to local clinical practice at the discretion of the 
investigator.  However, to ensure the scientific integrity of the study and to maintain the blind 
until database lock, it is recommended that patients completing the 24-week Tapering Phase 
be treated with open-label 3 mg/day of prednisone equivalent (in addition to TCZ). Higher 
doses of GC, e.g. 5 mg/day of prednisone equivalent may be required in patients who were 
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IX. Statistical Methods 
Primary Analysis 
The statistical analysis will assess the difference between the two arms in terms of change in 
DAS28 ESR from randomization (baseline) to Week 24 post-randomization. The primary analysis 
population will be the intent-to-treat (ITT) population, which will comprise all randomized patients 
according to the treatment assigned at randomization. The between-group comparison will be 
performed based on an analysis of covariance (ANCOVA) model including the baseline DAS28 
ESR and the other stratification factors applied at randomization.     
For ITT patients who are prematurely withdrawn from treatment during the 24-week Tapering 
Phase, the DAS28 ESR value at the time of study treatment discontinuation will be used in the 
analysis. For ITT patients who are on RA flare rescue medication at Week 24 post-randomization, 
the DAS28 ESR value at the time of rescue medication start will be used in the analysis. 
Determination of Sample Size 
This study primarily focuses on estimation rather than formal hypothesis testing. A sample size of 
226 randomized patients is expected to provide > 80% power to produce a two-sided 95% 
confidence interval with a half-width < 0.5 DAS28 ESR units. The calculation is based on a two-
sided t-test for a difference between the two arms and assumes a standard deviation of 1.33 units 
(conservative assumption based on data under stable TCZ treatment) and an analysis in the ITT 
population.  
Differences < 0.6 DAS28 ESR units would be considered of marginal clinical importance. There 
are no reference data for an accurate assumption regarding the expected between-arm difference, 
but assuming an observed difference of < 0.25 units (mean disease activity is expected to slightly 
decrease in the steroid taper arm and to be stable in the placebo-taper arm), the two-sided 95% 
confidence interval will exclude differences between the two arms > 0.6. 
For 226 patients to be randomized, taking into account that approximately 50% of included 
patients are expected to be "Lead-in failures" (i.e. not meeting the randomization criteria for Track 
TCZ-naïve patients), up to approximately 450 patients will need to be included into the study. 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
ANCOVA 
analysis of Co-variance 
Anti-CCP 
anti-cyclic citrullinated peptide antibody 
AST 
aspartate aminotransferase 
ATA 
anti-therapeutic antibody 
AUC 
area under the curve 
bDMARD 
biologic disease-modifying antirheumatic drug 
BMD 
bone mineral density 
BMI 
Body Mass Index 
BUN 
blood urea nitrogen   
CDAI 
clinical disease activity index 
CI 
confidence interval 
ClinRO 
clinician-reported outcome 
CNS 
central nervous system 
CRO 
contract research organization 
CRP 
C-reactive protein 
csDMARD 
conventional synthetic disease-modifying antirheumatic drug 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX-I 
C-terminal cross-linked telopeptide of type I collagen 
CXCL13 
C-X-C ligand 13 (B cell–attracting chemokine 1) 
DAS28 
Disease Activity Score in 28 joints 
DMARD 
disease-modifying antirheumatic drug 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ePRO 
electronic patient-reported outcome 
ESR 
erythrocyte sedimentation rate  
EOT 
end of treatment 
EULAR 
European League Against Rheumatism 


 
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Abbreviation 
Definition 
FAS 
Full Analysis Set 
FDA 
F/U 
Food and Drug Administration 
Follow-up 
GC 
glucocorticoid 
GH 
general health 
GI 
gastrointestinal 
GmTSS 
Genant-modified Total Sharp Score  
HAQ-DI 
HBcAb 
Health Assessment Questionnaire – Disability Index 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV Ab 
hepatitis C virus antibodies  
HDL 
high-density lipoprotein cholesterol 
HOMA 
Homeostasis Model Assessment  
hsCRP 
high-sensitivity C-reactive protein  
HPA 
hypothalamic-pituitary adrenal 
IA 
intraarticular 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee  
IGRA 
Interferon gamma release assay 
IL 
interleukin 
IV 
intravenous(ly) 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IxRS 
Interactive Response System 
JAK 
janus kinases 
LDA 
low disease activity 
LDH 
lactate dehydrogenase  
LDL 
low-density lipoprotein cholesterol 
LPLV 
last patient, last visit 
MMP 
matrix metalloproteinase 
MMR 
vaccine for measles, mumps, rubella  
MMRV 
vaccine for measles, mumps, rubella, and varicella  
MTX 
methotrexate 
NCI 
National Cancer Institute 


 
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Abbreviation 
Definition 
ND 
not done 
NE 
not evaluated / non-evaluable 
non-IMP 
non-investigational medicinal product 
NSAID 
non-steroidal anti-inflammatory drug 
OR 
odds ratio 
PD 
pharmacodynamic 
PINP 
pro-collagen serum type I N-terminal propeptide 
pJIA 
polyarticular juvenile idiopathic arthritis  
PK 
pharmacokinetic 
PP 
Per Protocol 
PPI 
proton pump inhibitor 
PRO 
patient-reported outcome 
QW 
once per week 
Q4W 
once every 4 weeks 
RA 
rheumatoid arthritis 
RAID 
Rheumatoid Arthritis Impact of Disease (scale) 
RBC 
red blood cell (count) 
RBR 
Research Biosample Repository 
RCT 
randomized controlled trial 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SDAI 
simplified disease activity index  
sICAM-1 
soluble intercellular adhesion molecule-1  
SJC 
swollen joint count  
sJIA 
systemic juvenile idiopathic arthritis  
TB 
tuberculosis 
TCZ 
tocilizumab 
TGF-β 
transforming growth factor-ß 
TJC 
tender joint count  
TNF-α 
tumour necrosis factor-α 
tsDMARD 
targeted synthetic disease-modifying antirheumatic drug 
TST 
tuberculin skin test 
ULN 
upper limit of normal 
US/USA 
United States of America 


 
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Abbreviation 
Definition 
VAS 
Visual Analogue Scale 
WBC 
white blood cell (count) 
WPAI:RA 
Work Productivity and Activity Impairment Questionnaire: 
Rheumatoid Arthritis 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON RHEUMATOID ARTHRITIS  
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by 
joint pain, swelling, stiffness, and progressive destruction of synovial joints of the hands 
and feet (Aletaha et al. 2010; Shetty et al. 2014). The incidence is highly variable 
between nations, but is typically around 40 cases per 100,000 (Symmons 2002). 
Prevalence estimates in adult populations range from approximately 0.3% to 1.0% 
(WHO 2003; Gabriel and Michaud, 2009; Montjardino et al. 2011). A study in the United 
Kingdom found the population minimum prevalence of RA is 1.16% in women and 
0.44% in men (Symmons et al. 2002). The reported prevalence of RA in the United 
States was about 1.5 million adults in 2007 (Myasoedova et al. 2010), and women were 
affected three times more than men (Jawaheer et al. 2006). Rheumatoid arthritis affects 
about 1% of adults aged > 35 years and > 2% of adults aged > 60 years (Helmick et al. 
2008; Shetty et al. 2014). Given its higher incidence in adults during their peak 
productivity years, requirement for long term treatment, and the prospect of severe 
disability and early mortality, RA carries a great economic impact (Aletaha et al. 2010; 
Simons et al. 2012).  
The etiology of RA is thought to be multifactorial and is not fully understood; however, 
pro-inflammatory cytokines (tumour necrosis factor [TNF]-α, interleukin [IL]-6, IL-1β) are 
known to play a role in the disease pathogenesis in RA by propagating inflammation and 
leading to joint destruction (Majithia and Geraci, 2007). IL-6 and the soluble IL-6 receptor 
are present in serum and synovial fluids and are seen in higher levels in patients with RA 
(Mihara et al. 2005). Multiple functions in which IL-6 mediates the systemic and articular 
features of RA make IL-6 blockade an attractive biologic target therapy for the treatment 
of RA (Kishimoto 2005). 
1.1.1 
Current Treatment Options  
The management of RA rests on several principles, including pharmacological treatment 
and non-pharmacological measures. Drug treatment comprises disease-modifying 
antirheumatic drugs (DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs) and 
glucocorticoids (GCs); with DMARDs being the mainstay of RA treatment, used either as 
monotherapy or as combination therapy. These agents are characterized by their 
capacity to interfere with the entire disease process, including to reduce or reverse signs 
and symptoms, disability, impairment of quality of life, inability to work, and progression 
of joint damage (Smolen et al. 2007; Smolen et al. 2014). The DMARDs form two major 
classes. The first class includes the conventional synthetic compounds (csDMARDs) of 
methotrexate (MTX), sulfasalazine and leflunomide and the targeted synthetic agent 
(tsDMARD) tofacitinib, which was specifically designed to target janus kinases (JAKs). 
The second class includes biological agents (bDMARDs), comprised of five available 
TNF-alpha inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab and 
infliximab), the T cell co-stimulation inhibitor, abatacept, the anti-B cell agent, rituximab, 
the interleukin (IL)-6 receptor (IL-6R)-blocking monoclonal antibody, tocilizumab (TCZ), 
the IL-1 inhibitor, anakinra, and the biosimilar (bs)-infliximab (Smolen et al. 2014). The 


 
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emergence of biological agents targeting the cytokines well-known to play a role in the 
pathogenesis of RA (TNF-alpha, IL-6, and IL-1β) has greatly improved the treatment of 
RA over the past decade (Shetty et al. 2014). 
1.1.2 
Treatment Recommendations  
The current European League Against Rheumatism (EULAR) guidelines for the 
management of RA recommend that therapy with DMARDs be started as soon as the 
diagnosis of RA is made, with the aim of reaching remission or low disease activity 
(LDA) (Smolen et al. 2014). The initial treatment strategy in active disease includes MTX 
(or sulfasalazine or leflunomide in cases of MTX contraindications or early intolerance). 
Low-dose glucocorticoids should be considered as part of the initial treatment strategy 
(in combination with one or more csDMARDs) for up to 6 months, and then tapered as 
rapidly as clinically feasible. If there is no improvement by at most 3 months after the 
start of treatment, or the target has not been reached by 6 months, therapy should be 
switched to another csDMARD (in the absence of poor prognostic factors), or a 
combination of csDMARDs, or augmented with a bDMARD (when poor prognostic 
factors are present), such as TCZ, a TNF inhibitor or abatacept, and, under certain 
circumstances, rituximab. If a first bDMARD has failed, it is recommended that the 
patient is treated with another bDMARD. Tofacitinib may be considered after biological 
treatment has failed, if available. For patients in persistent remission after having 
tapered glucocorticoids, tapering of bDMARDs can be considered, especially if this 
treatment is combined with a csDMARD. In cases of sustained long-term remission, 
cautious reduction of the csDMARD dose could be considered (Smolen et al. 2014). 
1.2 
GLUCOCORTICOIDS IN THE TREATMENT OF RA  
Since their discovery in 1948, glucocorticoids (GCs) have been among the most 
frequently used anti-inflammatory and immunosuppressive drugs for RA. More than half 
of patients with RA receive concomitant treatment with low-dose GCs (≤ 7.5 mg/day) 
more or less continuously, as evidenced by the percentage of RA patients treated with 
GC at inclusion in phase II–IV trials of biological drugs (Spies et al. 2011; Buttgereit 
2012). Over the past three decades, a reduction of mean initial prednisone dose from 
10.3 mg/day in 1980–1985 to 3.6 mg/day in 2000–2004, with 86% of patients seen in 
2000–2004 having initial doses < 5 mg/day (Pincus et al. 2015). 
Glucocorticoids have a well-established efficacy in controlling the disease symptoms and 
structural progression in RA, and are often used concomitantly with DMARDs (Hoes et 
al. 2010; Spies et al. 2011; Smolen et al. 2014; Santiago and da Silva, 2015). However, 
due to the pleiotropic actions of GCs, there is a considerable concern regarding their 
toxicity, especially at higher doses and longer duration of therapy (Spies et al. 2011). 
The variety of adverse events (AEs) reported to be associated with GC use comprises 
diabetes mellitus/glucose intolerance, cardiovascular disease (such as myocardial 
infarction, hypertension), obesity, osteoporosis, fractures, and infections, among others; 
refer to Table 1 (Schettler et al. 1999; Curtis et al. 2006; Da Silva et al. 2006; Hoes et al. 
2010; Huscher et al. 2009; McDonough et al. 2009; Spies et al. 2011; Strangfeld et al. 
2011; Aviña-Zubieta et al. 2013; Duru et al. 2013; Kawai et al. 2013; del Rincón et al. 
2014). Of note, the estimation of the risk of developing GC toxicity is challenging, as in 


 
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most studies AEs have not been assessed systematically (Hoes et al. 2010; Spies et al. 
2011). In addition, there is a considerable overlap between adverse experiences 
associated with RA itself, and the events considered as side effects of GCs, such as 
cardiovascular disease, osteoporosis and fractures, and decreased insulin sensitivity 
(Santiago and de la Silva, 2015).  
Table 1:  
Summary of Key Adverse Events Associated with GC Use in Patients with RA 
Placebo-controlled studies 
AE   
 
 
 
 
 
Dose range and application  
Osteoporosis   
 
 
 
chronic medium dose 
IM 
Cardiovascular disease (i.e. MI) chronic medium dose 
step-down 
IM 
Diabetes  
 
 
 
 
chronic medium dose 
IM 
Weight gain   
 
 
 
IM  
Renal dysfunction   
 
 
chronic medium dose 
step-down 
Peptic ulcer disease  
 
 
chronic medium dose  
Hypertension   
 
 
 
chronic medium dose 
step-down 
IM 
 
Uncontrolled Studies  
AE    
 
 
 
 
 
Dose range and application  
Osteoporosis   
 
 
 
chronic medium dose 
chronic high 
step-down 
Cardiovascular disease (i.e. MI) chronic medium dose 
chronic high 
Diabetes  
 
 
 
 
chronic medium dose 
chronic high 
step-down 
Weight gain   
 
 
 
chronic medium dose 
step-down 
Renal dysfunction   
 
 
chronic medium dose 
step-down 
Peptic ulcer disease  
 
 
chronic medium dose 
step-down 
Hypertension   
 
 
 
chronic medium dose 
chronic high 
step-down 
AE: adverse event; IM: intramuscular; MI: myocardial infarction 
Source: Duru et al. 2013 
Results from several recently published systematic reviews and meta-analyses generally 
support the adequate safety of low-to medium dose GCs, including over long-term. A 
meta-analysis of low- to medium-dose GCs used for at least 1 month found that the 
reported GC-related AE rate was 43/100 patient years in RA studies, which was lower 
compared to other inflammatory diseases (Hoes et al. 2009). A meta-analysis of six 


 
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randomized controlled trials (RCTs) with total of 689 patients, investigating the safety of 
medium to long-term (≥ 2 years) GC therapy in RA found no statistically significant 
differences between prednisolone (at 5 to 10 mg doses) and placebo in the number of 
patients withdrawn due to AEs (odds ratio [OR] = 1.09; 95% CI 0.52, 2.25), number of 
AEs per patient year (OR = 1.19; 95% CI 0.91, 1.57) or the number of serious AEs (OR 
= 1.06; 95% CI 0.67, 1.67). The efficacy/toxicity ratio for GC therapy was assessed as 
good (number needed to harm/number needed to treat = 0.25) (Ravindran et al. 2009).  
Conversely, a meta-analysis of seven studies found a significant reduction in both 
lumbar and femoral bone mineral density (BMD) in RA patients receiving low-dose GC 
(N=353) compared to controls (N=343), suggesting that low-dose GC treatment 
accelerates bone loss in patients with RA, which overcomes the potential benefit derived 
from disease control (Lee et al. 2008).  
However, a recent review of toxicity data from seven randomized controlled trials 
concluded, that the toxicity profile of low-dose GCs (up to 10 mg of prednisone 
equivalent/day for up to 2 years) in RA patients seems mild and hardly different from that 
described for placebo, except for weight gain and glaucoma. However, the evidence is 
scarce (limited to 1,100 patient years of exposure) and of poor quality to establish 
conclusions (Santiago and da Silva, 2015). 
Lastly, two dose-related patterns of GC AEs have been observed (Huscher et al. 2009). 
A linear relationship has been found for the following AEs: cushingoid phenotype, 
ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath and sleep 
disturbance. Threshold-related AEs comprise: glaucoma, depression/ listlessness and 
increase in blood pressure (>7.5 mg/day); epistaxis and weight gain (≥ 5 mg/day) and 
cataract (< 5 mg/day). 
The concept that the AEs associated with GC treatment are potentially serious and 
depend on the dose and duration of use led to recommendations that the minimum dose 
should be used for the shortest possible time, always in combination with other DMARDs 
(Smolen et al. 2014; Santiago and de la Silva, 2015). A EULAR task force has 
developed evidence-based recommendations for the best use and management of GC 
therapy in all rheumatic diseases (Hoes et al. 2007), and subsequent guidelines focusing 
on GC use in RA patients (Gorter et al. 2010; Smolen et al. 2014). The EULAR 
recommendations stipulate that low (≤ 7.5 mg/day) or moderate (7.5 – 30 mg/day) doses 
of GCs may contribute to a therapeutic benefit if they are given as initial and short 
duration treatment (Smolen et al. 2010; Smolen et al. 2014). The goal of initial low-dose 
oral GCs as a bridging add-on therapy on a DMARD background is to achieve low 
disease activity (DAS28 ≤ 3.2) and to aid reaching remission (DAS28 < 2.6) (GUIPCAR 
2007; Smolen et al. 2014; Caporali et al. 2015). The recommended treatment duration is 
up to 6 months, after which the GC should be tapered as rapidly as clinically feasible. 
Tapering is seen as either dose reduction or prolongation of intervals between 
applications (Smolen et al. 2014). The rapid control of disease activity with this regimen 
(both in terms of clinical and subclinical reduction of the inflammatory process), ensures 
long-standing structural benefits, which persist even after GC withdrawal (Hoes et al. 
2010; Caporali et al. 2015). If the initial regimen is greater than 5 mg/day, dosage 
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(possibly after 6 months of treatment), however there are no guidelines specifically 
addressing this issue; therefore, the decision to taper is made based on clinician 
expertise and patient preferences (Caporali et al. 2015). There is also limited information 
concerning GC withdrawal in the context of complex treatment regimens, including both 
biologic and non-biologic DMARDs (Caporali et al. 2015).  
1.3 
TOCILIZUMAB IN THE TREATMENT OF RA  
Tocilizumab (TCZ), is a recombinant humanized anti-IL-6 receptor monoclonal antibody, 
approved in several countries (in combination with MTX) for the treatment of: (1) severe, 
active and progressive RA in adults not previously treated with MTX; and (2) moderate 
to severe RA in adult patients who have not adequately responded to one or more 
DMARDs or cannot tolerate other approved drug classes for RA. In these patients, 
RoActemra can be given as monotherapy in case of intolerance to MTX or where 
continued treatment with MTX is inappropriate (RoActemra SmPC 2015; Al-Shakarchi et 
al. 2013; Shetty et al. 2014). In addition, TCZ has been approved in some countries for 
the treatment of systemic juvenile idiopathic arthritis (sJIA), polyarticular juvenile 
idiopathic arthritis (pJIA), and early RA. 
Tocilizumab given intravenously (IV) 8 mg/kg every 4 weeks (Q4W) has obtained first 
market approval for the treatment of RA in Japan in 2008 (where it is also approved for 
pJIA, sJIA and Castleman's disease), followed by Europe in 2009, in combination with 
MTX for the treatment of moderate to severe active RA in adult patients with inadequate 
response to, or intolerance of, DMARD or TNF antagonist therapy. It may also be 
administered as monotherapy in the same dose regimen in patients with methotrexate 
intolerance or with inadequate response to MTX. Since January 2011, in the United 
States, the indication for treatment with TCZ for RA patients with an inadequate 
response to one or more TNF antagonists was extended to patients with moderately to 
severely active RA, and the recommended starting dose is 4 mg/kg Q4W, with an 
increase to 8 mg/kg based on clinical response (Alten et al. 2010). 
The efficacy of TCZ IV as both monotherapy and combination therapy in patients with 
RA was demonstrated in several advanced phase randomized clinical trials (Al-
Shakarchi et al. 2013; Shetty et al. 2014). Of these, there were five pivotal Phase 3 trials 
and two open-label, long-term treatment extension studies. A brief description of the five 
pivotal double-blind, randomized, parallel group studies is provided below. 
OPTION (WA17822): In this study, 623 patients with moderate to severe active 
rheumatoid arthritis were randomly assigned to receive TCZ 8 mg/kg (n=205), TCZ 4 
mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable 
pre-study doses (10-25 mg/week). The primary endpoint was the proportion of patients 
with 20% improvement in signs and symptoms of rheumatoid arthritis according to 
American College of Rheumatology criteria (ACR20 response) at Week 24. The study 
met its primary endpoint; at 24 weeks, ACR20 responses were seen in significantly more 
patients receiving TCZ than in those receiving placebo (59% patients in the 8 mg/kg 
group, 48% in the 4 mg/kg group, 26% in the placebo group; odds ratio [OR] 4.0 [95% CI 
2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs 
placebo) (Smolen et al. 2008).  


 
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TOWARD (WA18063): In this study, 1,220 patients with moderate to severe active RA 
who had an inadequate response to current DMARD therapy, were randomized (2:1 
ratio) to treatment with TCZ 8 mg/kg or placebo every 4 weeks for 24 weeks (given in 
combination with background DMARD therapy). The study met its primary endpoint; at 
Week 24, the proportion of patients achieving ACR20 was significantly greater in the 
TCZ plus DMARD group than in the control group (61% versus 25%; p<0.0001) 
(Genovese et al. 2008). 
RADIATE (WA18062): This study randomized 499 patients with inadequate clinical 
response to one or more anti-TNF therapies to receive 8 mg/kg or 4 mg/kg TCZ or 
placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. 
The anti-TNF agent was discontinued prior to randomization. The study met its primary 
endpoint, as ACR20 was achieved at 24 weeks by significantly more patients in the TCZ 
8 mg/kg and 4 mg/kg groups compared to control (50.0%, 30.4% and 10.1% of patients, 
respectively; p<0.001 for both TCZ groups versus control). Patients responded 
regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 
remission (DAS28 < 2.6) rates at Week 24 were clearly dose related, being achieved by 
30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups, respectively (p<0.001 
for 8 mg/kg and p=0.053 for 4 mg/kg versus control) (Emery et al. 2008). 
AMBITION (WA17824): This study compared TCZ monotherapy (8 mg/kg every 4 
weeks) with MTX monotherapy (starting at 7.5 mg/week and titrated to 20 mg/week 
within 8 weeks) in 673 patients with active RA for whom previous treatment with 
MTX/biological agents had not failed. To enable sensitivity testing for the non-inferiority 
claim, the study also included a 3-arm, 8-week sub study that included a placebo arm. 
The study met its primary endpoint by demonstrating that TCZ compared to MTX 
treatment was associated with a higher ACR20 response (69.9% vs 52.5%; p<0.001) 
atWeek24. Similarly, DAS28 < 2.6 rate was significantly higher with TCZ versus control 
(33.6 vs 12.1%, respectively) at Week 24 (Jones et al. 2010). 
LITHE (WA17823): In this 2-year study, 1,196 patients with moderate to severe active 
RA who had an inadequate response to MTX were randomized to treatment with TCZ (8 
mg/kg or 4 mg/kg) or placebo every 4 weeks plus MTX. The study met its endpoints of 
reduction in signs and symptoms, prevention of joint damage and physical function.  At 
52 weeks, mean change in the total Genant-modified Total Sharp Score (GmTSS) was 
0.29 and 0.34 with TCZ 8 mg/kg plus MTX and 4 mg/kg plus MTX, respectively, versus 
1.13 with placebo plus MTX (p<0.0001 for both comparisons). Proportions of patients 
with ACR20, ACR50, and ACR70 improvement and with DAS28 remission were higher 
in those receiving 8 mg/kg TCZ than in those receiving placebo (p<0.0001 for all 
comparisons) (Kremer et al. 2011). During Year 2, patients continued the initial double-
blind treatment or switched to open-label 8 mg/kg TCZ-MTX. Co-primary endpoints at 
Week 104 were mean change from baseline in GmTSS and adjusted mean area under 
the curve (AUC) for change from baseline in the Health Assessment Questionnaire-
Disability Index (HAQ-DI). At Week 104, mean change from baseline in GmTSS was 
significantly lower for patients initially randomized to TCZ-MTX 4 mg/kg (0.58; p=0.0025) 
or 8 mg/kg (0.37; p<0.0001) than for patients initially randomized to placebo-MTX (1.96). 
Adjusted mean AUC of change from baseline in HAQ-DI was also significantly lower in 


 
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patients initially randomized to TCZ-MTX 4 mg/kg (-287.5; p<0.0001) or 8 mg/kg (-320.8; 
p<0.0001) than in patients initially randomized to placebo-MTX (-139.4). Signs and 
symptoms of RA were maintained or showed improvement (Fleischman et al. 2013). 
Treatment with TCZ IV was generally well tolerated in the above described clinical 
studies. Adverse events experienced during treatment with TCZ IV were usually mild to 
moderate in severity and no increase in the risk of serious adverse events (SAEs) was 
detected compared to controls. Precautions during treatment with TCZ are related to 
elevated liver enzymes, elevated low-density lipoprotein, infections, and gastrointestinal 
perforations (Al-Shakarchi et al. 2013; Shetty et al. 2014). 
For further details on these studies, refer to the Investigator’s Brochure for TCZ, and for 
additional key randomized controlled efficacy studies of TCZ IV in patients with RA, refer 
to the respective publications (Nishimoto et al. 2004; Maini et al. 2006; Nishimoto et al. 
2007; Nishimoto et al. 2009a; Yazici et al. 2013; Dougados et al. 2013; Gabay et al. 
2013; Weinblatt et al. 2013). 
Recently, SC administration of TCZ was approved by the Food and Drug Administration 
(FDA) for use in the US in patients with RA at a starting dose of 162 mg every other 
week in patients who weigh < 100 kg, with an increase in frequency to 162 mg every 
week based on clinical response. In patients who weigh ≥ 100 kg, the starting dose is 
162 mg every week. TCZ SC every other week is also approved in Japan, and in the 
European Union, a starting dose of TCZ-SC every week is approved, with modification to 
every other week for the management of laboratory abnormalities (Kivitz et al. 2014). 
Two Phase 3 double-blind, randomized controlled trials demonstrated the efficacy and 
safety of the SC formulation of TCZ in patients with RA, and are briefly described below. 
SUMMACTA (WA22762): This randomized, double-blind, parallel group study compared 
the efficacy and safety of SC versus IV administration of TCZ in patients with moderate 
to severe active RA with an inadequate response to DMARDs. A total of 1,262 patients 
were randomized to receive TCZ 162 mg SC weekly (plus IV placebo every 4 weeks), or 
TCZ 8 mg/kg IV every 4 weeks (plus SC placebo weekly) for 24 weeks. The double-blind 
period was followed by a 72-week open-label treatment with some switching of SC and 
IV administration (without placebo). Patients continued on their stable dose of DMARDs 
throughout the study. The study showed that TCZ 162 mg SC weekly was non-inferior to 
TCZ 8 mg/kg IV every 4 weeks, when both are combined with DMARDs. At Week 24, 
69.4% of TCZ SC-treated patients versus 73.4% of TCZ IV-treated patients achieved an 
ACR20 response (primary endpoint; weighted difference between groups -4.0%, 95% CI 
-9.2 to 1.2); hence the 12% non-inferiority margin was met. ACR50/70 responses, 
DAS28 and physical function improvements were comparable between the TCZ SC and 
TCZ IV groups. The safety profiles of TCZ SC and TCZ IV were similar, and the most 
common AE was infection. Injection-site reactions occurred more frequently in the TCZ 
SC group than in the TCZ IV group. No anaphylaxis was reported over the 24 weeks 
(Burmester et al. 2014). 
To further characterize the efficacy and safety of a lower dose of TCZ SC, the 
BREVACTA study compared TCZ SC 162 mg every other week with SC administration 


 
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of placebo every other week in adult patients with moderate to severe RA who had an 
inadequate response to ≥ 1 DMARDs. 
BREVACTA (NA25220): In this two-arm, randomized, double-blind, placebo-controlled, 
parallel-group study, 656 patients received 162 mg TCZ SC every other week, or a 
matching placebo regimen until Week 24 and 162 mg TCZ SC open-label from Week 24 
to Week 96. Data to Week 24, including the primary end point, are currently available. 
TCZ SC was superior to placebo for ACR20 response (primary endpoint) at Week 24 
(60.9% versus 31.5%; P < 0.0001). All secondary end points showed TCZ SC to be 
superior to placebo, including ACR50 (40% vs 12%, respectively; P < 0.0001), ACR70 
response (20% vs 5%, respectively; P < 0.0001) and DAS28 remission (DAS28 < 2.6; 
32% versus 4%; P < 0.0001). TCZ SC was well tolerated and its safety profile was 
comparable with that of previous intravenous TCZ studies. Adverse events and SAEs 
were comparable between the TCZ SC and placebo groups; 4.6% and 3.7% of patients 
had at least one SAE, respectively, and infection was the most common SAE in 2.1% 
and 1.8% of patients, respectively. There were 3 deaths in the TCZ SC group and none 
in the placebo group. More injection site reactions occurred with TCZ SC than placebo 
(7.1% versus 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred 
(Kivitz et al. 2014).  
There is also evidence of sustained long-term efficacy and a generally good safety 
profile of TCZ from extension studies. In an open-label, long-term extension of a Phase 
II multi-centre, double-blind, placebo-controlled trial, that enrolled 163 patients with 
refractory RA (Nishimoto et al. 2004), following an initial 3-month treatment, 143 patients 
continued to receive TCZ IV monotherapy (8 mg/kg) every 4 weeks. Concomitant 
therapy with NSAIDs and/or oral prednisolone (10 mg daily maximum) was permitted. Of 
the 143 patients, 94 (66%) had completed 5 years of follow-up. At 5 years, 79 (84%), 65 
(69%) and 41 (44%) of the patients achieved ACR20, ACR50, and ACR70 improvement, 
respectively. Remission defined as DAS28 less than 2.6 was achieved in 52 (55%) of 
the patients. Of the 88 patients receiving GCs at baseline, 78 (89%) were able to 
decrease their GC dose and 28 (32%) discontinued GCs (Nishimoto et al. 2009b). 
Additional evidence of a GC-sparing effect of TCZ is available from a recently published 
open label, observational, retrospective multi-centre study that evaluated the impact of 
TCZ treatment in 130 RA patients treated with oral GCs for > 3 months. The mean ± 
standard deviation (SD) baseline dose of GCs was 10.0 ± 8.2 mg/day prednisone 
equivalent (91.5, 51.5, 20.0 and 9.2% of patients received a daily dose of 5, 10, 15 and 
20 mg, respectively). During the study period there was a significant early GC-sparing 
effect. The mean daily dose of oral GCs fell from 10.0 mg at baseline to 8.7 mg at Week 
4, 8.0 mg at Week 8, 7.5 mg at Week 12, and 6.5 mg at Week 24 (p<0.0001). In parallel, 
among the 90 patients not receiving GCs at baseline, 13 received GCs during the study 
period. When these patients were included in the analysis, the mean daily dose of oral 
GCs fell from 9.1 mg at baseline to 8.2 mg at Week 4, 7.9 mg at Week 8, 7.5 mg at 
Week 12, and 6.4 mg at Week 24 (p<0.0001). 11.5% of the patients were able to stop 
GCs after 24 weeks. The mean DAS28 fell from 5.1 ± 1.4 at baseline to 3.0 ± 1.4 at 
Week 24 (p<0.0001) (Fortunet et al. 2014). The relevance of this rapid and long-lasting 
GC-sparing effect is underscored by findings of a post-marketing study involving nearly 


 
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4,000 patients, in which GC therapy with ≥ 5 mg/day prednisone equivalent was 
associated with severe infections during the first 24 weeks of TCZ (Koike et al. 2011), 
and earlier observations of gastrointestinal perforations in RA patients receiving GCs 
(Fortunet et al. 2014). 
1.4 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Clinical recommendations for the management of systemic GC therapy in RA state that 
a reduction and even a discontinuation should be attempted once remission or LDA has 
been reached; however, a GC reduction schedule has not yet been standardized. There 
are no formal recommendations on when and how to taper initial GC regimens from 
doses ≥ 5 mg/day; therefore, the decisions to taper are made based on clinician 
expertise and patient preferences (Caporali et al. 2015). There is also limited information 
concerning GC withdrawal in the context of complex treatment regimens, which include 
both biologic and non-biologic DMARDs (Caporali et al. 2015). In addition, complete 
discontinuation of GCs is often hampered by steroid withdrawal symptoms or the fear 
thereof. 
As detailed in Section 1.3, the efficacy and safety of TCZ in combination with MTX in the 
treatment of RA patients refractory to synthetic DMARDs or/and anti-TNF is well 
established. Tocilizumab can also be given as monotherapy in case of intolerance to 
MTX or when continued treatment with MTX is inappropriate. However, it has not been 
systematically investigated in a randomized double-blind study whether treatment with 
TCZ in patients receiving a moderate or low dose GC could also enable reduction or 
discontinuation of the GC while maintaining disease symptom control. Several 
observational studies provided preliminary evidence that this might be achievable. Data 
from Japanese studies of TCZ monotherapy (N=601) showed that of the 546 patients 
taking GCs at baseline, 77.8% were able to decrease their GC dose during the study 
period, while 35.2% discontinued GCs altogether (Nishimoto et al. 2010). A significant 
early GC-sparing effect was also reported in the above described retrospective 
observational study evaluating TCZ in 130 RA patients treated with oral GCs for > 3 
months. The study showed a significant, persistent decline in GC dose from 9.1 mg at 
baseline to 6.4 mg at Week 24 (p<0.0001), and complete discontinuation of GCs in 
11.5% of the patients (Fortunet et al. 2014). In a 12-months retrospective observational 
SPARE-1 study (N=307), the percentage of patients receiving prednisone at >10 mg/day 
and between 7.5 and 10 mg/day was reduced from 30% to 14%, and from 44% to 14%, 
respectively, and 20% of patients discontinued GCs altogether (Saraux et al. 2013). 
Further supportive evidence comes from the open-label ACT-ALONE study (ML25252) 
that aimed to determine the proportion of RA patients with LDA able to discontinue oral 
GC within 20 weeks, with confirmation of the GC-free status and maintained LDA 4 
weeks later. LDA was achieved with standard treatment including oral GC and TCZ 
(8mg/kg IV perfusion Q4W), with or without DMARD in a 6-month observation phase, 
and 
was 
followed 
by 
a 
28-week 
interventional 
phase, consisting 
of 
oral 
methylprednisolone according to a fixed dose reduction schedule over 20 weeks,  and 
TCZ, with or without DMARDs. Of the 43 patients analysed, 58.1% discontinued GC 
within 20 weeks with confirmation of LDA 4 weeks later, and 93.3% were able to reduce 
GC by ≥50% after 24 weeks, with disease activity and levels of pain and disability 


 
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remaining at a low level throughout the interventional phase of the study (Ribbens et al. 
2014). The GC-sparing effect of TCZ was also noted in the interim analysis (N=589) of 
the ongoing, prospective 2-year non-interventional ICHIBAN study. During the 
observation period, the mean daily GC dose decreased continuously from 9.4 at 
baseline to 5.3 mg/day at Week 104. Of the patients receiving GCs at baseline, 19.2% 
could discontinue GC treatment, 52.7% could reduce the dose, and a dose increase was 
necessary in only 10.0% of the patients. The proportion of patients not needing 
concomitant GC increased by 11.4% to 29.0% during observation and the proportion of 
daily GC dose ≤ 5 mg increased from 59.7% to 76.5% (Specker et al. 2014).  
A central feature of RA is an imbalance of cytokine production, with a relative excess of 
pro-inflammatory molecules, including IL-1, IL-6, IL-17, IL-18, and TNF-α, compared with 
anti-inflammatory mediators such as IL-10 or transforming growth factor-ß (TGF-ß) (de 
Paz et al. 2010). Glucocorticoids are potent inhibitors of inflammation, and this is at least 
partly due to their ability to inhibit the synthesis of pro-inflammatory cytokines (such as 
IL-1, IL-6, and TNF-α). In non-clinical models, adrenalectomy or GC antagonists were 
shown to potentiate TNF, IL-1 and IL-6 production (Fantuzzi and Ghezzi, 1993). In 
humans, plasma levels of IL-6 have been reported to decrease during prednisone 
treatment (Buttgereit et al. 2010). In addition, a genetic polymorphism characterized by 
high IL-10/low TNF-α expression has been found to be a predictor of response to GC 
therapy (de Paz et al. 2010). The mechanism of anti-inflammatory action of GCs also 
includes the apoptosis in mature T cells and an effect on the differentiation of T-cells. As 
such, there appears to be some redundancy in the anti-inflammatory effects of GCs and 
those of the humanized anti-IL 6 receptor antibody TCZ. Hence it is possible, that GCs 
do not contribute to the level of disease control achieved with TCZ to the same extent as 
observed during their co-administration with TNF inhibitors. 
Therefore the rationale for this study is to assess the potential GC-sparing effect of TCZ, 
and its ability to enable discontinuation of GCs. In addition, the study will explore 
potential factors associated with successful discontinuation of GCs. To eliminate 
potential patient and physician bias, GC treatment will be tapered and discontinued in a 
double-blind manner, starting from a dose-level of 5 mg/day prednisone.  At this dose 
level and below, GCs might not significantly contribute to disease control in patients who 
reached LDA state during treatment with TCZ.  
Furthermore, the goal of the study is to ultimately inform therapeutic regimens with TCZ 
which do not require low-dose steroids while keeping the level of disease control, 
thereby improve on the benefit risk ratio for patients and as such, a steroid reduction or 
elimination would be considered as a clear patient benefit. The potential risks of steroid 
withdrawal are managed by two strategies in this trial. First, a rescue medication scheme 
will be available to manage potential loss of efficacy in patients which taper steroids. 
Second, education and guidance about detection and management of potential steroid 
withdrawal syndrome will mitigate this rare but potential side-effect. In summary, the 
overall benefit risk assessment for patients participating in this trial is considered 
positive. 


 
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2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
 To compare the impact on disease activity of continued vs. tapered prednisone in 
RA patients with stable LDA (DAS28 ESR score ≤ 3.2), as assessed by the change 
in DAS28 ESR between randomization and Week 24 post-randomization. 
The key secondary efficacy objective for this study is as follows: 
 To compare the proportion of patients who continue vs. taper prednisone with LDA 
(DAS28 ESR score ≤ 3.2) at Week 24 post-randomization, who have not suffered a 
flare due to RA and who showed no confirmed adrenal insufficiency requiring 
replacement therapy. 
Other secondary efficacy objectives for this study are as follows: 
 To compare, between patients who continue vs. taper prednisone: 
- changes in disease activity measures, such as clinical disease activity index 
(CDAI) and simplified disease activity index (SDAI) from randomization to 
Week 24 post-randomization  
- the proportion of patients with ≥ 1 RA flare, the time to first RA flare and the 
number of RA flares 
- the proportion of patients with ≥ 1 administration of RA flare rescue medication, 
the time to first administration, and the number of administrations of RA flare 
rescue medication 
- cumulative prednisone exposure (dose) between randomization and Week 24 
post-randomization 
- the proportion of patients who maintain LDA (DAS28 ESR score ≤ 3.2) and the 
proportion of patients who maintain the baseline disease activity level at Week 
24 post-randomization  
- the proportion of patients who permanently discontinue study treatment due to 
insufficient RA flare control 
- changes in the ACR core set from randomization to post-randomization Week 
24 
- to identify predictors of successful prednisone dose-tapering at Week 24 post-
randomization. Variables that may be assessed include, but may not be limited 
to: age, gender, smoking status, body weight, duration of prior prednisone 
treatment, prior bDMARD therapy, use of csDMARDs at randomization, bone 
remodelling. 
 
2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 


 
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 To evaluate the safety and tolerability of TCZ during the randomized phase of the 
study, based on an assessment of adverse events (AEs), vital signs, physical 
examination and clinical laboratory tests, including immunogenicity, in patients with 
rheumatoid arthritis who continue vs taper prednisone   
 To describe the safety of the proposed prednisone-tapering scheme. 
2.3 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO)-related objectives for this study include the 
following: 
 To compare changes in PROs between patients with rheumatoid arthritis who 
continue vs taper prednisone, as measured by the: 
- Rheumatoid Arthritis Impact of Disease (RAID) 
- Health Assessment Questionnaire - Disability Index (HAQ-DI) 
- Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis 
(WPAI:RA). 
2.4 
EXPLORATORY OBJECTIVES  
The exploratory objectives for this study are as follows: 
 To explore variables pointing to a potential benefit of prednisone tapering (such as 
bone remodelling) in patients who continue vs taper prednisone. 
 To assess non-inherited biomarkers associated with RA biology and TCZ biology in 
patients who continue vs taper prednisone. 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a Phase IIIb/IV, two-arm, randomized, double-blind, placebo-controlled, parallel-
group, international, multicentre trial.  The primary study objective is to compare the 
change in disease activity (as assessed by DAS28 ESR) from randomization to Week 24 
post-randomization, in patients with stable LDA (DAS28 ESR score ≤ 3.2) who have 
been randomized to either continue or taper prednisone in a double-blinded fashion.  
Patients can enter and be randomized into this study via two tracks. In order to reach the 
randomization target of 226 patients, between 240 and 450 patients are planned to be 
recruited via both tracks in parallel over an approximately 1-year period. Given that the 
randomization ratio will differ between the two tracks, recruitment of patients into the two 
tracks will be steered to achieve the randomization target without exceeding the total 
number of 450 recruited patients. A Steering Committee will oversee the general 
conduct of the study. An independent Data Monitoring Committee (iDMC) will share 
responsibility for evaluating the safety of the patients participating in the trial at regular 
intervals throughout the study.   
Track TCZ-experienced patients 


 
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This track consists of patients who received TCZ for at least 24 weeks prior to 
randomization, either SC, at a dose of 162 mg once a week (QW), or IV, at a dose of 8 
mg/kg every 4 weeks (Q4W), not exceeding 800 mg/dose.  
Furthermore, eligible patients must have received 5 – 15 mg/day oral prednisone (or GC 
equivalent) for at least 20 weeks prior to the Screening Visit, although they must be on 5 
mg/day oral prednisone or GC equivalent at the Screening Visit.  Eligible patients must 
have a DAS28 ESR score ≤ 3.2 at the Screening Visit. (Eligibility criteria: see Section 
4.1.2 and Section 4.1.3). 
The TCZ-experienced Screening Visit occurs up to 6 weeks prior to randomization. 
TCZ-experienced patients will be switched to Sponsor provided open-label prednisone 5 
mg/day after signed informed consent, and as per Section 4.3.2.2.   
Patients on csDMARD therapy at the Screening Visit should be maintained on this 
therapy until the end of the study, and no new csDMARD may be initiated after the 
patient has signed the informed consent.  Modification of stable csDMARD therapy is 
restricted, as per Section 4.4.1.1.  
Oral and other systemic GCs not provided by the Sponsor are forbidden after signed 
informed consent.  Intra-articular or parenteral GCs are forbidden within 6 weeks prior to 
randomization (within 12 weeks prior to randomization for intra-articular triamcinolone).  
See Section 4.3.2.2 for specific instructions.   
During the Screening Period, other analgesics and anti-inflammatory drugs (e.g. NSAIDs, 
acetaminophen) are allowed. If clinically feasible and safe, investigators should 
encourage patients to withhold these drugs for 12-24 hours prior to the randomization 
visit at which the baseline efficacy assessment is conducted.  See Section 4.4.1.2 for 
specific instructions. 
Patients will be randomized and enrolled in the study if they meet the randomization 
criteria (see Section 4.5.10): 
a) Fulfils all inclusion and none of the exclusion criteria; 
b) Screening Visit occurred up to 6 weeks prior to randomization; 
 
c) DAS28 ESR score ≤ 3.2 at randomization; 
d) Receiving prednisone 5 mg/day, and no other oral GC, at randomization and for 
≥ 4 weeks prior to randomization; 
e) Received no intra-articular or parenteral GCs within 6 weeks prior to 
randomization (within 12 weeks prior to randomization for intra-articular 
triamcinolone). 
See Figure 2 for a graphical representation of the study design emphasizing the pre-
randomization period for Track TCZ-experienced patients.  
 




 
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Track TCZ-naïve patients 
This track consists of patients who have not received any prior treatment with TCZ, or 
whose previous TCZ treatment occurred > 12 months prior to screening, and TCZ was 
not discontinued due to lack of efficacy, side effects, or any other safety concerns.  
At the Screening Visit, eligible patients must have active RA defined by DAS28 
ESR > 3.2, must be considered by the investigator as inadequate responders to 
csDMARDs or bDMARDs, and must be receiving oral prednisone 5 to 15 mg/day (or GC 
equivalent).   
Patients fulfilling all eligibility criteria will be enrolled in the 24-week Lead-in Phase, 
during which time they will receive open-label TCZ SC at a dose of 162 mg QW or open-
label TCZ IV at a dose of 8 mg/kg Q4W, not exceeding 800 mg/dose. The choice 
between TCZ SC or TCZ IV will be made by the investigator, depending on the local 
availability and individual patient acceptance and tolerability of the SC formulation.  
During the Lead-in Phase, the dose of prednisone (or GC equivalent) will be tapered 
down to prednisone 5 mg/day (if clinically feasible) according to a scheme determined by 
the investigator.   
All patients who are not on prednisone 5 mg/day (or GC equivalent) at the Lead-in 
Week 20 Visit will be withdrawn from the study.   
Patients who are on prednisone 5 mg/day (or GC equivalent) at the Lead-in Week 20 
Visit will be treated the following way:  
 
Patients with a DAS28 ESR ≤ 3.2 at the Lead-in Week 20 Visit will be switched 
to Sponsor-provided open-label prednisone 5 mg/day for an additional 4 weeks. 
Patients on csDMARD therapy at the Lead-in Week 20 Visit should be 
maintained on this therapy until the end of the study, and no new csDMARD may 
be initiated after this visit.  Modification of stable csDMARD therapy is restricted, 
as per Section 4.4.1.1. 
 
Patients with a DAS28 ESR > 3.2 at the Lead-in Week 20 Visit will be withdrawn 
from the study, unless they have improved considerably: DAS28 ESR score < 4.4 
and a change in DAS28 ESR score ≥ 1.2 compared to baseline. Considerably 
improved patients at Lead in Week 20 (DAS28 ESR score > 3.2 and < 4.4 and 
a change in DAS28 ESR score ≥ 1.2 compared to baseline) may continue TCZ 
SC and prednisone 5 mg/day (or GC equivalent) treatment for an additional 4 
weeks. At the Lead-in Week 24 Visit, patients will be switched to Sponsor 
provided open-label prednisone 5 mg/day for an additional 4 weeks if: 
1. on prednisone 5 mg/day (or GC equivalent), and  
2. DAS28 ESR ≤ 3.2 (patients not meeting these criteria will be withdrawn).   
Patients on csDMARD therapy at the Lead-in Week 24 Visit should be 
maintained on this therapy until the end of the study, and no new csDMARD 
may be initiated after this visit.  Modification of stable csDMARD therapy is 
restricted, as per Section 4.4.1.1. 


 
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Oral and other systemic glucocorticoids not provided by the Sponsor are forbidden 
during the 4 weeks prior to randomization, but otherwise permitted during the Lead-in 
Phase.  Intra-articular or parenteral glucocorticoids are forbidden within 6 weeks prior to 
randomization (within 12 weeks prior to randomization for intra-articular triamcinolone).  
See Section 4.3.2.2 for specific instructions.   
During the Lead-in Phase, other analgesics and anti-inflammatory drugs (e.g. NSAIDs, 
acetaminophen) are allowed. If clinically feasible and safe, investigators should 
encourage patients to withhold these drugs for 12-24 hours prior to visits at which 
efficacy assessments are conducted.  See Section 4.4.1.2 for specific instructions. 
RA flares are treated according to standard clinical practice during the Screening and 
Lead-in Phase. 
Track TCZ-naïve patients will be randomized if they meet the following randomization 
criteria (as per Section 4.5.10): 
a) DAS28 ESR score ≤ 3.2 at most recent scheduled Lead-in Visit 4 weeks prior to 
randomization; 
b) DAS28 ESR score ≤ 3.2 at randomization; 
c) Receiving prednisone 5 mg/day, and no other oral GC, at randomization and for 
≥ 4 weeks prior to randomization; 
d) Received no intra-articular or parenteral GCs within 6 weeks prior to 
randomization (within 12 weeks prior to randomization for intra-articular 
triamcinolone). 
Patients who are withdrawn during the Lead-in Phase will attend a Study Treatment 
Discontinuation Visit, followed in 4 weeks by a Safety Monitoring Visit (see Appendix 3). 
These patients will be subsequently treated outside of the study according to local 
clinical practice at the discretion of the investigator. 
See Figure 3 for a graphical representation of the study design emphasizing the pre-
randomization period (including the Lead-in Phase) for Track TCZ-naïve patients. 




 
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Randomization 
Patients are eligible to be randomized for the study if they meet the randomization 
criteria (see Section 4.5.10). 
Randomization numbers will be generated by Roche or its designee and provided to the 
Interactive Response System (IxRS). Prior to entering the 24-week double-blind 
Tapering Phase, patients will be randomly assigned (1:1) to one of two treatment groups, 
either continuing 5 mg/day of prednisone or tapering prednisone in a double-blinded 
fashion.  It is predicted that approximately 95% of patients entering from Track TCZ-
experienced patients and 50% of patients entering from Track TCZ-naïve patients will be 
randomized, resulting in approximately 226 randomized patients in total.  
Track TCZ-naïve patients who do not meet the randomization criteria will attend a Study 
Treatment Discontinuation Visit, followed 4 weeks later by a Safety Monitoring Visit (see 
Appendix 3). These patients will be subsequently treated outside of the study according 
to local clinical practice at the discretion of the investigator. 
24-week Double-blind Tapering Phase 
During the 24-week Tapering Phase, randomized patients will receive double-blinded 
treatment with either:  
 
Blinded study prednisone 5 mg/day, or 
 
Blinded study tapering regimen consisting of 1 mg decrements of study 
prednisone every 4 weeks. Study prednisone will be replaced with increasing 
amounts of placebo during the tapering.   
All randomized patients will be treated with open-label TCZ SC (162 mg QW) or TCZ IV 
(8 mg/kg Q4W, not exceeding 800 mg/dose).  Initiation of new csDMARD is forbidden for 
all patients. Patients must have their existing csDMARD therapy maintained stable 
throughout the Tapering phase (see Section 4.4.1.1 for specific instructions): 
 
csDMARD dose may not be increased, 
 
csDMARD dose reductions or discontinuation is allowed for safety reasons.  
The use of systemic glucocorticoids which are not provided by the Sponsor are generally 
prohibited during the Tapering Phase, with the exception of treating or preventing 
serious illness, particularly serious infections or adrenal insufficiency or crisis (see 
Section 4.3.2.2 for specific instructions).   
Other analgesics and anti-inflammatory drugs (e.g. NSAIDs, acetaminophen) are 
allowed.  If clinically feasible and safe, investigators should encourage patients to 
withhold these drugs for 12-24 hours prior to visits at which efficacy assessments are 
conducted (see Section 4.4.1.2 for specific instructions). 
Patients who successfully complete the Tapering Phase will attend a Study Treatment 
Discontinuation visit at Week 24, and a Safety Follow-up Visit at Week 28 (see Appendix 
2). 


 
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Patients who are prematurely withdrawn from treatment during the 24-week Tapering 
Phase will attend a Study Treatment Discontinuation Visit, followed in 4 weeks by a 
Safety Monitoring Visit. These patients will be treated thereafter according to the 
investigator’s discretion and encouraged to attend the Week 24 Limited Assessment 
Visit (see Appendix 3). 
Patients who prematurely discontinue study medication will not be replaced. 
RA Flare Assessment and Treatment during the 24-week Double-blind Tapering Phase 
RA flare assessment and treatment must be conducted according to the 
instructions in Section 4.5.11. 
During the 24-week Tapering Phase, an RA flare may be detected at any scheduled or 
unscheduled visit, and is defined as: 
 
a current DAS28 ESR score > 3.2, and 
 
an increase in DAS28 ESR score > 0.6 from the randomization visit value. 
For a patient experiencing an RA flare, TCZ and study prednisone will continue to be 
dispensed as planned and the blind maintained.  The patient will also receive a 2-week 
course of RA flare rescue medication, consisting of 5 mg/day of Sponsor provided open-
label prednisone.  Dose increases to existing csDMARDs or addition of new csDMARDs 
or any other RA therapy is prohibited (as per Sections 4.4.1 and 4.4.2). 
Patients will need to be followed up with a Flare Assessment at the end of this 2-week 
course.  Patients will be determined to have either a resolved RA flare or a second RA 
flare, according to criteria defined in Section 4.5.11.  Patients will be withdrawn from 
the study treatment and followed up and treated as per Appendix 3 if RA flares do not 
resolve after treatment of the second RA flare. 
Safety Follow-up Phase 
Patients completing the 24-week Tapering Phase will undergo a Safety Follow-up Visit.  
This visit will occur 4 weeks after the completion of the Tapering Phase (i.e. at Week 28 
post-randomization).   
Post-study Treatment 
Management of patients completing the 24-week Tapering Phase, including treatment of 
any potential RA flares following completion of study treatment, will be according to local 
standard clinical practice at the discretion of the investigator. However to ensure the 
scientific integrity of the study and to maintain the blind until database lock, it is 
recommended that patients completing the 24-week Tapering Phase be treated with 
open-label 3 mg/day of prednisone and continue TCZ (SC or IV). Higher doses of 
prednisone, e.g. 5 mg/day may be required in patients who were receiving RA flare 
rescue medication at Week 24 post-randomization. 
The end of the trial is defined as the date of the last visit of the last participating patient 
in this study. Study unblinding will occur after data base lock, and patients will be 
subsequently informed as to their previously assigned treatment groups.  
A Schedule of Assessments is provided in Appendix 1, Appendix 2 and Appendix 3. 


 
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See Figure 4 for a graphical representation of the study design emphasizing the post-
randomization period applicable to all randomized patients from both tracks.  




 
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3.1.1 
Steering Committee  
The Steering Committee composed of Sponsor and external clinical representatives, will 
oversee the scientific validity and general conduct of the study as well as dissemination 
of the study results. Further details regarding the roles and responsibilities of the 
Steering Committee and its members are provided in the Steering Committee Charter. 
3.1.2 
Independent Data Monitoring Committee 
An iDMC will share responsibility for evaluating the safety of the patients participating in 
the trial at regular intervals throughout the study.  Efficacy data will only be provided if 
required by the iDMC to estimate risk-benefit for patients. 
The schedule of iDMC review will be determined by the iDMC and described in the iDMC 
Charter. Further details regarding the roles and responsibilities of the iDMC are provided 
in the iDMC Charter.   
3.2 
END OF STUDY 
The end of the trial is defined as the date of the last visit of the last participating patient 
in this study. This is expected to occur 28 weeks after the last patient has been 
randomized into the study. 
3.3 
RATIONALE FOR THE STUDY DESIGN 
This is a Phase IIIb/IV, two-arm, randomized, double-blind, placebo-controlled, parallel-
group, international, multicentre trial. As detailed in Section 1.4, given the potential 
redundancy in the anti-inflammatory effects of GCs and that of the humanized anti-IL 6 
receptor antibody TCZ, it is postulated that low-dose GCs do not contribute to the level 
of disease control achieved with TCZ to the same extent as observed during their co-
administration with TNF inhibitors. The current study was therefore designed to assess 
whether GCs can be successfully tapered, and eventually discontinued during treatment 
with TCZ, while maintaining LDA (DAS28 ESR score ≤ 3.2) state.  
The study will enrol both TCZ-experienced, and TCZ-naïve patients, who are inadequate 
responders to csDMARDs or bDMARDs. However, to allow for a comparable TCZ 
exposure before the prednisone tapering starts, patients with no prior exposure to TCZ 
will complete a 24 (or 28)-week Lead-in Phase, during which they will be treated with 
open label TCZ. Therefore patients will be entered and randomized into this study via 
two tracks; refer to Section 3.1 for details. To ensure adequate disease stability at a 
stable GC dose, criteria for randomization will include both a DAS28 ESR score ≤3.2 
and a stable dose of 5 mg/day of Sponsor-provided open-label prednisone for ≥4 weeks 
prior to, and at the randomization visit.  
To eliminate potential patient and physician bias, GC treatment will be tapered and 
discontinued in a double-blind manner, starting from a dose-level of 5 mg/day 
prednisone. This threshold was selected, because the potential contribution of GCs to 
disease control in patients who reached LDA state during treatment with TCZ is 
expected to diminish at or below the 5 mg/day prednisone dose. 


 
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The primary outcome measure is the change in disease activity (as assessed by DAS28 
ESR) from randomization to Week 24 post-randomization; a validated measure that is 
widely used in clinical trials involving RA patients; refer to Section 3.3.4 for details. 
3.3.1 
Rationale for the Study Drug Dose and Schedule 
3.3.1.1 
Tocilizumab 
A subcutaneous (SC) formulation of TCZ was developed to offer patients an additional 
option that may allow self-administration. The TCZ SC dose was selected based on 
pharmacokinetic/pharmacodynamics and limited efficacy and safety data from phase 1/2 
studies, as well as the results of the recently published SUMMACTA trial. In this 
randomized, double-blind, Phase III, non-inferiority clinical trial enrolling 1262 patients 
with moderately to severely active RA who did not respond to a DMARD, TCZ 162 mg 
SC QW was non-inferior to TCZ 8 mg/kg IV Q4W (both in combination with DMARDs), 
by producing a comparable ACR20 response (primary efficacy endpoint) at Week 24: 
69.4% (95% CI 65.5 to 73.2) versus 73.4% (95% CI 69.6 to 77.1), respectively 
(Burmester et al. 2014). 
3.3.1.2 
Prednisone 
The criteria for randomization include a stable dose of 5 mg/day of prednisone at 
randomization and for at least 4 weeks prior to randomization. This dose is reflective of 
the most commonly used initial dose of prednisone in RA (Pincus et al. 2015), as well as 
the dose used by more than half of patients enrolled in clinical trials of biological drugs 
(Spies et al. 2011; Buttgereit 2012). 
Randomized patients from both tracks will have been taking prednisone 5-15 mg/day (or 
GC equivalent) for at least 24 weeks prior to randomization. 
Patients randomized to the blinded prednisone mock taper arm will continue to receive 
prednisone 5 mg/day for 24 weeks. 
Patients randomized to the blinded prednisone taper arm will be tapered from 5 to 0 
mg/day according to a fixed schedule, in 1 mg/day decrements every four weeks. Given 
that current guidelines do not address the tapering schedule for GCs in patients with RA, 
the current study is expected to provide valuable data regarding the proposed monthly 
tapering schedule. 
3.3.2 
Rationale for Patient Population 
The selected study population comprises adults with at least 6-month history of RA 
diagnosed according to the ACR 1987 or ACR/EULAR 2010 criteria. The two-tier 
selection of study patients (TCZ-experienced patients enrolled via Track TCZ-
experienced patients and TCZ-naïve patients enrolled via Track TCZ-naïve patients) is 
introduced to allow patients with no prior exposure to TCZ to be enrolled, upon 
completion of a 24- (or 28)-week Lead-in TCZ treatment period. To evaluate whether 


 
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LDA can be maintained despite GC tapering during treatment with TCZ, patients will 
have to reach and maintain LDA during 4 weeks before they are randomized.  
3.3.3 
Rationale for Control Group 
Not applicable; in the current study a GC tapering schedule will be compared with no 
tapering. 
3.3.4 
Rationale for the Study Endpoints 
Several disease activity measures are currently available; of these, the 28-joint disease 
activity score (DAS28) and the ACR response criteria are the most commonly used, 
including as primary endpoints in registrational trials. The efficacy outcome measures 
used in the current study have been selected based on their clinical relevance in 
assessing disease activity status, clinical improvement, or patient-assessed changes in 
functional status or quality of life in patients with RA. Each of the selected outcomes 
have been validated and previously used in RA clinical trials. 
3.3.4.1 
28-Joint Disease Activity Score (DAS28) 
The Disease Activity Score (DAS) (Van der Heijde et al. 1990) and its modified version 
including 28 joint count (DAS28) (Prevoo et al. 1995) were developed to measure 
disease activity in patients with RA at a given time point.  
DAS28 has the following standardized cut-offs for disease activity and remission: 
 
DAS28 > 5.1 = high disease activity  
 
DAS28 between 3.2 and 5.1 = moderate disease activity 
 
DAS28 ≤ 3.2 = low disease activity 
 
DAS28 < 2.6 = remission 
A score of DAS28 > 3.2 is an indication of disease active enough to reinforce treatment 
dosage or to switch the DMARD (Pincus et al. 2006; Fransen et al. 2004; Mäkinen et al. 
2005). 
The DAS28 is a validated clinical index of multiple measures, including a formal 28-joint 
count, an acute phase reactant measure [either erythrocyte sedimentation rate (ESR) or 
C-reactive protein (CRP)], and a patient global assessment of disease activity (Prevoo et 
al. 1995). In the current study ESR will be used as acute phase reactant for determining 
the DAS28 ESR. 
3.3.4.2 
CDAI and SDAI 
The CDAI is a clinical assessment tool derived from the DAS28 and has high correlation 
to DAS28 scores (Smolen et al. 2003; Aletaha et al. 2005; Aletaha and Smolen, 2005). 
However, compared to DAS28, the CDAI is simpler to use and easier to calculate. The 
CDAI includes 28-joint counts (tender and swollen), patient and physician global 
assessment of disease activity, but does not require a blood test for evaluation of an 
acute phase reactant; therefore, complete results can be obtained and used to drive 


 
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treatment decisions at the same time as the patient’s visit. The maximum total score for 
CDAI is 76.  
The SDAI is the numerical sum of five outcome parameters: tender and swollen joint 
count (based on a 28-joint assessment), patient and physician global assessment of 
disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive protein 
(mg/dl, normal <1 mg/dl). The SDAI was validated on a total of 1,839 patients from three 
Phase 3 trials, and was found to correlate with a high level of statistical significance to 
the DAS 28 and HAQ scores. In addition, patients achieving the ACR 20, 50, 70 or 90% 
response showed proportionate changes in the SDAI (Smolen et al. 2003). 
3.3.4.3 
ACR Core Set and Response Criteria 
The American College of Rheumatology (ACR) Committee chose a core set of variables 
to be included in all RA clinical trials, by taking into account the sensitivity to change, the 
desire to eliminate redundant measures and attempting to select outcome measures that 
represented the breadth of RA manifestations. The ACR Core Set includes 7 disease 
activity measures: tender joint count [TJC], swollen joint count [SJC], patient’s 
assessment of pain, patient’s global assessment of disease activity, physician’s 
assessment of physical function, patient’s assessment of physical function, and an 
acute-phase reactant value  (high  sensitivity  C-reactive protein [hsCRP] or ESR). In 
addition, for DMARD trial durations of 1 year or longer, radiography or other imaging 
technique is performed (Felson et al. 1993; Boer et al. 1994; Felson and LaValley, 2014).  
The ACR definition of improvement in RA is a composite measure that can be used to 
categorize a patient as “improved” or “not improved” at one point in time compared with 
baseline. The ACR 20% improvement definition is based on 7 components and requires 
≥ 20% improvement in both the TJC and the SJC and ≥ 20% improvement in ≥ 3 of the 5 
secondary criteria: patient’s global assessment of disease activity, physician’s global 
assessment of disease activity, pain, physical function, and levels of an acute-phase 
reactant (Felson et al. 1995). The ACR 20% definition of improvement is considered the 
most widely used outcome measure in RA clinical trials (Felson and LaValley, 2014) and 
has been accepted by the US FDA as evidence of clinical efficacy of investigational 
antirheumatic drugs (FDA 1999).  
3.3.4.4 
HAQ-DI 
The disability section of the Stanford Health Assessment Questionnaire (HAQ-DI) is the 
most frequently used questionnaire worldwide to assess functional disability in RA 
patients. This measure of self-perceived disability contains 20 questions in eight 
categories and includes an additional section about aid from other people and devices 
needed to correct the disabilities recorded in the 20 questions, if applicable (Fries et al. 
1982). Scores range from 0 to 3, with higher scores indicating worse disability. A 
decrease of at least 0.22 in the HAQ-DI is considered the threshold for clinically 
meaningful improvement. 


 
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3.3.4.5 
Rheumatoid Arthritis Impact of Disease (RAID) Questionnaire 
Apart from patient-reported outcomes traditionally evaluated during the current standard 
assessment of RA (e.g. patient assessment of pain, functional disability and/or patient 
global assessment), other health domains are also important for the patient such as 
fatigue, wellbeing and sleep pattern. The Rheumatoid Arthritis Impact of Disease (RAID) 
score, a patient-reported composite index, was developed and validated under the 
umbrella of the EULAR (Gossec et al. 2009; Gossec et al. 2011; Heiberg et al. 2011; 
Boers 2011). The RAID comprises 7 domains (pain, function, fatigue, sleep, emotional 
well-being, physical well-being, and coping/self-efficacy), and evaluates the impact of RA 
on patient quality of life. Each of the 7 domains is evaluated as continuous variables on 
an 11-point Numerical rating scale (NRS), from 0 (best) to 10 (worst).  
The range of the final RAID value is 0-10 where higher figures indicate worse status. A 
change of at least 3 points (absolute) or 50% (relative) in the RAID score is considered a 
minimum clinically important improvement, and a maximal value of 2 defines an 
acceptable status (Dougados et al. 2012). 
3.3.4.6 
Work Productivity and Activity Impairment Questionnaire: 
Rheumatoid Arthritis (WPAI:RA) 
The WPAI:RA is a 6-item questionnaire evaluating the effect of rheumatoid arthritis on 
the patient’s ability to work and perform regular activities. The construct validity of a 
quantitative work productivity and activity impairment (WPAI) measure of health 
outcomes was tested for use in clinical trials, along with its reproducibility. All measures 
of work productivity and activity impairment were positively correlated with measures 
which had proven construct validity. Overall work productivity (health and symptom) was 
significantly related to general health perceptions and the global measures of 
interference with regular activity (Reilly et al. 1993).  
3.3.5 
Rationale for Biomarker Assessments  
Rheumatoid arthritis is characterized by autoimmune-mediated attack of the joint 
synovial lining resulting in destruction of bone and cartilage, and is a clinically and 
biologically heterogeneous disease with respect to its course, response to therapy, and 
outcome (McInnes and Schett, 2011; Nam et al. 2014).  Over the past years, significant 
progress has been made in the identification of biomarkers associated with response to 
biological DMARDs (Townsend, 2014). In particular, Dennis et al. demonstrated that 
response to TCZ was improved in patients with a “lymphoid” phenotype characterized by 
high levels of serum C-X-C motif chemokine 13 (CXCL13), and low levels of serum 
soluble intercellular adhesion molecule 1 (sICAM-1). They also showed that response to 
anti-TNF treatment was improved in RA patients with a “myeloid” phenotype 
characterised by high levels of sICAM-1 and low levels of CXCL13 (Dennis et al. 2014).    
Beside dynamic biomarkers (i.e. non-inherited biomarkers), response to TCZ in RA has 
been associated with genetic makeup of the patients (i.e. inherited biomarkers) (Wang et 
al. 2013).    
Based on this data, we intend to assess whether dynamic (non-inherited) biomarkers are 
predictive of response to TCZ and/or glucocorticoids (i.e., predictive biomarkers), 


 
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susceptibility to developing adverse events, or progression to a more severe disease 
state (i.e., prognostic biomarkers), can provide evidence of TCZ activity, or can increase 
the knowledge and understanding of disease biology.  In addition, in the subset of 
patients who consent to DNA sampling, we will explore the possible association of 
inherited biomarkers with response to TCZ and/or glucocorticoids. 
 
3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
 Change in DAS28 ESR between randomization and Week 24 post-randomization.   
The key secondary efficacy outcome measure for this study is as follows: 
 
The proportion of patients with LDA (DAS28 ESR score ≤ 3.2) at Week 24 post-
randomization, who have not suffered a flare due to RA and who showed no 
confirmed adrenal insufficiency that required replacement therapy. 
Other secondary efficacy outcome measures for this study are as follows: 
 Change in CDAI / SDAI between randomization and Week 24 post-randomization.  
The CDAI is composite score based on tender and swollen joint count, and the 
patient’s and physician’s assessment of global status. The SDAI includes the 
components of CDAI as well as CRP.  
 The proportion or patients with ≥ 1 RA flare, the time to first RA flare and the 
number of RA flares. 
 The proportion of patients with ≥ 1 administration of RA flare rescue medication, the 
time to first administration, and the number of administrations of RA flare rescue 
medication. 
 Cumulative prednisone exposure (dose) between randomization and Week 24 post-
randomization. 
 The proportion of patients who maintain LDA (DAS28 ESR score ≤ 3.2) and the 
proportion of patients who maintain the baseline disease activity level at Week 24 
post-randomization. 
 The proportion of patients who permanently discontinue study treatment due to 
insufficient RA flare control. 
 Changes in the ACR core set from randomization to post-randomization Week 24, 
including: swollen and tender joint counts; patient’s assessment of pain and global 
status; physician’s assessment of global status; HAQ-DI; and acute phase reactants 
(hsCRP and ESR). 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 


 
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 Nature, frequency and severity of adverse events (graded according to CTCAE v4.0) 
including non-serious and serious adverse events, and adverse events of special 
interest. 
 Changes in vital signs, physical findings, and clinical laboratory results during and 
following TCZ administration. 
 Assessment of immunogenicity: Immunogenicity sampling will be "event-driven"; for 
patients who experience a hypersensitivity reaction (including anaphylaxis), 
additional samples will be taken and tested for anti-TCZ antibodies, plasma TCZ 
levels (PK) and sIL-6R (PD) at time of event and 8 weeks after the event, as part of 
the standard immunogenicity sampling protocol. No immunogenicity sampling is 
required in case of injection site reactions. 
 Proportion of patients with confirmed adrenal insufficiency that required replacement 
therapy. 
3.4.3 
Patient-Reported Outcome Measures 
In addition to the patient-reported components of the ACR core set and of other 
composite disease activity measures, the PRO outcome measures for this study include 
the following where translations are available: 
 RAID score (measured at enrolment (Track TCZ-naïve patients only), randomization 
and at Week 24 post-randomization). 
 HAQ-DI score (assessed at baseline, randomization and at Week 24 post-
randomization). 
 WPAI:RA score (assessed at enrolment (Track TCZ-naïve patients only), 
randomization and at Week 24 post-randomization). 
3.4.4 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 In a subset of the study population, levels of bone turnover biomarkers at relevant 
time points. The following bone turnover biomarkers will be tested: (i) Pro-collagen 
serum type I N-terminal propeptide (PINP), a marker of bone formation; and (ii) 
Serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), a marker of 
cathepsin K-mediated bone collagen degradation believed to reflect systemic bone 
resorption.  
 Measure of non-inherited biomarkers associated with RA biology and TCZ biology 
may include: serum C-X-C ligand 13 (CXCL13, also known as B cell–attracting 
chemokine 1), soluble intercellular adhesion molecule-1 (sICAM-1), serum matrix 
metalloproteinase-3 (MMP-3); and peripheral blood gene expression signatures for 
interferon (IFN)-induced genes and Plasmablast-associated genes. 
 
Change in the modified Homeostasis Model Assessment (HOMA1) from the 
beginning to the end of the Lead-in Phase (Track TCZ-naïve patients only) . 


 
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 Change in HOMA1 from randomization to the end of the study (Week 24; both 
tracks). 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
There are two target populations for this study: 
Track TCZ-experienced patients: Patients with a DAS28 ESR score ≤ 3.2 who are 
currently receiving TCZ (SC or IV) and  5 mg/day of prednisone (or GC equivalent). 
Eligibility criteria are evaluated during Screening, which starts up to 6 weeks prior to 
randomization. 
Track TCZ-naïve patients: Patients with moderate to severe active RA with an 
inadequate response to current csDMARD or bDMARD therapy and who require current 
treatment with 5 to 15 mg/day of prednisone (or GC equivalent). Eligibility criteria are 
evaluated during Screening, which starts up to 4 weeks prior to enrolment in the Lead-in 
Phase. Following treatment with TCZ and glucocorticoid taper (if clinically feasible) 
during the 24-Week Lead-Phase, these patients are eligible for randomization if they 
maintain a DAS28 ESR score ≤ 3.2 and stable prednisone 5 mg/day for at least 4 weeks 
prior to randomization.  
4.1.1 
Management of Enrolment to Achieve the Randomization 
Target 
Study entry is possible via two tracks, Track TCZ-experienced patients, and Track TCZ-
naïve patients. It is currently estimated that about 95% of patients from Track TCZ-
experienced patients and about 50% of patients from Track TCZ-naïve patients will be 
eligible for randomization.  
To mitigate potential over enrolment for the required randomization target, the actual vs 
estimated number of randomized patients will be closely monitored and adjustments to 
the ratios of the above formula may be made. A potential measure to avoid unnecessary 
prolongation of the study in case of slower than planned randomization would be to 
close enrolment of Track TCZ-naïve patients, and complete the remainder of the study 
by enrolling Track TCZ-experienced patients only. Conversely, if the enrolment of Track 
TCZ-experienced patients is as fast as or faster than that of Track TCZ-naïve patients, 
then fewer patients will be enrolled to achieve the randomization target. 
4.1.2 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Track TCZ-experienced patients (study entry is enrolment following randomization): 
1. Able and willing to give written informed consent and comply with the requirements 
of the study protocol (including treatment on an outpatient basis). 
2. Age ≥ 18 years. 


 
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3. RA of ≥ 6 months duration diagnosed according to the revised 1987 American 
College of Rheumatology (ACR, formerly the American Rheumatism Association) 
criteria or 2010 ACR / EULAR criteria. 
4. Have received TCZ either SC (162 mg QW) or IV (8 mg/kg Q4W, not exceeding 800 
mg/dose) for the treatment of RA for at least 24 weeks prior to randomization. 
5. Have received 5 - 15 mg/day of prednisone (or GC equivalent) for the treatment of 
RA for at least 20 weeks prior to screening. 
6. Currently receiving 5 mg/day of oral prednisone (or GC equivalent) at the Screening 
Visit. 
7. Have a DAS28 ESR score ≤3.2 assessed 4 to 6 weeks prior to randomization 
(assessed at the Screening Visit or a visit prior to the Screening Visit). 
Track TCZ-naïve patients (study entry is enrolment into the Lead-in phase): 
1. Able and willing to give written informed consent and comply with the requirements 
of the study protocol (including treatment on an outpatient basis). 
2. Age ≥ 18 years. 
3. RA of ≥ 6 months duration diagnosed according to the revised 1987 ACR criteria or 
2010 ACR / EULAR criteria. 
4. Have active RA (defined as DAS28 ESR score > 3.2). 
5. Are considered by the investigator as inadequate responders to csDMARDs or 
bDMARDs. Are TCZ treatment naïve or last TCZ treatment was > 12 months prior to 
screening and TCZ was not discontinued due to lack of efficacy, side effects, or any 
other safety reasons. 
6. Are receiving 5 - 15 mg/day prednisone (or GC equivalent) for the treatment of RA. 
4.1.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
General 
1. Major surgery (including joint surgery) within 8 weeks prior to screening, or planned 
major surgery during the study and up to 6 months after randomization. 
2. Pregnant women or nursing (breastfeeding) mothers. 
3. In females of childbearing potential, a positive serum pregnancy test at screening. 
4. Females of childbearing potential unwilling or unable to use a reliable means of 
contraception (e.g., physical barrier [patient or partner], contraceptive pill or patch, 
spermicide and barrier, or intrauterine device) during study treatment and for a 
minimum of 3 months after the last dose of TCZ.  
5. Body weight of ≥ 150 kg. 
6. Lack of peripheral venous access. 
Disease-related 
7. RA of functional class IV, as defined by the ACR Classification of Functional Status 
in Rheumatoid Arthritis (see Appendix 7). 


 
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8. Rheumatic autoimmune disease other than RA, including systemic lupus 
erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or 
significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, 
or Felty syndrome).  Secondary Sjögren syndrome with RA may be allowed per the 
discretion of the investigator. 
9. Diagnosed with juvenile idiopathic arthritis or juvenile RA and/or RA before the age 
of 16 years. 
10. Prior or current inflammatory joint disease other than RA (e.g., gout, Lyme disease, 
sero-negative spondyloarthropathy, including reactive arthritis, psoriatic arthritis, 
arthropathy of inflammatory bowel disease), or prior or current joint infections. 
11. Previous history of primary or secondary adrenal insufficiency. 
Previous or Concomitant Prohibited Therapy 
12. Treatment with any investigational agent (tocilizumab excepted) within 4 weeks (or 
5 half-lives of the investigational drug, whichever is longer) of screening.  Treatment 
with csDMARDs, other DMARDS, and/or biologics for RA which is permanently 
discontinued within 5 half-lives prior to randomization. 
13. Previous treatment with any cell-depleting therapies, including investigational agents 
or approved therapies (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, 
anti-CD20). 
14. Treatment with IV gamma globulin, plasmapheresis or Prosorba column within 
6 months of screening. 
15. Intraarticular (IA) or parenteral GCs within 6 weeks prior to randomization (within 12 
weeks  for intra-articular triamcinolone). 
16. Previous treatment with oral or parenteral GCs for conditions other than RA, at any 
dose used continuously for > 1 week, during the last 1 year prior to screening.  
Current treatment with topical GC exceeding 20% of body surface area. 
17. Immunization with a live/attenuated vaccine within 30 days prior to screening. 
Patients must agree not to take live attenuated vaccines (including seasonal nasal flu 
vaccine, varicella vaccine for shingles or chickenpox, vaccines for measles, mumps 
or rubella without or with varicella [MMR or MMRV], oral polio vaccine and vaccines 
for yellow fever), within 30 days before the Screening Visit, throughout the duration 
of the trial and for 60 days following the last dose of study drug. 
18. Any previous treatment with alkylating agents such as chlorambucil or with total 
lymphoid irradiation. 
Laboratory Exclusion Criteria 
19. Inadequate haematological function indicated by any of the following: 
 
White blood cells (WBCs) < 3.0 x 109/L (3,000/mm3). 
 
Platelet count < 100 x 109/L (100,000/mm3). 
 
Haemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L). 
 
Absolute neutrophil count (ANC) < 2.0 x 109/L (2,000/mm3). 
 
Absolute lymphocyte count < 0.5 x 109/L (500/mm3). 


 
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20. Inadequate renal function indicated by serum creatinine > 1.4 mg/dL (> 124 µmol/L) 
in female patients and > 1.6 mg/dL (> 141 µmol/L) in male patients. 
21. Inadequate liver function indicated by any of the following: 
 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times 
the upper limit of normal (ULN). 
 
Total bilirubin > ULN. 
22. Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCV Ab). 
Previous or Concomitant Conditions 
23. History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies. 
24. Evidence of current serious uncontrolled cardiovascular (including uncontrolled 
hyperlipidemia), nervous system, pulmonary (including obstructive pulmonary 
disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or 
gastrointestinal (GI) disease. 
25. Current liver disease as determined by the investigator. 
26. History of diverticulitis, peptic ulcer disease, diverticulosis requiring antibiotic 
treatment, or chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative 
colitis, or other symptomatic lower GI conditions that might predispose to 
perforations. 
27. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or 
other opportunistic infections (including, but not limited to, tuberculosis [TB] and 
atypical 
mycobacterial 
disease, 
hepatitis 
B 
and 
C, 
Epstein-Barr 
virus, 
cytomegalovirus and herpes zoster, but excluding fungal infections of nail beds) on 
the day of enrolment.  Track TCZ-experienced patients are exempt if they have an 
active mild infection which does not warrant a treatment interruption as per protocol 
Section 5.1.1.2 or local standard of care. 
28. Neuropathies and/or other conditions that might interfere with pain evaluation (e.g. 
fibromyalgia) and/or are typically treated with systemic GCs unless related to primary 
disease under investigation. 
29. Any major episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to 
screening  
30. Active TB requiring treatment within the previous 3 years (patients previously treated 
for TB with no recurrence within 3 years are permitted). Patients failing to complete 
the TB evaluation (as per Appendix 9) by the end of screening are excluded. 
31. History of or currently active, primary or secondary immunodeficiency. 
32. Evidence of active malignant disease, malignancies diagnosed within the previous 
10 years (including haematological malignancies and solid tumours, except basal 
and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that 
was excised and cured), or breast cancer diagnosed within the previous 20 years. 
33. History of alcohol, drug or chemical abuse within 1 year prior to screening. 
34. Pre-existing central nervous system (CNS) demyelination or seizure disorders. 


 
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35. Any medical or psychological condition that in the opinion of the principal investigator 
would interfere with safe completion of the trial. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Randomization will be centralized and performed by means of an IxRS. Prior to entering 
the 24-week Tapering Phase, patients will be randomly assigned (1:1) to one of two 
treatment groups, either continuing 5 mg/day of prednisone or tapering prednisone in a 
double-blinded fashion.   
Randomization will be stratified by the following factors: 
 
Baseline DAS28 ESR (< 2 / ≥ 2) 
 
Country/Region 
 
Concomitant DMARD treatment (monotherapy / combination therapy) 
 
Weight (< 60 kg, ≥ 60 kg – 100 kg, ≥ 100 kg) 
The patient, investigator and study-related staff, the Sponsor and study monitors will be 
blinded to treatment assignment. 
The study prednisone (active drug or placebo) will be provided as over-encapsulated 
tablets so that the active drug and placebo are undistinguishable in terms of appearance, 
smell and taste. See Section 4.3.1.2 for prednisone wallet distribution. 
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS. Treatment codes should not be broken except in emergency situations. If the 
investigator wishes to know the identity of the study prednisone for any other reason, he 
or she should contact the Medical Monitor directly. The investigator should document 
and provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event). Patients who are unblinded will remain in the 
study and will continue to receive study treatment unless otherwise contraindicated.  
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (see Section 5.7) that are considered by the investigator or Sponsor to be 
related to study prednisone. 
 
4.3 
STUDY TREATMENT  
The Sponsor provides all Investigational Medicinal Products (IMPs).  The Sponsor does 
not provide non-IMP, with the exception of open-label prednisone (5 mg dose only). 
The IMPs to be used in this study are as follows: 
 
Test Product: open label TCZ (SC and IV) 


 
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 
Test Product: (blinded) Prednisone 
 
Comparator: (blinded) Placebo to prednisone 
Non-investigational medicinal products (non-IMPs) to be used in this study are as 
follows: 
 
Permitted therapy (Section 4.4.1)  
 
Open label Prednisone or GC during the Screening Period, Lead-in Phase, or 
Tapering Phase (including open label prednisone as RA flare rescue medication). 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Tocilizumab  
Tocilizumab (SC and IV) will be supplied by the Sponsor throughout the Lead-in Phase 
(Track TCZ-naïve patients only), and throughout the Tapering Phase for both tracks.   
Tocilizumab SC will be supplied in a 1-mL ready-to-use, single use pre-filled syringe with 
needle safety device.  Each syringe delivers 162 mg (0.9 mL) of TCZ SC.  
Tocilizumab IV will be supplied in vials (type I glass) with a stopper (butyl rubber) 
containing 10 ml concentrate for solution for infusion (sterile concentrate). Each ml of the 
concentrate contains 20 mg TCZ.  
Tocilizumab (SC and IV) must be stored at 2 – 8 ºC (do not freeze) and protected from 
light. Details of the packaging and labelling of the TCZ are provided in the protocol-
supporting documents.  
For 
information 
on 
the 
formulation 
and 
handling 
of 
TCZ, 
see 
the 
Tocilizumab Investigator's Brochure and local prescribing information (as applicable). 
4.3.1.2 
Prednisone  
Open-label prednisone tablets will be: 
 
offered during the 4 weeks preceding randomization for patients in both tracks  
 
provided for the treatment of any RA flare following randomization (during the 
24-week Tapering Phase).  
Prednisone tablets should be stored at temperatures below 25°C (77°F) in the original 
packaging in order to protect from light and humidity. 
Blinded study prednisone capsules will consist of active prednisone ± placebo, and 
will be provided throughout the Tapering Phase in pre-packaged patient-identified 
wallets. 
Prednisone capsules should be stored at room temperature below 30°C (86°F), and 
protected from moisture (Prednisone Prescribing Information, 2012). For information on 
handling prednisone, refer to the local prescribing information. 


 
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Patients who have been randomized to 5 mg/day of prednisone will receive 4 capsules 
of study prednisone every day, consisting of one 5 mg capsule and 3 placebo capsules 
(see Figure 5). 
 
Figure 5: 
Daily Prednisone Doses for patients continuing 5 mg/day of prednisone 
 
 
 
 
 
 
 
 
 
 
 
 
Patients randomized to tapered prednisone will have their active study prednisone 
replaced by an increasing amount of placebo capsules over the course of treatment (see 
Figure 6).  
Figure 6: 
Daily Prednisone Doses for patients on tapering prednisone 
 
 
 
 
 
 
 
 
 
 
 
 
D1 D2 D3 D4 D5 D6 D7 - D168 
Prednisone 5 mg capsule 
Placebo capsule 
Prednisone 1 mg capsule 
Placebo capsule 
4 mg 
3 mg 
2 mg 
1 mg 
0 mg 
Week 
1-4 
Week 
5-8 
Week 
9-12 
Week 
13-16 
Week 
17-24 


 
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Additional details of the packaging and labelling of study prednisone are provided in the 
protocol-supporting documents. For information on the formulation and handling of 
prednisone, please refer to the local prescribing information 
 
 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Tocilizumab  
The administration of TCZ is described according to study periods below. 
 
Screening and Randomization: Track TCZ-experienced patients 
This track consists of patients who are currently receiving TCZ (162 mg QW SC or 8 
mg/kg Q4W IV, not exceeding 800 mg/dose). Patients must have received TCZ for at 
least 24 weeks prior to randomization. Patients receiving TCZ IV will have the option to 
be switched to TCZ SC (at the investigator’s discretion) at the Randomization Visit, and 
this visit should coincide with the date of the next scheduled TCZ dose (or up to 4 days 
after the dose was due). TCZ SC initiation should be performed as per TCZ 
Administration instructions below. 
 
Lead-in Phase and Randomization: Track TCZ-naïve patients 
This track consists of patients who have not received any prior treatment with TCZ. 
Patients will enter a 24-week Lead-in Phase, during which time they will receive open-
label TCZ SC at a dose of 162 mg QW or open-label TCZ IV at a dose of 8 mg/kg Q4W, 
not exceeding 800 mg/dose. The choice between TCZ SC or TCZ IV will be made by the 
investigator, depending on the local availability and individual patient acceptance and 
tolerability of the SC formulation. (Patients eligible for a 4-week extension of the Lead-in 
Phase, as per Section 3.1, will receive 28 weeks of open-label TCZ). 
Patients transitioning from a previous bDMARD to TCZ (SC or IV) should receive their 
first TCZ dose at Lead-in Visit 1, and this visit should coincide with the date of the next 
scheduled administration of the previous bDMARD (or up to 7 days after the dose was 
due). Administration of TCZ (SC or IV) should be performed as per TCZ Administration 
instructions below. 
 
24-week Tapering Phase: All randomized patients 
During the 24-week Tapering Phase, randomized patients will receive open-label TCZ 
SC (162 mg QW) or TCZ IV (8 mg/kg Q4W, not exceeding 800 mg/dose). 
 
Post-study Treatment 
Management of patients completing the 24-week Tapering Phase will be according to 
local clinical practice at the discretion of the investigator. However, to ensure the 
scientific integrity of the study and to maintain the blind until database lock, it is 
recommended that patients completing the 24-week Tapering Phase continue treatment 
with TCZ (SC or IV) in addition to open-label prednisone to maintain disease control 
status. 


 
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TCZ Administration Instructions (Lead-in Phase and Tapering Phase) 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Any overdose or incorrect administration of TCZ should be noted on the Drug 
Administration electronic Case Report Form (eCRF).  Adverse events associated with an 
overdose or incorrect administration of TCZ should be recorded on the Adverse Event 
eCRF.   
TCZ SC Administration: 
TCZ SC will be administered at the dose of 162 mg QW.  
For SC TCZ use, the investigator should assess suitability of the patient for SC home 
use and instruct patients to inform a health care professional if they experience 
symptoms of allergic reaction before administering the next dose. Patients should seek 
immediate medical attention if developing symptoms of serious allergic reactions. 
During the Lead-in Phase and Tapering Phase, TCZ SC injections are given 
subcutaneously using a pre-filled syringe with a needle safety device. The 
recommended injection sites are in the front of the middle part of the thigh and the lower 
part of the abdomen below the navel (belly button), except for the 2 inch area directly 
around the navel.  If a caregiver is giving the injection, the outer area of the upper arms 
could also be used.  Injections are not to be administered to areas where the skin is not 
intact or is tender, bruised, red or hard. 
The first-time ever injection of TCZ SC (initiation of TCZ SC) should be performed under 
the supervision of a qualified healthcare professional, and as per requirements for 
administration described in the local TCZ product information / package insert (if TCZ 
SC approved locally). Furthermore, patients and their caregivers should be trained to 
perform the TCZ SC injections at this visit.  Once the patient or the patient’s caregiver 
have demonstrated competence to administer the injection correctly, TCZ SC injections 
can be administered by the patient or the patient’s caregiver at the site or at the patient’s 
home.  If a patient is unable or does not wish to administer TCZ SC at home, clinic staff 
can perform injections during a physician or clinic visit or at the patient’s home. 
Tocilizumab SC injections should be given on the same day every week whenever 
possible.  If the weekly schedule cannot be met for any reason, injections can be given ≤ 
2 days prior to the scheduled day, or ≤ 4 days after the scheduled day. 
TCZ IV Administration: 
TCZ IV will be administered at the recommended dose of 8 mg/kg body weight Q4W, not 
exceeding 800 mg/dose. TCZ IV infusions should be given within ± 4 days of the 
scheduled treatment day. 
The medicinal product should be diluted to a final volume of 100 ml with sterile, non-
pyrogenic sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic technique; 
refer to the local TCZ product information / package insert for details. After dilution, TCZ 
should be administered as an IV infusion over 1 hour. 


 
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All TCZ IV infusions will be administered at the clinical site, by a qualified healthcare 
professional, and as per requirements for administration described in the local TCZ 
product information / package insert. 
4.3.2.2 
Prednisone and other Systemic Glucocorticoids 
The administration of prednisone and other systemic glucocorticoids (GC) is described 
according to study periods below. A suggested glucocorticoid equivalence table is 
provided in Appendix 12. 
 
Screening: Track TCZ-experienced patients 
Prednisone or GC administered during Screening is non-IMP. 
Patients are switched to Sponsor-provided open-label 5 mg/day prednisone at the 
Screening Visit and for the duration of the screening period, after signing informed 
consent, and only if they are currently on oral prednisone 5 mg/day or GC equivalent.  
Patients not on prednisone 5 mg/day (or GC equivalent) will have failed screening.    
 
Screening and Lead-in Phase: Track TCZ-naïve patients 
Prednisone or GC administered during the Screening or Lead-in phase is non-IMP. 
Eligible patients must be receiving 5 to 15 mg of prednisone (or GC equivalent) per day 
at screening.  Patients will enter a 24-week Lead-in Phase, during which time they will 
continue their open-label prednisone (or GC equivalent). During the Lead-in Phase, the 
dose of prednisone will be tapered down to 5 mg/day (if clinically feasible) according to a 
scheme determined by the investigator. All patients who are not on prednisone 5 mg/day 
(or GC equivalent) at Lead-in Week 20 are discontinued from the study.   
 
Patients on 5 mg/day of prednisone (or GC equivalent) and with a DAS28 ESR 
score ≤ 3.2 at Lead-in Week 20 must be switched to Sponsor-provided open-label 5 
mg/day prednisone for the remainder of the Lead-in period (until Lead-in Week 24 / 
Randomization Visit).  
 
Patients who are on 5 mg/day of prednisone (or GC equivalent) and with a DAS28 
ESR score > 3.2 at Lead-in Week 20 are discontinued from the study unless they 
have improved considerably (DAS28 ESR score < 4.4 and a change in DAS28 ESR 
score ≥1.2 compared to baseline).  Considerably improved patients may continue in 
the Lead-in Phase and are re-assessed at Lead-in Week 24.  If these patients are 
on 5 mg/day of prednisone (or GC equivalent) and have a DAS28 ESR score ≤ 3.2 
at Lead-in Week 24, they must be switched to Sponsor provided open-label 5 
mg/day prednisone for the remainder of the Lead-in period (until Lead-in Week 28 / 
Randomization Visit). 
 
24-week Tapering Phase: All randomized patients: Study Prednisone 
Study prednisone (defined as active prednisone ± placebo) is IMP. 
Track TCZ-experienced and Track TCZ-naïve patients will be randomly assigned (1:1) to 
one of two treatment groups, to either continue or taper prednisone in a double-blinded 
fashion.   


 
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Patients randomized to tapered prednisone will receive 4 over-encapsulated tablets 
throughout the 24 weeks of Tapering Phase, consisting of a tapering dose of study 
prednisone, starting with 4 mg/day, with decrements of 1 mg every 4 weeks. Patients will 
have their study prednisone replaced with increasing amounts of placebo over the 
course of the Tapering Phase. 
Patients randomized to continuing prednisone will receive 5 mg/day of study prednisone 
as 4 over-encapsulated tablets throughout the 24 weeks of Tapering Phase. 
Study prednisone should be taken in the morning. 
 
24-week Tapering Phase: All randomized patients: RA Flare Rescue 
Prednisone 
Prednisone administered as a RA flare rescue medication is non-IMP. 
Patients experiencing an RA flare during the 24-week Tapering Phase must be treated 
with Sponsor provided Flare Rescue Prednisone according to Section 4.5.11. 
(Note: patients experiencing an RA flare during the Lead-in Phase are treated as per 
local practice). 
 
All Study Phases: Non-Sponsor Systemic Glucocorticoid Administration 
Non-Sponsor systemic GC (i.e. oral prednisone and other systemic GC compounds and 
formulations not provided by the Sponsor) administration is highly restricted: 
o All Patients: Use of intra-articular or parenteral GCs within 6 weeks prior to 
randomization (within 12 weeks prior to randomization for intra-articular 
triamcinolone) will disqualify the patient from randomization (as per: Exclusion 
Criteria Section 4.1.3).   
o Track TCZ-naïve patients: Non-Sponsor systemic GC (any route of 
administration) for any purpose (including RA) must not be used after 4 weeks 
prior to randomization and throughout the 24-week double-blind Tapering 
Phase.  Only Sponsor-provided Study prednisone or RA flare rescue 
prednisone (see above) may be used; see Randomization Criteria (Section 
4.5.10). 
o Track TCZ-experienced patients: Non-Sponsor systemic GC (any route of 
administration) for any purpose (including RA) must not be used after signed 
informed consent and throughout the 24-week double-blind Tapering Phase.  
Only Sponsor-provided Study prednisone or RA flare rescue prednisone (see 
above) may be used. 
Short-term non-Sponsor systemic GC is permitted after randomization when deemed 
necessary for treatment or prevention of serious illness, in particular serious infections 
and adrenal insufficiency or adrenal crisis (see: Recommendations for Management of 
Adrenal Insufficiency Appendix 11).  This administration will be made according to the 
medical judgment of the investigator, and should be documented in the eCRFs.  
Treatment should be stopped as soon as clinically safe.   


 
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Patients receiving any form of non-Sponsor systemic GC after randomization will be 
assessed by the Steering Committee to determine inclusion of these patients in the final 
per-protocol analysis, on a case by case basis.  
 
Post-study Treatment 
Management of patients completing the 24-week Tapering Phase, including treatment of 
any potential RA flares following completion of study treatment, will be according to local 
clinical practice at the discretion of the investigator. However, to ensure the scientific 
integrity of the study and to maintain the blind until database lock, it is recommended 
that patients completing the 24-week Tapering Phase be treated with open-label 
3 mg/day of prednisone (and continue TCZ SC or IV) to maintain disease control status. 
Higher doses of GC, e.g. 5 mg/day of prednisone (or GC equivalent) may be required in 
patients who were receiving RA flare rescue medication at Week 24 post-randomization.  
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Patients will be required to document intake of the study medication in their daily diaries. 
Any overdose or incorrect administration of prednisone or study prednisone should be 
noted on the Drug Administration eCRF.  Adverse events associated with an overdose 
or incorrect administration of prednisone or study prednisone should be recorded on the 
Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (TCZ SC, TCZ IV, and study prednisone) 
will be provided by the Sponsor. The study site will acknowledge receipt of IMPs using 
the IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. The Drug Inventory Log 
will also be verified against the IMP administrations entered by the patients in their daily 
diaries.  


 
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4.3.4 
Post-Trial Access to Tocilizumab SC or IV 
Currently, the Sponsor does not have any plans to provide TCZ or any other study 
treatments or interventions to patients who have completed the study. For patients 
receiving TCZ SC during the Tapering Phase: the Sponsor will not continue to provide 
the TCZ SC formulation as patients will either revert to the TCZ IV formulation if the SC 
formulation is not yet available, or continue with the SC formulation if it is commercially 
marketed in their country. 
The Sponsor will evaluate whether to continue providing TCZ in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, available 
at the following Web site: 
http://www.roche.com/policy continued access to investigational medicines.pdf 
 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Treatments considered necessary for the patient’s benefit and not categorized as 
prohibited 
therapy 
are 
permitted. 
Important 
restrictions, 
prohibitions, 
or 
recommendations apply for several frequently administered therapies (see Section 
4.4.1.1 through Section 4.4.1.7). 
4.4.1.1 
Open-label csDMARDs 
Patients receiving stable doses of csDMARDs prior to the initial Screening Visit (Track 
TCZ-experienced patients), at the Lead-in Week 20 Visit (Track TCZ-naïve patients on 
track for randomization at Lead-in Week 24), and at the extension Lead-in Week 24 
(Track TCZ-naïve patients ineligible for randomization at Lead-in Week 24 but granted a 
4 week Lead extension), should continue this treatment(s) going forward. Permitted 
csDMARDs are: hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine. 
Dose increases or new csDMARD initiation is prohibited after the aforementioned 
visits. Dose should be stable for at least 4 weeks prior to randomization, dose 
reductions or discontinuation may only be performed for safety reasons, and these 
changes must be documented in the eCRF. 
Any overdose or incorrect administration of csDMARDs should be noted on the Drug 
Administration eCRF. Adverse events associated with an overdose or incorrect 
administration of csDMARDs should be recorded on the Adverse Event eCRF. 
4.4.1.2 
Analgesics and Anti-inflammatories 
(This section does not apply to glucocorticoids, see Section 4.4.1.6 below.) 
Medications with analgesic and anti-inflammatory properties are permitted, as per 
clinical practice.  These medications include NSAIDs, acetaminophen, opioids, and 
some other classes (e.g. anti-depressants, anti-convulsants).  


 
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Patients may be taking these medications as stable doses over the longer term.  There 
is no additional guidance for these patients.   
Alternatively, patients may be taking these medications sporadically or occasionally – 
these are often prescribed “as needed.” For patients receiving occasional doses, if 
clinically feasible and safe, investigators should encourage patients to withhold these 
medications 12-24 hours prior to a visit where clinical efficacy assessments are 
performed and recorded (with the exception of the initial Screening Visit, since the 
patient informed consent is not yet signed). 
4.4.1.3 
Proton Pump Inhibitors 
Oral corticosteroids and NSAIDs are permitted during the study. Based on the current 
clinical evidence, it is generally recognized that the use of glucocorticoids and/or 
NSAIDs is associated with GI ulceration that may potentially lead to gastric perforation. 
Therefore, investigators should consider whether patients who receive glucocorticoids 
and/or NSAIDs should also receive prophylactic treatment with proton pump inhibitors 
(PPI) at a recommended dose or H2-receptor blockers at a maximum recommended 
dose. 
4.4.1.4 
Glucocorticoid-Induced Osteopenia/Osteoporosis Therapy 
Patients should receive oral calcium and 25-hydroxy vitamin D supplementation unless 
contraindicated (calcium 1200−1500 mg and vitamin D 800–1000 IU daily in divided 
doses). Unless contraindicated, bisphosphonate therapy (e.g., alendronate 70 mg 
weekly or zolendronate 4 mg annually) will also be administered at the discretion of the 
investigator for the prevention of glucocorticoid-induced osteoporosis. Participants with 
documented osteoporosis will be treated with approved drugs for osteoporosis according 
to local practice or clinical guidelines. 
4.4.1.5 
Lipid-lowering Therapy 
Use of lipid-lowering agents in patients with elevated lipids is strongly encouraged at any 
time during the study in conjunction with the investigator’s clinical judgment and 
guidelines, such as those described in the third report from the National Cholesterol 
Education Program Adult Treatment Panel III (2002). 
4.4.1.6 
Open-label Systemic Glucocorticoids 
Significant restrictions and prohibitions are listed in Section 4.3.2.2. 
4.4.1.7 
Drug Interactions Guidance for Permitted Therapy 
The expression of hepatic CYP450 enzymes is suppressed by pro-inflammatory 
cytokines such as IL-6. Thus, it is expected that for any drug with a potent anti-cytokine 
inhibition such as TCZ, CYP450 suppression may be reversed when introduced in 
patients with rheumatoid arthritis. Investigators are advised that patients who are taking 
drugs which are individually adjusted and are metabolized via CYP3A4, CYP1A2, 
CYP2B6, CYP2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, 
phenprocoumon, phenytoin, cyclosporine, or benzodiazepines) should be monitored 


 
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during the first 2 weeks following start of TCZ treatment, and an increase in dose of 
these drugs may be necessary to maintain therapeutic effect. After cessation of TCZ 
treatment, patients should be monitored over 8 weeks to determine whether dose 
reduction may be needed (see Tocilizumab Investigator’s Brochure for more details). For 
drugs metabolized by CYP2D6 and CYP2C19, no dose adjustment is anticipated. 
The investigator should consult the prescribing information for any concomitant 
medication 
as 
well 
as 
the 
Internet 
references 
provided 
(http://medicine.iupui.edu/clinpharm/ddis/table.aspx).  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding medications. 
4.4.2 
Prohibited Therapy 
Treatment with the following medications or medication classes is prohibited. 
 
Therapies with washout periods and other prohibitions listed in the exclusion 
criteria (see Section 4.1.3) are prohibited during the Lead-in Phase (Track TCZ-
naïve) and the Tapering Phase (both tracks). 
 
Initiation of a new csDMARD during the 4 weeks prior to randomization  (See 
Section 4.4.1.1) 
 
Immunomodulating and immunosuppressant therapies with known efficacy in RA, 
and which are not expressly permitted, from the time of the initial Screening Visit 
or 4 weeks prior to randomization (whichever is longer). Permitted RA therapies 
are hydroxychloroquine, leflunomide, methotrexate, sulfasalazine, and TCZ.  
Prohibited therapies include (but are not limited to):  
o Abatacept 
o Azathioprine 
o Cyclosporine 
o Gold 
o Tofacitinib 
o TNF-inhibitor biologics 
o Rituximab 
 
Significant restrictions and prohibitions regarding the use of systemic GCs are 
listed in Section 4.3.2.2. 
 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 (Screening and Lead-in Phase), Appendix 2 (24 Week Tapering 
Phase) and Appendix 3 (Early Treatment Discontinuations) for the Schedule of 
Assessments performed during the study. 


 
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4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.   
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before entering the study.  The investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure, as applicable. Patients may be re‑screened or re-tested depending 
on the inclusion/exclusion criteria they fail and upon authorization by the Sponsor. 
An Eligibility Screening Form documenting the investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
In addition, the randomization criteria (see Section 4.5.10) must be completed and 
reviewed to confirm that patients meet all randomization criteria before being 
randomized.  The investigator will maintain a log to record details of all patients entered 
into the study but not randomized, recording the reasons why patients were not 
randomized, if applicable. 
4.5.2 
Demographic Data and Medical History 
Medical history includes clinically significant diseases, surgeries, RA history (including 
prior therapies and procedures), reproductive status, smoking history, use of alcohol and 
drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 4 
weeks prior to the screening visit. NSAIDs will be recorded at screening as the average 
dose taken over the past 12 weeks. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems. Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF. During the study, changes from baseline abnormalities should be recorded in 
patient notes. New or worsened clinically significant abnormalities should be recorded as 
adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs, Height, Weight and Body Mass Index 
Vital signs will include measurements of temperature, respiratory rate, pulse rate, and 
systolic and diastolic blood pressures while the patient is in a seated position. 
In addition, the patient’s height (screening only) and body weight (screening and Week 
24) will be measured, and body mass index (BMI) calculated. 


 
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4.5.5 
Concomitant Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
the Screening Visit through to the Safety Follow-up Visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.  
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
All laboratory, biomarker, and other biological samples are described below.  The 
definitive schedule for obtaining these samples is the Table of Assessments, see 
Appendix 1, Appendix 2 and Appendix 3.  The Central Laboratory Services Manual 
 provides specific technical instructions for collection, processing, storage 
and shipment of each type of sample.   
Mandatory Laboratory tests conducted by the Site or Local Laboratory: 
 
Erythrocyte sedimentation rate (ESR) is performed at the site by the Westergren 
method and using kits provided by the central laboratory. 
 
Pregnancy test.  All women who are not post-menopausal (≥ 12 months of non-
therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test 
at screening (Beta HCG) (Central Laboratory).  Urine pregnancy tests will be 
performed at specified subsequent visits, and are conducted at the site using kits 
provided by the Central Laboratory.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test (Central Laboratory). 
 
The patient may need confirmatory liver function testing in the event of an elevated 
liver function test finding which may lead to study drug discontinuation, as described 
in Section 4.6.2 and Section 5.1.1.7. The first sample should be sent to the local 
laboratory to facilitate rapid clinical decision making.  Another sample (collected at 
the same time as the first sample) should be sent to the Central laboratory. 
 
Tuberculosis: Interferon gamma release assay (IGRA) (Central Laboratory) and/or 
the tuberculin skin test [TST] (conducted at the site) for tuberculosis; as per local 
practice and instructions in Appendix 9.  
Mandatory Laboratory tests sent to and conducted by the Central Laboratory: 
Fasting is mandatory: 
 Fasting lipid panel (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-
density lipoprotein [HDL] cholesterol, triglycerides) 
 Fasting C-peptide (serum) 
 Fasting glucose (plasma) 
 Fasting HbA1c (whole blood) 
Patients will need to arrive for these tests in the fasted state. Patient should fast for 12 
hours prior to the test.  The patient may drink only water.  Tea, coffee, diet drinks, or 
other beverages are not allowed.  The patient should not smoke, chew gum, or exercise 


 
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during this time.  Study medications are allowed only if scheduled.  Other medications 
are allowed or prohibited during fasting as per investigator judgment.  
Fasting not required: 
 Rheumatoid factor (e.g latex test), anti-cyclic citrullinated peptide (anti-CCP) 
antibody 
 High sensitivity C-reactive protein (hsCRP) 
 HbSAg, HCV Ab (For Track TCZ-experienced patients, HbSAg and HCV Ab will 
only be tested in case of clinical suspicion based on history or clinical evidence of 
exposure.) 
 Tuberculosis: IGRA (Central Laboratory) and/or the TST (conducted at site) for 
tuberculosis; as per local practice and instructions in Appendix 9.  
 Haematology (white blood cell count, red blood cell count, haemoglobin, 
haematocrit, platelet count, differential count [neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells]) 
 Blood chemistry (sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen [BUN] or urea, creatinine, total protein, albumin, phosphorus, calcium, total 
and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, lactate 
dehydrogenase [LDH]).   
 25-OH Vitamin D 
 Urinalysis by “dipstick” method (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, red blood cells [RBCs], WBCs, casts, 
crystals, epithelial cells, bacteria). 
 Pregnancy test.  All women who are not post-menopausal (≥ 12 months of non-
therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test 
at screening (Beta HCG) (Central Laboratory).  Urine pregnancy tests will be 
performed at specified subsequent visits, and are conducted at the site using kits 
provided by the Central Laboratory.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test (Central Laboratory). 
 Biomarker assessment, including bone turnover markers (PINP, CTX-I). 
 Immunogenicity sampling is conducted for all patients during screening. For patients 
who experience a hypersensitivity reaction (including anaphylaxis) additional 
samples will be taken and tested for anti-TCZ antibodies, plasma TCZ levels (PK) 
and sIL-6R (PD) at time of event and 8 weeks after the event, as part of the 
standard immunogenicity sampling protocol. Blood samples will be sent to a Roche-
approved designated laboratory for analysis of anti-TCZ antibodies, TCZ, IL-6 and 
sIL-6R concentration determination. See the Central Laboratory Services Manual 
(
 for detailed instructions. 
 RNA: whole blood samples for RNA extraction will be used for the analysis of gene 
expression including but not limited to gene signatures related to response to TCZ 
and to glucocorticoid. 


 
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 Protein biomarkers: serum samples will be used for the analysis of protein 
biomarkers including but not limited to CXCL13, sICAM-1, and MMP3. 
 Serum cortisol may be measured after the last patient completes the study from 
stored leftover samples (if any) obtained for the other tests in this section. 
Optional Laboratory tests sent to and conducted by the Central Laboratory: 
The following tests are collected for the Research Biosample Repository (RBR) only if 
the patient has provided additional and separate consent and if other conditions are met, 
as detailed in Section 4.5.12: 
 DNA: Whole blood for DNA extraction (genetic sampling). 
4.5.7 
Homeostasis Model Assessment 
Homeostatic model assessment (HOMA) is a method for assessing β-cell function and 
insulin resistance (IR) from basal (fasting) glucose and insulin or C-peptide 
concentrations (Matthews et al. 1985). The model has been widely used and validated 
since it was first published in 1985. It’s validation included comparisons with a number of 
well-validated methods used to measure IR and β-cell function (Herman et al. 1999; 
Wallace et al. 2004).  
Fasting C-peptide, a robust measure of insulin secretion, can substitute insulin in the 
HOMA model to assess IR (Wallace et al. 2004). In the current study, HOMA1 will be 
assessed using C-peptide as a measure of insulin secretion, at Lead-in Visit 1 (Track 
TCZ-naïve patients only), randomization and Week 24 (both tracks). 
4.5.8 
Evaluations of Rheumatoid Arthritis 
This section lists the efficacy assessments which must be performed by the investigator.  
Assessments not performed by the investigator but required for analysis of outcomes are 
described at the end of this section. 
4.5.8.1 
Swollen Joint Count and Tender Joint Count  
Joints will be assessed and classified as swollen/not swollen and tender/not tender by 
pressure and joint manipulation on physical examination (see Appendix 8). To ensure 
consistent joint evaluation throughout the study, individual patients should be evaluated 
by the same efficacy assessor for all study visits.  
Joint prosthesis, arthrodesis or fused joints will not be taken into consideration for 
swelling or tenderness. 
For clarification of how to assess joints which have undergone a procedure 
please see below: 
 Surgery – joints which have been replaced or fused at any time prior to or at any time 
during the study should be documented as not evaluable (NE) for the duration of the 
study. Any joints which have undergone synovectomy at any time prior to or at any 
time during the study (including chemical and radiological synovectomy) should be 
documented as NE for the duration of the study. 


 
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 
IA injection – Any joint which has received a steroid IA should be documented as not 
done (ND) for the following 12 weeks. After this time the joint may be assessed again. 
 Arthrocentesis – Any joint which has fluid drained (and no steroid injected) will not be 
assessed at the next scheduled visit and will be graded as not done. After this time 
the joint may be assessed again. 
4.5.8.2 
Physician’s Global Assessment of Disease Activity VAS  
The overall assessment of current disease activity will be made on a 100 mm horizontal 
VAS (see Appendix 10).  
4.5.8.3 
DAS28 ESR 
The DAS28 ESR is a combined index for measuring disease activity in RA. The DAS28 
ESR scale ranges from 0 to 10, where higher scores represent higher disease 
activity.  
The investigator will calculate the DAS28 ESR using the following formula: 
DAS28 ESR = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × ln(ESR)) + (0.014 × GH) 
Where,  
 
TJC = tender joint count on 28 joints (Appendix 8) 
 
SJC = swollen joint count on 28 joints (Appendix 8) 
 
ln = natural log 
 
ESR = erythrocyte sedimentation rate (mm/hr) (Section 4.5.6)  
 
GH = general health, i.e., patient’s global assessment of disease activity 
(100-mm VAS) (Section 4.5.9 and Appendix 10). 
4.5.8.4 
Morning Stiffness 
Morning stiffness will be collected at the visits defined in the schedule of assessments.  
The investigator will answer the following question in the eCRF:  
 
Does the patient's morning stiffness due to rheumatoid arthritis last longer than 
15 minutes? 
4.5.8.5 
Assessments not conducted at the site 
The following assessments of RA are calculated and/or assessed during the analysis of 
outcomes based on the assessments and laboratory data collected during the study. 
 
American College of Rheumatology (ACR) Core Set and Response Criteria (see 
Section 3.3.4.3) 
 
Clinical Disease Activity Index (CDAI) (see Section 3.3.4.2) 
 
Simplified Clinical Disease Activity Index (SDAI) (see Section 3.3.4.2). 


 
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4.5.9 
Patient-Reported Outcomes 
Patient-reported outcomes (PRO) data will be collected via questionnaires to more fully 
characterize the patient’s course of treatment. The questionnaires will be translated as 
required in the local language. To ensure instrument validity and that data standards 
meet health authority requirements, questionnaires scheduled for administration during a 
clinic visit should be completed prior to the performance of all efficacy assessments and 
the administration of study treatment. 
4.5.9.1 
Health Assessment Questionnaire - Disability Index (HAQ-DI) 
The Stanford Health Assessment Questionnaire - Disability Index is a patient- 
completed questionnaire specific for RA. It consists of 20 questions referring to 8 
component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and 
activities (Appendix 4). 
4.5.9.2 
Rheumatoid Arthritis Impact of Disease (RAID) Questionnaire 
The RAID is a patient-completed questionnaire specific for RA consisting of a 1-10 
rating for pain, functional disability, fatigue, sleep, physical well-being, emotional well-
being and coping.  Scores are weighted to produce a final numerical result (see 
Appendix 5).  
4.5.9.3 
Work Productivity and Activity Impairment Questionnaire: 
Rheumatoid Arthritis V2.0 or V2.1 (WPAI:RA) 
The WPAI:RA is a patient-completed questionnaire.  It consists of 6 questions to assess 
work productivity and activity impairment (see English US V2.0 in Appendix 6).  
Translations are available at: http://www.reillyassociates.net/WPAI_Translations-2.html. 
V2.1 should be used instead of V2.0 if available in local language.   
4.5.9.4 
Patient’s Global Assessment of Disease Activity VAS  
The overall assessment of current disease activity will be made on a 100 mm horizontal 
VAS (see Appendix 10). 
4.5.10 
Randomization Criteria 
Upon completion of the Screening Phase (Track TCZ-experienced patients) or the Lead-
in Phase (Track TCZ-naïve patients), patients are eligible to be randomized for the study 
if they meet all of the following randomization criteria: 
Track TCZ-experienced Patients Randomization Criteria 
a) Fulfils all inclusion and none of the exclusion criteria; 
b) Screening Visit occurred up to to 6 weeks prior to randomization; 
 
c) DAS28 ESR score ≤ 3.2 at randomization; 
d) Receiving prednisone 5 mg/day, and no other oral GC, at randomization and for 
≥ 4 weeks prior to randomization; 


 
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e) Received no intra-articular or parenteral GCs within 6 weeks prior to 
randomization (within 12 weeks prior to randomization for intra-articular 
triamcinolone). 
Track TCZ-naïve Patients Randomization Criteria  
a) DAS28 ESR score ≤ 3.2 at most recent scheduled Lead-in Visit 4 weeks prior to 
randomization; 
b) DAS28 ESR score ≤ 3.2 at randomization; 
c) Receiving prednisone 5 mg/day, and no other oral GC, at randomization and for 
≥ 4 weeks prior to randomization; 
d) Received no intra-articular or parenteral GCs within 6 weeks prior to 
randomization (within 12 weeks prior to randomization for intra-articular 
triamcinolone). 
4.5.11 
RA Flare Assessment  and Treatment (24 Week Tapering Phase) 
For patients experiencing an RA flare (detected during a scheduled or unscheduled visit), 
defined as an increase in DAS28 ESR > 0.6 from the randomization visit value and a 
current DAS28 ESR > 3.2, TCZ and study prednisone will continue to be dispensed as 
planned and the blind maintained.   
In addition, patients will receive a 2-week course of RA flare rescue medication, 
consisting of 5 mg of open-label prednisone daily.  The patient will be asked to come for 
a Flare Assessment Visit at the end of this 2-week course.   
If the patient’s RA is still active (DAS28 ESR > 3.2) at this visit, this will be considered to 
be a second RA flare and a second 2-week course of RA flare rescue medication should 
be initiated, consisting of 5 mg of open-label prednisone daily.   
At the end of this second 2-week course, the patient will be re-assessed at another Flare 
Assessment Visit. If the patient’s RA is still active (DAS28 ESR > 3.2) at this visit, the 
patient will attend a Study Treatment Discontinuation Visit, followed in 4 weeks by a 
Safety Monitoring Visit. Note that if the end of either 2-week course of RA flare rescue 
medication coincides with a standard planned study visit, a separate Flare Assessment 
Visit does not need to be completed. These patients will be subsequently treated 
according to local clinical practice at the discretion of the investigator and encouraged to 
attend a Limited Week 24 Assessment Visit, at 24 weeks post-randomization (see 
Appendix 3). 
The investigator may opt to not treat DAS28-ESR elevation formally meeting the RA 
flare criteria in the exceptional circumstance that the elevation is not due to RA flare (e.g. 
prominent ESR elevation due to acute infection and not due to RA). In this case, the 
investigator must enter an associated adverse event in the eCRF. 


 
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4.5.12 
Samples for Research Biosample Repository 
4.5.12.1 
Overview of the Research Biosample Repository 
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research. RBR specimens will be used to achieve the 
following objectives: 
 To study the association of biomarkers with efficacy, adverse events, or disease 
worsening 
 To increase knowledge and understanding of disease biology 
 To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays. 
 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.12) will not be 
applicable at that site. 
4.5.12.3 
Sample Collection 
The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers related to TCZ mode of action, IL-6 
biology, GC biology, RA biology, or biology of related diseases: 
 
Residual serum 
 
Residual whole blood for RNA extraction. 
The following samples will be collected for research purposes, including but not limited 
to research on genetic (inherited) biomarkers related to TCZ mode of action, IL-6 biology, 
GC biology, RA biology, or biology of related diseases: 


 
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 
Whole blood for DNA extraction (genetic sampling). In the current study, collection 
of whole blood for DNA extraction will be optional, i.e. it will be performed in a 
subset of the study population. 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RBR page of the eCRF. For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.   
RBR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database. The RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 4.5.12.4 and Section 8.4.  The genetic biomarker specimens will 
undergo additional processes to ensure confidentiality, as described below.   
4.5.12.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RBR specimens and associated data.  Upon receipt 
by the RBR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number. Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labelled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RBR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RBR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 


 
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4.5.12.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the RBRResearch Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.12.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason. If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF. The patient will be 
provided with instructions on how to withdraw consent after the trial is closed. A patient's 
withdrawal from Study MA29585 does not, by itself, constitute withdrawal of specimens 
from the RBR.  Likewise, a patient's withdrawal from the RBR does not constitute 
withdrawal from Study MA29585. 
4.5.12.7 
Monitoring and Oversight 
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 Patient withdrawal of consent at any time 


 
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 Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study  
 Investigator or Sponsor determines it is in the best interest of the patient 
 
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study after randomization will not 
be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
 Pregnancy 
 Anaphylaxis or serious hypersensitivity (Immunogenicity testing required, see 
Section 4.5.6)  
 Gastrointestinal perforation 
 Persistent increases in ALT and/or AST > 3 x ULN, confirmed by repeat testing (see 
Section 5.1.1.7) (repeat testing sample may be sent to a local laboratory to facilitate 
rapid medical decision making) 
 First occurrence of ALT and/or AST elevation > 5 x ULN, after value confirmed by 
repeat testing (see Section 5.1.1.7) (repeat testing sample may be sent to a local 
laboratory to facilitate rapid medical decision making) 
 Criteria meeting the definition of Hy’s Law: ALT or AST elevation > 3 x ULN and 
total bilirubin elevation > 2 x ULN without initial findings of cholestasis (such as 
elevated alkaline phosphatase) 
 ANC < 0.5  x 109/L 
 Platelet count < 50 x 103/μL 
 Malignancies (except local basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix uteri that have been excised and cured) 
 Central demyelinating event 
 Two consecutive RA disease flares post-randomization not responding to treatment 
as described in Section 4.5.11. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.   
Any patient who permanently and prematurely discontinues IMP (TCZ or study 
prednisone) during the Lead-in or Tapering Phase will attend a Study Treatment 
Discontinuation Visit, followed in 4 weeks by a Safety Monitoring Visit. Randomized 
patients are encouraged to attend a Limited Assessment Week 24 Visit, at 24 weeks 
post-randomization. These visits and waivers to these visits are detailed in Appendix 3.  


 
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Any patient who prematurely discontinues study medication will be subsequently treated 
according to local clinical practice at the discretion of the investigator.  
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 Patient enrolment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 Excessively slow recruitment 
 Poor protocol adherence 
 Inaccurate or incomplete data recording 
 Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 No study activity (i.e., all patients have completed and all obligations have been 
fulfilled). 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Adherence to the planned study drug dose regimen is required unless an adjustment is 
necessary for safety reasons. The following sections provide an overview of the main 
risks and precautions associate with the use of the study drugs, including risk mitigation 
and dose modification rules, where applicable. 
5.1.1 
Precautions Related to Treatment with Tocilizumab 
5.1.1.1 
Hypersensitivity reactions 
Serious hypersensitivity reactions have been reported in association with infusion of TCZ. 
Such reactions may be more severe, and potentially fatal in patients who have 
experienced hypersensitivity reactions during previous infusions even if they have 
received premedication with steroids and antihistamines. For IV TCZ use, appropriate 
treatment should be available for immediate use in the event of an anaphylactic reaction 
during the IV administration of TCZ. For SC TCZ use, suitability of the patient for SC 
home use should be assessed and patients should be instructed to inform a health care 
professional if they experience symptoms of allergic reaction before administering the 
next dose. Patients should seek immediate medical attention if developing symptoms of 


 
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serious allergic reactions. If an anaphylactic reaction or other serious hypersensitivity 
reaction occurs, administration of TCZ should be stopped immediately and TCZ should 
be permanently discontinued. 
5.1.1.2 
Infection and Serious Infections 
Serious and sometimes fatal infections have been reported in patients receiving 
immunosuppressive agents including TCZ. Tocilizumab treatment must not be initiated 
in patients with active infections. Administration of TCZ should be interrupted if a patient 
develops a serious infection until the infection is controlled. Healthcare professionals 
should exercise caution when considering the use of TCZ in patients with a history of 
recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes 
and interstitial lung disease which may predispose patients to infections. 
5.1.1.3 
Tuberculosis 
As recommended for other biological treatments, RA patients should be screened for 
latent TB infection prior to starting TCZ therapy. Patients with latent TB should be 
treated with standard anti-mycobacterial therapy before initiating TCZ. Patients should 
be instructed to report if signs/symptoms (e.g., persistent cough, wasting/weight loss, 
low grade fever) suggestive of a TB infection occur during or after therapy with TCZ. See 
Appendix 9 for details. 
5.1.1.4 
Gastrointestinal Perforation 
Events of diverticular perforations as complications of diverticulitis have been reported 
uncommonly with TCZ in RA patients. Patients presenting with symptoms potentially 
indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or 
unexplained change in bowel habits with fever should be evaluated promptly for early 
identification of diverticulitis which can be associated with gastrointestinal perforation. 
5.1.1.5 
Demyelinating Disorders 
The potential for central demyelination with TCZ is currently unknown. Patients should 
be closely monitored for signs and symptoms potentially indicative of central 
demyelinating disorders. Physicians should exercise caution in considering the use of 
the study medications in patients with pre-existing or recent onset demyelinating 
disorders. Treatment with the study medications should be interrupted during 
assessment of a potential demyelination event and only resumed if the benefit of 
continuing study drug is favourable. 
5.1.1.6 
Viral Reactivation 
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. 
5.1.1.7 
Active Hepatic Disease, Hepatic Impairment, Hepatic 
transaminase elevations 
Treatment with TCZ, particularly when administered concomitantly with MTX, may be 
associated with elevations in hepatic transaminases. In RA patients, ALT and AST levels 


 
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should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by 
every 12 weeks thereafter. For ALT or AST elevations > 3–5 x ULN, confirmed by repeat 
testing, TCZ treatment should be interrupted. For recommended modifications based on 
transaminases see Table 2. 
Table 2: 
Treatment Modifications in Case of Elevations in ALT & AST 
ALT and/or AST 
Action 
> 1* to 3 x ULN 
Dose-modify concomitant DMARDs if appropriate. 
TCZ SC: 
 
For persistent increases in this range, reduce TCZ dose frequency to 
every other week injection or interrupt TCZ until ALT or AST have 
normalised. 
 
Restart with weekly or every other week injection, as clinically 
appropriate. 
TCZ IV: 
 
For persistent increases in this range, reduce TCZ dose to 4 mg/kg or 
interrupt TCZ until ALT or AST have normalised. 
 
Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate. 
> 3 to 5 x ULN 
Interrupt TCZ dosing until < 3 x ULN and follow recommendations above 
for > 1 to 3 x ULN. 
For persistent increases > 3 x ULN (confirmed by repeat testing), 
discontinue TCZ. 
> 5 x ULN 
Confirm value by repeat testing. 
Discontinue TCZ. 
> 3 x ULN and Other 
Criteria** (Hy’s Law) 
Discontinue TCZ. 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; TCZ: tocilizumab; ULN: upper limit of 
normal 
* ULN or patient’s baseline, whichever is higher. 
** Other criteria: total bilirubin elevation > 2 x ULN without initial finding of cholestasis (such as elevated 
alkaline phosphatase. 
Patients withdrawn from the study due to elevated liver function tests must have repeat 
tests performed, as clinically appropriate, until levels return to baseline. If the patient’s 
liver function tests have not returned to baseline within 6 months (or sooner, if deemed 
necessary by the investigator), an ultrasound and/or liver biopsy should be considered. 
If a liver biopsy is performed for any reason, the biopsy report should be forwarded to 
Roche and the prepared histologic slides will be requested by Roche and centrally 
reviewed by a third party. 
5.1.1.8 
Haematological Abnormalities 
Decreases in neutrophil and platelet counts have occurred following treatment with TCZ 
8 mg/kg in combination with MTX. There may be an increased risk of neutropenia in 
patients who have previously been treated with a TNF antagonist. Severe neutropenia 
may be associated with an increased risk of serious infections. For recommended dose 
modifications based on ANC, see Table 3. 


 
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Table 3: 
Treatment Modifications in Case of Decreases in Neutrophil Count 
ANC (cells x 109/L) 
Action to Be Taken 
> 1 
Maintain dose 
0.5 – 1 
Interrupt TCZ dosing. 
TCZ SC: 
 
When ANC increases > 1 x 109/L, resume TCZ dosing every other 
week and increase to every week injection, as clinically appropriate. 
TCZ IV: 
 
When ANC increases > 1 x 109/L, resume TCZ at 4 mg/kg and 
increase to 8 mg/kg, as clinically appropriate. 
< 0.5 
Discontinue TCZ 
 ANC: absolute neutrophil count; TCZ: tocilizumab 
Patients withdrawn from the study due to a reduced neutrophil count must be followed 
closely for signs of infection, with treatment as deemed appropriate by the investigator, 
and must have a repeat WBC count with differential performed weekly until the ANC is 
above 1.0 x 109/L (1000 cells/mm³). If the ANC does not return to above 1.0 x 109/L 
(1000 cells/mm³) within 2 months (or sooner if deemed necessary by the investigator), a 
haematology referral is recommended. 
For recommended dose modifications based on platelet counts, see Table 4. 
Table 4: 
Treatment Modifications in Case of Decreases in Platelet Count 
Platelet count (cells 
x 103/μl) 
Action to Be Taken 
> 100 
Maintain dose 
50 – 100 
Interrupt TCZ dosing. 
TCZ SC: 
 
When platelet count increases > 100 x 103/μL, resume TCZ dosing 
every other week and increase to every week injection, as clinically 
appropriate.  
TCZ IV: 
 
When platelet count increases > 100 x 103/μL, resume TCZ at 4 
mg/kg and increase to 8 mg/kg, as clinically appropriate.  
< 50 
Discontinue TCZ 
 
Patients withdrawn from the study due to a reduced platelet count must repeat platelets 
weekly until the count is above 100 x 103/μL (100,000 cells/mm³). If the platelets do not 
return to above 100 x 103/μL (100,000 cells/mm³) within 2 months (or sooner if deemed 
necessary by the investigator), a haematology referral is recommended. 
5.1.1.9 
Elevated Lipid Parameters 
Elevations in lipid parameters including total cholesterol, LDL cholesterol, HDL 
cholesterol, and triglycerides were observed in patients treated with TCZ. In the majority 
of patients, there was no increase in atherogenic indices, and elevations in total 


 
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cholesterol responded to treatment with lipid lowering agents. Patients should be 
managed according to local clinical guidelines for management of hyperlipidaemia. 
5.1.1.10 
Other Potential Risks 
The risk of malignancy is increased in patients with RA, and immunomodulatory 
medicinal products may increase the risk of malignancy. 
Live and live attenuated vaccines should not be given concurrently with TCZ, as clinical 
safety has not been established. 
5.1.2 
Precautions Related to Glucocorticoid Use 
Rare instances of anaphylactoid reactions have occurred in patients receiving GC 
therapy.  
Cardio-Renal:  
GCs can cause elevation of blood pressure, salt and water retention, increased 
excretion of potassium, and increased calcium excretion. Literature reports also suggest 
an apparent association between use of GCs and left ventricular free wall rupture after a 
recent myocardial infarction. 
Endocrine: 
GCs can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with 
the potential for corticosteroid insufficiency after withdrawal of treatment, which may 
persist for up to 12 months after discontinuation of therapy.  
Metabolic clearance of corticosteroids is decreased in hypothyroid patients and 
increased in hyperthyroid patients. 
Infections: 
Prednisone is contraindicated in systemic fungal infections. 
Patients who are on GCs are more susceptible to infections than are healthy individuals. 
Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any 
location of the body may be associated with the use of GCs alone or in combination with 
other immunosuppressive agents that affect cellular immunity, humoral immunity, or 
neutrophil function. These infections may be mild, but may be severe and at times fatal. 
With increasing doses of GCs, the rate of occurrence of infectious complications 
increases. GCs may also mask some signs of current infection. 
If GCs are indicated in patients with latent tuberculosis or tuberculin reactivity, close 
observation is necessary as reactivation of the disease may occur. Chickenpox and 
measles can have a more serious or even fatal course in patients on GCs. 
Vaccines: 
Administration of live or live, attenuated vaccines is contraindicated in patients receiving 
immunosuppressive doses of GCs. Killed or inactivated vaccines may be administered. 
However, the response to such vaccines may be diminished and cannot be predicted. 
Ophthalmic: 


 
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Use of GCs may produce posterior subcapsular cataracts, glaucoma with possible 
damage to the optic nerves, and may enhance the establishment of secondary ocular 
infections due to bacteria, fungi or viruses. 
For further details regarding the warnings and precautions related to GC use, refer to the 
local prescribing information. 
5.1.3 
Management of Specific Adverse Events 
Guidelines for management of specific laboratory abnormalities are outlined in Table 2, 
Table 3 and Table 4.   
5.1.3.1 
Management of Adrenal Insufficiency 
As noted in Section 5.1.2, GCs can produce reversible HPA axis suppression with the 
potential for adrenal insufficiency after the beginning of glucocorticoids tapering which 
may persist for up to 12 months.  Patients will be informed about this risk, and should be 
educated on reporting symptoms suggestive of adrenal insufficiency. 
Management of potential adrenal insufficiency in study patients will be at the 
investigator’s discretion. In case of a clinical suspicion of adrenal insufficiency, a short 
ACTH stimulation test may be performed, preferably before initiation of replacement 
treatment. Recommendations for the management of adrenal insufficiency are provided 
in Appendix 11, however their use is optional.  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 Any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 


 
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 Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies). 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 Is fatal (i.e., the adverse event actually causes or leads to death) 
 Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
 This does not include any adverse event that had it occurred in a more severe form 
or was allowed to continue might have caused death. 
 Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
 Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 


 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest (AESI) are required to be reported by the investigator 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions). Any non-serious event in a tocilizumab AESI 
category that the investigator judges to be of special interest with regard to the benefit-
risk or safety profile for tocilizumab, should be identified by the investigator as a 
tocilizumab AESI. Adverse events of special interest categories for this study include the 
following: 
 Serious and/or medically significant infections, including all opportunistic infections 
and non-serious infections as defined by those treated with IV anti-infectives 
 Suspected transmission of an infectious agent by TCZ, as defined below: 
- Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 Myocardial infarction / acute coronary syndrome 
 Gastrointestinal perforations, including related fistulae and related intra-abdominal 
abscesses 
 Malignancies 
 Anaphylaxis / hypersensitivity reactions 
 Demyelinating disorders 
 Stroke, including transient ischemic attack events 
 Serious and/or medically significant bleeding events requiring transfusion, or 
bleeding with hospital visit for evaluation (including emergency department or 
outpatient clinic) 
 Serious and/or medically significant hepatic events, including: 
- events with a hepatic clinical diagnosis 
- hepatic abnormality resulting in permanent discontinuation of TCZ 
- cases of potential drug-induced liver injury, including cases meeting the 
definition of Hy’s Law as per Section 4.6.2, and repeated here: 
o ALT or AST elevation > 3 x ULN and total bilirubin elevation > 2 x ULN 
without initial findings of cholestasis (such as elevated alkaline 
phosphatase). 


 
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5.2.4 
Selected Adverse Events   
Not applicable. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and in the Adverse Event eCRF page. 
After informed consent has been obtained but prior to the initiation of treatment 
(Track TCZ-experienced patients – prior to the initiation of treatment in the Tapering 
Phase; Track TCZ-naïve patients – prior to the initiation of treatment in the Lead-in 
Phase), only serious adverse events caused by a protocol-mandated intervention (e.g., 
invasive procedures such as biopsies, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events). 
After the initiation of treatment (Track TCZ-experienced patients – after the initiation 
of treatment in the Tapering Phase; Track TCZ-naïve patients – after the initiation of 
treatment in the Lead-in Phase), all adverse events will be reported until 4 weeks after 
the last dose of TCZ / study prednisone.  After this period, the investigator should report 
any serious adverse events that are believed to be related to prior study drug treatment 
(see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation time points.  Examples of 
non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity. Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 




 
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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events in the Adverse Event eCRF page.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field in the Adverse Event 
eCRF page. 
5.3.5.1 
Injection Site Reactions and Infusion Reactions  
Adverse events that occur during or within 24 hours after TCZ administration and are 
judged to be related to TCZ injection (TCZ SC) or infusion (TCZ IV) should be captured 
as a diagnosis (e.g., "injection-site reaction" or “infusion reaction”, respectively in the 
Adverse Event eCRF page.  If possible, avoid ambiguous terms such as "systemic 
reaction."  Associated signs and symptoms should be recorded in the dedicated 
Injection/Infusion Reaction eCRF page. If a patient experiences both a local and 
systemic reaction to the same dose of TCZ, each reaction should be recorded 
separately in the Adverse Event eCRF page, with signs and symptoms also recorded 
separately in the dedicated Injection/Infusion Reaction eCRF page. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than injection reactions (see Section 5.3.5.1), a diagnosis (if 
known) should be recorded in the Adverse Event eCRF page rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded in the Adverse Event eCRF page.  If 
a diagnosis is subsequently established, all previously reported adverse events based 
on signs and symptoms should be nullified and replaced by one adverse event report 
based on the single diagnosis, with a starting date that corresponds to the starting date 
of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event in the Adverse Event eCRF page.  For example: 
 If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported in the eCRF. 
 If vomiting results in severe dehydration, both events should be reported separately 
in the eCRF. 


 
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 If a severe gastrointestinal haemorrhage leads to renal failure, both events should 
be reported separately in the eCRF. 
 If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately in the eCRF. 
 If neutropenia is accompanied by an infection, both events should be reported 
separately in the eCRF. 
All adverse events should be recorded separately in the Adverse Event eCRF page if it 
is unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation time points.  Such events should only be recorded once in the 
Adverse Event eCRF page.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded in the Adverse Event 
eCRF page.  If the event becomes serious, it should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF page should be 
updated by changing the event from "non-serious" to "serious," providing the date that 
the event became serious, and completing all data fields related to serious adverse 
events. 
A recurrent adverse event is one that resolves between patient evaluation time points 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event in the Adverse Event eCRF page. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 Is accompanied by clinical symptoms 
 Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 Results in a medical intervention (e.g., potassium supplementation for hypokalaemia) 
or a change in concomitant therapy 
 Is clinically significant in the investigator’s judgment  
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded in the Adverse Event eCRF page. 


 
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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded in the Adverse Event eCRF page, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalaemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once in the Adverse Event eCRF page (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 Is accompanied by clinical symptoms 
 Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 Results in a medical intervention or a change in concomitant therapy 
 Is clinically significant in the investigator’s judgment  
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded in 
the Adverse Event eCRF page. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once in the Adverse Event eCRF page (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The following finding (as defined by Hy’s law) is considered to be an indicator of severe 
liver injury: 
 
ALT or AST elevation > 3 x ULN and total bilirubin elevation > 2 x ULN without 
initial findings of cholestasis (such as elevated alkaline phosphatase). 
A patient with these findings must be discontinued from study medication as per Section 
4.6.2.   
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded in the Adverse Event eCRF page (see Section 
5.3.5.2) and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event), either as a serious adverse event or an adverse event of special 
interest (see Section 5.2.2, Section 5.2.3 and Section 5.4.2). 


 
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5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded in the Adverse 
Event eCRF page and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to worsening of rheumatoid arthritis. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept in the Adverse Event eCRF page.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without pre-existing heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded in the Adverse Event eCRF page.  
If the cause of death later becomes available (e.g., after autopsy), "unexplained death" 
should be replaced by the established cause of death. 
If the death is attributed to worsening of rheumatoid arthritis, this should be recorded in 
the Adverse Event eCRF page.   
5.3.5.9 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded in the General Medical History and Baseline 
Conditions eCRF page. 
A pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events in the Adverse Event eCRF page, it is important to convey the 
concept that the pre-existing condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Rheumatoid Arthritis 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease (i.e. worsening of RA) should not be recorded as adverse events.  
These data will be captured as efficacy assessment data only.  In most cases, the 
expected pattern of worsening will be based on ACR criteria.  Every effort should be 
made to document the worsening of RA through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to the worsening of RA, it should be reported 
as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   


 
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The following hospitalization scenarios are not considered to be adverse events: 
 Hospitalization for respite care 
 Planned hospitalization required by the protocol (e.g., for study drug administration) 
 Hospitalization for a pre-existing condition, provided that all of the following criteria 
are met: 
- The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease 
- The patient has not experienced an adverse event. 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
 Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available. 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded in the Adverse Event eCRF page.  If the associated adverse event fulfils 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
Limited safety data related to overdosing of TCZ are available (see Tocilizumab 
Investigator’s Brochure). 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 


 
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 Serious adverse events (see Section 5.4.2 for further details) 
 Adverse events of special interest (see Section 5.4.2 for further details) 
 Pregnancies (see Section 5.4.3 for further details) 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
 New signs or symptoms or a change in the diagnosis 
 Significant new diagnostic test results 
 Change in causality based on new information 
 Change in the event’s outcome, including recovery 
 Additional narrative information on the clinical course of the event. 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls. The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur Prior to Initiation of Treatment  
After informed consent has been obtained but prior to the initiation of treatment (Track 
TCZ-experienced patients – prior to the initiation of treatment in the Tapering Phase; 
Track TCZ-naïve patients – prior to the initiation of treatment in the Lead-in Phase), only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event / Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Initiation of Treatment 
After initiation of treatment (Track TCZ-experienced patients: after the initiation of 
treatment in the Tapering Phase; Track TCZ-naïve patients: after the initiation of 
treatment in the Lead-in Phase), SAEs and  adverse events of special interest will be 
reported until 4 weeks after the last dose of TCZ / study prednisone. Investigators should 


 
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record all case details that can be gathered immediately (i.e., within 24 hours after 
learning of the event) in the Adverse Event eCRF page and submit the report via the 
electronic data capture (EDC) system.  
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators. Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months of the last dose 
of TCZ / study prednisone.   A Pregnancy Report Form provided to investigators should 
be completed and submitted to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the pregnancy) either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators. Pregnancy should not 
be recorded in the Adverse Event eCRF page. The investigator should discontinue study 
drug and counsel the patient, discussing the risks of the pregnancy and the possible 
effects on the foetus.  Monitoring of the patient should continue until conclusion of the 
pregnancy. Any serious adverse events associated with the pregnancy (e.g., an event in 
the foetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported in the Adverse Event eCRF page. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Not applicable. 
5.4.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded in the Adverse Event eCRF page, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded in the Adverse Event 
eCRF page, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 


 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
in the Adverse Event eCRF page and in the patient’s medical record to facilitate source 
data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
Reporting instructions provided in Section 5.4.3.1 should be followed. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
until 4 weeks after the last dose of TCZ / study prednisone), if the event is believed to be 
related to prior IMP treatment.   
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
 Tocilizumab Investigator's Brochure  
 United States Product Insert for prednisone. 


 
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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An iDMC will monitor the incidence of the above-listed anticipated events during the 
study.   
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The present section outlines the planned statistical analysis of the study. Full details will 
be specified in a separate Statistical Analysis Plan (SAP), which will be finalized prior to 
locking of the study database at the end of the study. The SAP may include exploratory 
analyses not explicitly mentioned in this section. 
The main analysis of efficacy and safety will be comparative and concern the two arms 
of the Tapering Phase. The present section will mainly focus on this part of the study. 
The lead-in phase will be evaluated separately and details of specific analyses including 
both phases, in particular of key safety variables, will be provided in the SAP.  
The main analysis populations will be defined as follows: 
 
Full Analysis Set (FAS): all included patients. 
 
Safety population: all patients receiving at least one dose of any of the study 
medications in the Tapering Phase, with patients grouped according to the 
treatment actually received during this phase. 
 
Intent-to-treat (ITT) population: all randomized patients, with patients grouped 
according to the treatment assigned at randomization. 
 
Per-Protocol (PP) population: subset of the ITT population excluding patients 
not fulfilling one or more of the criteria for randomization and patients with other 
protocol violations described in the SAP, grouped according to the treatment 
actually received during the randomized phase. 
Unless otherwise indicated, all statistical hypotheses will be tested at the 5% 
significance level (i.e. no correction for multiple testing will be employed), and against 
two-sided alternatives. Corresponding 95% confidence intervals will be provided as 
appropriate. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This study primarily focuses on estimation rather than formal hypothesis testing.  A 
sample size of 226 randomized patients is expected to provide > 80% power to produce 
a two-sided 95% confidence interval with a half-width < 0.5 DAS28 ESR units. The 
calculation is based on a two-sided t-test for a difference between the two arms and 
assumes a standard deviation of 1.33 units (conservative assumption based on data 
under stable TCZ treatment) and an analysis in the ITT population. Differences < 
0.6 DAS28 ESR units would be considered of marginal clinical importance. There are no 


 
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reference data for an accurate assumption regarding the expected between-arm 
difference, but assuming an observed difference of < 0.25 units (mean disease activity is 
expected to slightly decrease in the steroid taper arm and to be stable in the placebo-
taper arm), the two-sided 95% confidence interval will exclude differences between the 
two arms > 0.6. 
For 226 patients to be randomized, taking into account that approximately 50% of 
included patients are expected to be "Lead-in failures" (i.e. not meeting the 
randomization criteria for Track TCZ-naïve patients), up to approximately 450 patients 
will need to be included into the study. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Descriptive statistics will be used in evaluating the conduct of the study. Variables 
evaluated in this analysis will include the rate and reasons of screening failure, the 
dropout rate prior to randomization for the two tracks and during the Tapering Phase, 
and the frequency and type of protocol violations.  
Compliance with study medication (including medication errors) will be summarized. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Unless indicated otherwise, for the analysis of the randomized phase, the assessments 
at the randomization visit will constitute baseline.  
To assess the comparability of treatment arms at baseline, a descriptive analysis of 
relevant background information, including demographic data, medical history, 
concomitant treatment and baseline data, will be performed by treatment arm for the ITT 
population.   
6.4 
EFFICACY ANALYSES 
The primary analysis population for the primary and secondary efficacy analyses will be 
the ITT population. Supportive analyses of the primary endpoint, of the key secondary 
endpoint and of other selected secondary endpoints will be conducted in the PP 
population. 
6.4.1 
Primary Efficacy Endpoint 
The statistical analysis will assess the difference between the two arms in terms of 
change in DAS28 ESR score from baseline to Week 24 post-randomization. The 
between-group comparison will be performed based on an analysis of covariance 
(ANCOVA) model including the baseline DAS28 ESR score and other stratification 
factors applied at randomization.   
For ITT patients who are prematurely withdrawn from treatment during the 24-week 
Tapering Phase, the DAS28 ESR value at the time of study treatment discontinuation 
will be used in the analysis. For ITT patients who are on RA flare rescue medication at 
Week 24 post-randomization, the DAS28 ESR value at the time of rescue medication 
start will be used in the analysis. 


 
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6.4.2 
Secondary Efficacy Endpoints 
The analysis of secondary efficacy endpoints will be exploratory.  
The key secondary efficacy analysis (comparison of the proportion of patients with LDA 
(DAS28 ESR score ≤ 3.2) at Week 24 post-randomization, who have not suffered a flare 
due to RA and who showed no confirmed adrenal insufficiency that required 
replacement therapy) will be carried out by means of a logistic regression model 
including the same explanatory variables used for the analysis of the primary efficacy 
endpoint.    
Disease activity measures such as CDAI, SDAI and HAQ-DI will be analysed as 
described for the primary efficacy endpoint. Details of the analysis methodology for other 
secondary endpoints will be provided in the SAP. 
6.5 
SAFETY ANALYSES 
Safety will be assessed in the safety population in terms of adverse events, clinical 
laboratory results, physical examination, and vital signs. Adverse events will be 
summarized by mapped term, appropriate thesaurus level, and toxicity grade. For 
adverse events of special interest, incidence rates will also be provided as well as 
summaries. More details will be outlined in the SAP. 
6.6 
PATIENT-REPORTED OUTCOME ANALYSES 
Patient-reported outcomes will include the Patient’s Global Assessment of Disease 
Activity, and data from the HAQ-DI, RAID and WPAI:RA questionnaires. Details of the 
analysis methodology for these secondary endpoints will be provided in the SAP. 
6.7 
EXPLORATORY ANALYSES  
An exploratory subgroup analysis of TCZ experienced and TCZ naïve patients will be 
performed. Other exploratory analyses will be described in the SAP.  
6.8 
INTERIM ANALYSES 
6.8.1 
Planned Interim Analyses 
Interim analyses of safety, and potentially also efficacy data if requested by the iDMC to 
assess risk-benefit, will be conducted in the context of the periodic data reviews by the 
iDMC and further details will be provided in the iDMC charter.  There are no statistical 
stopping rules based on efficacy or safety variables for this study. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data. Data entered manually will be collected via EDC using 
eCRFs. Sites will be responsible for data entry into the EDC system. In the event of 


 
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discrepant data, the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. Central laboratory data will be sent directly to the Sponsor , using 
the Sponsor's standard procedures to handle and process the electronic transfer of 
these data.   
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.   
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.  
Data from paper PRO questionnaires will be entered into the EDC system by site staff.   
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 


 
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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review. The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting), with the E.U. Clinical Trial Directive (2001/20/EC), as well as 
applicable local laws.   
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language. The Sponsor 
or its designee must review and approve any proposed deviations from the Sponsor's 


 
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sample Informed Consent Forms or any alternate consent forms proposed by the site 
(collectively, 
the 
"Consent 
Forms") 
before 
IRB/EC 
submission. 
The 
final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  Patients who decline to participate will not provide a 
separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written safety reports or 
other safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 


 
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authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives 
of 
national 
and 
local 
health 
authorities, 
Sponsor 
monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., the date of the last 
visit of the last participating patient in this study). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 


 
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9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study is sponsored by Roche, who has overall responsibility for this study. 
CROs will be responsible for medical monitoring, data management support, 
randomization (IxRS) and statistical analysis. 
A Steering Committee will oversee the general conduct of the study.   
An iDMC will share responsibility for evaluating the safety of the patients participating in 
the trial at regular intervals throughout the study.   
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf  
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multi-centre trials only in their entirety and not as individual centre 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 


 
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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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11. 
APPENDICES 
 
 










 
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Lead-in Phase only: the next scheduled visit is cancelled for patients who permanently and prematurely discontinue IMP (TCZ SC or TCZ 
IV).  These patients must then attend the visits listed in Appendix 3. 
1. Track TCZ-experienced patients only: The Screening Visit must occur up to 6 weeks prior to Randomization. The Randomization Visit is 
shown in Appendix 2. 
2. Track TCZ-naïve patients only: candidate patients may have their initial Screening Visit up to 4 weeks prior to enrolment in the Lead-in Phase.  
Lead-in Visit 1 is shown in this Appendix. 
3. Written informed consent for participation in the study must be obtained before performing any study-specific screening tests or evaluations 
(Section 4.5.1). 
4. All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility criteria (see Section 4.1) before entering 
the study.  The investigator will maintain a screening log to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
5. Demographic data and medical history will be collected as per Section 4.5.2. 
6. Complete physical examination will be performed as per Section 4.5.3.  
7. Patient Reported Outcomes: see Appendix 4, Appendix 5, Appendix 6, and Appendix 10. 
 
RA Evaluation (Efficacy) 
8. Joints are assessed for swelling (66 joints) and tenderness (68 joints) as per Appendix 8. 
9. 28 joints are assessed for swelling and tenderness for calculating the DAS 28. See Appendix 8. 
10. Physician Global VAS: see Appendix 10. 
11. Morning Stiffness: see Section 4.5.8.4  
12. DAS28 ESR Calculation: the eCRF will automatically calculate the DAS28 ESR.  However, in case the related data are not entered into 
the eCRF during the visit, the investigator will have to calculate the DAS28 ESR manually for purposes of medical decision making, 
including to assess whether or not the patient has a flare which requires treatment. See Section 4.5.8.3 for further details. 
 
Safety and Other Assessments 
13. Vital signs: temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position.  
Screening, LI Week 20 and Week 24 post randomization only: body weight and body mass index (BMI) (Height collected at screening only). 
(Section 4.5.4.) 


 
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14. Concomitant Therapy includes all medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by the patient (Section 4.5.5). 
15. Adverse events must be collected and reported as per Section 5.  Please note: 
 After informed consent has been obtained but prior to the initiation of treatment in the Tapering Phase, only SAEs caused by a protocol-
mandated intervention should be reported.   
 After the initiation of treatment in the Tapering Phase, all AEs will be reported until 4 weeks after the last dose of TCZ / study prednisone.  After 
this period, the investigator should report any SAEs that are believed to be related to prior study treatment.  
 The investigator should follow each AE until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all SAEs considered to be 
related to study drug or trial-related procedures until a final outcome can be reported. 
 
Laboratory (Local and Central) 
16. Please refer to the Central Laboratory Services Manual 
 for instructions regarding all laboratory tests (including those to be 
performed locally using kits provided by the Central Laboratory).  All laboratory assessments are described in Section 4.5.6. 
17. All women who are not post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile are subject to 
pregnancy testing (i.e., Beta-HCG urine and serum).  Serum Beta-HCG is conducted at baseline for all patients.  
18. The patient may need confirmatory liver function testing in the event of an elevated liver function test finding which may lead to study drug 
discontinuation, as described in Section 4.6.2 and Section 5.1.1.7. The first sample should be sent to the local laboratory to facilitate rapid 
clinical decision making.  Another second sample (collected at the same time as the first sample) should be sent to the Central laboratory. 
19. Tuberculosis Testing instructions apply as per Appendix 9.  All Track TCZ-naïve patients and some Track TCZ-experienced patients will require 
either a tuberculosis skin test (conducted at the site without kit provided by Central Lab) or a QuantiFERON (sent to the Central Laboratory and 
special handling applies. Refer to the Central Laboratory Services Manual (
.  Investigators should take into consideration the time 
required to obtain the results of these tests. 
20. Patient should fast for 12 hours prior to the test.  The patient may drink only water.  Tea, coffee, diet drinks, or other beverages are not allowed.  
The patient should not smoke, chew gum, or exercise during this time.  Study medications are allowed only if scheduled.  Other medications are 
allowed or prohibited during fasting as per investigator judgment. 
21. Rheumatoid factor (e.g. latex test), anti-cyclic citrullinated peptide antibody  
22. Hepatitis B surface antigen, hepatitis B core antibody and hepatitis C virus antibodies will only be tested if clinical suspicion based on history or 
clinical evidence of exposure (Section 4.5.6). 


 
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23. Immunogenicity sampling will be conducted for all patients during screening.  Subsequent sampling is "event-driven" in patients who experience 
anaphylaxis or other hypersensitivity reaction (serious or non-serious).  Sampling is conducted at the time of the event and again at 8 weeks 
after the event.  The instructions in the Central Laboratory Services Manual 
 must be followed. 
24. Track TCZ-naïve patients only: The instructions for mandatory switching to Sponsor provide open-label (SP-OL) prednisone are in Section 
4.3.2.2.  Patients who granted an extension will only be switched to SP-OL prednisone at Lead-in Week 24 if they meet the criteria specified in 
Section 4.3.2.2. 
Track TCZ-experienced patients only: Patients who have signed informed consent and are on prednisone 5 mg/day (or GC equivalent) at the 
Screening Visit are immediately switched to SP-OL prednisone, as per Section 4.3.2.2. 
. 






 
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RA Evaluation 
3. Joints are assessed for tenderness (68 joints) and swelling (66 joints).  Of these, 28 joints are 
simultaneously assessed for DAS 28 calculation.  See Appendix 8. 
4. Physician Global VAS: see Appendix 10. 
5. Morning Stiffness: see Section 4.5.8.4  
6. DAS28 ESR Calculation: the eCRF will automatically calculate the DAS28 ESR.  However, in 
case the related data are not entered into the eCRF during the visit, the investigator will have 
to calculate the DAS28 ESR manually for purposes of medical decision making, including to 
assess whether or not the patient has a RA flare which requires treatment. See Section 
4.5.8.3 for further details. 
Other Assessments 
7. Vital signs: temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures 
while the patient is in a seated position.  Screening, LI Week 20 and Week 24 post 
randomization only: body weight and body mass index (BMI) (Height collected at screening 
only). (Section 4.5.4.) 
8. Concomitant Therapy includes all medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient (Section 4.5.5). 
9. Adverse events must be collected and reported as per Section 5.  Please note: 
 After informed consent has been obtained but prior to the initiation of treatment in the 
Tapering Phase, only SAEs caused by a protocol-mandated intervention should be reported.   
 After the initiation of treatment in the Tapering Phase, all AEs will be reported until 4 weeks 
after the last dose of TCZ / study prednisone.  After this period, the investigator should report 
any SAEs that are believed to be related to prior study treatment.  
 The investigator should follow each AE until the event has resolved to baseline grade or better, 
the event is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all SAEs considered to be 
related to study drug or trial-related procedures until a final outcome can be reported. 
Laboratory (Local and Central) 
10. Please refer to the Central Laboratory Services Manual 
 for instructions 
regarding all laboratory tests (including those to be performed locally using kits provided by 
the Central Laboratory).  All laboratory assessments are described in Section 4.5.6. 
11. All women who are not post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile are subject to pregnancy testing (i.e., Beta-HCG urine and serum).  
12. The patient may need confirmatory liver function testing in the event of an elevated liver 
function test finding which may lead to study drug discontinuation, as described in Section 
4.6.2 and Section 5.1.1.7. The first sample should be sent to the local laboratory to facilitate 
rapid clinical decision making.  Another second sample (collected at the same time as the first 
sample) should be sent to the Central laboratory. 
13. Patient should fast for 12 hours prior to the test.  The patient may drink only water.  Tea, 
coffee, diet drinks, or other beverages are not allowed.  The patient should not smoke, chew 
gum, or exercise during this time.  Study medications are allowed only if scheduled.  Other 
medications are allowed or prohibited during fasting as per investigator judgment. 


 
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14. DNA samples may be drawn only if the site has been granted approval for RBR sampling and 
if the patient has given specific consent to participate in this optional research (see Section 
4.5.12). 
15. Immunogenicity sampling is "event-driven" in patients who experience anaphylaxis or other 
hypersensitivity reaction (serious or non-serious).  Sampling is conducted at the time of the 
event and again at 8 weeks after the event. The instructions in the Central Laboratory 
Services Manual 
 must be followed. No immunogenicity sampling is required in 
case of injection site reactions. 
16. Patients must be treated with RA flare rescue medication and attend a Flare Assessment visit 
if a RA flare is detected at any scheduled or unscheduled visit. Important instructions apply, 
see Section 4.5.11. 






 
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5. DAS28 ESR Calculation: the eCRF will automatically calculate the DAS28 ESR.  However, in 
case the related data are not entered into the eCRF during the visit, the investigator will have 
to calculate the DAS28 ESR manually for purposes of medical decision making, including to 
assess whether or not the patient has a RA flare which requires treatment. See Section 
4.5.8.3 for further details. 
Other Assessments 
6. Vital signs: temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures 
while the patient is in a seated position.  Study Treatment D/C Visit only: body weight and 
body mass index (BMI) (Height collected at screening only). (Section 4.5.4.) 
7. Concomitant Therapy includes all medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient (Section 4.5.5). 
8. Adverse events must be collected and reported as per Section 5.  Please note: 
 All AEs will be reported until 4 weeks after the last dose of TCZ / study prednisone.   
 After this period, the investigator should report any SAEs that are believed to be related to 
prior study treatment.  
 The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.   
 Every effort should be made to follow all SAEs considered to be related to study drug or trial-
related procedures until a final outcome can be reported. 
Laboratory (Local and Central) 
9. Please refer to the Central Laboratory Services Manual (
) for instructions 
regarding all laboratory tests (including those to be performed locally using kits provided by 
the Central Laboratory).  All laboratory assessments are described in Section 4.5.6. 
10. All women who are not post-menopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile are subject to pregnancy testing (i.e., Beta-HCG urine 
and serum).  
11. The patient may need confirmatory liver function testing in the event of an elevated liver 
function test finding which may lead to study drug discontinuation, as described in Section 
4.6.2 and Section 5.1.1.7. The first sample should be sent to the local laboratory to facilitate 
rapid clinical decision making.  Another second sample (collected at the same time as the first 
sample) should be sent to the Central laboratory. 
12. Patient should fast for 12 hours prior to the test.  The patient may drink only water.  Tea, 
coffee, diet drinks, or other beverages are not allowed.  The patient should not smoke, chew 
gum, or exercise during this time.  Study medications are allowed only if scheduled.  Other 
medications are allowed or prohibited during fasting as per investigator judgment. 
13. Immunogenicity sampling is "event-driven" in patients who experience anaphylaxis or other 
hypersensitivity reaction (serious or non-serious).  Sampling is conducted at the time of the 
event and again at 8 weeks after the event. The instructions in the Central Laboratory 
Services Manual 
 must be followed. No immunogenicity sampling is required in 
case of injection site reactions. 


 
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APPENDIX 4: HEALTH ASSESSMENT QUESTIONNAIRE (HAQ-DI) 
 
 
 
 
 
 


 
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APPENDIX 5: RHEUMATOID ARTHRITIS IMPACT OF DISEASE (RAID) 
QUESTIONNAIRE 


 
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RAID SCORING AND CALCULATION RULES 
The RAID is calculated based on 7 Numerical rating scales (NRS) questions. Each NRS 
is assessed as a number between 0 and 10.  The 7 NRS correspond to pain, function, 
fatigue, sleep, emotional well-being, physical well-being, and coping/self-efficacy. 
 
1. CALCULATION 
 
Pain NRS value (range 0-10) x 0.21 + 
Function NRS value (range 0-10) x 0.16 + 
Fatigue NRS value (range 0-10) x 0.15 + 
Physical well-being NRS value (range 0-10) x 0.12 + 
Sleep NRS value (range 0-10) x 0.12 + 
Emotional well-being NRS value (range 0-10) x 0.12 + 
Coping NRS value (range 0-10) x 0.12 =   
 
RAID final value 
The range of the final RAID value is 0-10 where higher figures indicate worse status. 
 
2. MISSING DATA IMPUTATION 
 
If one of the 7 NRS values composing the RAID is missing, the imputation is as 
follows: 
a. calculate the mean value of the 6 other (non-missing) NRS (range, 0-10) 
b. impute this value for the missing NRS 
c. then, calculate the RAID as explained above. 
 
If two or more of the NRS values are missing, the RAID is considered as missing 
value (no imputation). 


 
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APPENDIX 6: WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE RHEUMATOID ARTHRITIS ENGLISH-US 
V2.0 (WPAI:RA) 
 
 
The following questions ask about the effect of your rheumatoid arthritis on your ability to work 
and perform regular activities.  Please fill in the blanks or circle a number, as indicated. 
 
1. 
Are you currently employed (working for pay)?  _____ 
NO 
___ 
YES 
  
If NO, check “NO” and skip to question 6. 
 
The next questions are about the past seven days, not including today.  
2. During the past seven days, how many hours did you miss from work because of problems 
associated with your rheumatoid arthritis?  Include hours you missed on sick days, times you 
went in late, left early, etc., because of your rheumatoid arthritis.  Do not include time you 
missed to participate in this study. 
 
_____ HOURS 
 
3. During the past seven days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS  (If “0”, skip to question 6.) 
 
5. During the past seven days, how much did your rheumatoid arthritis affect your productivity 
while you were working?   
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully 
as usual.  If rheumatoid arthritis affected your work only a little, choose a low number.  
Choose a high number if rheumatoid arthritis affected your work a great deal.   
Consider only how much rheumatoid arthritis affected  
productivity while you were working. 
Rheumatoid 
arthritis had no 
effect on my work 
 
 
 
 
 
 
 
 
 
 
 
Rheumatoid arthritis 
completely prevented 
me from working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 


 
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6. During the past seven days, how much did your rheumatoid arthritis affect your 
ability o do your regular daily activities, other than work at a job?   
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If rheumatoid arthritis affected your activities only a little, 
choose a low number.  Choose a high number if rheumatoid arthritis affected your 
activities a great deal.   
 
Consider only how much rheumatoid arthritis affected your ability  
to do your regular daily activities, other than work at a job. 
Rheumatoid 
arthritis had no 
effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
Rheumatoid 
arthritis completely 
prevented me from 
doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
WPAI:RA  V2.0 (US English) 


 
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APPENDIX 7: ACR REVISED CRITERIA FOR THE CLASSIFICATION OF 
FUNCTIONAL CAPACITY IN RHEUMATOID ARTHRITIS 
 
 
 
 
 
 
Class I 
Complete functional capacity with ability to carry on all usual duties without handicaps. 
 
Class II 
Functional capacity adequate to conduct normal activities despite handicap of 
discomfort or limited mobility of one or more joints. 
 
Class III 
Functional capacity adequate to perform only few or none of the duties of usual 
occupation or self-care. 
 
Class IV 
Largely or wholly incapacitated with subject bedridden or confined to wheel chair, 
permitting little or no self-care. 
 




 
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APPENDIX 9: TUBERCULOSIS EVALUATION DURING SCREENING 
 
General Guidance 
Benefit-risk in patient with current or history of active or latent TB 
The benefit–risk balance of study-drug therapy should account for the fact that some 
patients previously treated for latent or active TB have developed active TB while being 
treated with tocilizumab. The potential risk of re-infection should be evaluated. 
Priority of country-specific guidelines 
Local country-specific guidelines must be followed for screening, test selection, test 
interpretation, diagnosis, and treatment of active and latent TB. 
If no local guidelines exist for treatment of immunocompromised individuals, then the 
U.S. guidelines (located at: http://www.cdc.gov/tb/) must be followed. 
Patient counselling 
All patients should be instructed to seek medical advice if signs or symptoms (e.g., 
persistent cough, wasting/weight loss, low-grade fever) suggestive of TB occur during or 
after therapy with study drug. 
1. Tuberculosis Evaluation: Initial Assessment 
All patients must receive a complete physical examination, medical history and 
concomitant medications assessment as per the Schedule of Assessments after signing 
 
informed consent.  Based on these assessments, the investigator may exempt only the 
following patients from TB evaluation (TB; Mycobacterium tuberculosis infection): 
 
Track-TCZ experienced patients for whom there is no clinical suspicion of latent 
or active TB (e.g. no signs and symptoms of TB, no history of exposure or 
infection); 
 
Any patient already receiving antibiotic therapy for previously diagnosed latent 
TB at the time of signing informed consent and for whom there is no clinical 
suspicion of active TB.  Important note: these patients must have completed ≥ 
4 weeks antibiotic therapy prior to Enrolment.  Antibiotic therapy should continue 
during screening and the study (if patient enrolled) as per local guidelines. 
All other patients must undergo additional TB evaluation (items 2-4), as described below. 
2. Tuberculosis Evaluation: TST and IGRA 
All patients selected for additional TB evaluation must receive one of the following tests 
during the study screening window:  
 
tuberculin skin test (TST), or  
 
interferon gamma releasing assay (IGRA) (Central Laboratory) 


 
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The choice of test must be based on local guidelines; however, investigators should note:   
 
An IGRA is typically preferred in patients with history of bacille Calmette Guérin 
vaccination (BCG vaccine).  
 
There is a risk of false-negative TST results due to immunosuppression, natural 
waning of immunity, and technical limitations (including reader variability) 
 
IGRA sensitivity is diminished by HIV infection and active TB.   
3. Tuberculosis Evaluation: Other Tests  
Additional assessments to confirm/exclude active and latent TB, if appropriate, should 
be conducted according to local guidelines during the study screening window.   It is the 
investigator’s responsibility to be familiar with local TB testing guidelines and practices 
and to determine the need for additional testing. 
 
Chest x-ray; 
 
Bacteriologic or histologic examinations (e.g. AFB smear, AFB cultures); 
 
Other tests (e.g. MRI, TB nucleic acid amplification test, NAAT). 
The results of all tests performed for purposes of TB evaluation must be 
available prior to the end of the screening window.  Investigators should take 
into account the time required to obtain results for TSTs and IGRAs.  IGRA 
results are available a few days after the Central Laboratory receives the blood 
sample; attention must be paid to special sample handling. TSTs are 
performed locally and require a patient follow up visit at 48 to 72 hours 
following administration. 
4. Tuberculosis Evaluation: Diagnosis and Treatment 
All patients in whom active or latent TB has been excluded may enrol in the study if all 
other inclusion and no exclusion criteria are met. 
All patients diagnosed with active or latent TB must be treated in accordance with local 
guidelines and a physician with expertise in the treatment of TB should be consulted.  
Furthermore, the following apply: 
All patients diagnosed with active TB during screening may not enrol in the study 
See exclusion criterion № 27 
Track TCZ-naïve patients diagnosed with latent TB during screening 
Patients are eligible for enrolment in the Lead-in Phase after completing ≥ 4 weeks 
treatment and meeting all inclusion and exclusion criteria at re-screening. 
Track TCZ-experienced patients diagnosed with latent TB during screening 


 
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Patients are eligible for enrolment only if the following conditions are true: 
 
TCZ was interrupted at the time of initiation of latent TB antibiotic therapy; 
 
TCZ was restarted after completing ≥ 4 weeks of latent TB treatment; 
 
All inclusion and exclusion criteria are met at re-screening; 
 
Randomization criteria are met at the randomization visit. 


 
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APPENDIX 10: GLOBAL ASSESSMENT OF DISEASE ACTIVITY VAS 
 
The overall assessment of current disease activity will be made on a 100 mm horizontal 
visual analogue scale (VAS).   
 
Patient Global VAS 
The patient should complete this assessment prior to the performance of all efficacy 
assessments and the administration of study treatment.   
 
 
 
 
 
 
 
 
 
 
 
Physician Global VAS 
 
The investigator should complete this assessment prior to administration of study 
treatment.   
 
 
 
 
 
 
 
 
 
 
No Arthritis 
Symptoms 
Maximum 
Arthritis 
Symptoms 
Maximum 
Arthritis 
Disease 
Activity 
No Arthritis 
Disease 
Activity