A Phase IV Study to Evaluate Decreased Dose Frequency in Patients With Systemic Juvenile Arthritis (SJIA) Who Experience Laboratory Abnormalities During Treatment With Tocilizumab
Phase: PHASE4
Conditions: Juvenile Idiopathic Arthritis
Sponsor: Hoffmann-La Roche

 
Official Title: 
 
A PHASE IV STUDY TO EVALUATE DECREASED DOSE 
FREQUENCY IN PATIENTS WITH SYSTEMIC JUVENILE 
IDIOPATHIC ARTHRITIS (SJIA) WHO EXPERIENCE 
LABORATORY ABNORMALITIES DURING TREATMENT WITH 
TOCILIZUMAB 
NCT Number: 
NCT01734382 
Document Date: 
Protocol Version 3: 07 January 2016 
 
 

 
Title
07-Jan-2016 19:25:33
Date and Time (UTC)
Company Signatory
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 WA28029, Version 3 
PROTOCOL 
TITLE: 
A PHASE IV STUDY TO EVALUATE 
DECREASED DOSE FREQUENCY IN PATIENTS 
WITH SYSTEMIC JUVENILE IDIOPATHIC 
ARTHRITIS (SJIA) WHO EXPERIENCE 
LABORATORY ABNORMALITIES DURING 
TREATMENT WITH TOCILIZUMAB 
PROTOCOL NUMBER: WA28029 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2012-000444-10 
IND NUMBER: 
11972 
TEST PRODUCT: 
Tocilizumab (RO4877533) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  16 July 2012 
DATES AMENDED: 
Version 2:  18 March 2013 
Version 3:  See electronic date stamp below. 

Tocilizumab—F. Hoffmann-La Roche Ltd 
2/Protocol WA28029, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol WA28029 has been amended to include the addition of a preliminary 
screening assessment (Screening Evaluation 1) and a run-in phase of ≤ 24 weeks 
(Part 1).  The proposed modifications are intended to increase enrollment by helping to 
identify patients with resolved laboratory abnormalities in Part 1 on the tocilizumab (TCZ) 
Q2W regimen who will be eligible to participate in the decreased dose frequency phase 
(Part 2). 
The preliminary screening evaluation (Screening Evaluation 1) followed by a run-in 
phase (Part 1) of ≤ 24 weeks will enable both TCZ naive and non-naive patients to enter 
the study.  Patients who fulfil all eligibility criteria in the Screening Evaluation 1 may 
enter Part 1 and receive TCZ dosed by body weight (12 mg/kg for patients < 30 kg; 
8 mg/kg for patients ≥ 30 kg) by IV infusion Q2W until they experience an event of 
neutropenia, thrombocytopenia, or liver enzyme abnormality as per the criteria provided 
in Section 4.1, Table 5.  Following the occurrence and resolution of this laboratory 
abnormality, patients who have a successful final screening evaluation (Screening 
Evaluation 2) may enter the main study (Part 2), which will evaluate a reduction on TCZ 
dosing frequency to Q3W and Q4W.  Patients who have experienced a resolved 
laboratory abnormality on commercially available TCZ Q2W may enter Part 2 directly 
without participating in Part 1, as per the initial protocol, following a successful screening 
evaluation (Screening Evaluation 2) (Section 3.1.1, Synopsis, and Appendix 1). 
Additional changes to the protocol are as follows: 
• 
Change in the time between diagnosis of systemic juvenile idiopathic arthritis (sJIA) 
and treatment with biologics from 6 months to 1 month for entry into Part 1 and 2.  
This change is to align with the 2013 update of the American College of 
Rheumatology recommendations (Ringold et al. 2013) for the treatment of children 
with sJIA, which allows earlier therapy with biologic agents (including TCZ) 
(Section 4.1).   
• 
Change in the requirement for withdrawal from Part 2 due to flare from an obligatory 
requirement to withdraw to withdrawal at the discretion of the investigator 
(Sections 3.1.1, 3.1.2.1, 3.1.2.2, 3.1.3, 3.4.1, 4.5.1.1, 6.4).  
• 
Clarify that the patient must have 5 consecutive Q3W infusions (12 weeks on Q3W) 
before moving onto Q4W dosing (Section 3.1.1, 3.1.2.1, 3.1.2.2., 4.2.2.1).   
• 
The requirement to collect growth velocity as data (for assessment of growth rate 
and Tanner stages) was removed as it is not required to be collected for this study 
(Section 4.4.1.2). 
• 
Clarify that samples for anti-TCZ antibodies, TCZ PK, and sIL-6R will be collected 
for patients who prematurely withdraw (at Withdrawal Visit 1) (Appendix 1). 

 
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• 
Clarify the conditions under which a chest radiograph is required at study entry.  A 
chest X-ray is only required at screening for patients who test positive for 
tuberculosis [TB] and have not previously received TB treatment (Section 4.4.1.11). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

 
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PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
“Non-serious” was removed when referring to serious adverse events of special interest 
throughout the protocol.  
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.1:  BACKGROUND ON SYSTEMIC JUVENILE IDIOPATHIC 
ARTHRITIS (SJIA) 
…Anakinra, a receptor antagonist to interleukin (IL)-1, has met with some success for 
the treatment of the systemic complaints associated with sJIA but has not been utilized 
as frequently as expected due to the daily requirements for a subcutaneous injection 
(Haines 2007).  Canakinumab is an antagonist to the cytokine IL-1β and was approved 
in the EU in September 2013 for the treatment of sJIA in patients aged 2 years and 
older who have responded inadequately to previous therapy with NSAIDs and systemic 
corticosteroids.…   
SECTION 1.2:  BACKGROUND ON TOCILIZUMAB 
TCZ 8 mg/kg IV has been approved in more than 110 countries, including Japan, the 
European Union, and the United States, for use in adult patients with moderately to 
severely active RA who have an inadequate response to one or more disease-modifying 
anti-rheumatic drugs (DMARDs) including and/or tumor necrosis factor (TNF) 
antagonists (Summary of Product Characteristics for RoACTEMRA 2009; ACTEMRA®, 
English-Translated Version 7 2008).  In the United States, TCZ IV has been approved in 
patients with RA who have had an inadequate response to TNF antagonist therapies 
(USPI for ACTEMRA® [tocilizumab] 2011).  Additionally, TCZ was approved for use in 
JIA, sJIA, and Castleman’s disease in India and Japan (ACTEMRA®, English Translated 
Version 7 2008).  TCZ is approved for the treatment of active sJIA arthritis in patients 
2 years of age and older in several countries, including Japan, India, Switzerland, 
Mexico, the European Union and the United States.  In the United States and European 
Union, the approved dose regimen is 8 mg/kg every 2 weeks (Q2W) for sJIA patients 
weighing ≥ 30 kg and 12 mg/kg Q2W for sJIA patients weighing < 30 kg (Summary of 
Product Characteristics for RoACTEMRA 2009; USPI for ACTEMRA® [tocilizumab] 
2011). 
SECTION 1.3:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The efficacy and safety of TCZ in children with sJIA was demonstrated in the ongoing 
pivotal study, WA18221.… 
Patients who have experienced a laboratory abnormality on Q2W TCZ may benefit from 
reducing their TCZ dose by increasing the interval between doses to 3 or 4 weeks. 

 
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5/Protocol WA28029, Version 3 
Increasing the TCZ dosing interval carries the risk of underexposure to drug leading to 
disease flare or MAS but the likelihood of this is reduced in this study by recruiting 
patients into Part 2 with good disease control and reducing the dosing interval in a 
controlled stepwise manner (to every 3 weeks [Q3W] then every 4 weeks [Q4W] if 
required). 
SECTION 2:  OBJECTIVES FOR PART 2 
SECTION 2.1:  EFFICACY OBJECTIVE 
The primary efficacy objective for Part 2 of this study is as follows: 
• 
To explore the efficacy of TCZ in reduced dosing frequency regimens (Q3W and 
Q4W, as appropriate) using Juvenile Arthritis Disease Activity Score (JADAS)-71, 
JIA flare, and fever (attributable to sJIA). 
 
SECTION 2.2:  SAFETY OBJECTIVE 
The safety objective for Part 2 of this study is as follows: 
• 
To evaluate the safety of TCZ in reduced dosing frequency regimens 
 
SECTION 2.3:  PHARMACODYNAMIC OBJECTIVE 
The primary pharmacodynamic (PD) objective for Part 2 of this study is as follows: 
• 
To describe the pharmacodynamics, using sIL-6R and C-reactive protein (CRP), 
and immunogenicity of TCZ in reduced dosing frequency regimens 
 
SECTION 2.4:  PHARMACOKINETIC OBJECTVE 
The pharmacokinetic (PK) objective for Part 2 of this study is as follows: 
• 
To describe the pharmacokinetics of TCZ in reduced dosing frequency regimens 
 
SECTION 2.5:  PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objectives for Part 2 of this study are as follows: 
• 
To describe parent/patient global assessment of disease activity overall well-being 
with TCZ in reduced dosing frequency regimens. 
 
SECTION 3.1.1:  Overview 
This is a 9652-week, 2 part, Phase IV study to explore the efficacy, safety, 
pharmacokinetics, pharmacodynamics, and immunogenicity of TCZ in reduced dosing 
frequency regimens in patients with adequately controlled sJIA (JADAS Minimal Disease 
Activity cut-off of 3.8 at screening and baseline for Part 2[Consolaro et al. 2012]) who 
have experienced a laboratory abnormality which has resolved (per inclusion criteria in 
Section 4.1.1) at any time on TCZ twice weekly dosing.  Following a successful 
screening evaluation, 
Run-In Phase (Part 1) 
At the Screening Evaluation 1 (see Appendix 1-A), TCZ naive patients or TCZ 
non-naive patients who fulfil all eligibility criteria for Screening Evaluation 1 may 
enter the open-label run-in phase (Part 1) and receive TCZ dosed by body weight 

 
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(12 mg/kg for patients < 30 kg; 8 mg/kg for patients ≥ 30 kg) by IV infusion Q2W for 
up to 24 weeks or until they experience a laboratory abnormality of neutropenia, 
thrombocytopenia, or liver enzyme abnormality as per the criteria provided in Table 5.  
The TCZ dose will be calculated using the baseline body weight (< 30 kg or ≥ 30 kg) and 
will not be changed until a patient’s weight falls into the other body weight category on 
three separate, consecutive occasions in Part 1.  Patients will be assessed Q2W for 
safety.  No reductions or changes of concomitant MTX dosing can occur during Part 1 
of the study (i.e., due to improvement or worsening of symptoms) except for 
documented safety reasons.   
Patients who do not experience a laboratory abnormality in Part 1, or experience a 
laboratory abnormality but do not meet the eligibility criteria for Part 2, will complete 
Part 1 through to Week 24, followed by the Part 1 withdrawal visits. 
Main Study (Part 2)  
Patients on TCZ Q2W who have experienced a laboratory abnormality (per Table 5; 
either during Part 1 or prior to the study) that has subsequently resolved, who have 
adequate disease control, and who fulfil all the inclusion criteria and none of the 
exclusion criteria of Screening Evaluation Part 2, may enter the main study (Part 2).  
Once patients have entered Part 2 of the study, they will receive TCZ dosed by body 
weight (12 mg/kg for patients < 30 kg; 8 mg/kg for patients ≥ 30 kg) by IV infusion Q3W 
for a minimum of 45 consecutive infusions.  The dose will be calculated using the Part 2 
baseline body weight and will not be changed during the first 12 weeks of the Part 2 of 
the study.  Patients on Q3W will be assessed Q3W for safety and efficacy responses.  
No reductions or changes of concomitant NSAIDs, corticosteroids, or MTX dosing can 
occur during the first 12 weeks of Part 2 of the study (and until 5 4 consecutive Q3W 
infusions have been given) except for documented safety reasons, including laboratory 
abnormalities.  In addition, the doses of NSAIDs, corticosteroids, and MTX should 
remain stable in any patient who moves to Q4W dosing, during the first 12 weeks of 
Q4W dosing. 
In Part 2, eEach patient will start and maintain Q3W dosing of TCZ in the study up to 
52 weeks unless the patient experiences an event of neutropenia, thrombocytopenia, or 
liver enzyme abnormality as per the criteria provided in Section 3.1.2.  Following the 
occurrence and resolution of this laboratory abnormality, patients who have maintained 
adequate disease control (JADAS ≤ 3.8 and absence of fever attributable to sJIA) will 
move to Q4W dosing of TCZ.  Patients who have not completed a minimum of 4 5 
consecutive Q3W infusions will remain on Q3W dosing until 54; consecutive Q3W doses 
have been completed before moving to Q4W dosing.  If during this time, a patient should 
experience any additional laboratory abnormalities as per the criteria provided in 
Section 3.1.2, he or she may move directly to Q4W dosing after resolution, at the 
discretion of the investigator, and the Sponsor must be notified. 

 
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Patients who do not meet the criteria to switch from Q3W to Q4W will complete Part 2 
through to Week 52, followed by the Part 2 withdrawal visits. 
Patients who experience a JIA flare or fever attributable to sJIA (see definition in 
Section 4.5.1.1) at any time during Part 2 willmay be withdrawn from the study at the 
discretion of the investigator.   
Patients will undergo safety and safety laboratory assessments during Part 1 of the 
study.  Safety, safety laboratory, PK, PD, and efficacy assessments will be performed 
during Part 2 as described in the schedule of assessments (see Appendix 1).  During 
Part 1, and Aafter the first 12 weeks of Part 2 of the study, the dose of TCZ can be 
adjusted according to changes in body weight:  if a patient’s body weight increases 
above 30 kg for on 3 successive consecutive visits (while it was below 30 kg at baseline 
for Part 1 or Part 2, respectively), on the third visit the dose of TCZ will be decreased to 
8 mg/kg; if a patient’s body weight decreases below 30 kg (while it was above 30 kg at 
baseline for Part 1 or Part 2, respectively) for on 3 successive consecutive visits, the 
dose of TCZ will be increased on the third visit to 12 mg/kg. 
All patients who are discontinued from Part 1 or Part 2 of the study for any reason must 
return for the Withdrawal Visit 1 and for follow-up safety assessments,  (Withdrawal 
Visits 2, 3, and 4,) up to and including 12 weeks after the last administration of study 
drug.  They may be required to return for visits beyond 12 weeks after discontinuation 
from treatment with TCZ for safety reasons (to be documented in the electronic Case 
Report Form [eCRF] and interactive voice response system [IXRS]). 
Figure 1 below provides an overview of the proposed Phase IV of this study design. 
SECTION 3.1.2:  Management of Laboratory Abnormalities and TCZ Dose 
Frequency 
Management of neutropenia, thrombocytopenia, and elevated liver function tests to be 
implemented in this protocol for patients in Part 1 and Part 2 who have achieved a 
JADAS 71 minimal disease activity of 3.8 at screening and at baseline (and maintained 
adequate disease control at the time of any subsequent laboratory abnormalities 
experienced during the study) are summarized below.  
SECTION 3.1.2.1:  Hematologic Abnormalities 
For patients in Part 1 and Part 2 (achieving and maintaining a JADAS  71 minimal 
disease activity of 3.8), the laboratory abnormality guidance in Table 2 and Table 3, and 
Table 4 should be followed.  Patients experiencing a JIA flare or fever attributable to 
sJIA should be withdrawn from the study (at the discretion of the investigator). 
SECTION 3.1.2.2:  Elevated Liver Enzymes 
For patients in Part 1 and Part 2, the laboratory abnormality guidance in Table 4 
should be followed.  Patients experiencing a JIA flare or fever attributable to sJIA 
should be withdrawn from the study (at the discretion of the investigator). 

 
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SECTION 3.1.3:  Criteria for Withdrawal from the Study 
Patients who experience a JIA flare or fever attributable to sJIA relative to baseline of 
Part 2 (as per the definition provided in Section 4.4.1.1) at any visit in Part 2 oftime on 
the study or experience fever associated with sJIA at any visit will may be withdrawn 
from the study at the discretion of the investigator. 
Patients who experience any adverse event that in the opinion of the investigator or the 
Sponsor precludes further study participation (in Part 1 or 2) will be withdrawn from the 
study. 
SECTION 3.3.1:  Rationale for Test Product Dosage 
In Part 2 of the study, iInstead of being given Q2W, TCZ will be administered IV every 
3 or 4 weeks for up to 1 year in patients who have previously experienced at least one 
laboratory abnormality on the previous Q2W dose regimen (either in Part 1 or on 
commercial TCZ prior to entry into Part 2).  Efficacy, safety, pharmacokinetics, 
pharmacodynamics, and immunogenicity will be assessed upon reduction of dosing 
frequency in these patients. 
SECTION 3.4.1:  Efficacy Outcome Measures 
The efficacy outcome measures for Part 2 of this study are as follows: 
• 
JIA flare relative to baseline of Part 2 will be used to determine those patients not 
maintaining efficacy who are to can be withdrawn from the study at the discretion of 
the investigator (as per Section 4.5.1.1). 
• 
Fever (attributable to sJIA) will be measured at each study visit of Part 2 in 
patients on Q3W and Q4W dosing (as  appropriate) to describe efficacy and to 
determine patients not maintaining efficacy who are tocan be withdrawn from the 
study at the discretion of the investigator (as per Section 4.5.1.1 and 
Section 4.5.1.2). 
 
SECTION 3.4.2:  Safety Outcome Measures 
The safety outcome measures in Part 1 and 2 of this study are as follows: 
 
SECTION 3.4.3:  Pharmacokinetic and Pharmacodynamic Outcome 
Measures 
The PK/PD outcome measures for Part 2 of the study are as follows: 
 
SECTION 3.4.4:  Patient-Reported Outcome Measures 
The PRO outcome measures for thisPart 2 of the study are as follows: 
• 
The CHAQ (see Appendix 2) 
• 
Parents/patients global assessment of disease activityoverall well-being 
 
SECTION 4.1:  PATIENTS 
Children aged 2 years up to and including aged 17 years with sJIA ≥ 16 months and 
currently receiving TCZ who have experienced a predefined, resolved laboratory 

 
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abnormality (see Section 4.1.1, Inclusion Criteria Part 24) at any time during TCZ Q2W 
treatment will be eligible to participate in thisPart 2 of the study.   
SECTION 4.1.1:  Inclusion Criteria 
Part 1 and Part 2 
All patients entering Part 1 or entering Part 2 without participating in Part 1Patients 
must meet the following criteria for study entry into Part 1 or Part 2: 
• 
sJIA symptoms lasting for at least  1 month since diagnosis of sJIA  
• 
Fertility: 
Female not of child bearing potential, or 
Female of child bearing potential practicing effective contraceptive measures, 
having a negative urine pregnancy test within 3 weeks prior to randomization; or 
Sterile male, or 
Non sterile male practicing effective contraceptive measures with female partner of 
child bearing potential.  (Females of childbearing potential must be using a reliable 
means of contraception [abstinence being a possible option] throughout the study 
and up to 12 weeks after the last infusion of study drug.) 
For female patients of reproductive potential (unless surgically sterile with 
absence of ovaries and/or uterus): agreement to remain abstinent or use single 
or combined contraceptive methods that result in a failure rate of < 1% per 
year during the treatment period and for at least 6 months after the last dose of 
TCZ 
Abstinence is acceptable only if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Examples of contraceptive methods with a failure rate of < 1% per year 
include tubal ligation; male sterilization; hormonal implants; established, 
proper use of combined oral or injected hormonal contraceptives; and 
certain intrauterine devices.  Alternatively, two methods (e.g., two barrier 
methods, such as a condom and a cervical cap) may be combined to achieve 
a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide. 
For male patients of reproductive potential: agreement to remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of < 1% per year during the treatment period and for at least 
6 months after the last dose of TCZ 
Abstinence is acceptable only if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 

 
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symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
• 
Must meet one of the following: 
Not receiving MTX or discontinued MTX at least 4 weeks prior to the Part 1 or 
Part 2 baseline visit, or 
Taking MTX for at least 12 weeks immediately prior to the Part 1 or Part 2 
baseline visit and on a stable dose of ≤ 20 mg/m2 for at least 8 weeks prior to 
the Part 1 or Part 2 baseline visit, together with either folic acid or folinic acid 
according to local standard of care 
 
Patients entering Part 1 who are naïve to TCZ therapy must also meet the following 
inclusion criterion: 
• 
History of inadequate clinical response (in the opinion of the treating physician) to 
NSAIDs and corticosteroids  
 
Part 2 
All patients entering Part 2 (either directly without participating in Part 1, or via 
Part 1) must meet the following additional criteria for entry into Part 2: 
• 
JADAS-71 score of 3.8 or less and absence of fever (related to sJIA) at screening 
and baseline of Part 2 (Consolaro et al. 2012) 
• 
Neutropenia, thrombocytopenia, or elevated ALT/AST (as per criteria in Table 5) 
previously experienced (and resolved) on the labeled dose (Q2W) of TCZ at any 
time. 
• 
Not currently receiving oral corticosteroids, or taking oral corticosteroids at a stable 
dose for a minimum of 2 weeks prior to the Part 2 baseline visit at no more than 
10 mg/day or 0.2 mg/kg/day, whichever is less 
• 
Not taking NSAIDs, or taking no more than one type of NSAID at a stable dose for a 
minimum of 2 weeks prior to the Part 2 baseline visit, with the dose being less than 
or equal to the maximum recommended daily dose 
 
SECTION 4.1.2:  Exclusion Criteria 
Patients entering Part 1, or entering Part 2 without participating in Part 1, who meet 
any of the following criteria will be excluded from study entry: 
General 
• 
Not fully recovered from recent surgery or less than 6 weeks since surgery, at the 
time of screening visit; or planned surgery during Part 1 and the initial 12 weeks of 
Part 2 of the study (for patients entering Part 1) or the initial 12 weeks of Part 2 of 
the study (for patients entering Part 2 without participating in Part 1) 
 
General Safety 
• 
Pregnant, lactating, or intending to become pregnant during study conduct and up to 
6 months12 weeks after the last administration of study drug 

 
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• 
Significant cardiac [e.g., congenital heart disease, valvular heart disease, 
constrictive pericarditis (unrelated to sJIA), myocarditis] or pulmonary disease, 
(e.g., asthma for which the patient has required the use of oral or parenteral 
corticosteroids for ≥ 2 weeks within 6 months prior to the baseline visit of Part 1 or 
Part 2, or cystic fibrosis) 
 
Laboratory Exclusions at Screening 
The following additional laboratory exclusion criteria apply to patients entering Part 1 
of the study who are TCZ-naive and are initiating therapy with TCZ: 
• 
AST or ALT > 1.5 ULN (upper limit of normal for age and sex) 
• 
Total bilirubin > 1.3 mg/dL (> 23 μmol/L) 
• 
Platelet count < 150 x 103/μL (< 150,000/mm3) 
• 
WBC count < 5,000/mm3 (< 5.0 x 109/L) 
• 
Neutrophil count < 2,500/ mm3 (< 2.5 x 109/L) 
 
SECTION 4.2.1.1:  Tocilizumab 
All TCZ vials must be stored at a controlled temperature of 2°C−8°C, and handled 
according to Good Manufacturing Practice and Good Clinical Practice (GCP) procedures.  
A temperature log must be kept recording the storage temperature of the TCZ and 
placebo and infusion bags at least once a day. 
SECTION 4.2.2.1:  Tocilizumab 
Part 1 
TCZ dosed by body weight (12 mg/kg for patients < 30 kg; 8 mg/kg for patients ≥ 30 kg) 
will be administered IV Q2W for ≤ 24 weeks or until the patient experiences an event of 
neutropenia, thrombocytopenia, or liver enzyme abnormality as per the criteria 
provided in Table 5.  Following the occurrence and resolution of this laboratory 
abnormality, patients who have a final successful screening evaluation (Screening 
Evaluation 2) may enter Part 2 of the study.  
Patients who do not experience a laboratory abnormality in Part 1, or experience a 
laboratory abnormality but do not meet the eligibility criteria for Part 2, will complete 
Part 1 through to Week 24, followed by the Part 1 withdrawal visits.  
Part 2 
TCZ dosed by body weight (12 mg/kg for patients < 30 kg; 8 mg/kg for patients ≥ 30 kg) 
will be administered IV Q3W for a minimum of 12 consecutive weeks (4 5 consecutive 
infusions), switching to Q4W (if required), in response to predefined laboratory 
abnormalities for patients eligible to continue treatment for the duration of the study 
(52 weeks in total).   
Patients who do not meet the criteria to switch from Q3W to Q4W will complete Part 2 
through to Week 52, followed by the Part 2 withdrawal visits. 

 
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TCZ will be supplied in vials containing 10 mL of a sterile solution of 20 mg TCZ/mL.  
One vial will be used for any child ≤ 16.5 kg.  A 2 vial combination will be used for a body 
weight of > 16.5 but ≤ 50 kg.  A 3 vial combination will be used for patients with a body 
weight of > 50 kg but ≤ 75 kg.  A 4 vial combination will be used for patients with a body 
weight of > 75 but ≤ 100 kg.  A 5 vial combination will be used for patients with a body 
weight of > 100 kg but ≤ 125 kg.  A 6 vial combination will be used for patients with a body 
weight of > 125 kg but ≤ 150 kg.  The last recorded body weight of a patient should be 
used for calculating TCZ volume for each infusion.  The TCZ dose will be calculated 
using the Part 1 or Part 2 baseline body weight (< 30 kg or ≥ 30 kg) and will not be 
changed until a patient’s weight falls into the other body weight category on three 
separate, consecutive occasions.  The number of vials to be used for each body weight 
category is described in Table 6.   
For a 50-mL infusion bag the initial infusion speed should also be 10 mL/hr for 
15 minutes and then increased to 65 mL/hr.  Total infusion time should be no less than 
1 hour.  In order to flush the remaining study drug through the IV set, 10 mL of normal 
saline will be administered immediately following the infusion of study drug.  The volume 
of the saline flush should not be included in the total infusion volume recorded in the 
eCRF.  The time the “saline flush” is completed should be noted as the time when the 
infusion is complete. along with tThe timing of any related post-infusion blood draws (PK) 
that are required should also be noted. 
SECTION 4.2.3:  Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study (TCZ) 
during Part 1 and Part 2 will be provided by the Sponsor.  The investigational site will 
acknowledge receipt of IMPs, using the IXRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.  
SECTION 4.2.4:  Post-Trial Access to TCZ 
The Sponsor does not intendwill offer post-trial access to providethe study drug TCZ or 
other study interventionsfree of charge to eligible patients after conclusion of the study or 
any earlierin accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient withdrawal as TCZwill be eligible to receive study drug after the end of the 
study if all of the following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 

 
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A patient will not be eligible to receive study drug after the end of the study if any of 
the following conditions are met: 
• 
The study drug is commercially available marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for sJIA patients, within the countries selected to 
participate in this trial. 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for sJIA 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:  
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf. 
SECTION 4.3.1:  Permitted Therapy 
Methotrexate: 
Part 1 and 2, MTX is permitted but not required during this study.  If a patient has been 
on MTX in the past they should have discontinued MTX at least 4 weeks prior to the 
baseline visit of Part 1 and 2 of the study.  Those patients receiving MTX should have 
been taking MTX for at least 12 weeks immediately prior to the baseline visit of Part 1 
and Part 2 and should be receiving a stable dose of ≤ 20 mg/m2 for at least 8 weeks prior 
to the baseline visit of Part 1 and 2 of the study, together with at least the minimum 
recommended dose of either folic acid or folinic acid according to the local standard of 
care.  During the study, if applicable, the MTX dose may be decreased at any time for 
documented reasons of safety but not for efficacy (improvement in symptoms) during 
Part 1 and the first 12 weeks of Part 2 of the study (and until 54 consecutive Q3W 
infusions have been given).  If any patient should move to Q4W dosing, the MTX dose 
should also remain stable until 3 consecutive Q4W infusions of TCZ have been given. 
Steroids: 
There are no restrictions on the use of steroids in Part 1 of the study. 
For Part 2 of the study, Ppatients who are not currently receiving oral corticosteroids or 
are taking oral corticosteroids at a stable dose for a minimum of 2 weeks prior to the 
Part 2 baseline visit at no more than 10 mg/day or 0.2 mg/kg/day, whichever is less, are 
allowed in the study.  If patients are receiving oral corticosteroids, the dose should 
remain stable during the first 12 weeks of Part 2 (until 5 consecutive 3 weekly 
infusions have been given), and for patients moving to 4 weekly dosing, until 
3 consecutive 4 weekly infusions of TCZ have been given.   

 
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Intra-articular (IA), intramuscular (IM), IV, and long-acting corticosteroids (such as 
dexamethasone) are not permitted within 4 weeks of baseline of Part 2 or throughout 
Part 2 of the study. 
Injection of IA corticosteroids during the first 12 weeks of Part 2 of the study (and until 
45 consecutive 3 weekly infusions have been given) is strongly discouraged as these 
may affect the exploratory efficacy endpoints.  The same applies for patients moving to 
4 weekly dosing, until 3 consecutive 4 weekly infusions of TCZ have been given.  
Injections of IA corticosteroids are not permitted within 4 weeks of baseline of Part 2 of 
the study; during Part 2; a maximum of 2 joint injections will be allowed in 1 year during 
the study, and the related joint will be considered active for 3 months following the 
injection.  If an IA injection is absolutely required, no more than 1 joint should be injected 
with the smallest possible dose appropriate to the size of the joint being injected.   
Corticosteroids can be changed for reasons of safety (e.g., asthma attack, serositis) to 
maximum of 30 mg/day or 0.5 mg/kg/day prednisone or equivalent, whichever is less, for 
a maximum dosing period of < 14 days, after which the corticosteroid dosage must be 
returned to the Part 2 baseline dosage. 
NSAIDs: 
There are no restrictions on the use of NSAIDs in Part 1 of the study. 
For Part 2 of the study, Ppatients who are not taking NSAIDs, or taking no more than 
one type of NSAID at a dose that has remained stable for > 2 weeks prior to the baseline 
visit of Part 2 of the study and is less than or equal to the maximum recommended daily 
dose are included in Part 2 of the study.  The dose of NSAID must remain stable 
throughout the first 12 weeks of Part 2 of the study (and until 45 consecutive Q3W 
infusions have been given).  In addition, for patients moving to Q4W dosing, the dose of 
NSAIDs should remain stable for the first 12 weeks of Q4W dosing.  The dose may be 
lowered for documented reasons of safety and only tapered for efficacy after 
45 consecutive doses have been completed for Q3W dosing (12 weeks), and 
3 consecutive doses have been completed for Q4W dosing (12 weeks). 
Acetaminophen (Paracetamol) and Other Analgesics: 
Normal-release acetaminophen (not extended release) may be used for pain as required.  
Analgesics should not be taken within 6 hours prior to a visit where clinical efficacy 
assessments are performed in Part 2 of the study.  The administration of analgesics 
should always be recorded in the eCRF. 

 
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Iron and Folic Acid: 
Iron supplementation can be prescribed based on investigator’s assessment of 
risk−benefit for treatment of the anemia with iron.  Folic acid should be administered to 
patients receiving MTX in Part 1 and Part 2 of the study. 
Contraceptives: 
Female patients of childbearing potential should use a reliable means of contraception 
during and for a minimum of 3 months after TCZ therapy.  Patients who use oral 
contraceptives, hormone replacement therapy, or other maintenance therapy should 
continue their use. 
SECTION 4.3.2:  Prohibited Therapy  
DMARDs: 
Leflunomide is not allowed at any time during the study.  Discontinuation of leflunomide 
should be followed by standardized cholestyramine washout.  Leflunomide levels must 
be documented to be below the limit of detection prior to the baseline visit of Part 1 or 
Part 2. 
Cyclophosphamide is not permitted at any time during the study and within 3 months 
prior to the baseline visit of Part 1 or Part 2. 
Etoposide (VP16) is not permitted at any time during the study or within 3 months prior 
to the baseline visit of Part 1 or Part 2. 
Treatment with DMARDs (other than MTX) or immunosuppressants, including but not 
limited to:  hydroxychloroquine, chloroquine, gold, azathioprine, D-penicillamine, 
sulfasalazine, cyclosporine, thalidomide, or biologics (e.g., anti TNFs, anti IL 1 agents) 
must have been discontinued within 6 weeks prior to the baseline visit (Part 1 or Part 2) 
and leflunomide must have been discontinued within 12 weeks prior to the Part 1 or 
Part 2 baseline visit. 
If the patient has received previous treatment with any of the following biologic agents 
other than TCZ, these must have been discontinued according to the following timelines 
prior to the baseline visit of either Part 1 or 2, and are not permitted during the study: 
• 
Etanercept must have been discontinued within ≥ 2 weeks prior to baseline. 
• 
Anakinra must have been discontinued within ≥ 4 days prior to baseline. 
• 
Abatacept must have been discontinued within ≥ 12weeks prior to baseline. 
• 
Infliximab or adalimumab must have been discontinued within ≥ 8 weeks prior to 
baseline. 
• 
Canakinumab must have been discontinued within ≥ 20 weeks prior to baseline. 
• 
Rilonacept must have been discontinued within ≥ 6 weeks prior to baseline. 
• 
Golimumab must have been discontinued within ≥ 10 weeks prior to baseline. 

 
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• 
Certrolizumab pegol must have been discontinued within ≥ 10 weeks prior to 
baseline. 
 
IA, IM, IV, and long-acting corticosteroids (such as dexamethasone) are not permitted 
within 4 weeks of baseline of Part 2 or throughout Part 2 of the study. 
Immunoglobulin: 
Administration of IV immunoglobulin is not permitted during the entire study or within 
4 weeks prior to the baseline visit of Part 2 of the study.  For active varicella infection 
(chickenpox) or significant exposure to varicella zoster infection in a patient without a 
history of chickenpox (varicella IgG titer available from screening), varicella zoster 
immunoglobulins can be given at the discretion of the investigator. 
Hyaluronic Acid and Plasmapheresis: 
IA injections of hyaluronic acid and plasmapheresis are not permitted at any time during 
the study. 
Cell-Depleting Therapies: 
Previous treatment with any cell depleting therapy, including any investigational agents, 
(e.g., anti-CD19 and anti-CD20) or cell-depleting therapy during the study at any time 
is not permitted in the study. 
Stem Cell Transplant: 
PatientsPrevious treatment with a history of prior stem cell transplant, or stem cell 
transplant during the study at any time, are is not permitted in the study. 
Vaccines: 
Live or attenuated vaccines are not permitted within 4 weeks of the baseline visit of 
Part 1 or 2 of the study, or at any time during the study conduct, or within 12 weeks 
following the last administration of study drug.  Patients are advised to be brought up to 
date with vaccines prior to start of the study, as appropriate. 
SECTION 4.4.1.1:  Efficacy-Clinical Assessments 
For the efficacy assessments in Part 2 of the study, the baseline score will be taken as 
the assessment prior to dosing at Visit 1 Day 1 of Part 2.  Clinical measures of efficacy 
will be evaluated for patients on Q3W and Q4W TCZ as applicable. 
• 
Fever (attributable to sJIA) 
• 
JIA definition of disease flare (worsening in patients with JIA) is defined in this trial: 
Recurrence of fever or JIA flare defined as any 3 of the 6 core outcome 
variables worsening by at least 30% relative to baseline visit of Part 2, with no 
more than 1 of the remaining variables improving by more than 30% since the 
Part 2 baseline evaluation at Part 2 Visit 1, Week 0.   
 

 
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SECTION 4.4.1.2:  Medical History and Demographic Data 
Medical history and demographic data will be taken at the times indicated in the 
Schedule of Assessments for Part 1 or Part 2 of the study (see Appendix 1).  
Demographic data will be recorded as well as medical history and concomitant illnesses.  
A history of all DMARDs used in the past will be recorded, and the use of biologic 
medications will be specifically asked for.  Medical history will also include prior 
immunizations/vaccines and growth velocity. 
SECTION 4.4.1.3:  Vital Signs 
Vital signs (pulse rate, systolic, and diastolic blood pressure, and temperature) will be 
taken at the times indicated in the Schedule of Assessments in Part 1 and 2 of the 
study (see Appendix 1).  Assessments will be taken with the patient having been in a 
semi-supine position for at least 5 minutes. 
Vital signs will be taken pre-infusion, every 30 minutes during infusion, and 30 minutes 
after the infusion is completed.  All readings will be recorded in the eCRF.  Additional 
readings may be taken at the discretion of the investigator in the event of an 
infusion-related reaction (hypotension and/or fever). 
Vital signs recordings will start with the screening period and continue throughout the 
study up to and including the Week 52 visit or last dosing visit, as outlined in the 
Schedule of Assessments (see Appendix 1).  
SECTION 4.4.1.4:  Height and Weight Measurements 
Height and weight will be measured as outlined in the Schedule of Assessments in 
Part 1 and 2 of the study (see Appendix 1).  Height will be measured in a standing 
position using a wall mounted stadiometer or equivalent as per local practice.  Weight 
should be determined to the nearest 0.1 kg.  For body weight measurements, the patient 
will wear typical daytime clothes but shoes, outerwear, and accessories should be 
removed. 
SECTION 4.4.1.5:  Physical Examinations 
A general physical examination will be performed and recorded as “normal” or 
“abnormal” at the times indicated in the Schedule of Assessments in Part 1 and 2 of the 
study (see Appendix 1).… 
SECTION 4.4.1.6:  Physician’s Global Assessment of Disease Activity 
The physician’s global assessment of disease activity is the physician’s assessment of 
the patient’s current disease activity on a 100 mm horizontal VAS.  The extreme left end 
of the line should be described as “arthritis inactive” (symptom-free and no arthritis 
symptoms) and the extreme right end as “arthritis very active.”  This should be 
completed by the treating physician at the times indicated in the Schedule of 
Assessments for Part 2 of the study (see Appendix 1). 

 
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SECTION 4.4.1.7:  Joint Assessments 
The joint assessor will evaluate if the joints are swollen, tender/painful, and limited as 
per standard Rheumatology International Trials Organisation/Pediatric Rheumatology 
Collaborative Study Group (PRINTO/PRCSG) rheumatologic examination form (or 
equivalent).  The joint counts (swollen, tender/painful, limited, and active) will be 
evaluated at the times indicated in the Schedule of Assessments for Part 2 of the study 
(see Appendix 1).… 
SECTION 4.4.1.8:  Temperature 
The patient’s temperature will be taken at the times indicated in the Schedule of 
Assessments for Part 1 and 2 of the study (see Appendix 1).  Additional supplemental 
temperatures may be measured as deemed necessary.  Temperature recordings will 
start with the screening period for Part 1 and 2 of the study and continue throughout the 
study up to and including the Week 52 visit/withdrawal (WD1) or the last dosing visit as 
outlined in the schedule of assessments. 
SECTION 4.4.1.9:  Laboratory Assessments 
Samples of blood and urine will be obtained as indicated in the Schedule of 
Assessments (see Appendix 1) for the tests listed below for Part 1 and 2 of the study.  
On days when fasting labs are required (such as lipid profiles), blood samples will be 
taken after an 8-hour fast.  These visits are identified in the schedule of assessments as 
fasting labs.  Normal ranges for the local site study laboratory parameters must be 
supplied to Roche before the study starts. 
Hematology (Parts 1 and 2):  CBC:  hemoglobin, hematocrit, RBC, mean corpuscular 
volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, 
WBC and differential, platelets, reticulocytes (centrally) 
Blood chemistry (Parts 1 and 2):  AST, ALT, alkaline phosphatase, total protein, 
albumin, total, direct and indirect bilirubin, urea, uric acid, creatinine, glucose, potassium, 
sodium, chloride, calcium, phosphorous, LDH 
Urinalysis (Parts 1 and 2):  Dipstick for blood, protein and glucose (performed locally 
or microscopic examination fresh specimen sent to central laboratory, if abnormal and 
applicable), pregnancy testing when applicable (Tanner stage 2 or above or onset of 
menarche during the study) 
Screening tests (Parts 1 or 2):  Hepatitis B surface antigen, hepatitis C antibody, 
HgbA1c, high-sensitivity C-reactive protein (hsCRP), fibrinogen, Epstein-Barr virus (EBV) 
titer, varicella IgG testing, ESR 
Acute phase reactants (Part 2):  hsCRP, serum ferritin, C4, C3, ESR to be performed 
locally.  
 has defined an ESR of < 20mm/hr for both girls and boys as normal 
utilizing the 
-supplied kits). 

 
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Fibrinogen, D-dimer (Part 2): 
Lipid profile (Part 2):  Total cholesterol, HDL, LDL, triglycerides 
Immunology profile (Part 2):  IgG, immunoglobulin M, immunoglobulin A 
PK/PD (Part 2):  TCZ, IL-6, sIL-6R 
Immunogenicity assessments/anti-TCZ antibodies (Parts 1 and 2):  Anti-TCZ 
antibodies will be collected for all study patients to evaluate immunogenicity of TCZ as 
described in Section 5.1.1.6. 
SECTION 4.4.1.10:  Patient-Reported Outcomes 
PRO data will be elicited from the patients in Part 2 of the study to more fully 
characterize the clinical profile of TCZ.  The PRO instruments, translated as required in 
the local language, will be distributed by the investigator staff and completed in their 
entirety by the parent/guardian/patient.  To ensure instrument validity and that data 
standards meet health authority requirements, PRO questionnaires should be 
self-administered at the investigational site prior to the completion of other study 
assessments and the administration of study treatment. 
SECTION 4.4.1.10.1:  Childhood Health Assessment Questionnaire 
The CHAQ takes less than 10 minutes to administer and in this study the version that is 
completed by the parent or guardian will be used.  This assessment will be done at visits 
as specified in the Schedule of Assessments for Part 2 of this study (see Appendix 2). 
The form should be completed by the parent/guardian as appropriate.  To ensure 
consistency the form should be completed throughout the study by the same individual 
who completed the baseline global assessment of overall well-being (see Appendix 2). 
Disability Index 
The functional ability instrument used in Part 2 of this study for calculating the JIA flare 
is the Disability Index of the CHAQ (see Appendix 2). It is an adaptation of the Stanford 
Health Assessment Questionnaire (HAQ) for use in children.  Three components are 
evaluated:  1) difficulty in performing daily functions, 2) use of special aids, and 3) 
assistance from other people.  The CHAQ was adapted from the HAQ by adding several 
new questions, so that there is at least one question for each function that is relevant to 
children of all ages.  This way, bias due to developmental difference can be minimized. 
Parent’s/Patient’s Global Overall Well-BeingAssessment of Disease 
Activity 
The patient’s overall assessment of their current disease activity overall well-being is 
recorded on a 100 mm horizontal visual analogue scale (VAS) in Part 2 of this study.  
The left-hand extreme of the line should be described as “very well” (symptom-free and 
no arthritis symptoms) and the right-hand extreme as “very poor” (maximum arthritis 
disease activity).   

 
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Parental/Patient Pain Index 
In addition to the Disability Index, in the CHAQ (see above) there is a Pain Index, which 
is measured separately in Part 2 of this study.  The level of pain is determined by the 
presence of pain, which is measured on a 100 mm horizontal VAS.  This scale is 
anchored at the left-hand extreme of the line as “no pain” and the right-hand extreme as 
“very severe pain.”   
SECTION 4.4.1.11:  PPD and Chest Radiograph (CXR) 
Patients will have a PPD test (5 TU) (or equivalent as per local practice, 
e.g., Quantiferon gold) performed at screening (of Part 1 or 2 of the study) unless a 
negative PPD has already been documented within the last year.  Those patients with a 
positive PPD at screening may not participate in the study unless they have initiated 
therapy for latent TB for at least 4 weeks prior to baseline with the remaining course of 
therapy continuing during study participation, and have negative a chest X ray for active 
disease within 6 months of screening, as per local practice requirements.  The PPD test 
will be considered positive according to the local guidelines for immunosuppressed 
patients.  The definition of a positive PPD test may be applied as determined by the 
clinical circumstances and investigator according to published guidelines and/or local 
standards endorsed by the medical society.  If no published guidelines are available for 
a given country outside the United States, the U.S. guidelines must be followed.  
Patients will have a TB screening test per local standard (e.g., PPD skin test or 
Quantiferon® test).  
A chest X-ray (CXR) is required under the following conditions: 
• 
If a patient’s TB testing is positive at screening (of Part 1 or Part 2) and the 
patient has not previously received TB treatment, then a CXR is required at 
screening.   
• 
If a patient eventually is enrolled (Part 1 or Part 2), TCZ administration would be 
delayed until the patient has received at least 4 weeks of TB treatment therapy per 
exclusion criteria. 
 
A chest x-Ray may be required under the following conditions: 
• 
If a patient’s TB testing is negative at screening (of Part 1 or 2), then a CXR 
should be done if consistent with local requirements but is not strictly required.  
 
A chest X-ray is not required under the following conditions: 
• 
If a patient’s TB testing is positive and the patient has previously completed TB 
treatment or has been receiving TB treatment for at least 4 weeks prior to receiving 
TCZ and has had a negative CXR ≤ 6 months of screening (of Part 1 or 2), then 
he/she is eligible to enroll without repeat CXR at screening (if consistent with local 
practice requirements).   

 
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• 
A CXR obtained ≤ 90 days of baseline (of Part 1 or 2) can be utilized for screening 
purposes, if consistent with local practices. 
 
Patients asked to participate in this study will have received corticosteroid therapy and 
often other immunosuppressive drugs.  It has been reported that the PPD response 
alone is not always sufficient for screening children with JIA for TB 
(Kasapcopur et al. 2006).  In addition, patients with significant cardiac abnormalities are 
excluded from study participation (see Section 4.1.2, Exclusion Criteria for General 
Safety20).  As a result, a negative chest radiograph is required at the time that TCZ 
therapy was or is initiated, or as per local practice requirements.  The chest radiograph 
should be interpreted by a board-certified radiologist and the interpretation should 
include a statement of the following at a minimum: 
 
SECTION 4.4.2.1:  Screening and Pretreatment Assessments 
Patients whose guardian has given written informed consent will undergo a thorough two 
screening examinations: one within 4 weeks before the start of the Part 1 (Screening 
Evaluation 1, for patients entering Part 1) and one within 4 weeks of Part 2 of the 
study (Screening Evaluation 2, for patients entering into Part 2 directly, or entering 
Part 2 via Part 1).  TCZ infusions may continue to be received during the sScreening 
periodEvaluation 2, but there must be at least 10 days clear between the last TCZ 
infusion during screening and the first study TCZ infusion received at baseline.  During 
the Screening Evaluation visits 1 and 2 (for patients entering the study via Part 1 or 
Part 2)( visit(s), inclusion/exclusion criteria will be checked, a medical examination 
(including ; and demographics, medical history, concomitant medication, medications, 
demographics, and complete, physical examination), body, height and weight, vital signs 
and temperature, and; laboratory safety tests (screening labs [hepatitis B surface 
antigen, hepatitis C antibody, HgbA1c, hsCRP, fibrinogen, EBV titer, and varicella IgG, 
and ESR]; hematology; blood chemistry, and; urine pregnancy [female patients who are 
able to become pregnant]) will all be performed; TB screening and chest X-ray (if 
applicable) will also be performed.  The CHAQ score, the number of joints with active 
arthritis and number of joints with limited range of motion (joint assessment), global 
assessment of the severity of the disease by the physician (physician global), and global 
assessment of overall well-being by the patient or parent (patient/parent global) will also 
be evaluated at Screening Evaluation 2 as per the schedule of assessments (see 
Appendix 1).     
Patients must fulfill all entry criteria to be accepted into the study.  Patients who fail to 
meet the entry criteria may be rescreened once for Part 1 or Part 2 of the study, at the 
discretion of the investigator. 
Patients, who have experienced a laboratory abnormality that has subsequently resolved 
during Part 1, may be screened to enter the Part 2.  If a patient fails Screening 
Evaluation 2, the patient may continue participating in Part 1 (returns to Part 1 at the 
visit after their last visit) up to 24 weeks.  If the patient is still not eligible for Part 2 

 
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after 24 weeks, the patient will be withdrawn from Part 1 and attend the Part 1 
withdrawal visits.  However if the patient experiences the relevant laboratory 
requirements (per Table 5) after discontinuing the study while on commercial TCZ, 
they may be rescreened once for Part 2 of the study at the discretion of the investigator.  
Patients can be screened for Part 2 a total of two times. 
Under no circumstances will patients who enroll in Part 1 or Part 2 this study and have 
completed treatment as specified, be permitted to re-enroll into the same part of in the 
study.  However, patients who have participated in Part 1 without meeting eligibility 
criteria for Part 2 may be rescreened for Part 2 (see above).    
See Appendix 1 for the schedule of screening and pretreatment assessments for Part 1 
and Part 2. 
SECTION 4.4.2.2:  Assessments during Treatment 
See Appendix 1 for the Schedule of Assessments performed during the treatment period 
in Part 1 and Part 2. 
SECTION 4.4.2.3:  Assessments at Study Completion/Early Termination 
Visit 
Patients who complete all infusion visits in the study in Part 1 and Part 2 as outlined in 
the Schedule of Assessments, or discontinue from the study early, will be asked to 
return to the clinic 2 weeks after the last dose of study drug for a follow-up visit (WD1) 
and then subsequently 2 weeks later for WD2, another 4 weeks later for WD3 and a 
further 4 weeks later for WD4.  If the investigator withdraws a patient due to sJIA flare 
or fever attributable to sJIA, tThe visit at which JIA flare assessment shows flare of 
disease may be used as the study completion/early termination visit. 
See Appendix 1 for the Schedule of Assessments performed at the study 
completion/early termination visit for Part 1 and 2. 
SECTION 4.4.2.4:  Follow-up Assessments 
After the study completion/early termination visit, adverse events should be followed as 
outlined in Section 5.5 and Section 5.6 for Part 1 and Part 2 of the study. 

 
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SECTION 4.5.1:  Patient Discontinuation 
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time (Part 1 and 2).  In addition, patients have the right to 
voluntarily discontinue study drug or withdraw from the study at any time for any reason.  
Reasons for discontinuation of study drug or withdrawal from the study may include, but 
are not limited to, the following: 
 
SECTION 4.5.1.1:  Discontinuation from Study Drug 
Patients must discontinue the study drug if they experience any of the following at any 
time (Part 1 and 2): 
• 
sJIA flare (Part 2 only and at the discretion of the investigator) 
• 
Fever attributable to sJIA (Part 2 only and at discretion of investigator) 
 
In the case that the patient prematurely discontinues from the study the 
parents/guardians should be asked if they can still be contacted for further information.  
The outcome of that discussion should be documented in both the medical records and 
in the eCRF.  If lost to follow up, the investigator should contact the patient’s 
parents/guardian or a responsible relative by telephone followed by registered mail or 
through a personal visit to establish as completely as possible the reason for the 
withdrawal.  A complete final evaluation at the time of the patient’s withdrawal should be 
made with an explanation of why the patient is withdrawing from the study. 
SECTION 4.5.1.2:  Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study in both Part 1 and Part 2.  Parents/guardians should be asked if they can still be 
contacted for further information.  The primary reason for withdrawal from the study 
should be documented on the appropriate eCRF.   
If lost to follow-up, the investigator should contact the patient’s parents/guardian or a 
responsible relative by telephone followed by registered mail or through a personal visit 
to establish as completely as possible the reason for the withdrawal.  A complete final 
evaluation at the time of the patient’s withdrawal should be made with an explanation 
of why the patient is withdrawing from the study.  
SECTION 5.1:  SAFETY PLAN 
The safety of patients in Part 1 and Part 2 of the study will be assessed by physical 
examination, assessment of vital signs, screening for TB and treatment as applicable, 
laboratory assessments (see Section 4), and the collection of adverse events. 
SECTION 5.1.1.:  Adverse Events of Special Interest and Risk Mitigation 
StrategiesRisks associated with TCZ Therapy and Risk 
Mitigation Strategies 
This section describes the known and potential risks of TCZ therapy, and risk 
mitigation strategies that should be followed during this study (Part 1 and Part 2). 

 
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Adherence to the planned dose regimen of TCZ is required unless an adjustment is 
necessary for safety reasons.  The following risk mitigation and dose modification rules 
apply to patients receiving the study drug in Part 1 and 2 of the study.  
Recommendations for vigilance with signs and symptoms of particular safety events of 
interest are summarized in the following sections.  For study visits (Part 1 and Part 2) at 
which the study drug dose is held due to toxicity, all other study assessments should be 
performed as per study schedule.  For management of neutropenia, thrombocytopenia, 
and elevated liver enzymes in the study, see Section 3.1.2.   
SECTION 5.1.1.6:  Hypersensitivity or Anaphylaxis 
…A blood sample for the presence of anti-TCZ antibodies should be obtained (refer to 
the schedule of assessments).  The patient must be withdrawn from Part 1 or 2 of the 
study. 
Samples for aAnti-TCZ antibodies, TCZ PK, and sIL-6R will be collected for all study 
patients to evaluate immunogenicity of TCZ at baseline and Week 24 for patients on 
Q2W in Part 1; baseline, Week 6, 12, 24, 36, and 48 (for patients on Q3W dosing in 
Part 2) or and at baseline, 8 weeks, and 12 weeks after switching to Q4W  Week 8 (for 
patients on Q4W dosing in Part 2) and at the last study visit, or at the time of early 
withdrawal from the study (visit  WD1) for Part 1 or Part 2.  Event-driven sampling (at 
the time of the event and also at least 6 weeks after the last dose) will occur for all 
patients experiencing serious infusion-related or allergic reactions or any hypersensitivity 
event (including non-serious events) leading to treatment withdrawal in Part 1 or Part 2.   
SECTION 5.1.2:  Laboratory Test Abnormalities 
Laboratory test results in Part 1 and Part 2 of the study will be recorded on the 
laboratory results e-form of the eCRF, or appear on electronically produced laboratory 
reports submitted directly from the central laboratory, if applicable.… 
The following laboratory abnormalities are considered exempt from the above, and 
should not be recorded as adverse events in the eCRF:  serum amyloid A, serum ferritin, 
hsCRP and ESR. 
SECTION 5.2.3:  Non Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) 
Non serious All adverse events of special interest are required to be reported by the 
investigator to the Sponsor within 24 hours after learning of the event (see Section 5.4.2 
for reporting instructions).   
Adverse events of special interest for this study include the following: 
• 
Suspected transmission of an infectious agent by the study drug (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 

 
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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.). 
• 
Adverse events of special interest for Actemra in this study are provided in the 
current AESI guidance document.  
• 
Infections, including all opportunistic infections, and non serious infections as 
defined by those treated with IV anti infectives)  
• 
Myocardial infarction/acute coronary syndrome 
• 
GI perforations and related events 
• 
Malignancies 
• 
Anaphylaxis/hypersensitivity reactions 
• 
Demyelinating disorders 
• 
Stroke 
• 
Bleeding events 
• 
Hepatic events 
 
SECTION 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, parent or guardian, or noted by study 
personnel, will be recorded in the patient’s medical record and on the Adverse Event 
eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies; 
see Section 5.4.2 for instructions for reporting serious adverse events). 
SECTION 5.3.4:  Assessment of Causality of Adverse Events 
For patients receiving TCZ in combination with other therapiesy, causality to TCZ will 
be assessed for TCZ individually for each protocol mandated therapy. 
SECTION 5.3.5.3:  Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens.  If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.  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 should be 
updated by changing the event from "non-serious" to "serious," providing the date that 

 
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26/Protocol WA28029, Version 3 
the event became serious, and completing all data fields related to serious adverse 
events. 
SECTION 5.3.5.10:  Hospitalization or Prolonged Hospitalization 
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. 
 
SECTION 5.3.5.11:  Adverse Events Associated with an Overdoses or Error 
in Drug Administration 
SECTION 5.4:  IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
The investigator must report the following events to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Non serious aAdverse events of special interest (see Section 5.4.2 for further 
details)  
• 
Pregnancies (see Section 5.4.3 for further details) 
 
SECTION 5.4.2.1:  Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 3 months after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
EDC system.  A report will be generated and sent to Roche Safety Risk Management by 
the 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 e-mailing the form with 
use of the fax number or e-mail 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. 
SECTION 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 90 days after the last dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator within 
24 hours after learning of the pregnancy and submitted via the EDC system.  A 
pregnancy report will automatically be generated and sent to Roche Safety Risk 

 
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Management.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  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 fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy 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 pregnancy), 
either by faxing or by scanning and e-mailing the form with use of the fax number or 
e-mail address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. a Pregnancy 
Report worksheet and Pregnancy Fax Coversheet should be completed and faxed to 
Roche Safety Risk Management or its designee within 24 hours after learning of the 
pregnancy, using the fax numbers provided to investigators (see "Protocol Administrative 
and Contact Information and List of Investigators"). 
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Safety data will be presented for the safety population and efficacy data will be 
presented for the all TCZ population.  All patients in Part 1 will commence treatment 
with the TCZ Q2W regimen; all patients in Part 2 will commence treatment with a 
Q3W dosing frequency regimen.   
Basic safety reporting will occur for Part 1 of the study and full reporting (including 
PK, PD, and efficacy assessments) will occur for Part 2. 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
Part 2 of the study will enroll patients already receiving TCZ who have experienced a 
predefined laboratory abnormality on Q2W TCZ.  A sample size of approximately 
20 patients in Part 2 who complete 5 consecutive Q3W treatments up to Week 12 has 
been deemed adequate for the objectives of this study.  In addition, 20 patients in Part 2 
would ensure 95% probability of observing at least one adverse event when the 
underlying incidence of that event is ≥ 14%. 
In addition to the 6 patients enrolled in Part 2 as of May 2015 (under Protocol 
Version 2), approximately an additional 65 patients will be enrolled into Part 1 of the 
study (under Protocol Version 3).  On investigation of Study WA18221 data, it was 
found that 46% (52 of 112) of patients experienced a resolved laboratory abnormality 
on TCZ Q2W, per the Part 2 entry criteria at any point during the study:  25% 
(28 of 112) of TCZ naive patients during the study from 0-6 months, and 31% 
(32 of 102) of TCZ non-naive patients between Months 12 and 18 in the study.  Based 
on these percentages, 65 patients enrolled in the run-in period of this study (Part 1) 

 
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will result in approximately 16-20 TCZ naive/non-naive patients eligible for Part 2, 
which when added to the 6 patients currently enrolled in Part 2, will result in 
approximately 20 patients in Part 2, even taking into account the JADAS (and absence 
of fever attributable to sJIA) entry requirement for Part 2, and the possibility of 
withdrawals.  
The study will enroll a minimum of 20 patients already receiving TCZ who have 
experienced a predefined laboratory abnormality at any time on Q2W TCZ prior to 
enrolment in the study.  A sample size of approximately 20 patients who complete 
4 consecutive Q3W treatments up to Week 12 has been deemed adequate for the 
objectives of this study.  In addition, a sample size of 20 would ensure 95% probability of 
observing at least one adverse event when the underlying incidence of that event 
is ≥ 14%. 
SECTION 6.3:  SUMMARIES OF TREATMENT GROUP COMPARABILITY 
No formal assessment of treatment group comparability will be performed.  All patients 
will receive TCZ, dose determined based on weight (8 mg/kg ≥ 30 kg or 12 mg/kg < 30 kg) 
and given TCZ Q2W (Part 1), and then TCZ Q3W (Part 2) and Q4W (for those patients 
who experience a repeat laboratory abnormality during Part 2).  All baseline data, 
including demographics, baseline characteristics, patient disposition, infusion data, and 
concurrent treatment, will be summarized.  No testing of baseline characteristics will be 
performed. 
Part 1 Baseline is defined as the first dose of TCZ received in Part 1 of the study.  
Part 2 baseline is defined as the first dose of TCZ received in Part 2 of the study (see 
Appendix 1 for the schedule of assessments). 
SECTION 6.4:  EFFICACY ANALYSES 
No formal hypothesis testing is planned for this study.  All efficacy data will be presented 
descriptively.  Summaries by visit will be presented for the all TCZ population (all 
patients to commence treatment with a Q3W dosing frequency regimen at baseline of 
Part 2 [Week 0]).  In addition, separate subgroup summaries for patients moving on to a 
Q4W dosing frequency regimen during the study will be produced if sufficient data exists.  
Data will be summarized from the first Q4W dosing visit.  All summaries will be based on 
observed case data.  No imputation of missing data will be performed. 
Assessment of efficacy will be based on JADAS-71 scores during Part 2 of the study 
and assessment of fever (attributable to sJIA). 
JIA flare relative to Part 2 baseline will be assessed at each visit in Part 2 to determine 
if a patient should be withdrawn based on lack of efficacy at the discretion of the 
investigator.  Component scores in the assessment of JIA flare (physician global 
assessment of disease activity [100 mm horizontal VAS], patient/parent global 
assessment of overall well-being [100 mm horizontal VAS], number of joints with active 

 
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arthritis [0−71], number of joints with limitation of movement, CHAQ, and ESR) will be 
summarized or listed as appropriate. 
SECTION 6.5:  SAFETY ANALYSES 
Safety will be assessed based on reporting of adverse events, vital signs, clinical 
laboratory assessments, concomitant medications, and physical examination (for Part 1 
and Part 2 of the study separately).  All safety data will be reported based on the safety 
population and will be listed or summarized descriptively as appropriate.  Full details of 
all safety reporting will be provided in the SAP. 
SECTION 6.6:  PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Nonlinear mixed effects modeling (using NOMMEM software) (Beal et al. 1992) will be 
used to analyze the serum TCZ concentration-time data collected in this study in Part 2 
of the study.  The current PK model developed for sJIA patients from previous studies 
(Studies MRA316JP, LRO320, and WA18221) will be used to analyze the serum TCZ 
concentration-time data. 
The following systemic exposure parameters will be estimated for all patients who 
provide adequate PK samples: 
• 
AUCτ during a dosing interval at week 12 of Part 2; τ = 3 weeks for Q3W and 
τ = 4 weeks for Q4W 
• 
Cmax post infusion at Week 12 of Part 2 
• 
Cmin at end of a dosing interval at Week 12 of Part 2 
 
SECTION 6.7:  PATIENT-REPORTED OUTCOMES 
PROs in this study include the CHAQ questionnaire (see Section 4.4.1.10.1 and 
Appendix 2) and the patient/parent global assessment of overall well-being 100 mm 
horizontal VAS.  The left-hand extreme of the line should be described as “very well” 
(symptom-free and no arthritis symptoms) and the right-hand extreme as “very poor” 
(maximum arthritis disease activity), which are all part of the 6 core JIA American 
College of Rheumatology components.  Data will be summarized or listed as appropriate. 
SECTION 9.4:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Authorship will be determined by mutual agreement (with the Paediatric Rheumatology 
International Trials Organisation (PRINTO at www.printo.it) and the Pediatric 
Rheumatology Collaborative Study Group (PRCSG at www.prcsg.org) 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. 
FIGURE 1:  Overview of Study Design 
Figure 1 has been updated to reflect changes to the protocol. 

 
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TABLE 2:  Neutropenia Management 
Table 2 has been updated to reflect changes to the protocol. 
TABLE 3:  Thrombocytopenia Management 
Table 3 has been updated to reflect changes to the protocol. 
TABLE 4:  Management of Elevated Liver Enzymes 
Table 4 has been updated to reflect changes to the protocol. 
TABLE 5:  Laboratory Abnormalities Serving as Inclusion Criteria for Part 2 
When Experienced (with Resolution) on Q2W2 Weekly TCZ 
 
APPENDIX 1:  Schedule of Assessments  
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
 

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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 37 
PROTOCOL SYNOPSIS .................................................................................... 38 
1. 
BACKGROUND .......................................................................................... 47 
1.1 
Background on Systemic Juvenile Idiopathic 
Arthritis (sJIA)........................................................................ 47 
1.2 
Background on Tocilizumab .................................................. 47 
1.3 
Study Rationale and Benefit–Risk Assessment..................... 48 
2. 
OBJECTIVES FOR PART 2........................................................................ 50 
2.1 
Efficacy Objective.................................................................. 50 
2.2 
Safety Objective .................................................................... 50 
2.3 
Pharmacodynamic Objective................................................. 50 
2.4 
Pharmacokinetic Objective .................................................... 50 
2.5 
Patient-Reported Outcome Objectives .................................. 50 
3. 
STUDY DESIGN ......................................................................................... 50 
3.1 
Description of Study .............................................................. 50 
3.1.1 
Overview................................................................................ 50 
3.1.2 
Management of Laboratory Abnormalities and 
TCZ Dose Frequency ............................................................ 53 
3.1.2.1 
Hematologic Abnormalities.................................................... 54 
3.1.2.2 
Elevated Liver Enzymes ........................................................ 56 
3.1.3 
Criteria for Withdrawal from the Study................................... 58 
3.2 
End of Study.......................................................................... 58 
3.3 
Rationale for Study Design.................................................... 58 
3.3.1 
Rationale for Test Product Dosage........................................ 58 
3.4 
Outcome Measures ............................................................... 59 
3.4.1 
Efficacy Outcome Measures.................................................. 59 
3.4.2 
Safety Outcome Measures .................................................... 59 
3.4.3 
Pharmacokinetic and Pharmacodynamic 
Outcome Measures ............................................................... 59 
3.4.4 
Patient-Reported Outcome Measures ................................... 59 

 
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4. 
MATERIALS AND METHODS .................................................................... 59 
4.1 
Patients.................................................................................. 59 
4.1.1 
Inclusion Criteria.................................................................... 60 
4.1.2 
Exclusion Criteria................................................................... 61 
4.2 
Study Treatment.................................................................... 63 
4.2.1 
Formulation, Packaging, and Handling.................................. 64 
4.2.1.1 
Tocilizumab ........................................................................... 64 
4.2.2 
Dosage, Administration, and Compliance.............................. 64 
4.2.2.1 
Tocilizumab ........................................................................... 64 
4.2.3 
Investigational Medicinal Product Accountability ................... 66 
4.2.4 
Post-Trial Access to TCZ....................................................... 66 
4.3 
Concomitant Therapy ............................................................ 67 
4.3.1 
Permitted Therapy ................................................................. 67 
4.3.2 
Prohibited Therapy ................................................................ 69 
4.4 
Study Assessments ............................................................... 70 
4.4.1 
Description of Study Assessments ........................................ 70 
4.4.1.1 
Efficacy-Clinical Assessments............................................... 70 
4.4.1.2 
Medical History and Demographic Data ................................ 72 
4.4.1.3 
Vital Signs.............................................................................. 72 
4.4.1.4 
Height and Weight Measurements ........................................ 72 
4.4.1.5 
Physical Examinations........................................................... 72 
4.4.1.6 
Physician’s Global Assessment of Disease 
Activity ................................................................................... 73 
4.4.1.7 
Joint Assessments................................................................. 73 
4.4.1.8 
Temperature.......................................................................... 73 
4.4.1.9 
Laboratory Assessments ....................................................... 73 
4.4.1.10 
Patient-Reported Outcomes .................................................. 75 
4.4.1.11 
PPD and Chest Radiograph .................................................. 75 
4.4.2 
Timing of Study Assessments ............................................... 77 
4.4.2.1 
Screening and Pretreatment Assessments............................ 77 
4.4.2.2 
Assessments during Treatment............................................. 78 
4.4.2.3 
Assessments at Study Completion/Early 
Termination Visit.................................................................... 78 
4.4.2.4 
Follow-Up Assessments ........................................................ 78 

 
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4.5 
Patient, Study, and Site Discontinuation................................ 79 
4.5.1 
Patient Discontinuation.......................................................... 79 
4.5.1.1 
Discontinuation from Study Drug........................................... 79 
4.5.1.2 
Withdrawal from Study........................................................... 79 
4.5.2 
Study and Site Discontinuation.............................................. 80 
5. 
ASSESSMENT OF SAFETY....................................................................... 81 
5.1 
Safety Plan ............................................................................ 81 
5.1.1 
Risks associated with TCZ Therapy and Risk 
Mitigation Strategies .............................................................. 81 
5.1.1.1 
Opportunistic Infections and Serious Infections..................... 81 
5.1.1.2 
Gastrointestinal Perforations ................................................. 82 
5.1.1.3 
Demyelinating Disorders........................................................ 82 
5.1.1.4 
Cardiovascular Events and Elevated Lipids........................... 82 
5.1.1.5 
Malignancies.......................................................................... 83 
5.1.1.6 
Hypersensitivity or Anaphylaxis............................................. 83 
5.1.2 
Laboratory Test Abnormalities............................................... 84 
5.1.2.1 
Laboratory Test Abnormalities Suggestive of 
MAS....................................................................................... 84 
5.2 
Safety Parameters and Definitions ........................................ 85 
5.2.1 
Adverse Events ..................................................................... 85 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 86 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 86 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 87 
5.3.1 
Adverse Event Reporting Period ........................................... 87 
5.3.2 
Eliciting Adverse Event Information ....................................... 88 
5.3.3 
Assessment of Severity of Adverse Events ........................... 88 
5.3.4 
Assessment of Causality of Adverse Events ......................... 88 
5.3.5 
Procedures for Recording Adverse Events............................ 89 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 89 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 89 

 
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5.3.5.3 
Persistent or Recurrent Adverse Events................................ 90 
5.3.5.4 
Abnormal Laboratory Values ................................................. 90 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 91 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 91 
5.3.5.7 
Deaths ................................................................................... 92 
5.3.5.8 
Preexisting Medical Conditions.............................................. 92 
5.3.5.9 
Lack of Efficacy or Worsening of sJIA ................................... 92 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 92 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 93 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 93 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 94 
5.4.1 
Emergency Medical Contacts................................................ 94 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 95 
5.4.2.1 
Events That Occur after Study Drug Initiation........................ 95 
5.4.3 
Reporting Requirements for Pregnancies.............................. 96 
5.4.3.1 
Pregnancies in Female Patients............................................ 96 
5.4.3.2 
Abortions ............................................................................... 96 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 96 
5.5 
Follow-Up of Patients after Adverse Events .......................... 96 
5.5.1 
Investigator Follow-Up........................................................... 96 
5.5.2 
Sponsor Follow-Up ................................................................ 97 
5.6 
Post-Study Adverse Events................................................... 97 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 97 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 98 
6.1 
Determination of Sample Size ............................................... 98 
6.2 
Summaries of Conduct of Study............................................ 99 
6.3 
Summaries of Treatment Group Comparability ..................... 99 
6.4 
Efficacy Analyses .................................................................. 99 
6.5 
Safety Analyses................................................................... 100 

 
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6.6 
Pharmacokinetic AND Pharmacodynamic 
Analyses.............................................................................. 100 
6.7 
Patient-Reported Outcomes ................................................ 101 
6.8 
Interim Analyses.................................................................. 101 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 101 
7.1 
Data Quality Assurance....................................................... 101 
7.2 
Electronic Case Report Forms............................................. 102 
7.3 
Source Data Documentation................................................ 102 
7.4 
Use of Computerized Systems ............................................ 102 
7.5 
Retention of Records........................................................... 103 
8. 
ETHICAL CONSIDERATIONS.................................................................. 103 
8.1 
Compliance with Laws and Regulations .............................. 103 
8.2 
Informed Consent ................................................................ 103 
8.3 
Institutional Review Board or Ethics Committee.................. 104 
8.4 
Confidentiality...................................................................... 105 
8.5 
Financial Disclosure ............................................................ 105 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 105 
9.1 
Study Documentation .......................................................... 105 
9.2 
Site Inspections ................................................................... 106 
9.3 
Administrative Structure....................................................... 106 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 106 
9.5 
Protocol Amendments ......................................................... 107 
10. REFERENCES ......................................................................................... 108 

 
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LIST OF TABLES 
Table 1 
Guidelines Per Current E.U. SmPC and USPI Labels for 
Managing Laboratory Abnormalities ........................................... 49 
Table 2 
Neutropenia Management .......................................................... 55 
Table 3 
Thrombocytopenia Management ................................................ 56 
Table 4 
Management of Elevated Liver Enzymes.................................... 57 
Table 5 
Laboratory Abnormalities Serving as Inclusion Criteria for 
Part 2 When Experienced (with Resolution) on Q2W TCZ ......... 61 
Table 6 
Tocilizumab Dosage ................................................................... 65 
Table 7 
Adverse Event Severity Grading Scale ....................................... 88 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design........................................................... 53 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 110 
Appendix 2 
Childhood Health Assessment Questionnaire (CHAQ) 
(Example Only-Not for Use)...................................................... 119 
Appendix 3 
Definition of MAS (Macrophage Activation Syndrome) ............. 122 

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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IV STUDY TO EVALUATE 
DECREASED DOSE FREQUENCY IN 
PATIENTS WITH SYSTEMIC JUVENILE 
IDIOPATHIC ARTHRITIS (SJIA) WHO 
EXPERIENCE LABORATORY 
ABNORMALITIES DURING TREATMENT WITH 
TOCILIZUMAB 
PROTOCOL NUMBER: 
WA28029 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2012-000444-10 
IND NUMBER: 
11972 
TEST PRODUCT: 
Tocilizumab (RO4877533) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the original form in your study files.  Please return a copy to the study monitor. 
 

 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IV STUDY TO EVALUATE DECREASED DOSE 
FREQUENCY IN PATIENTS WITH SYSTEMIC JUVENILE 
IDIOPATHIC ARTHRITIS (SJIA) WHO EXPERIENCE 
LABORATORY ABNORMALITIES DURING TREATMENT WITH 
TOCILIZUMAB 
PROTOCOL NUMBER: 
WA28029 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2012-000444-10 
IND NUMBER: 
11972 
TEST PRODUCT: 
Tocilizumab (RO4877533) 
PHASE: 
IV 
INDICATION: 
systemic Juvenile Idiopathic Arthritis (sJIA) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
Objectives 
Efficacy Objective 
The primary efficacy objective for Part 2 of this study is as follows: 
• 
To explore the efficacy of tocilizumab (TCZ) in reduced dosing frequency regimens (every 
3 weeks [Q3W] and every 4 weeks [Q4W], as appropriate) using Juvenile Arthritis Disease 
Activity Score (JADAS)-71, JIA flare, and fever (attributable to systemic Juvenile 
Idiopathic Arthritis [sJIA]) 
 
Safety Objective 
The safety objective for Part 2 of this study is as follows: 
• 
To evaluate the safety of TCZ in reduced dosing frequency regimens 
 
Pharmacodynamic Objective 
The primary pharmacodynamic (PD) objective for Part 2 of this study is as follows: 
• 
To describe the pharmacodynamics, using sIL-6R and C-reactive protein (CRP), and 
immunogenicity of TCZ in reduced dosing frequency regimens 
 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for Part 2 of this study is as follows: 
• 
To describe the pharmacokinetics of TCZ in reduced dosing frequency regimens 
 
Patient-Reported Outcome Objectives 
The patient-reported outcome (PRO) objectives for Part 2 of this study are as follows: 
• 
To describe the Child Health Assessment Questionnaire (CHAQ) outcomes with TCZ in 
reduced dosing frequency regimens 
• 
To describe parent/patient global assessment of overall well-being with TCZ in reduced 
dosing frequency regimens 
 

 
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Study Design 
Description of Study 
This is a 96-week, two part, Phase IV study to explore the efficacy, safety, pharmacokinetics, 
pharmacodynamics, and immunogenicity of TCZ in reduced dosing frequency regimens in 
patients with adequately controlled sJIA (JADAS Minimal Disease Activity cut-off of 3.8 at 
screening and baseline for Part 2 who have experienced a laboratory abnormality which has 
resolved (per inclusion criteria in protocol) on TCZ twice weekly dosing.  
Run-In Phase (Part 1) 
At the Screening Evaluation 1 (see protocol), TCZ naive patients or TCZ non-naive patients 
who fulfil all eligibility criteria for Screening Evaluation 1 may enter the open-label run-in 
phase (Part 1) and receive TCZ dosed by body weight (12 mg/kg for patients < 30 kg; 8 mg/kg 
for patients ≥ 30 kg) by IV infusion every 2 weeks [Q2W] for up to 24 weeks or until they 
experience a laboratory abnormality of neutropenia, thrombocytopenia, or liver enzyme 
abnormality as per the criteria provided in the protocol.  The TCZ dose will be calculated 
using the baseline body weight (< 30 kg or ≥ 30 kg) and will not be changed until a patient’s 
weight falls into the other body weight category on three separate, consecutive occasions in 
Part 1.  Patients will be assessed Q2W for safety.  No reductions or changes of concomitant 
methotrexate [MTX] dosing can occur during Part 1 of the study (i.e., due to improvement or 
worsening of symptoms) except for documented safety reasons.   
Patients who do not experience a laboratory abnormality in Part 1, or experience a laboratory 
abnormality but do not meet the eligibility criteria for Part 2, will complete Part 1 through to 
Week 24, followed by the Part 1 withdrawal visits. 
Main Study (Part 2)  
Patients on TCZ Q2W who have experienced a laboratory abnormality (per protocol; either 
during Part 1 or prior to the study) that has subsequently resolved, who have adequate 
disease control, and who fulfil all the inclusion criteria and none of the exclusion criteria of 
Screening Evaluation Part 2, may enter the main study (Part 2).  Once patients have entered 
Part 2 of the study, they will receive TCZ dosed by body weight (12 mg/kg for patients < 30 kg; 
8 mg/kg for patients ≥ 30 kg) by IV infusion Q3W for a minimum of 5 consecutive infusions.  The 
dose will be calculated using Part 2 baseline body weight and will not be changed during the 
first 12 weeks of the Part 2 of the study.  Patients on Q3W will be assessed for safety and 
efficacy responses.  No reductions or changes of concomitant NSAIDs, corticosteroids, or MTX 
dosing can occur during the first 12 weeks of Part 2 of the study (and until 5 consecutive Q3W 
infusions have been given) except for documented safety reasons, including laboratory 
abnormalities.  In addition, the doses of NSAIDs, corticosteroids, and MTX should remain stable 
in any patient who moves to Q4W dosing, during the first 12 weeks of Q4W dosing. 
In Part 2, each patient will start and maintain Q3W dosing of TCZ in the study up to 52 weeks 
unless the patient experiences an event of neutropenia, thrombocytopenia, or liver enzyme 
abnormality as per the criteria provided in protocol.  Following the occurrence and resolution of 
this laboratory abnormality, patients who have maintained adequate disease control (JADAS 
≤ 3.8 and absence of fever attributable to sJIA) will move to Q4W dosing of TCZ.  Patients who 
have not completed a minimum of 5 consecutive Q3W infusions will remain on Q3W dosing until 
5 consecutive Q3W doses have been completed before moving to Q4W dosing.  If during this 
time, a patient should experience any additional laboratory abnormalities as per the criteria 
provided in the protocol, he or she may move directly to Q4W dosing after resolution, at the 
discretion of the investigator, and the Sponsor must be notified. 
Patients who move to Q4W dosing of TCZ because of an event of neutropenia, 
thrombocytopenia, or liver enzyme abnormality will remain on Q4W dosing for the remainder of 
the study. 
Patients who do not meet the criteria to switch from Q3W to Q4W will complete Part 2 
through to Week 52, followed by the Part 2 withdrawal visits. 
Patients who experience a JIA flare or fever attributable to sJIA (see definition in the protocol) at 
any time during Part 2 may be withdrawn from the study at the discretion of the investigator.   
Patients will undergo safety and safety laboratory assessments during Part 1 of the study.  
Safety, safety laboratory, PK, PD, and efficacy assessments will be performed during Part 2 
as described in the schedule of assessments.  During Part 1, and after the first 12 weeks of 

 
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Part 2 of the study, the dose of TCZ can be adjusted according to changes in body weight:  if a 
patient’s body weight increases above 30 kg on 3 consecutive visits (while it was below 30 kg at 
baseline for Part 1 or Part 2, respectively), on the third visit the dose of TCZ will be decreased 
to 8 mg/kg; if a patient’s body weight decreases below 30 kg (while it was above 30 kg at 
baseline for Part 1 or Part 2, respectively) on 3  consecutive visits, the dose of TCZ will be 
increased on the third visit to 12 mg/kg. 
All patients who are discontinued from Part 1 or Part 2 of the study for any reason must return 
for the Withdrawal Visit 1 and follow-up safety assessments, Withdrawal Visits 2, 3, and 4 up to 
and including 12 weeks after the last administration of study drug.  They may be required to 
return for visits beyond 12 weeks after discontinuation from treatment with TCZ for safety 
reasons (to be documented in the electronic Case Report Form [eCRF] and interactive voice 
response system [IXRS]). 
Number of Patients 
Approximately 65 patients will be enrolled in the Part 1 with an aim to enroll 20 patients into 
Part 2 of the study.   
Target Population 
Inclusion Criteria 
Part 1 and Part 2 
All patients entering Part 1 or entering Part 2 without participating in Part 1 must meet the 
following criteria for entry into Part 1 or Part 2: 
• 
Aged 2 years up to and including 17 years at screening into trial 
• 
sJIA according to International League of Associations for Rheumatology (ILAR) 
classification (2001) 
• 
sJIA symptoms lasting for at least 1 month since diagnosis of sJIA  
• 
Fertility: 
For female patients of reproductive potential (unless surgically sterile with 
absence of ovaries and/or uterus): agreement to remain abstinent or use single or 
combined contraceptive methods that result in a failure rate of < 1% per year 
during the treatment period and for at least 6 months after the last dose of TCZ 
Abstinence is acceptable only if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not acceptable 
methods of contraception. 
Examples of contraceptive methods with a failure rate of < 1% per year 
include tubal ligation; male sterilization; hormonal implants; established, 
proper use of combined oral or injected hormonal contraceptives; and certain 
intrauterine devices.  Alternatively, two methods (e.g., two barrier methods, 
such as a condom and a cervical cap) may be combined to achieve a failure 
rate of < 1% per year.  Barrier methods must always be supplemented with 
the use of a spermicide. 
For male patients of reproductive potential: agreement to remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of < 1% per year during the treatment period and for at least 
6 months after the last dose of TCZ 
Abstinence is acceptable only if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not acceptable 
methods of contraception. 
• 
Must meet one of the following: 
Not receiving MTX or discontinued MTX at least 4 weeks prior to the Part 1 or 
Part 2 baseline visit, or 
Taking MTX for at least 12 weeks immediately prior to the Part 1 or Part 2 
baseline visit and on a stable dose of ≤ 20 mg/m2 for at least 8 weeks prior to the 

 
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Part 1 or Part 2 baseline visit, together with either folic acid or folinic acid 
according to local standard of care 
• 
Written informed consent for study participation obtained from parent or legal guardian, with 
assent as appropriate by the patient, depending on the level of the patient’s understanding 
• 
Parental or guardian written agreement to comply with the requirements of the study 
protocol 
 
Patients entering Part 1 who are naïve to TCZ therapy must also meet the following 
inclusion criterion: 
• 
History of inadequate clinical response (in the opinion of the treating physician) to 
NSAIDs and corticosteroids 
 
Part 2 
All patients entering Part 2 (either directly without participating in Part 1, or via Part 1) 
must meet the following additional criteria for entry into Part 2: 
• 
JADAS-71 score of 3.8 or less and absence of fever (related to sJIA) at screening and 
baseline of Part 2  
• 
Neutropenia, thrombocytopenia, or elevated ALT/AST (as per criteria in protocol) previously 
experienced (and resolved) on the labeled dose (Q2W) of TCZ  
• 
Not currently receiving oral corticosteroids, or taking oral corticosteroids at a stable dose 
for a minimum of 2 weeks prior to the Part 2 baseline visit at no more than 10 mg/day or 
0.2 mg/kg/day, whichever is less 
• 
Not taking NSAIDs, or taking no more than one type of NSAID at a stable dose for a 
minimum of 2 weeks prior to the Part 2 baseline visit, with the dose being less than or 
equal to the maximum recommended daily dose 
 
Exclusion Criteria 
Patients entering Part 1, or entering Part 2 without participating in Part 1, who meet any of 
the following criteria will be excluded from study entry: 
General 
• 
Wheelchair bound or bedridden 
• 
Any other auto-immune, rheumatic disease, or overlap syndrome other than sJIA 
• 
Not fully recovered from recent surgery or less than 6 weeks since surgery, at the time of 
screening visit; or planned surgery during Part 1 and the initial 12 weeks of Part 2 of the 
study (for patients entering Part 1) or the initial 12 weeks of Part 2 of the study (for 
patients entering Part 2 without participating in Part 1) 
• 
Lack of peripheral venous access 
 
General Safety 
• 
Pregnant, lactating, or intending to become pregnant during study conduct and up to 
6 months after the last administration of study drug 
• 
Any significant concurrent medical or surgical condition which would jeopardize the patient’s 
safety or ability to complete the trial 
• 
History of significant allergic or infusion reactions to prior TCZ infusion, and/or presence of 
anti-TCZ antibodies by confirmatory and/or neutralizing assay at screening 
• 
Inborn conditions characterized by a compromised immune system 
• 
Known HIV infection or other acquired forms of immune compromise 
• 
History of alcohol, drug, or chemical abuse within 6 months of screening 
• 
Evidence of serious uncontrolled concomitant diseases, including but not limited to the 
nervous, renal, hepatic, or endocrine systems 

 
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• 
Any active acute, subacute, chronic, or recurrent bacterial, viral, or systemic fungal infection 
including but not limited to: 
Acute or chronic renal / bladder infections 
Acute or chronic pulmonary infections 
• 
History of atypical tuberculosis (TB) 
• 
Active TB requiring treatment within 2 years prior to the screening visit 
• 
Positive purified protein derivative (PPD) at screen (or equivalent result based on local 
methodology, e.g., Quantiferon gold), unless treated with anti-TB therapy for at least 
4 weeks prior to receiving study drug and chest radiograph is negative for active TB within 
6 months of screening visit according to local practice 
• 
Any major episode of infection requiring hospitalization or treatment during screening or 
treatment with IV antibiotics completing within 4 weeks of the screening visit or oral 
antibiotics completing within 2 weeks of the screening visit 
• 
History of reactivation or new onset of a systemic infection, such as herpes zoster or 
Epstein Barr virus, within 2 months of the screening visit 
• 
Hepatitis B surface Antigen or hepatitis C Ab positive 
• 
Chronic hepatitis⎯viral or autoimmune 
• 
Significant cardiac [e.g., congenital heart disease, valvular heart disease, constrictive 
pericarditis (unrelated to sJIA), myocarditis] or pulmonary disease, (e.g., asthma for which 
the patient has required the use of oral or parenteral corticosteroids for ≥ 2 weeks within 
6 months prior to the baseline visit of Part 1 or Part 2, or cystic fibrosis) 
• 
History or concurrent serious gastrointestinal (GI) disorders, such as ulcer or inflammatory 
bowel disease, Crohn’s disease, ulcerative colitis, or other symptomatic lower GI conditions, 
including ulcer and perforation 
• 
History of or current cancer or lymphoma 
• 
Uncontrolled diabetes mellitus with elevated hemoglobin (Hgb) A1c as defined by 
age-specific standards 
• 
History of macrophage activation syndrome (MAS) within 3 months prior to the screening 
visit 
 
Excluded Previous or Concomitant Therapy 
• 
Participation in another interventional clinical trial within the past 30 days or 5 serum 
half-lives of the investigative medication or the PD effect of the investigative medication, 
whichever is longer 
• 
Prior stem cell transplant at any time 
• 
Prohibited therapy as described in protocol 
 
Laboratory Exclusions at Screening 
• 
Serum creatinine > 1.5 × upper limit of normal (ULN) (for age and sex) 
• 
Hemoglobin < 7.0 g/dL (< 4.3 mmol/L) 
 
The following additional laboratory exclusion criteria apply to patients entering Part 1 of the 
study who are TCZ-naive and are initiating therapy with TCZ: 
• 
AST or ALT > 1.5 ULN (upper limit of normal for age and sex) 
• 
Total bilirubin > 1.3 mg/dL (> 23 μmol/L) 
• 
Platelet count < 150 x 103/μL (< 150,000/mm3) 
• 
WBC count < 5,000/mm3 (< 5.0 x 109/L) 
• 
Neutrophil count < 2,500/ mm3 (< 2.5 x 109/L) 
 

 
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Length of Study 
The total length of this study will be approximately 6 years and 1 month from screening of the 
first patient to completion of the last patient visit.  For an individual patient the length of time in 
the study (from screening to completion) may be up to 96 weeks (i.e., Part 1 screening up to 
4 weeks, Part 1 up to 24 weeks, Part 2 screening up to 4 weeks, Part 2 up to 52 weeks, 
followed by safety follow-up to 12 weeks).    
End of Study 
The end of the study will occur when the last participating patient completes the last scheduled 
visit in the study, or if the Sponsor decides to discontinue the study.   
Efficacy Outcome Measures 
The efficacy outcome measures for Part 2 of this study are as follows: 
• 
JADAS-71 will be utilized to describe efficacy in patients on Q3W and Q4W dosing as 
appropriate in this study 
• 
JIA flare relative to baseline of Part 2 will be used to determine those patients not 
maintaining efficacy who can be withdrawn from the study at the discretion of the 
investigator 
• 
Fever (attributable to sJIA) will be measured at each study visit of Part 2 in patients on 
Q3W and Q4W dosing (as  appropriate) to describe efficacy and to determine patients not 
maintaining efficacy who can be withdrawn from the study at the discretion of the 
investigator 
 
Safety Outcome Measures 
The safety outcome measures in Part 1 and 2 for this study are as follows: 
• 
Adverse events (including adverse events of special interest) 
• 
Serious adverse events 
• 
Clinical laboratory results 
Pharmacodynamic and Pharmacokinetic Outcome Measures 
The PK/PD outcome measures for Part 2 of the study are as follows: 
• 
Serum TCZ concentration and population PK model predicted PK exposures (area under 
the serum concentration-time profile [AUCτ], maximum concentration observed [Cmax], and 
minimum concentration under steady-state conditions within a dosing interval [Cmin]) for 
Q3W and Q4W dosing regimens as appropriate 
• 
Serum IL-6 and sIL-6R levels and inflammatory markers (CRP and erythrocyte 
sedimentation rate [ESR]) 
• 
Anti-TCZ antibodies 
 
Patient-Reported Outcome Measures 
The PRO outcome measures for this Part 2 of the study are as follows: 
• 
The CHAQ 
• 
Parents/patients global assessment of overall well-being 
 
Investigational Medicinal Products 
TCZ (200 mg/10 mL) vial (concentrate for solution for infusion) RO 487-7533/F01 will be 
supplied.  Study drug packaging will be overseen by the Roche clinical trial supplies department 
and will include a label with the identification required by local law, the protocol number, drug 
identification and dosage.  The packaging and labeling of the study drug will be in accordance 
with Roche standard and local regulations.  The study drug must be stored according to the 
details on the product label.   
All TCZ vials must be stored at a controlled temperature of 2°C−8°C, and handled according to 
Good Manufacturing Practice and Good Clinical Practice procedures.   

 
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For further details, see the most recently published version of the Investigator's Brochure for 
TCZ. 
Statistical Methods 
Basic safety reporting will occur for Part 1 of the study and full reporting (including efficacy, 
PK, and PD assessments) will occur for Part 2. 
Efficacy Analysis 
No formal hypothesis testing is planned for this study.  All efficacy data will be presented 
descriptively.  Summaries by visit will be presented for the all TCZ population (all patients to 
commence treatment with a Q3W dosing frequency regimen at baseline of Part 2 [Week 0]).  In 
addition, separate subgroup summaries for patients moving on to a Q4W dosing frequency 
regimen during the study will be produced if sufficient data exists.  Data will be summarized 
from the first Q4W dosing visit.  All summaries will be based on observed case data.  No 
imputation of missing data will be performed. 
Full details of all planned efficacy analyses will be provided in the SAP. 
Assessment of efficacy will be based on JADAS-71 during Part 2 of the study and assessment 
of fever (attributable to sJIA). 
JIA flare relative to Part 2 baseline will be assessed at each visit in Part 2 to determine if a 
patient should be withdrawn based on lack of efficacy at the discretion of the investigator.  
Component scores in the assessment of JIA flare (physician global assessment of disease 
activity [100 mm horizontal VAS], patient/parent global assessment of overall well-being 
[100 mm horizontal VAS], number of joints with active arthritis [0−71], number of joints with 
limitation of movement, CHAQ, and ESR) will be summarized or listed as appropriate. 
Determination of Sample Size   
The purpose of this study is to explore the efficacy, safety, pharmacokinetics, 
pharmacodynamics, and immunogenicity of TCZ in a reduced dosing frequency regimen in 
patients with adequately controlled sJIA who have experienced a predefined resolved laboratory 
abnormality on TCZ Q2W dosing.  This is a non-powered, descriptive study. 
Part 2 of the study will enroll patients already receiving TCZ who have experienced a 
predefined laboratory abnormality on Q2W TCZ.  A sample size of approximately 20 patients 
in Part 2 who complete 5 consecutive Q3W treatments up to Week 12 has been deemed 
adequate for the objectives of this study.  In addition, 20 patients in Part 2 would ensure 95% 
probability of observing at least one adverse event when the underlying incidence of that 
event is ≥ 14%. 
In addition to the 6 patients enrolled in Part 2 as of May 2015 (under Protocol Version 2), 
approximately an additional 65 patients will be enrolled into Part 1 of the study (under 
Protocol Version 3).  On investigation of Study WA18221 data, it was found that 46% (52 of 
112) of patients experienced a resolved laboratory abnormality on TCZ Q2W, per the Part 2 
entry criteria at any point during the study:  25% (28 of 112) of TCZ naive patients during 
the study from 0-6 months, and 31% (32 of 102) of TCZ non-naive patients between Months 
12 and 18 in the study.  Based on these percentages, 65 patients enrolled in the run-in period 
of this study (Part 1) will result in approximately 16-20 TCZ naive/non-naive patients 
eligible for Part 2, which when added to the 6 patients currently enrolled in Part 2, will 
result in approximately 20 patients in Part 2, even taking into account the JADAS (and 
absence of fever attributable to sJIA) entry requirement for Part 2, and the possibility of 
withdrawals. 
Interim Analyses 
Interim analyses may be performed at the discretion of the sponsor, for regulatory reporting 
purposes. 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AUCτ 
area under the serum concentration-time profile 
CHAQ 
Childhood Health Assessment Questionnaire 
Cmax 
maximum concentration observed 
Cmin 
minimum concentration under steady-state conditions 
within a dosing interval 
CRP 
C-reactive protein 
CXR 
chest X-ray 
DMARDs 
disease modifying anti-rheumatic drugs 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EBV 
Epstein-Barr virus 
EDC 
electronic data capture 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HAQ 
Health Assessment Questionnaire 
Hgb 
hemoglobin 
hsCRP 
high-sensitivity C-reactive protein 
IA 
intra-articular 
ICH 
International Conference on Harmonisation 
IL 
interleukin 
ILAR 
International League of Associations for Rheumatology 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
Investigational New Drug application 
IXRS 
interactive voice response system 
IRB 
Institutional Review Board 
IV 
intravenous 
JADAS 
Juvenile Arthritis Disease Activity Score 
JIA 
juvenile idiopathic arthritis 
MAS 
macrophage activation syndrome 
MTX 
methotrexate 
NCEP 
National Cholesterol Education Program 
NSAID 
nonsteroidal anti-inflammatory drug 

 
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Abbreviation 
Definition 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPD 
purified protein derivative 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
RA 
rheumatoid arthritis 
SAP 
statistical analysis plan 
sIL-6 
soluble interleukin-6 
sJIA 
systemic Juvenile Idiopathic Arthritis 
TB 
tuberculosis 
TCZ 
tocilizumab 
TNF 
tumour necrosis factor 
ULN 
upper limit of normal 
USPI 
U.S. Prescribing Information 
VAS 
visual analogue scale 
WD 
withdrawal 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON SYSTEMIC JUVENILE IDIOPATHIC 
ARTHRITIS (SJIA) 
Systemic Juvenile Idiopathic Arthritis (sJIA) is a subset of juvenile idiopathic arthritis 
(JIA), which comprises between 10% and 20% of all cases of JIA.  sJIA is characterized 
by arthritis of at least 6 weeks duration accompanied by fever of at least 2 weeks 
duration and extra-articular features, with onset under the age of 16 years and no 
identifiable cause.  The onset of fever can precede the development of arthritis by a few 
weeks to several years, although most patients have arthritis at disease onset.  Patients 
with sJIA may follow a monocyclic course with complete remission within 2 years of 
disease onset, a polycyclic course characterized by exacerbations of systemic disease, 
or a course of persistent polyarthritis.  The mean duration of active disease is 5 to 
6 years, but some patients have persistent disease well into their adult years.  sJIA has 
the highest mortality rate among all subsets of JIA (Cassidy 2001).  The increased 
mortality is principally due to macrophage activation syndrome (MAS) and infections 
(Ravelli and Martini 2007).   
Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticosteroids are used for 
symptomatic treatment of sJIA and pulses of intravenous (IV) methylprednisolone have 
been found to be effective against clinical and biological parameters of inflammation.  It 
remains unclear whether these treatments prevent progressive joint destruction. 
Methotrexate (MTX) is the most commonly used second-line agent but its benefit 
remains unclear.  Anakinra, a receptor antagonist to interleukin (IL)-1, has met with 
some success for the treatment of the systemic complaints associated with sJIA but has 
not been utilized as frequently as expected due to the daily requirements for a 
subcutaneous injection (Haines 2007).  Canakinumab is an antagonist to the cytokine 
IL-1β and was approved in the EU in September 2013 for the treatment of sJIA in 
patients aged 2 years and older who have responded inadequately to previous therapy 
with NSAIDs and systemic corticosteroids.  Cyclosporin is used primarily for MAS.  
Tocilizumab (TCZ) is approved for the treatment of active sJIA in the European Union, 
United States, Japan, and other regions (Summary of Product Characteristics for 
RoACTEMRA; U.S. Prescribing Information [USPI] for ACTEMRA® [tocilizumab]).   
1.2 
BACKGROUND ON TOCILIZUMAB 
The clinical and laboratory features of sJIA are suggestive of a cytokine-mediated 
process (Woo 2000).  Patients with sJIA have been found to have significantly elevated 
soluble IL-6 (sIL-6) levels during active disease but not during remission 
(De Benedetti et al. 1991; Keul 1998).  During active disease, patients with sJIA 
demonstrate fluctuations in serum IL-6 that parallel the classical daily fever (Prieur 1996).  
sIL-6 levels have been found to correlate with the extent and severity of joint 
involvement and with platelet counts (De Benedetti et al. 1991), and elevations in sIL-6 
have been associated with growth stunting in sJIA (De Benedetti et al. 1997).  The large 

 
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quantities of sIL-6 present in IL-6/sIL-6R complexes have been found to be of biological 
relevance in vivo (De Benedetti et al. 1994).   
TCZ (RO4877533) is a recombinant, humanized, anti-human monoclonal antibody of the 
IgG1 sub-class directed against the sIL-6R and membrane-IL-6R (Tocilizumab 
[RO4877533] Investigator’s Brochure).  It inhibits the function of IL-6.  IL-6 is a 
pleiotropic cytokine, present at elevated levels in patients with rheumatoid arthritis (RA) 
(Tocilizumab [RO4877533] Investigator’s Brochure).  IL-6 signaling involves both a 
specific IL-6R and a ubiquitous signal-transducing protein, gp130, that is also utilized by 
other members of the IL-6 family.  The biological activities of IL-6 contribute to both 
systemic and local arthritis symptoms.  The ability of IL-6 to induce B-cell differentiation 
may lead to the formation of rheumatoid factor and other autoantibodies.  In joints, IL-6 
promotes osteoclast activation and induces the release of matrix metalloproteinases, 
thus contributing to joint damage.  In patients with RA or sJIA, IL-6 levels correlate with 
markers of disease activity and clinical symptoms, and animal studies support the 
concept that this cytokine plays a role in the development of inflammatory arthritis.  
Clinical trials with TCZ have shown that blocking IL-6 signaling reduces RA and sJIA 
symptoms and markers of disease activity.  Current evidence thus strongly supports the 
association between IL-6 and RA and sJIA (Tocilizumab [RO4877533] Investigator’s 
Brochure).   
TCZ IV has been approved in more than 110 countries, including Japan, the European 
Union, and the United States, for use in adult patients with moderately to severely active 
RA who have an inadequate response to one or more disease-modifying anti-rheumatic 
drugs (DMARDs) including tumor necrosis factor (TNF) antagonists (Summary of 
Product Characteristics for RoACTEMRA; ACTEMRA®, English-Translated Version 7; 
USPI for ACTEMRA® [tocilizumab]).  Additionally, TCZ was approved for use in JIA, sJIA, 
and Castleman’s disease in India and Japan (ACTEMRA®, English Translated 
Version 7).  TCZ is approved for the treatment of active sJIA arthritis in patients 2 years 
of age and older in several countries, including Japan, India, Switzerland, Mexico, the 
European Union and the United States.  In the United States and European Union, the 
approved dose regimen is 8 mg/kg every 2 weeks (Q2W) for sJIA patients weighing 
≥ 30 kg and 12 mg/kg Q2W for sJIA patients weighing < 30 kg (Summary of Product 
Characteristics for RoACTEMRA; USPI for ACTEMRA® [tocilizumab]). 
See the most recently published Tocilizumab Investigator's Brochure for details on 
nonclinical and clinical studies (Tocilizumab [RO4877533] Investigator’s Brochure).   
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
The efficacy and safety of TCZ in children with sJIA was demonstrated in the pivotal 
study, WA18221.  In addition, supportive data are available from three completed 
Japanese studies; MRA316JP, a Phase III study; MRA317JP, a long-term extension 
study; and MRA324JP, an expanded-use study.  Results from study WA18221 and 
supportive data led to the approval of TCZ for treatment of children with active sJIA in 

 
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the European Union, United States, and other regions (Tocilizumab [RO4877533] 
Investigator’s Brochure). 
TCZ treatment is associated with certain laboratory abnormalities, including 
thrombocytopenia, neutropenia, and liver enzyme abnormalities.  Current 
recommendations in sJIA are to stop TCZ dosing until the laboratory abnormality 
resolves as shown in Table 1 (Tocilizumab [RO4877533] Investigator’s Brochure).  The 
purpose of this study is to investigate the use of less frequent dosing upon reinitiating 
treatment in patients who have achieved a high level of efficacy with TCZ but have 
experienced these laboratory abnormalities. 
Table 1 
Guidelines Per Current E.U. SmPC and USPI Labels for Managing 
Laboratory Abnormalities 
Neutropenia 
ANC > 1.0 × 109/L 
• 
Maintain dose 
ANC 0.5 to 1.0 × 109/L 
• 
Interrupt TCZ 
• 
When ANC increases to > 1.0 × 109/L resume TCZ 
ANC < 0.5 × 109/L 
• 
Discontinue TCZ 
Thrombocytopenia 
Platelets 50 to 100 × 109/L 
• 
Dose modify concomitant MTX if appropriate 
• 
Interrupt TCZ 
• 
When platelet count is > 100 × 109/L resume TCZ 
Platelets < 50 × 109/L 
• 
Discontinue TCZ 
Elevated Liver Enzymes 
ALT/AST > 1 to 3 × ULN 
• 
Dose modify MTX if appropriate 
• 
For persistent increases in this range, interrupt TCZ until 
ALT/AST have normalized. 
ALT/AST > 3 to 5 × ULN 
• 
Dose modify MTX if appropriate 
• 
Interrupt TCZ dosing until < 3 × ULN and follow 
recommendations above for > 1 to 3 × ULN 
ALT/AST > 5 × ULN 
• 
Discontinue TCZ 
MTX = methotrexate; SmPC = Summary of Product Characteristics; TCZ = tocilizumab; 
ULN = upper limit of normal; USPI = United States product insert. 
 
Patients who have experienced a laboratory abnormality on Q2W TCZ may benefit from 
reducing their TCZ dose by increasing the interval between doses to 3 or 4 weeks. 
Increasing the TCZ dosing interval carries the risk of underexposure to drug leading to 
disease flare or MAS but the likelihood of this is reduced in this study by recruiting 
patients into Part 2 with good disease control and reducing the dosing interval in a 

 
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controlled stepwise manner (to every 3 weeks [Q3W] then every 4 weeks [Q4W] if 
required). 
2. 
OBJECTIVES FOR PART 2 
2.1 
EFFICACY OBJECTIVE 
The primary efficacy objective for Part 2 of this study is as follows: 
• 
To explore the efficacy of TCZ in reduced dosing frequency regimens (Q3W and 
Q4W, as appropriate) using Juvenile Arthritis Disease Activity Score (JADAS)-71, 
JIA flare, and fever (attributable to sJIA) 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for Part 2 of this study is as follows: 
• 
To evaluate the safety of TCZ in reduced dosing frequency regimens 
 
2.3 
PHARMACODYNAMIC OBJECTIVE 
The primary pharmacodynamic (PD) objective for Part 2 of this study is as follows: 
• 
To describe the pharmacodynamics, using sIL-6R and C-reactive protein (CRP), 
and immunogenicity of TCZ in reduced dosing frequency regimens 
 
2.4 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for Part 2 of this study is as follows: 
• 
To describe the pharmacokinetics of TCZ in reduced dosing frequency regimens 
 
2.5 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objectives for Part 2 of this study are as follows: 
• 
To describe the Child Health Assessment Questionnaire (CHAQ) outcomes with 
TCZ in reduced dosing frequency regimens 
• 
To describe parent/patient global assessment of overall well-being with TCZ in 
reduced dosing frequency regimens 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview 
This is a 96-week, 2 part, Phase IV study to explore the efficacy, safety, 
pharmacokinetics, pharmacodynamics, and immunogenicity of TCZ in reduced dosing 
frequency regimens in patients with adequately controlled sJIA (JADAS Minimal Disease 
Activity cut-off of 3.8 at screening and baseline for Part 2 who have experienced a 
laboratory abnormality which has resolved (per inclusion criteria in Section 4.1.1) on 
TCZ twice weekly dosing.   

 
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Run-In Phase (Part 1) 
At the Screening Evaluation 1 (see Appendix 1-A), TCZ naive patients or TCZ 
non-naive patients who fulfil all eligibility criteria for Screening Evaluation 1 may 
enter the open-label run-in phase (Part 1) and receive TCZ dosed by body weight 
(12 mg/kg for patients < 30 kg; 8 mg/kg for patients ≥ 30 kg) by IV infusion Q2W for 
up to 24 weeks or until they experience a laboratory abnormality of neutropenia, 
thrombocytopenia, or liver enzyme abnormality as per the criteria provided in Table 5.  
The TCZ dose will be calculated using the baseline body weight (< 30 kg or ≥ 30 kg) and 
will not be changed until a patient’s weight falls into the other body weight category on 
three separate, consecutive occasions in Part 1.  Patients will be assessed Q2W for 
safety.  No reductions or changes of concomitant MTX dosing can occur during Part 1 
of the study (i.e., due to improvement or worsening of symptoms) except for 
documented safety reasons.   
Patients who do not experience a laboratory abnormality in Part 1, or experience a 
laboratory abnormality but do not meet the eligibility criteria for Part 2, will complete 
Part 1 through to Week 24, followed by the Part 1 withdrawal visits. 
Main Study (Part 2)  
Patients on TCZ Q2W who have experienced a laboratory abnormality (per Table 5; 
either during Part 1 or prior to the study) that has subsequently resolved, who have 
adequate disease control, and who fulfil all the inclusion criteria and none of the 
exclusion criteria of Screening Evaluation Part 2, may enter the main study (Part 2).  
Once patients have entered Part 2 of the study, they will receive TCZ dosed by body 
weight (12 mg/kg for patients < 30 kg; 8 mg/kg for patients ≥ 30 kg) by IV infusion Q3W 
for a minimum of 5 consecutive infusions.  The dose will be calculated using Part 2 
baseline body weight and will not be changed during the first 12 weeks of the Part 2 of 
the study.  Patients on Q3W will be assessed for safety and efficacy responses.  No 
reductions or changes of concomitant NSAIDs, corticosteroids, or MTX dosing can occur 
during the first 12 weeks of Part 2 of the study (and until 5 consecutive Q3W infusions 
have been given) except for documented safety reasons, including laboratory 
abnormalities.  In addition, the doses of NSAIDs, corticosteroids, and MTX should 
remain stable in any patient who moves to Q4W dosing, during the first 12 weeks of 
Q4W dosing. 
In Part 2, each patient will start and maintain Q3W dosing of TCZ in the study up to 
52 weeks unless the patient experiences an event of neutropenia, thrombocytopenia, or 
liver enzyme abnormality as per the criteria provided in Section 3.1.2.  Following the 
occurrence and resolution of this laboratory abnormality, patients who have maintained 
adequate disease control (JADAS ≤ 3.8 and absence of fever attributable to sJIA) will 
move to Q4W dosing of TCZ.  Patients who have not completed a minimum of 
5 consecutive Q3W infusions will remain on Q3W dosing until 5 consecutive Q3W doses 
have been completed before moving to Q4W dosing.  If during this time, a patient should 
experience any additional laboratory abnormalities as per the criteria provided in 

 
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Section 3.1.2, he or she may move directly to Q4W dosing after resolution, at the 
discretion of the investigator, and the Sponsor must be notified. 
Patients who move to Q4W dosing of TCZ because of an event of neutropenia, 
thrombocytopenia, or liver enzyme abnormality will remain on Q4W dosing for the 
remainder of the study. 
Patients who do not meet the criteria to switch from Q3W to Q4W will complete Part 2 
through to Week 52, followed by the Part 2 withdrawal visits. 
Patients who experience a JIA flare or fever attributable to sJIA (see definition in 
Section 4.5.1.1) at any time during Part 2 may be withdrawn from the study at the 
discretion of the investigator.   
Patients will undergo safety and safety laboratory assessments during Part 1 of the 
study.  Safety, safety laboratory, PK, PD, and efficacy assessments will be performed 
during Part 2 as described in the schedule of assessments (see Appendix 1).  During 
Part 1, and after the first 12 weeks of Part 2 of the study, the dose of TCZ can be 
adjusted according to changes in body weight:  if a patient’s body weight increases 
above 30 kg on 3 consecutive visits (while it was below 30 kg at baseline for Part 1 or 
Part 2, respectively), on the third visit the dose of TCZ will be decreased to 8 mg/kg; if a 
patient’s body weight decreases below 30 kg (while it was above 30 kg at baseline for 
Part 1 or Part 2, respectively) on 3  consecutive visits, the dose of TCZ will be increased 
on the third visit to 12 mg/kg. 
All patients who are discontinued from Part 1 or Part 2 of the study for any reason must 
return for the Withdrawal Visit 1 and follow-up safety assessments, Withdrawal Visits 2, 
3, and 4 up to and including 12 weeks after the last administration of study drug.  They 
may be required to return for visits beyond 12 weeks after discontinuation from treatment 
with TCZ for safety reasons (to be documented in the electronic Case Report Form 
[eCRF] and interactive voice response system [IXRS]). 
Figure 1 below provides an overview of Phase IV of this study design. 

 
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Figure 1 Overview of Study Design  
 
JIA = juvenile idiopathic arthritis; TCZ = tocilizumab; Q2W = every 2 weeks; Q3W = every 3 weeks; 
Q4W = every 4 weeks. 
* Patients who do not experience a laboratory abnormality in Part 1, or experience a 
laboratory abnormality but do not meet the eligibility criteria for Part 2, will complete 
Part 1 through to Week 24 followed by the Part 1 withdrawal visits. 
** Patients who have experienced a predefined laboratory abnormality on commercially 
available Q2W TCZ that has resolved, and have a JADAS ≤ 3.8 and who meet all other 
eligibility criteria, can directly enter Part 2. 
 
The schedule of assessments is provided in Appendix 1. 
3.1.2 
Management of Laboratory Abnormalities and TCZ Dose 
Frequency 
Decreases in neutrophil and platelet counts and elevations in ALT and AST have been 
observed following treatment with TCZ (approximately 40% of patients experienced at 
least 1 of these laboratory abnormalities in the first year of the WA18221 study).   

 
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Management of neutropenia, thrombocytopenia, and elevated liver function tests to be 
implemented in this protocol for patients in Part 1 and Part 2 are summarized below.  
For patients taking other concomitant medications associated with hematologic or 
hepatic toxicity, the reduction or interruption of the suspected medication is 
recommended prior to modifying TCZ.  If any of the laboratory criteria in Section 3.1.2.1 
and Section 3.1.2.2 are met, MAS must be excluded (see Appendix 3). 
3.1.2.1 
Hematologic Abnormalities 
For patients in Part 1 and Part 2, the laboratory abnormality guidance in Table 2 and 
Table 3 should be followed.  Patients experiencing a JIA flare or fever attributable to 
sJIA should be withdrawn from the study (at the discretion of the investigator). 

 
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If total bilirubin is > 3 mg/dL do not dose study drug (repeat bilirubin, liver function tests 
[including AST, ALT] in 1 week).  If bilirubin returns to below the upper limit of normal 
(ULN) continue TCZ infusions.  Discontinuation of treatment is recommended if 
2 consecutive total bilirubin values taken at least 1 week apart are > 3 mg/dL. 
If any of the above abnormal laboratory criteria are met, MAS must be excluded.  Cases 
of MAS will be treated according to standard of care for treatment of MAS per the 
investigator’s discretion, and the Sponsor must be notified. 
If a liver biopsy is performed for any reason, the biopsy report should be forwarded to 
Roche.  The prepared histologic slides will be requested by Roche and centrally 
reviewed by a third party.  Patients who are 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. 
3.1.3 
Criteria for Withdrawal from the Study 
Patients who experience a JIA flare or fever attributable to sJIA relative to baseline of 
Part 2 (as per the definition provided in Section 4.4.1.1) at any visit in Part 2 of the 
study may be withdrawn from the study at the discretion of the investigator. 
Patients who experience any adverse event that in the opinion of the investigator or the 
Sponsor precludes further study participation (in Part 1 or 2) will be withdrawn from the 
study. 
3.2 
END OF STUDY 
The end of the study will occur when the last participating patient completes the last 
scheduled visit in the study, or if the Sponsor decides to discontinue the study.   
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Test Product Dosage 
In this study, doses of 8 mg/kg for patients ≥ 30 kg and 12 mg/kg for patients < 30 kg will 
be used, as per the approved global TCZ sJIA label.  
In Part 2 of the study, instead of being given Q2W, TCZ will be administered IV every 
3 or 4 weeks for up to 1 year in patients who have previously experienced at least one 
laboratory abnormality on the previous Q2W dose regimen (either in Part 1 or on 
commercial TCZ prior to entry into Part 2).  Efficacy, safety, pharmacokinetics, 
pharmacodynamics, and immunogenicity will be assessed upon reduction of dosing 
frequency in these patients. 

 
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3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for Part 2 of this study are as follows: 
• 
JADAS-71 will be utilized to describe efficacy in patients on Q3W and Q4W dosing 
as appropriate in this study (as per Section 4.4.1.1) 
• 
JIA flare relative to baseline of Part 2 will be used to determine those patients not 
maintaining efficacy who can be withdrawn from the study at the discretion of the 
investigator (as per Section 4.5.1.1) 
• 
Fever (attributable to sJIA) will be measured at each study visit of Part 2 in 
patients on Q3W and Q4W dosing (as  appropriate) to describe efficacy and to 
determine patients not maintaining efficacy who can be withdrawn from the study at 
the discretion of the investigator (as per Section 4.5.1.1 and Section 4.5.1.2). 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures in Part 1 and 2 of this study are as follows: 
• 
Adverse events (including adverse events of special interest) 
• 
Serious adverse events 
• 
Clinical laboratory results 
 
3.4.3 
Pharmacokinetic and Pharmacodynamic Outcome Measures 
The PK/PD outcome measures for Part 2 of the study are as follows: 
• 
Serum TCZ concentration and population PK model predicted PK exposures (area 
under the serum concentration-time profile [AUCτ], maximum concentration 
observed [Cmax], and minimum concentration under steady-state conditions within a 
dosing interval [Cmin]) for Q3W and Q4W dosing regimens as appropriate 
• 
Serum IL-6 and sIL-6R levels and inflammatory markers (CRP and erythrocyte 
sedimentation rate [ESR]) 
• 
Anti-TCZ antibodies 
 
3.4.4 
Patient-Reported Outcome Measures 
The PRO outcome measures for Part 2 of the study are as follows: 
• 
The CHAQ (see Appendix 2) 
• 
Parents/patients global assessment of overall well-being 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Children aged 2 years up to and including aged 17 years with sJIA ≥ 1 month and 
currently receiving TCZ who have experienced a predefined, resolved laboratory 
abnormality (see Section 4.1.1, Inclusion Criteria Part 2) during TCZ Q2W treatment will 
be eligible to participate in Part 2 of the study.   

 
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4.1.1 
Inclusion Criteria 
Part 1 and Part 2 
All patients entering Part 1 or entering Part 2 without participating in Part 1 must 
meet the following criteria for entry into Part 1 or Part 2: 
• 
Aged 2 years up to and including 17 years at screening into trial 
• 
sJIA according to International League of Associations for Rheumatology (ILAR) 
classification (2001) 
• 
sJIA symptoms lasting for at least 1 month since diagnosis of sJIA  
• 
Fertility: 
For female patients of reproductive potential (unless surgically sterile with 
absence of ovaries and/or uterus): agreement to remain abstinent or use single 
or combined contraceptive methods that result in a failure rate of < 1% per 
year during the treatment period and for at least 6 months after the last dose of 
TCZ 
Abstinence is acceptable only if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Examples of contraceptive methods with a failure rate of < 1% per year 
include tubal ligation; male sterilization; hormonal implants; established, 
proper use of combined oral or injected hormonal contraceptives; and 
certain intrauterine devices.  Alternatively, two methods (e.g., two barrier 
methods, such as a condom and a cervical cap) may be combined to achieve 
a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide. 
For male patients of reproductive potential: agreement to remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of < 1% per year during the treatment period and for at least 
6 months after the last dose of TCZ 
Abstinence is acceptable only if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
• 
Must meet one of the following: 
Not receiving MTX or discontinued MTX at least 4 weeks prior to the Part 1 or 
Part 2 baseline visit, or 
Taking MTX for at least 12 weeks immediately prior to the Part 1 or Part 2 
baseline visit and on a stable dose of ≤ 20 mg/m2 for at least 8 weeks prior to 
the Part 1 or Part 2 baseline visit, together with either folic acid or folinic acid 
according to local standard of care 

 
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• 
Written informed consent for study participation obtained from parent or legal 
guardian, with assent as appropriate by the patient, depending on the level of the 
patient’s understanding 
• 
Parental or guardian written agreement to comply with the requirements of the study 
protocol 
 
Patients entering Part 1 who are naïve to TCZ therapy must also meet the following 
inclusion criterion: 
• 
History of inadequate clinical response (in the opinion of the treating physician) to 
NSAIDs and corticosteroids  
 
Part 2 
All patients entering Part 2 (either directly without participating in Part 1, or via 
Part 1) must meet the following additional criteria for entry into Part 2: 
• 
JADAS-71 score of 3.8 or less and absence of fever (related to sJIA) at screening 
and baseline of Part 2  
• 
Neutropenia, thrombocytopenia, or elevated ALT/AST (as per criteria in Table 5) 
previously experienced (and resolved) on the labeled dose (Q2W) of TCZ  
 
Table 5 
Laboratory Abnormalities Serving as Inclusion Criteria for Part 2 
When Experienced (with Resolution) on Q2W TCZ 
Abnormality 
Results Range 
Neutropenia 
ANC 0.5 to 1.0 × 109/L 
Thrombocytopenia 
Platelets 50 to 100 × 109/L 
Elevated liver enzymes 
ALT/AST > 1 to 3 × ULN 
TCZ = tocilizumab; ULN = upper limit of normal. 
 
• 
Not currently receiving oral corticosteroids, or taking oral corticosteroids at a stable 
dose for a minimum of 2 weeks prior to the Part 2 baseline visit at no more than 
10 mg/day or 0.2 mg/kg/day, whichever is less 
• 
Not taking NSAIDs, or taking no more than one type of NSAID at a stable dose for a 
minimum of 2 weeks prior to the Part 2 baseline visit, with the dose being less than 
or equal to the maximum recommended daily dose 
 
4.1.2 
Exclusion Criteria 
Patients entering Part 1, or entering Part 2 without participating in Part 1, who meet 
any of the following criteria will be excluded from study entry: 
General 
• 
Wheelchair bound or bedridden 
• 
Any other auto-immune, rheumatic disease, or overlap syndrome other than sJIA 

 
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• 
Not fully recovered from recent surgery or less than 6 weeks since surgery, at the 
time of screening visit; or planned surgery during Part 1 and the initial 12 weeks of 
Part 2 of the study (for patients entering Part 1) or the initial 12 weeks of Part 2 of 
the study (for patients entering Part 2 without participating in Part 1) 
• 
Lack of peripheral venous access 
 
General Safety 
• 
Pregnant, lactating, or intending to become pregnant during study conduct and up to 
6 months after the last administration of study drug 
• 
Any significant concurrent medical or surgical condition which would jeopardize the 
patient’s safety or ability to complete the trial 
• 
History of significant allergic or infusion reactions to prior TCZ infusion, and/or 
presence of anti-TCZ antibodies by confirmatory and/or neutralizing assay at 
screening 
• 
Inborn conditions characterized by a compromised immune system 
• 
Known HIV infection or other acquired forms of immune compromise 
• 
History of alcohol, drug, or chemical abuse within 6 months of screening 
• 
Evidence of serious uncontrolled concomitant diseases, including but not limited to 
the nervous, renal, hepatic, or endocrine systems 
• 
Any active acute, subacute, chronic, or recurrent bacterial, viral, or systemic fungal 
infection including but not limited to: 
Acute or chronic renal/bladder infections 
Acute or chronic pulmonary infections 
• 
History of atypical tuberculosis (TB) 
• 
Active TB requiring treatment within 2 years prior to the screening visit 
• 
Positive purified protein derivative (PPD) at screen (or equivalent result based on 
local methodology, e.g., Quantiferon gold), unless treated with anti-TB therapy for at 
least 4 weeks prior to receiving study drug and chest radiograph is negative for 
active TB within 6 months of screening visit according to local practice 
• 
Any major episode of infection requiring hospitalization or treatment during 
screening or treatment with IV antibiotics completing within 4 weeks of the screening 
visit or oral antibiotics completing within 2 weeks of the screening visit 
• 
History of reactivation or new onset of a systemic infection, such as herpes zoster or 
Epstein Barr virus, within 2 months of the screening visit 
• 
Hepatitis B surface Antigen or hepatitis C Ab positive 
• 
Chronic hepatitis⎯viral or autoimmune 
• 
Significant cardiac [e.g., congenital heart disease, valvular heart disease, 
constrictive pericarditis (unrelated to sJIA), myocarditis] or pulmonary disease, 
(e.g., asthma for which the patient has required the use of oral or parenteral 

 
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corticosteroids for ≥ 2 weeks within 6 months prior to the baseline visit of Part 1 or 
Part 2, or cystic fibrosis) 
• 
History or concurrent serious gastrointestinal (GI) disorders, such as ulcer or 
inflammatory bowel disease, Crohn’s disease, ulcerative colitis, or other 
symptomatic lower GI conditions, including ulcer and perforation 
• 
History of or current cancer or lymphoma 
• 
Uncontrolled diabetes mellitus with elevated hemoglobin (Hgb) A1c as defined by 
age-specific standards (Silverstein et al. 2005) 
• 
History of MAS within 3 months prior to the screening visit 
 
Excluded Previous or Concomitant Therapy 
• 
Participation in another interventional clinical trial within the past 30 days or 5 serum 
half-lives of the investigative medication or the PD effect of the investigative 
medication, whichever is longer 
• 
Prior stem cell transplant at any time 
• 
Prohibited therapy as described in Section 4.3.2 
 
Laboratory Exclusions at Screening 
• 
Serum creatinine > 1.5 × ULN (for age and sex) 
• 
Hemoglobin < 7.0 g/dL (< 4.3 mmol/L) 
 
The following additional laboratory exclusion criteria apply to patients entering Part 1 
of the study who are TCZ-naive and are initiating therapy with TCZ: 
• 
AST or ALT > 1.5 ULN (upper limit of normal for age and sex) 
• 
Total bilirubin > 1.3 mg/dL (> 23 μmol/L) 
• 
Platelet count < 150 x 103/μL (< 150,000/mm3) 
• 
WBC count < 5,000/mm3 (< 5.0 x 109/L) 
• 
Neutrophil count < 2,500/ mm3 (< 2.5 x 109/L) 
 
4.2 
Study Treatment  
Category 
Treatment 
Investigational medicinal products:  
test product 
TCZ 
Concomitant therapy 
MTX, NSAIDs, prednisone, 
or corticosteroid equivalent 
NSAID = nonsteroidal anti-inflammatory drug; 
MTX = methotrexate; TCZ = tocilizumab. 
 

 
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4.2.1 
Formulation, Packaging, and Handling 
4.2.1.1 
Tocilizumab 
TCZ (200 mg/10 mL) vial (concentrate for solution for infusion) RO 487-7533/F01 will be 
supplied.  Study drug packaging will be overseen by the Roche clinical trial supplies 
department and will include a label with the identification required by local law, the 
protocol number, drug identification and dosage.  The packaging and labeling of the 
study drug will be in accordance with Roche standard and local regulations.  The study 
drug must be stored according to the details on the product label. 
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery.  
All TCZ vials must be stored at a controlled temperature of 2°C−8°C, and handled 
according to Good Manufacturing Practice and Good Clinical Practice (GCP) procedures.  
A temperature log must be kept recording the storage temperature of the TCZ and 
infusion bags at least once a day. 
The investigator or designated person (e.g., pharmacist) will be responsible for 
maintaining accurate records for all supplies used.  Opened TCZ vials will be stored, still 
containing any residual volume of fluid, at room temperature for the purposes of 
monitoring of drug accountability. 
After accounting of supplies, the Sponsor will give written authorization to the 
investigator to return or destroy any remaining study drug as instructed.  Under no 
circumstances is the investigator to allow the study drugs to be used other than as 
directed by the protocol. 
For further details, see the most recently published version of the Investigator's Brochure 
for TCZ. 
4.2.2 
Dosage, Administration, and Compliance 
4.2.2.1 
Tocilizumab 
Part 1 
TCZ dosed by body weight (12 mg/kg for patients < 30 kg; 8 mg/kg for patients ≥ 30 kg) 
will be administered IV Q2W for ≤ 24 weeks or until the patient experiences an event of 
neutropenia, thrombocytopenia, or liver enzyme abnormality as per the criteria 
provided in Table 5.  Following the occurrence and resolution of this laboratory 
abnormality, patients who have a final successful screening evaluation (Screening 
Evaluation 2) may enter Part 2 of the study.  

 
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Patients who do not experience a laboratory abnormality in Part 1, or experience a 
laboratory abnormality but do not meet the eligibility criteria for Part 2, will complete 
Part 1 through to Week 24, followed by the Part 1 withdrawal visits.  
Part 2 
TCZ dosed by body weight (12 mg/kg for patients < 30 kg; 8 mg/kg for patients ≥ 30 kg) 
will be administered IV Q3W for a minimum of 12 consecutive weeks (5 consecutive 
infusions), switching to Q4W in response to predefined laboratory abnormalities for 
patients eligible to continue treatment for the duration of the study (52 weeks in total).   
Patients who do not meet the criteria to switch from Q3W to Q4W will complete Part 2 
through to Week 52, followed by the Part 2 withdrawal visits. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
TCZ will be supplied in vials containing 10 mL of a sterile solution of 20 mg TCZ/mL.  
The TCZ dose will be calculated using the Part 1 or Part 2 baseline body weight 
(< 30 kg or ≥ 30 kg) and will not be changed until a patient’s weight falls into the other 
body weight category on three separate, consecutive occasions.  The number of vials to 
be used for each body weight category is described in Table 6.   
Table 6 
Tocilizumab Dosage 
Weight (kg) 
Number of Vials 
Dose 
≤ 16.5 
1 
12 mg/kg 
> 16.5 − ≤ 30 
2 
12 mg/kg 
> 30 − ≤ 50 
2 
8 mg/kg 
> 50 − ≤ 75 
3 
8 mg/kg 
> 75 − ≤ 100 
4 
8 mg/kg 
> 100 − ≤ 125 
5 
8 mg/kg 
> 125 − ≤ 150 
6 
8 mg/kg 
 
For the preparation of the infusion bag for a patient < 30 kg, 0.6 mL per kg of the patient’s 
body weight will be withdrawn from a 50 mL infusion bag.  This volume will be replaced 
in the saline bag with an equal volume of TCZ.  For a patient ≥ 30 kg, 0.4 mL per kg of 
the patient’s body weight will be withdrawn from a 100 mL infusion bag.  This volume will 
be replaced in the saline bag with an equal volume of TCZ.  
The TCZ vials will be stored at a temperature of 2°C−8°C.  The infusion bag of study 
drug (after it has been prepared) may be stored at 2°C−8°C for 24 hours providing that 
the infusion is prepared aseptically and allowed to return to room temperature before 

 
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administration (1 to 2 hours depending on ambient room temperatures).  A temperature 
log must be kept in order to monitor the ambient temperature in the pharmacy and the 
refrigerators storing the vials of study drug. 
For a 50-mL infusion bag the initial infusion speed should also be 10 mL/hr for 
15 minutes and then increased to 65 mL/hr.  Total infusion time should be no less than 
1 hour.  In order to flush the remaining study drug through the IV set, 10 mL of normal 
saline will be administered immediately following the infusion of study drug.  The volume 
of the saline flush should not be included in the total infusion volume recorded in the 
eCRF.  The time the “saline flush” is completed should be noted as the time when the 
infusion is complete.  The timing of any related post-infusion blood draws (PK) that are 
required should also be noted. 
All study drug volumes must be recorded in eCRF.  Additional details of the infusion 
preparation and medication volumes will be provided by the Sponsor and in the infusion 
bag preparation instructions. 
TCZ will be administered at room temperature by controlled infusion into a peripheral 
vein over a 1-hour period.  The option to administer study drug via a pre-existing central 
line may be considered under certain circumstances and must be discussed with the 
clinical pharmacologist and/or medical monitor prior to the implementation. 
4.2.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study (TCZ) 
during Part 1 and Part 2 will be provided by the Sponsor.  The investigational 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 upon 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. 
4.2.4 
Post-Trial Access to TCZ 
The Sponsor will offer post-trial access to the study drug TCZ free of charge to eligible 
patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 

 
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A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after the end of the study if any of 
the following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for sJIA 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for sJIA 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:  
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf. 
4.3 
CONCOMITANT THERAPY 
4.3.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study completion/early termination visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
Methotrexate: 
Part 1 and 2, MTX is permitted but not required during this study.  If a patient has been 
on MTX in the past they should have discontinued MTX at least 4 weeks prior to the 
baseline visit of Part 1 and 2 of the study.  Those patients receiving MTX should have 
been taking MTX for at least 12 weeks immediately prior to the baseline visit of Part 1 
and Part 2 and should be receiving a stable dose of ≤ 20 mg/m2 for at least 8 weeks prior 
to the baseline visit of Part 1 and 2 of the study, together with at least the minimum 
recommended dose of either folic acid or folinic acid according to the local standard of 
care.  During the study, if applicable, the MTX dose may be decreased at any time for 
documented reasons of safety but not for efficacy (improvement in symptoms) during 

 
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Part 1 and the first 12 weeks of Part 2 of the study (and until 5 consecutive Q3W 
infusions have been given).  If any patient should move to Q4W dosing, the MTX dose 
should also remain stable until 3 consecutive Q4W infusions of TCZ have been given. 
Steroids: 
There are no restrictions on the use of steroids in Part 1 of the study. 
For Part 2 of the study, patients who are not currently receiving oral corticosteroids or 
are taking oral corticosteroids at a stable dose for a minimum of 2 weeks prior to the 
Part 2 baseline visit at no more than 10 mg/day or 0.2 mg/kg/day, whichever is less, are 
allowed in the study.  If patients are receiving oral corticosteroids, the dose should 
remain stable during the first 12 weeks of Part 2 (until 5 consecutive 3 weekly 
infusions have been given), and for patients moving to 4 weekly dosing, until 
3 consecutive 4 weekly infusions of TCZ have been given.   
Intra-articular (IA), intramuscular (IM), IV, and long-acting corticosteroids (such as 
dexamethasone) are not permitted within 4 weeks of baseline of Part 2 or throughout 
Part 2 of the study. 
Injection of IA corticosteroids during the first 12 weeks of Part 2 of the study (and until 
5 consecutive 3 weekly infusions have been given) is strongly discouraged as these may 
affect the exploratory efficacy endpoints.  The same applies for patients moving to 
4 weekly dosing, until 3 consecutive 4 weekly infusions of TCZ have been given.  
Injections of IA corticosteroids are not permitted within 4 weeks of baseline of Part 2 of 
the study; during Part 2 a maximum of 2 joint injections will be allowed in 1 year, and 
the related joint will be considered active for 3 months following the injection.  If an IA 
injection is absolutely required, no more than 1 joint should be injected with the smallest 
possible dose appropriate to the size of the joint being injected.   
Corticosteroids can be changed for reasons of safety (e.g., asthma attack, serositis) to 
maximum of 30 mg/day or 0.5 mg/kg/day prednisone or equivalent, whichever is less, for 
a maximum dosing period of < 14 days, after which the corticosteroid dosage must be 
returned to the Part 2 baseline dosage. 
NSAIDs: 
There are no restrictions on the use of NSAIDs in Part 1 of the study. 
For Part 2 of the study, patients who are not taking NSAIDs, or taking no more than one 
type of NSAID at a dose that has remained stable for > 2 weeks prior to the baseline visit 
of Part 2 of the study and is less than or equal to the maximum recommended daily 
dose are included in Part 2 of the study.  The dose of NSAID must remain stable 
throughout the first 12 weeks of Part 2 of the study (and until 5 consecutive Q3W 
infusions have been given).  In addition, for patients moving to Q4W dosing, the dose of 
NSAIDs should remain stable for the first 12 weeks of Q4W dosing.  The dose may be 

 
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lowered for documented reasons of safety and only tapered for efficacy after 
5 consecutive doses have been completed for Q3W dosing (12 weeks), and 
3 consecutive doses have been completed for Q4W dosing (12 weeks). 
Acetaminophen (Paracetamol) and Other Analgesics: 
Normal-release acetaminophen (not extended release) may be used for pain as required.  
Analgesics should not be taken within 6 hours prior to a visit where clinical efficacy 
assessments are performed in Part 2 of the study.  The administration of analgesics 
should always be recorded in the eCRF. 
Iron and Folic Acid: 
Iron supplementation can be prescribed based on investigator’s assessment of 
risk−benefit for treatment of the anemia with iron.  Folic acid should be administered to 
patients receiving MTX in Part 1 and Part 2 of the study. 
4.3.2 
Prohibited Therapy 
DMARDs: 
Leflunomide is not allowed at any time during the study.  Discontinuation of leflunomide 
should be followed by standardized cholestyramine washout.  Leflunomide levels must 
be documented to be below the limit of detection prior to the baseline visit of Part 1 or 
Part 2. 
Cyclophosphamide is not permitted at any time during the study and within 3 months 
prior to the baseline visit of Part 1 or Part 2. 
Etoposide (VP16) is not permitted at any time during the study or within 3 months prior 
to the baseline visit of Part 1 or Part 2. 
Treatment with DMARDs (other than MTX) or immunosuppressants, including but not 
limited to:  hydroxychloroquine, chloroquine, gold, azathioprine, D-penicillamine, 
sulfasalazine, cyclosporine, thalidomide, must have been discontinued within 6 weeks 
prior to the baseline visit (Part 1 or Part 2) and leflunomide must have been 
discontinued within 12 weeks prior to the Part 1 or Part 2 baseline visit. 
If the patient has received previous treatment with any of the following biologic agents 
other than TCZ, these must have been discontinued according to the following timelines 
prior to the baseline visit of either Part 1 or 2, and are not permitted during the study: 
• 
Etanercept must have been discontinued within ≥ 2 weeks prior to baseline. 
• 
Anakinra must have been discontinued within ≥ 4 days prior to baseline. 
• 
Abatacept must have been discontinued within ≥ 12weeks prior to baseline. 
• 
Infliximab or adalimumab must have been discontinued within ≥ 8 weeks prior to 
baseline. 
• 
Canakinumab must have been discontinued within ≥ 20 weeks prior to baseline. 

 
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• 
Rilonacept must have been discontinued within ≥ 6 weeks prior to baseline. 
• 
Golimumab must have been discontinued within ≥ 10 weeks prior to baseline. 
• 
Certrolizumab pegol must have been discontinued within ≥ 10 weeks prior to 
baseline. 
 
IA, IM, IV, and long-acting corticosteroids (such as dexamethasone) are not permitted 
within 4 weeks of baseline of Part 2 or throughout Part 2 of the study. 
Immunoglobulin: 
Administration of IV immunoglobulin is not permitted during the entire study or within 
4 weeks prior to the baseline visit of Part 2 of the study.  For active varicella infection 
(chickenpox) or significant exposure to varicella zoster infection in a patient without a 
history of chickenpox (varicella IgG titer available from screening), varicella zoster 
immunoglobulins can be given at the discretion of the investigator. 
Hyaluronic Acid and Plasmapheresis: 
IA injections of hyaluronic acid and plasmapheresis are not permitted at any time during 
the study. 
Cell-Depleting Therapies: 
Previous treatment with any cell depleting therapy, including any investigational agents, 
(e.g., anti-CD19 and anti-CD20) or cell-depleting therapy during the study at any time 
is not permitted. 
Stem Cell Transplant: 
Previous treatment with prior stem cell transplant, or stem cell transplant during the 
study at any time, is not permitted. 
Vaccines: 
Live or attenuated vaccines are not permitted within 4 weeks of the baseline visit of 
Part 1 or 2 of the study, or at any time during the study, or within 12 weeks following 
the last administration of study drug.  Patients are advised to be brought up to date with 
vaccines prior to start of the study, as appropriate. 
4.4 
STUDY ASSESSMENTS  
4.4.1 
Description of Study Assessments 
4.4.1.1 
Efficacy-Clinical Assessments 
For the efficacy assessments in Part 2 of the study, the baseline score will be taken as 
the assessment prior to dosing at Visit 1 Day 1 of Part 2.  Clinical measures of efficacy 
will be evaluated for patients on Q3W and Q4W TCZ as applicable. 

 
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• 
JADAS-71 composite disease activity score for JIA, composed of the following 
4 measures: 
Physician global assessment of disease activity by visual analogue scale 
(100 mm horizontal visual analogue scale [VAS]) 
Parent/patient global assessment of overall well-being (100 mm horizontal VAS) 
Number of joints with active arthritis (out of 71)  
ESR 
• 
Fever (attributable to sJIA) 
Absence of fever at screening visit is defined as a temperature measurement 
< 38°C.  
Presence of fever at each study visit (per the Schedule of Assessments in (see 
Appendix 1) is defined as a temperature measurement ≥ 38°C 
(Ruperto et al. 2010). 
• 
JIA definition of disease flare (worsening in patients with JIA) is defined in this trial: 
Recurrence of fever or JIA flare defined as any 3 of the 6 core outcome 
variables worsening by at least 30% relative to baseline visit of Part 2, with no 
more than 1 of the remaining variables improving by more than 30% since the 
Part 2 baseline evaluation at Part 2 Visit 1, Week 0.   
If either the number of joints with active arthritis or the number of joints with 
limitation of motion is used in the calculation of flare for a study visit in a patient, 
then a minimum worsening of at least 2 active joints or 2 joints with limitation of 
motion must be present.   
If either the physician global assessment or the parent/patient global 
assessment are used in the calculation of flare for a study visit in a patient, then 
a minimum worsening of at least 2 units on a scale from 0 to 10 must be 
present (Lovell et al. 2000).   
For ESR, a worsening of at least 30% will not be considered if the value of ESR 
is still within normal ranges. 
 
The JIA core outcome variables consist of: 
• 
Physician Global Assessment of Disease Activity (100 mm horizontal VAS) 
• 
Parent/patient global assessment of overall well-being (100 mm horizontal VAS) 
• 
Number of joints with active arthritis (out of 71) 
• 
Number of joints with limitation of movement (out of 67) 
• 
Laboratory measure of acute phase reaction (ESR will be used in this study) 
• 
Functional ability determined by CHAQ Disability Index 
Assessments should be made as described in the Schedule of Assessments in 
Appendix 1. 

 
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4.4.1.2 
Medical History and Demographic Data 
Medical history and demographic data will be taken at the times indicated in the 
Schedule of Assessments for Part 1 or Part 2 of the study (see Appendix 1).  
Demographic data will be recorded as well as medical history and concomitant illnesses.  
A history of all DMARDs used in the past will be recorded, and the use of biologic 
medications will be specifically asked for.  Medical history will also include prior 
immunizations/vaccines. 
4.4.1.3 
Vital Signs 
Vital signs (pulse rate, systolic, and diastolic blood pressure, and temperature) will be 
taken at the times indicated in the Schedule of Assessments in Part 1 and 2 of the 
study (see Appendix 1).  Assessments will be taken with the patient having been in a 
semi-supine position for at least 5 minutes. 
Vital signs will be taken pre-infusion, every 30 minutes during infusion, and 30 minutes 
after the infusion is completed.  All readings will be recorded in the eCRF.  Additional 
readings may be taken at the discretion of the investigator in the event of an 
infusion-related reaction. 
Vital signs recordings will start with the screening period and continue throughout the 
study up to and including the last dosing visit, as outlined in the Schedule of 
Assessments (see Appendix 1).  
4.4.1.4 
Height and Weight Measurements 
Height and weight will be measured as outlined in the Schedule of Assessments in 
Part 1 and 2 of the study (see Appendix 1).  Height will be measured in a standing 
position using a wall mounted stadiometer or equivalent as per local practice.  Weight 
should be determined to the nearest 0.1 kg.  For body weight measurements, the patient 
will wear typical daytime clothes but shoes, outerwear, and accessories should be 
removed. 
4.4.1.5 
Physical Examinations 
A general physical examination will be performed and recorded as “normal” or 
“abnormal” at the times indicated in the Schedule of Assessments in Part 1 and 2 of the 
study (see Appendix 1).  Abnormalities should be specified.  Any persisting 
abnormalities should be stated each time the examination is performed.  Diagnosis of 
new abnormalities should be recorded as adverse events if clinically appropriate.  The 
presence of specific physical examination findings that are associated with active sJIA, 
such as splenomegaly, hepatomegaly, and lymphadenopathy, will be recorded.  Entries 
in the musculoskeletal examination portion should only record findings such as 
deformities, dislocations, subluxations contractures fusions, or specific muscle atrophy 
or weakness and not the presence or absence of signs of joint inflammation such as 
swelling or tenderness. 

 
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4.4.1.6 
Physician’s Global Assessment of Disease Activity 
The physician’s global assessment of disease activity is the physician’s assessment of 
the patient’s current disease activity on a 100 mm horizontal VAS.  The extreme left end 
of the line should be described as “arthritis inactive” (symptom-free and no arthritis 
symptoms) and the extreme right end as “arthritis very active.”  This should be 
completed by the treating physician at the times indicated in the Schedule of 
Assessments for Part 2 of the study (see Appendix 1). 
4.4.1.7 
Joint Assessments 
The joint assessor will evaluate if the joints are swollen, tender/painful, and limited as 
per standard Rheumatology International Trials Organisation/Pediatric Rheumatology 
Collaborative Study Group (PRINTO/PRCSG) rheumatologic examination form (or 
equivalent).  The joint counts (swollen, tender/painful, limited, and active) will be 
evaluated at the times indicated in the Schedule of Assessments for Part 2 of the study 
(see Appendix 1).  The trained and certified joint assessor should be a pediatric 
rheumatologist or skilled arthritis assessor.  Roche will ensure that primary joint 
assessors have received training to become qualified and will require documentation 
that such training was received.  One back-up joint assessor can be trained at the site by 
the primary joint assessor for planned or unscheduled absences.  To ensure consistent 
joint evaluation throughout the trial, it is requested that joint assessments be carried out 
by the primary joint assessor for all study visits, whenever possible. 
4.4.1.8 
Temperature 
The patient’s temperature will be taken at the times indicated in the Schedule of 
Assessments for Part 1 and 2 of the study (see Appendix 1).  Additional supplemental 
temperatures may be measured as deemed necessary.  Temperature recordings will 
start with the screening period for Part 1 and 2 of the study and continue throughout the 
study up to and including the withdrawal (WD1) or the last dosing visit as outlined in the 
schedule of assessments. 
4.4.1.9 
Laboratory Assessments 
Samples of blood and urine will be obtained as indicated in the Schedule of 
Assessments (see Appendix 1) for the tests listed below for Part 1 and 2 of the study.  
On days when fasting labs are required (such as lipid profiles), blood samples will be 
taken after an 8-hour fast.  These visits are identified in the schedule of assessments as 
fasting labs.  Normal ranges for the local site study laboratory parameters must be 
supplied to Roche before the study starts. 
For samples collected at non-dosing visits as indicated in the Schedule of Assessments 
(see Appendix 1), there is the option to have these samples collected at home if consent 
is obtained.  If a patient decides to participate in the home nursing for collection of blood 
at non-dosing visits, the home nursing network will communicate with the patient’s site to 
organize a nurse to visit the patient at home on scheduled non-dosing visit days to 
collect the relevant samples. 

 
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The total volume of blood loss for laboratory assessments (including all safety, efficacy, 
and PK/PD samples) does not exceed the per visit and per cumulative visits 
recommendations by the Seattle Children’s Hospital (Seattle Children’s Hospital 
Research Foundation 2001) and the National Institutes of Health for the expected 
average weights of the patient population from age 2 years (13 kg) up to and including 
age 17 years (65 kg). 
Biological samples taken from all patients may be infectious and will be classified as 
“infectious specimens” for dispatch purposes. 
The procedures for the collection, handling, and shipping of laboratory samples are 
specified in the Study Laboratory Reference Manual. 
Hematology (Parts 1 and 2):  CBC:  hemoglobin, hematocrit, RBC, mean corpuscular 
volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, 
WBC and differential, platelets, reticulocytes (centrally) 
Blood chemistry (Parts 1 and 2):  AST, ALT, alkaline phosphatase, total protein, 
albumin, total, direct and indirect bilirubin, urea, uric acid, creatinine, glucose, potassium, 
sodium, chloride, calcium, phosphorous, LDH 
Urinalysis (Parts 1 and 2):  Dipstick for blood, protein and glucose (performed locally 
or microscopic examination fresh specimen sent to central laboratory, if abnormal and 
applicable), pregnancy testing when applicable (Tanner stage 2 or above or onset of 
menarche during the study) 
Screening tests (Parts 1 or 2):  Hepatitis B surface antigen, hepatitis C antibody, 
HgbA1c, high-sensitivity C-reactive protein (hsCRP), fibrinogen, Epstein-Barr virus (EBV) 
titer, varicella IgG testing, ESR 
Acute phase reactants (Part 2):  hsCRP, serum ferritin, C4, C3, ESR to be performed 
locally.  
 has defined an ESR of < 20 mm/hr for both girls and boys as normal 
utilizing the 
-supplied kits). 
Fibrinogen, D-dimer (Part 2): 
Lipid profile (Part 2):  Total cholesterol, HDL, LDL, triglycerides 
Immunology profile (Part 2):  IgG, immunoglobulin M, immunoglobulin A 
PK/PD (Part 2):  TCZ, IL-6, sIL-6R 
Immunogenicity assessments/anti-TCZ antibodies (Parts 1 and 2):  Anti-TCZ 
antibodies will be collected for all study patients to evaluate immunogenicity of TCZ as 
described in Section 5.1.1.6. 

 
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4.4.1.10 
Patient-Reported Outcomes 
PRO data will be elicited from the patients in Part 2 of the study to more fully 
characterize the clinical profile of TCZ.  The PRO instruments, translated as required in 
the local language, will be distributed by the investigator staff and completed in their 
entirety by the parent/guardian/patient.  To ensure instrument validity and that data 
standards meet health authority requirements, PRO questionnaires should be 
self-administered at the investigational site prior to the completion of other study 
assessments and the administration of study treatment. 
4.4.1.10.1 
Childhood Health Assessment Questionnaire  
The CHAQ takes less than 10 minutes to administer and in this study the version that is 
completed by the parent or guardian will be used.  This assessment will be done at visits 
as specified in the Schedule of Assessments for Part 2 of this study (see Appendix 2). 
The form should be completed by the parent/guardian as appropriate.  To ensure 
consistency the form should be completed throughout the study by the same individual 
who completed the baseline global assessment of overall well-being (see Appendix 2). 
Disability Index 
The functional ability instrument used in Part 2 of this study for calculating the JIA flare 
is the Disability Index of the CHAQ (see Appendix 2). It is an adaptation of the Stanford 
Health Assessment Questionnaire (HAQ) for use in children.  Three components are 
evaluated:  1) difficulty in performing daily functions, 2) use of special aids, and 3) 
assistance from other people.  The CHAQ was adapted from the HAQ by adding several 
new questions, so that there is at least one question for each function that is relevant to 
children of all ages.  This way, bias due to developmental difference can be minimized. 
Parent’s/Patient’s Global Overall Well-Being  
The patient’s overall assessment of their overall well-being is recorded on a 100 mm 
horizontal visual analogue scale (VAS) in Part 2 of this study.  The left-hand extreme of 
the line should be described as “very well” (symptom-free and no arthritis symptoms) 
and the right-hand extreme as “very poor” (maximum arthritis disease activity).   
Parental/Patient Pain Index 
In addition to the Disability Index, in the CHAQ (see above) there is a Pain Index, which 
is measured separately in Part 2 of this study.  The level of pain is determined by the 
presence of pain, which is measured on a 100 mm horizontal VAS.  This scale is 
anchored at the left-hand extreme of the line as “no pain” and the right-hand extreme as 
“very severe pain.”   
4.4.1.11 
PPD and Chest Radiograph 
Patients will have a PPD test (5 TU) (or equivalent as per local practice, 
e.g., Quantiferon gold) performed at screening (of Part 1 or 2 of the study) unless a 
negative PPD has already been documented within the last year.  The PPD test will be 
considered positive according to the local guidelines for immunosuppressed patients.  

 
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The definition of a positive PPD test may be applied as determined by the clinical 
circumstances and investigator according to published guidelines and/or local standards 
endorsed by the medical society.  If no published guidelines are available for a given 
country outside the United States, the U.S. guidelines must be followed.  
Patients will have a TB screening test per local standard (e.g., PPD skin test or 
Quantiferon® test).  
A chest X-ray (CXR) is required under the following conditions: 
• 
If a patient’s TB testing is positive at screening (of Part 1 or Part 2) and the 
patient has not previously received TB treatment, then a CXR is required at 
screening.   
• 
If a patient eventually is enrolled (Part 1 or Part 2), TCZ administration would be 
delayed until the patient has received at least 4 weeks of TB treatment therapy per 
exclusion criteria. 
 
A chest x-Ray may be required under the following conditions: 
• 
If a patient’s TB testing is negative at screening (of Part 1 or 2), then a CXR 
should be done if consistent with local requirements but is not strictly required.  
 
A chest X-ray is not required under the following conditions: 
• 
If a patient’s TB testing is positive and the patient has previously completed TB 
treatment or has been receiving TB treatment for at least 4 weeks prior to receiving 
TCZ and has had a negative CXR ≤ 6 months of screening (of Part 1 or 2), then 
he/she is eligible to enroll without repeat CXR at screening (if consistent with local 
practice requirements).   
• 
A CXR obtained ≤ 90 days of baseline (of Part 1 or 2) can be utilized for screening 
purposes, if consistent with local practices. 
 
Patients asked to participate in this study will have received corticosteroid therapy and 
often other immunosuppressive drugs.  It has been reported that the PPD response 
alone is not always sufficient for screening children with JIA for TB 
(Kasapcopur et al. 2006).  In addition, patients with significant cardiac abnormalities are 
excluded from study participation (see Section 4.1.2, Exclusion Criteria for General 
Safety).  As a result, a negative chest radiograph is required at the time that TCZ therapy 
was or is initiated, or as per local practice requirements.  The chest radiograph should 
be interpreted by a board-certified radiologist and the interpretation should include a 
statement of the following at a minimum: 
• 
No evidence of active TB 
• 
No evidence of any active infection including TB 
• 
No evidence of malignancy 
• 
No evidence of significant heart disease 
 

 
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4.4.2 
Timing of Study Assessments 
4.4.2.1 
Screening and Pretreatment Assessments 
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.   
The legal guardian for each patient must sign and date the most current Institutional 
Review Board (IRB)/Ethics Committee (EC) approved written informed consent before 
any study-specific assessments or procedures are performed.  Assent may be obtained 
from the patient depending on his/her understanding.  An original signed consent form 
will be retained by the investigator and the parent/guardian/patient will receive a copy to 
take home. 
Patients whose guardian has given written informed consent will undergo two screening 
examinations: one within 4 weeks before the start of Part 1 (Screening Evaluation 1, for 
patients entering Part 1) and one within 4 weeks of Part 2 of the study (Screening 
Evaluation 2, for patients entering into Part 2 directly, or entering Part 2 via Part 1).  
TCZ infusions may continue to be received during Screening Evaluation 2, but there 
must be at least 10 days clear between the last TCZ infusion during screening and the 
first study TCZ infusion received at baseline.  During the Screening Evaluation visits 1 
and 2 (for patients entering the study via Part 1 or Part 2), inclusion/exclusion criteria, 
demographics, medical history, concomitant medication, physical examination, height 
and weight, vital signs, laboratory safety tests (screening labs [hepatitis B surface 
antigen, hepatitis C antibody, HgbA1c, hsCRP, fibrinogen, EBV titer, and varicella IgG, 
and ESR]; hematology; blood chemistry; urine pregnancy [female patients who are able 
to become pregnant]), TB screening, and chest X-ray (if applicable) will be performed.  
The CHAQ score, the number of joints with active arthritis and number of joints with 
limited range of motion (joint assessment), global assessment of the severity of the 
disease by the physician (physician global), and global assessment of overall well-being 
by the patient or parent (patient/parent global) will also be evaluated at Screening 
Evaluation 2 as per the schedule of assessments (see Appendix 1).     
Patients must fulfill all entry criteria to be accepted into the study.  Patients who fail to 
meet the entry criteria may be rescreened once for Part 1 or Part 2 of the study, at the 
discretion of the investigator. 
Patients, who have experienced a laboratory abnormality that has subsequently resolved 
during Part 1, may be screened to enter the Part 2.  If a patient fails Screening 
Evaluation 2, the patient may continue participating in Part 1 (returns to Part 1 at the 
visit after their last visit) up to 24 weeks.  If the patient is still not eligible for Part 2 
after 24 weeks, the patient will be withdrawn from Part 1 and attend the Part 1 
withdrawal visits.  However if the patient experiences the relevant laboratory 
requirements (per Table 5) after discontinuing the study while on commercial TCZ, 

 
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they may be rescreened once for Part 2 of the study at the discretion of the investigator.  
Patients can be screened for Part 2 a total of two times. 
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 and signed by the investigator (or designee).  A screen failure log must be 
maintained by the investigator. 
Patients cannot commence enrolment procedures until all entry criteria have been 
fulfilled.  Where the clinical significance of abnormal laboratory test results is considered 
uncertain, screening laboratory tests may be repeated. 
Once a patient has fulfilled the entry criteria, patients will be enrolled into the study.  The 
patient numbers will be generated by Roche or its designee. 
Under no circumstances will patients who enroll in Part 1 or Part 2 and have completed 
treatment as specified, be permitted to re-enroll into the same part of the study.  
However, patients who have participated in Part 1 without meeting eligibility criteria 
for Part 2 may be rescreened for Part 2 (see above).    
See Appendix 1 for the schedule of screening and pretreatment assessments for Part 1 
and Part 2. 
4.4.2.2 
Assessments during Treatment 
See Appendix 1 for the Schedule of Assessments performed during the treatment period 
in Part 1 and Part 2. 
4.4.2.3 
Assessments at Study Completion/Early Termination Visit 
Patients who complete visits in the study in Part 1 and Part 2 as outlined in the 
Schedule of Assessments, or discontinue from the study early, will be asked to return to 
the clinic 2 weeks after the last dose of study drug for a follow-up visit (WD1) and then 
subsequently 2 weeks later for WD2, another 4 weeks later for WD3 and further 4 weeks 
later for WD4.  If the investigator withdraws a patient due to sJIA flare or fever 
attributable to sJIA, the visit at which JIA flare assessment shows flare of disease may 
be used as the study completion/early termination visit. 
See Appendix 1 for the Schedule of Assessments performed at the study 
completion/early termination visit for Part 1 and 2. 
4.4.2.4 
Follow-Up Assessments 
Patients who terminate study participation by withdrawing consent will not be required to 
return for any follow-up assessments. 

 
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Patients and/or parents/legal guardians who discontinue study drug infusions for 
adverse events or other reasons and have not withdrawn consent should complete all 
withdrawal visits. 
After the study completion/early termination visit, adverse events should be followed as 
outlined in Section 5.5 and Section 5.6 for Part 1 and Part 2 of the study. 
See Appendix 1 for the Schedule of Follow-Up Assessments (visits WD1−WD4). 
4.5 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.5.1 
Patient Discontinuation 
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time (Part 1 and 2).  In addition, patients have the right to 
voluntarily discontinue study drug or withdraw from the study at any time for any reason.  
Reasons for discontinuation of study drug or withdrawal from the study may include, but 
are not limited to, the following: 
• 
Patient/guardians may request withdrawal of consent at any time 
• 
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 
• 
Lost to follow up 
• 
Death 
 
4.5.1.1 
Discontinuation from Study Drug 
Patients must discontinue the study drug if they experience any of the following at any 
time (Part 1 and 2): 
• 
Pregnancy 
• 
Anaphylaxis or serious hypersensitivity as per Section 5.1.1.6    
• 
sJIA flare (Part 2 only and at the discretion of the investigator) 
• 
MAS 
• 
Fever attributable to sJIA (Part 2 only and at discretion of investigator) 
 
Patients who discontinue study drug prematurely will be asked to return to the clinic for a 
study completion/early termination visit (see Section 4.4.2.3) and may undergo follow-up 
assessments (see Section 4.4.2.4).  The primary reason for premature study drug 
discontinuation should be documented on the appropriate page of the eCRF.  Patients 
who discontinue study drug prematurely will not be replaced. 
4.5.1.2 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study in both Part 1 and Part 2.  Parents/guardians should be asked if they can still be 

 
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contacted for further information.  The primary reason for withdrawal from the study 
should be documented on the appropriate eCRF.   
If lost to follow-up, the investigator should contact the patient’s parents/guardian or a 
responsible relative by telephone followed by registered mail or through a personal visit 
to establish as completely as possible the reason for the withdrawal.  A complete final 
evaluation at the time of the patient’s withdrawal should be made with an explanation 
of why the patient is withdrawing from the study.  
Patients will not be followed for any reason after consent has been withdrawn.  Patients 
who withdraw from the study will not be replaced. 
If the reason for removal of a patient from the study is an adverse event, the principal 
specific event will be recorded on the eCRF.  The patient should, if possible, not be 
withdrawn from the study but only the study drug and if possible, the patient should be 
followed until the adverse event has resolved (see Section 5.5). 
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of patients should be avoided.  Should a patient decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
4.5.2 
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 enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program.   
The Sponsor has the right to replace a site at any time.  Reasons for replacing 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 GCP 
 

 
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The investigator may also withdrawal a patient from the study at any time.  Reasons for 
withdrawing a patient from the study may include, but are not limited to, the following: 
• 
Non-compliance with the requirements of the study 
• 
Any adverse event that in the opinion of the investigator or the Sponsor precludes 
further study participation 
• 
It is in the best interest of the patient 
 
When applicable, parents/guardians should be informed of circumstances under which 
their child’s participation may be terminated by the investigator without the 
parent’s/guardian’s consent.  The investigator may withdraw patients from the study in 
the event of intercurrent illness, adverse events, treatment failure after a prescribed 
procedure, lack of compliance with the study and/or study procedures (e.g., dosing 
instructions, study visits), cure, or any reason where it is felt by the investigator that it is 
in the best interest of the patient to be discontinued from the study.  Any administrative 
or other reasons for withdrawal must be documented and explained to the patient and/or 
parent/legal guardian. 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety of patients in Part 1 and Part 2 of the study will be assessed by physical 
examination, assessment of vital signs, screening for TB and treatment as applicable, 
laboratory assessments (see Section 4), and the collection of adverse events. 
5.1.1 
Risks associated with TCZ Therapy and Risk Mitigation 
Strategies 
This section describes the known and potential risks of TCZ therapy, and risk 
mitigation strategies that should be followed during this study (Part 1 and Part 2). 
Adherence to the planned dose regimen of TCZ is required unless an adjustment is 
necessary for safety reasons.  The following risk mitigation and dose modification rules 
apply to patients receiving the study drug in Part 1 and 2 of the study.  
Recommendations for vigilance with signs and symptoms of particular safety events of 
interest are summarized in the following sections.  For study visits (Part 1 and Part 2) at 
which the study drug dose is held due to toxicity, all other study assessments should be 
performed as per study schedule.  For management of neutropenia, thrombocytopenia, 
and elevated liver enzymes in the study, see Section 3.1.2.   
5.1.1.1 
Opportunistic Infections and Serious Infections 
Physicians should exercise caution when considering the use of TCZ in patients with a 
history of recurring infection or with underlying conditions (e.g., diabetes) that may 
predispose patients to infections.  TCZ should not be administered to patients with active 
infection.  The effects of TCZ on CRP, neutrophils, and the signs and symptoms of 
infection should be considered when evaluating a patient for a potential infection.  

 
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Vigilance for timely detection of serious infection is recommended for patients receiving 
biologic agents as signs and symptoms of acute inflammation may be lessened due to 
suppression of the acute phase reaction.  Patients/legal guardians must be instructed to 
contact their child’s physician immediately when any symptoms suggesting infection 
appear in order to assure rapid evaluation and appropriate treatment.  If a patient 
develops a serious infection, administration of TCZ is to be interrupted until the infection 
is controlled.  The physician must consider the benefit − risk before resuming treatment 
with TCZ. 
5.1.1.2 
Gastrointestinal Perforations 
Although uncommon in the pediatric population, patients/legal guardians should be 
made aware of the symptomatology potentially indicative of diverticular disease, and 
they should be instructed to alert their healthcare provider as soon as possible if these 
symptoms arise.  Timely diagnosis and appropriate treatment may reduce the potential 
for complications of diverticulitis and thus reduce the risk of GI perforations.  In patients 
with a history of symptomatic diverticulosis, diverticulitis or chronic ulcerative lower GI 
disease, such as Crohn’s disease, ulcerative colitis, or other chronic lower GI conditions 
that might predispose the patient to GI perforations, the physician should consider the 
benefit-risk before using TCZ.  Discontinuation of TCZ is recommended for patients who 
develop GI perforations.  
5.1.1.3 
Demyelinating Disorders 
The impact of treatment with TCZ on demyelinating disorders is not known; events were 
reported rarely in adult RA patients.  Patients should be closely monitored for signs and 
symptoms potentially indicative of central demyelinating disorders.  Physicians should 
exercise caution in considering the use of TCZ in patients with pre-existing or 
recent-onset demyelinating disorders.  Treatment with TCZ should be interrupted during 
assessment of a potential demyelination event and only resumed if the benefit of 
continuing study drug is favorable. 
5.1.1.4 
Cardiovascular Events and Elevated Lipids 
Patients with RA have an increased risk for cardiovascular disorders; therefore, risk 
factors for cardiovascular disease (e.g., hypertension, hyperlipidemia) should be 
managed as part of their standard of care.  For pediatric patients that are at higher risk 
for cardiovascular disease with an LDL cholesterol ≥ 130 mg/dL, the National Cholesterol 
Education Program (NCEP) guidelines for children and adolescents recommends 
changes in diet with nutritional counseling and other lifestyle interventions, such as 
increased physical activity.  For patients 8 years and older with an LDL cholesterol of 
≥ 190 mg/dL (or LDL ≥ 160 mg/dL with a family history of early heart disease or 
2 additional risk factors present or LDL ≥ 130 mg/dL if diabetes mellitus is present), 
pharmacologic intervention should be considered.  

 
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It is worth noting that the same values are used for all children, from 2 to 18 years of age. 
After 18 years of age, the concentrations presented in the NCEP report for adults would 
be used (Daniels et al. 2008). 
5.1.1.5 
Malignancies 
The impact of immunosuppression on the development of malignancies is not known.  
No imbalance of malignancies was observed in controlled clinical trials of TCZ.  It is 
recognized that identification of such events in TCZ-treated patients may require a 
longer period of surveillance. 
5.1.1.6 
Hypersensitivity or Anaphylaxis 
An infusion/dose reaction is defined as an adverse event occurring during and within 
24 hours after the infusion of TCZ.  This may include hypersensitivity reactions or 
anaphylactic reactions.  Signs of a possible hypersensitivity reaction include but are not 
limited to: 
• 
Fever, chills, pruritus, urticaria, angioedema, and skin rash 
• 
Cardiopulmonary reactions, including chest pain, dyspnea, hypotension, or 
hypertension 
 
Healthcare professionals administering TCZ infusions should be trained in the 
appropriate administration procedures, be able to recognize the symptoms associated 
with potential anaphylactic or hypersensitivity reactions, and have the appropriate 
medication available for immediate use in case of anaphylaxis or hypersensitivity 
reaction during or after administration of TCZ.  Healthcare professionals should also 
instruct patients to seek medical attention if they experience symptoms of a 
hypersensitivity reaction outside of the clinic.  If a patient has symptoms of anaphylaxis 
or serious hypersensitivity, or requires an interruption of the study drug because of 
symptoms of anaphylaxis or hypersensitivity, administration of TCZ must be 
discontinued permanently.  The patient should be treated according to the standard of 
care for management of the hypersensitivity reaction.  A blood sample for the presence 
of anti-TCZ antibodies should be obtained (refer to the schedule of assessments).  The 
patient must be withdrawn from Part 1 or 2 of the study. 
Samples for anti-TCZ antibodies, TCZ PK, and sIL-6R will be collected for all study 
patients to evaluate immunogenicity of TCZ at baseline and Week 24 for patients on 
Q2W in Part 1; baseline, Week 6, 12, 24, 36, and 48 (for patients on Q3W dosing in 
Part 2) and at baseline, 8 weeks, and 12 weeks after switching to Q4W for patients on 
Q4W dosing in Part 2 and at the last study visit, or at the time of early withdrawal from 
the study (visit  WD1) for Part 1 or Part 2.  Event-driven sampling (at the time of the 
event and also at least 6 weeks after the last dose) will occur for all patients 
experiencing serious infusion-related or allergic reactions or any hypersensitivity event 
(including non-serious events) leading to treatment withdrawal in Part 1 or Part 2.   

 
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5.1.2 
Laboratory Test Abnormalities 
Laboratory test results in Part 1 and Part 2 of the study will be recorded on the 
laboratory results e-form of the eCRF, or appear on electronically produced laboratory 
reports submitted directly from the central laboratory, if applicable.  Any laboratory result 
abnormality fulfilling the criteria for a serious adverse event should be reported as such, 
in addition to being recorded as an adverse event in the eCRF.  Any treatment-emergent 
abnormal laboratory result that is clinically significant (i.e., meeting one or more of the 
following conditions) should be recorded as a single diagnosis on the adverse event 
e-form in the eCRF: 
• 
Accompanied by clinical symptoms 
• 
Leading to a change in study drug (e.g., dose interruption or permanent 
discontinuation) 
• 
Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, or 
treatment) 
 
This applies to any protocol and non-protocol specified safety and efficacy laboratory 
result from tests performed after the first dose of study drug, which falls outside the 
laboratory reference range and meets the clinical significance criteria.  This does not 
apply to any abnormal laboratory result that falls outside the laboratory reference range 
but does not meet the clinical significance criteria (these will be analyzed and reported 
as laboratory abnormalities); those that are considered adverse events of the type 
explicitly exempted by the protocol; or those which are a result of an adverse event that 
has already been reported. 
The following laboratory abnormalities are considered exempt from the above, and 
should not be recorded as adverse events in the eCRF:  serum amyloid A, serum ferritin, 
hsCRP and ESR. 
5.1.2.1 
Laboratory Test Abnormalities Suggestive of MAS 
Special attention will be taken to the early reporting and identification of MAS-related 
features or MAS-like events to Roche. 
The occurrence of laboratory findings or clinical criteria suggestive of MAS or MAS-like 
events with or without unusual features should be reported to Roche as a serious 
adverse event (see Section 5.2.2).  Specific information about these events will be 
collected to obtain a complete description of the event. 
Any patients with the clinical findings and supporting laboratory evidence of MAS (see 
Appendix 3) should have TCZ treatment interrupted and be treated appropriately for 
MAS.  These patients will be withdrawn from the study.  Please see Section 3.1.3.  

 
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The definition of MAS (see Appendix 3) was developed to assist physicians to 
distinguish between active sJIA and MAS.  It should be noted that some of the laboratory 
features associated with TCZ administration and related to its blocking of IL-6 action are 
similar to some of the laboratory features often associated with the diagnosis of MAS 
(features such as a decline in WBC count, neutrophil count, platelet count, serum 
fibrinogen, and ESR, all of which occur most notably within the week following TCZ 
administration).  Ferritin levels frequently decrease with TCZ administration, but often 
increase with MAS and, therefore, can be a useful differential laboratory analysis.  
Characteristic clinical findings of MAS (CNS dysfunction, hemorrhages, and 
hepatosplenomegaly) should accompany laboratory findings when establishing the 
diagnosis of MAS in the context of IL-6 inhibition.  Clinical experience and clinical status 
of the patient and timing of the laboratory specimens in relation to TCZ administration 
must guide interpretation of these laboratory data and their potential significance.  
Please refer to the latest Roche TCZ Investigator’s Brochure for more information about 
MAS (Tocilizumab [RO4877533] Investigator’s Brochure). 
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; measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; and 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 GCP, 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 unfavorable 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 5.3.5.9  
• 
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 

 
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• 
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: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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 5.3.5.10) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 (rated as mild, moderate, or severe, or according to National Cancer 
Institute Common Terminology Criteria for Adverse Events; 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 
within 24 hours after learning of the event (see Section 5.4.2 for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
To further evaluate the adverse events of special interest, detailed information about 
these events should be documented and reported. The documentation and reporting 
requirements for such adverse events will be described in a separate document 
(ACTEMRA® [Tocilizumab] events of special interest guidance document). 
As noted in Section 5.2.2, investigators will submit reports of all reportable serious 
adverse events, regardless of attribution, all protocol-defined events of special interest 

 
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(including events of special interest), and pregnancies to the Roche Drug Safety within 
24 hours of learning of the event. For initial serious adverse event and protocol-defined 
events of special interest reports (including events of special interest), investigators 
should record all case details that can be gathered within 24 hours on an adverse event 
eCRF and submit the report through the electronic data capture (EDC) system. 
All adverse events of special interest are required to be reported by the investigator to 
the Sponsor within 24 hours after learning of the event (see Section 5.4.2 for reporting 
instructions).   
Adverse events of special interest for this study include the following: 
• 
Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6 
• 
Suspected transmission of an infectious agent by the study drug.  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.). 
• 
Adverse events of special interest for Actemra in this study are provided in the 
current AESI guidance document.  
 
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 Section 5.4 through 
Section 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, parent or guardian, or noted by study 
personnel, will be recorded in the patient’s medical record and on the Adverse Event 
eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies; 
see Section 5.4.2 for instructions for reporting serious adverse events). 

 
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After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 3 months after the last dose of study drug.  After this period, 
investigators should report any deaths, serious adverse events, or other adverse events 
of concern that are believed to be related to prior treatment with study drug (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 timepoints.  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 
Table 7 provides guidance for assessing adverse event severity.  
Table 7 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 

 
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For patients receiving TCZ in combination with other therapies, causality to TCZ will be 
assessed for TCZ individually. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the adverse event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the adverse event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF 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 on the Adverse Event 
eCRF.  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. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring 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.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by a mild, non-serious infection, only neutropenia 
should be reported on the eCRF. 
• 
If neutropenia is accompanied by a severe or serious infection, both events should 
be reported separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 

 
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5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens.  If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.  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 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 timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
• 
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 hypokalemia) 
or a change in concomitant therapy 
• 
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 × ULN associated with cholecystitis), only the 
diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, 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 “hyperkalemia.” 

 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
• 
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 
• 
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 on the 
Adverse Event eCRF.  Abnormalities in vital signs will be interpreted in reference to age 
and gender specific normal values. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor within 24 hours after learning of the event, either as a 
serious adverse event or a adverse event of special interest (see Section 5.4.2). 

 
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5.3.5.7 
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 on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of sJIA. 
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 on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term “sudden death” should only be used 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 of 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 on the Adverse Event eCRF.  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 progression of sJIA, "sJIA progression” should be recorded 
on the Adverse Event eCRF.   
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
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 on the Adverse Event eCRF, it is important to convey the concept 
that the pre-existing condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.5.9 
Lack of Efficacy or Worsening of sJIA 
Medical occurrences or symptoms of deterioration that are anticipated as part of sJIA do 
not need to be recorded as an adverse event.   
JIA flares as assessed and notified by the external collaborative groups will be recorded 
in the relevant flare eform in the eCRF.  Fever attributable to sJIA as assessed by the 
investigator will be recorded in the relevant flare eform in the eCRF. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization 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 serious adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)  
 
Hospitalization for a preexisting 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 suffered an adverse event 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Elective hospitalizations or surgical procedures that are the result of a patient's 
pre-existing condition(s) and which have not worsened since receiving study drug.  
Examples may include, but are not limited to:  joint replacement surgery, physical 
therapy rehabilitation, and diagnostic testing.  Such events must still be recorded as 
adverse events in the eCRF. 
• 
Hospitalization to receive study drug such as infusions of TCZ unless it is prolonged 
(more than 24 hours) due to safety issues. 
• 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available. 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects.   
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.  
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor within 24 hours after 
learning of the event (see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data.  However, if any patient 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, site staff will alert the investigator, who will determine if the criteria 
for an adverse event have been met and will document the outcome of this assessment 

 
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in the patient's medical record per site practice.  If the event meets the criteria for an 
adverse event, it will be reported on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
The investigator must report the following events to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to study drug: 
• 
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 within 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 
MEDICAL MONITOR (ROCHE MEDICAL RESPONSIBLE) CONTACT 
INFORMATION  
Primary Contact 
Medical Monitor: Dr. 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Secondary Contact 
Medical Monitor: Dr. 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
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 

 
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available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information and List of Investigators").  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
For reports of serious adverse events and adverse events of special interest, 
investigators should record all case details that can be gathered within 24 hours on the 
Adverse Event eCRF and submit the report via the EDC system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system (ACTEMRA® 
[Tocilizumab] events of special interest guidance document). 
To further evaluate the adverse events of special interest, detailed information about 
these events should be documented and reported.  The documentation and reporting 
requirements for such adverse events will be described in a separate document 
(ACTEMRA® [Tocilizumab] events of special interest guidance document). 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Adverse Event of Special Interest Case Report Form and Fax Coversheet should 
be completed and faxed to Roche Safety Risk Management or its designee within 
24 hours after learning of the event, using the fax numbers provided to investigators (see 
"Protocol Administrative and Contact Information and List of Investigators").  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
5.4.2.1 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 3 months after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
EDC system.  A report will be generated and sent to Roche Safety Risk Management by 
the 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 e-mailing the form with 
use of the fax number or e-mail 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. 

 
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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 90 days after the last dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator within 
24 hours after learning of the pregnancy and submitted via the EDC system.  A 
pregnancy report will automatically be generated and sent to Roche Safety Risk 
Management.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  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 fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy 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 pregnancy), 
either by faxing or by scanning and e-mailing the form with use of the fax number or 
e-mail address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.  
5.4.3.2 
Abortions 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor within 24 hours after learning 
of the event (see Section 5.4.2).   
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor within 24 hours after learning of the event (see Section 5.4.2). 
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 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 

 
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verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
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 
At the study completion/early termination visit, the investigator should instruct each 
patient to report to the investigator any subsequent adverse events that the patient’s 
personal physician believes could be related to prior study drug treatment or study 
procedures.   
The investigator should notify the Sponsor of any death, serious adverse event, or other 
adverse event of concern occurring at any time after a patient has discontinued study 
participation if the event is believed to be related to prior study drug treatment or study 
procedures.  The Sponsor should also be notified if the investigator becomes aware of 
the development of cancer or a congenital anomaly/birth defect in a subsequently 
conceived offspring of a patient that participated in this study. 
The investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the investigator 
should report the event directly to Roche Safety Risk Management via telephone (see 
"Protocol Administrative and Contact Information and List of Investigators"). 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
TCZ Investigator's Brochure 
 
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. 

 
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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Full details of all statistical issues and planned statistical summaries will be specified in a 
separate Statistical Analysis Plan (SAP), which will be finalized prior to locking of the 
study database.   
All data to be presented will be descriptive and no hypothesis testing will be performed.     
Analysis Populations will be defined as follows: 
• 
All TCZ population:  All patients who have received at least one dose of study drug.   
• 
Safety population:  All patients who have received at least one dose of study drug 
and who have at least one post-baseline assessment of safety. 
 
Safety data will be presented for the safety population and efficacy data will be 
presented for the all TCZ population.  All patients in Part 1 will commence treatment 
with the TCZ Q2W regimen; all patients in Part 2 will commence treatment with a 
Q3W dosing frequency regimen.   
Basic safety reporting will occur for Part 1 of the study and full reporting (including 
PK, PD, and efficacy assessments) will occur for Part 2. 
Separate subgroup summaries may be presented for the patients who enter into a Q4W 
dosing frequency regimen during the study, if sufficient data exists.  In addition, 
dependent on sufficient data, data by dose group (8 mg/kg ≥ 30 kg or 12 mg/kg < 30 kg) 
may be presented. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is to explore the efficacy, safety, pharmacokinetics, 
pharmacodynamics, and immunogenicity of TCZ in a reduced dosing frequency regimen 
in patients with adequately controlled sJIA who have experienced a predefined resolved 
laboratory abnormality on TCZ Q2W dosing.  This is a non-powered, descriptive study. 
Part 2 of the study will enroll patients already receiving TCZ who have experienced a 
predefined laboratory abnormality on Q2W TCZ.  A sample size of approximately 
20 patients in Part 2 who complete 5 consecutive Q3W treatments up to Week 12 has 
been deemed adequate for the objectives of this study.  In addition, 20 patients in Part 2 
would ensure 95% probability of observing at least one adverse event when the 
underlying incidence of that event is ≥ 14%. 
In addition to the 6 patients enrolled in Part 2 as of May 2015 (under Protocol 
Version 2), approximately an additional 65 patients will be enrolled into Part 1 of the 

 
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study (under Protocol Version 3).  On investigation of Study WA18221 data, it was 
found that 46% (52 of 112) of patients experienced a resolved laboratory abnormality 
on TCZ Q2W, per the Part 2 entry criteria at any point during the study:  25% 
(28 of 112) of TCZ naive patients during the study from 0-6 months, and 31% 
(32 of 102) of TCZ non-naive patients between Months 12 and 18 in the study.  Based 
on these percentages, 65 patients enrolled in the run-in period of this study (Part 1) 
will result in approximately 16-20 TCZ naive/non-naive patients eligible for Part 2, 
which when added to the 6 patients currently enrolled in Part 2, will result in 
approximately 20 patients in Part 2, even taking into account the JADAS (and absence 
of fever attributable to sJIA) entry requirement for Part 2, and the possibility of 
withdrawals.  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The conduct and integrity of the study will be assessed based on all descriptive data 
provided.  Blinding and major protocol violations affecting analysis populations are not 
applicable to this study. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
No formal assessment of treatment group comparability will be performed.  All patients 
will receive TCZ, dose determined based on weight (8 mg/kg ≥ 30 kg or 12 mg/kg < 30 kg) 
and given TCZ Q2W (Part 1), and then TCZ Q3W (Part 2) and Q4W (for those patients 
who experience a repeat laboratory abnormality during Part 2).  All baseline data, 
including demographics, baseline characteristics, patient disposition, infusion data, and 
concurrent treatment, will be summarized.  No testing of baseline characteristics will be 
performed. 
Part 1 Baseline is defined as the first dose of TCZ received in Part 1 of the study.  
Part 2 baseline is defined as the first dose of TCZ received in Part 2 of the study (see 
Appendix 1 for the schedule of assessments). 
6.4 
EFFICACY ANALYSES 
No formal hypothesis testing is planned for this study.  All efficacy data will be presented 
descriptively.  Summaries by visit will be presented for the all TCZ population (all 
patients to commence treatment with a Q3W dosing frequency regimen at baseline of 
Part 2 [Week 0]).  In addition, separate subgroup summaries for patients moving on to a 
Q4W dosing frequency regimen during the study will be produced if sufficient data exists.  
Data will be summarized from the first Q4W dosing visit.  All summaries will be based on 
observed case data.  No imputation of missing data will be performed. 
Full details of all planned efficacy analyses will be provided in the SAP. 
Assessment of efficacy will be based on JADAS-71 during Part 2 of the study and 
assessment of fever (attributable to sJIA). 

 
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JIA flare relative to Part 2 baseline will be assessed at each visit in Part 2 to determine 
if a patient should be withdrawn based on lack of efficacy at the discretion of the 
investigator.  Component scores in the assessment of JIA flare (physician global 
assessment of disease activity [100 mm horizontal VAS], patient/parent global 
assessment of overall well-being [100 mm horizontal VAS], number of joints with active 
arthritis [0−71], number of joints with limitation of movement, CHAQ, and ESR) will be 
summarized or listed as appropriate. 
6.5 
SAFETY ANALYSES 
Safety will be assessed based on reporting of adverse events, vital signs, clinical 
laboratory assessments, concomitant medications, and physical examination (for Part 1 
and Part 2 of the study separately).  All safety data will be reported based on the safety 
population and will be listed or summarized descriptively as appropriate.  Full details of 
all safety reporting will be provided in the SAP. 
Verbatim terms for adverse events reported during the study will be mapped to the 
appropriate thesaurus level.  All adverse events will be coded and tabulated by body 
system and preferred term for individual events within each body system and will be 
presented in descending frequency.  Adverse events will also be tabulated by severity 
and relationship to study drug.  Serious adverse events and adverse events leading to 
withdrawal will be presented separately.   
Vital signs data will be summarized or listed, as appropriate.  Values outside the normal 
ranges and marked abnormalities will be flagged.  Concomitant medications will be 
presented in listings or summary tables as appropriate. 
Clinical laboratory data will be summarized or listed as appropriate.  Values outside 
normal ranges will be flagged.   
6.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Nonlinear mixed effects modeling (using NOMMEM software) (Beal et al. 1992) will be 
used to analyze the serum TCZ concentration-time data collected in this study in Part 2 
of the study.  The current PK model developed for sJIA patients from previous studies 
(Studies MRA316JP, LRO320, and WA18221) will be used to analyze the serum TCZ 
concentration-time data. 
The following systemic exposure parameters will be estimated for all patients who 
provide adequate PK samples: 
• 
AUCτ during a dosing interval at week 12 of Part 2; τ = 3 weeks for Q3W and 
τ = 4 weeks for Q4W 
• 
Cmax post infusion at Week 12 of Part 2 
• 
Cmin at end of a dosing interval at Week 12 of Part 2 
 

 
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TCZ serum concentrations and computed PK parameters will be listed and summarized 
descriptively.  Mean and median serum concentrations versus time will be plotted on 
linear scales. 
Serum concentration of PD markers will be summarized descriptively by dose frequency.  
Mean and median serum concentrations versus time will be presented graphically  
TCZ serum concentration response relationship (PD markers and efficacy parameters) 
will be explored. 
6.7 
PATIENT-REPORTED OUTCOMES  
PROs in this study include the CHAQ questionnaire (see Section 4.4.1.10.1 and 
Appendix 2) and the patient/parent global assessment of overall well-being 100 mm 
horizontal VAS.  The left-hand extreme of the line should be described as “very well” 
(symptom-free and no arthritis symptoms) and the right-hand extreme as “very poor” 
(maximum arthritis disease activity), which are all part of the 6 core JIA American 
College of Rheumatology components.  Data will be summarized or listed as appropriate. 
6.8 
INTERIM ANALYSES 
Interim analyses may be performed at the discretion of the sponsor, for regulatory 
reporting purposes. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor 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 discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document 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. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 

 
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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and a 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. 
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 investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 

 
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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, electronic PRO data, Informed Consent Forms/informed assent 
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 GCP 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).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. Food and Drug Administration (FDA) regulations and 
applicable local, state, and federal laws.  Studies conducted in the EU/ European 
Environment Agency (EEA) will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) 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 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. 

 
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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 or their legally authorized representatives 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. 
For sites in the United States, each Informed Consent Form may also include patient 
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the 
site utilizes a separate Authorization Form for patient authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies. 
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 9.5). 
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 

 
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105/Protocol WA28029, Version 3 
local health authority and IRB/EC.  Investigators may receive written IND 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 
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 only be 
disclosed to third parties 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 the U.S. FDA and other 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., last patient, last 
visit). 
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, which includes an audit trail containing a complete record of all changes 
to data. 

 
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106/Protocol WA28029, Version 3 
9.2 
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. 
9.3 
ADMINISTRATIVE STRUCTURE 
The study will be overseen by a Steering Committee who will monitor the conduct of the 
study to ensure that expectations for study outcomes can be met and to provide a 
method for delivering recommendations and actions regarding conduct and 
management of trials as they evolve.  Periodically, dependent on enrollment, the 
Steering Committee may evaluate the conduct of trials according to GCP guidelines and 
assess data for expectedness including demographics, efficacy, and safety.  Upon study 
completion, the committee will review the Clinical Study Report.  Further details are 
provided in the Steering Committee Charter. 
A central laboratory will be used to analyze the majority of samples detailed in 
Section 4.4.1.9 and results will be made available to the investigational sites. 
An IXRS vendor will be used to enroll the patients into the study. 
External collaborative groups will confirm the JIA flare and JADAS-71 calculations to the 
investigational sites as required. 
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  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. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement (with the Paediatric Rheumatology 
International Trials Organisation (PRINTO at www.printo.it) and the Pediatric 
Rheumatology Collaborative Study Group (PRCSG at www.prcsg.org) 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. 

 
Tocilizumab—F. Hoffmann-La Roche Ltd 
107/Protocol WA28029, Version 3 
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. 
9.5 
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). 

 
Tocilizumab—F. Hoffmann-La Roche Ltd 
108/Protocol WA28029, Version 3 
10. 
REFERENCES 
ACTEMRA® (Tocilizumab) events of special interest guidance document. Current 
version. 
ACTEMRA®, English-Translated Version 7. June 2008. Chugai Pharmaceutical Co., Ltd. 
Beal SL, Boeckman AJ, Sheiner LB. NONMEM user’s guide, parts IVIII. San Francisco: 
Division of Clinical Pharmacology-University of California, 1992.  
Cassidy JT, Petty RE. Juvenile rheumatoid arthritis. Cassidy JT, Petty RE, eds. 
Textbook of pediatric rheumatology 2001:218−322. 
Consolaro A, Bracciolini G, Ruperto N, et al. Remission, minimal disease activity and 
acceptable symptom state in juvenile idiopathic arthritis. Arthritis & Rheumatism 
2012. 
Daniels SR, Greer FR. Lipid screening and cardiovascular health in children. Committee 
on Nutrition. Pediatrics 2008;122:198−208. 
De Benedetti F, Massa M, Robbioni P, Ravelli A, et al. Correlation of serum interleukin-6 
levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid 
arthritis. Arthritis Rheum 1991;34:1158−63. 
De Benedetti F, Alonzi T, Moretta A et al. Interleukin 6 causes growth impairment in 
transgenic mice through a decrease in insulin-like growth factor-I. A model for 
stunted growth in children with chronic inflammation. J Clin Invest 1997;99:643−50. 
De Benedetti F, Massa M, Pignatti P, et al. Serum soluble interleukin-6 (IL-6) receptor 
and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J 
Clin Invest 1994;93:2114−9. 
F. Hoffmann-La Roche Ltd. Summary of Product Characteristics for RoACTEMRA. Date 
of first authorization: 16 January 2009. Detailed information on this medicinal 
product is available on the website of the European Medicines Agency 
(EMEA):http://www.emea.europa.eu/. Roche Registration Limited.  
Haines KA. Juvenile idiopathic arthritis therapies in the 21st Century. Bull NYU Hosp Jt 
Dis 2007;65(3):205−11. 
Kasapcopur O, Kiray E, Bas V, et al. The tuberculin response in juvenile idiopathic 
arthritis patients vaccinated with Bacillus-Calmette-Guerin. Ann Rheum Dis 
2006;65(supp ii):240. 
Keul R et al. A possible role for soluble IL-6 receptor in the pathogenesis of systemic 
onset juvenile chronic arthritis. Cytokine 1998;10:729−34. 
Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile 
rheumatoid arthritis. N Engl J Med 2000;342:763−69. 
Prieur AM, Roux-Lombard P, Dayer JM. Dynamics of fever and the cytokine network in 
systemic juvenile arthritis. Rev Rheum Engl 1996;63:163−70. 

 
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Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007;369(9563):767−78. 
Ringold S, Weiss PF, Beukelman T, et al. 2013 Update of the 2011 American college of 
rheumatology recommendations for the treatment of juvenile idiopathic arthritis. 
Arthritis & Rheum 2013;65:2499−51. 
Ruperto N, Giannini EH, Pistorio A, et al. Is it time to move to active comparator trials in 
juvenile idiopathic arthritis? A review of current study designs. Arthritis Rheum 
2010;62:3131−39. 
Ruperto N, Martini A, for the Paediatric Rheumatology International Trials Organisation 
(PRINTO). Quality of life in juvenile idiopathic arthritis patients compared to healthy 
children. Clin Exp Rheumatol 2001; 19 (suppl.23):S1−S172. 
Ruperto N, Ravelli A, Pistorio A, et al., for the Paediatric Rheumatology International 
Trials Organisation (PRINTO): Cross-cultural adaptation and psychometric 
evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the 
Child Health Questionnaire (CHQ) in 32 countries. Review of the general 
methodology. Clin Exp Rheumatol 2001; 19 (Suppl. 23): S1−9. 
Seattle Children’s Hospital Research Foundation. Children’s Hospital and Regional 
Medical Center Laboratory Maximum allowable blood draw volumes. Adapted by 
Rhona Jack. August 2001. Available from:  www.seattlechildrens.org/pdf/blood-
volume-chart.pdf. 
Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with 
type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care 
2005;28(1):186−212. 
Tocilizumab (RO4877533) Investigator’s Brochure. Current version. 
U.S. Prescribing Information (USPI) for ACTEMRA® (tocilizumab). Genentech Inc. 
Available from http://www.gene.com/gene/products/information/actemra/pdf/pi.pdf. 
Woo P. Anti-TNF therapy and its relevance to juvenile idiopathic arthritis. Anti-TNF 
therapy: changing the face of juvenile idiopathic arthritis: Syllabus of the 7th 
European Paediatric Rheumatology Congress. September 2000. 
 

 
Tocilizumab—F. Hoffmann-La Roche Ltd 
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Appendix 1  
Schedule of Assessments 
APPENDIX 1-A:  PART 1/RUN-IN PHASE (≤ 24 WEEKS) 
Part 1 Visits (Run-in Phase)  
Withdrawal Visits 
VISIT   
Screening 
Evaluation 1
Baseline 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11
12
13 
WD1a 
WD2a 
WD3a
WD4a
Weeks from Baseline 
for Part 1 ( ± 3 days)
≤ 4 weeks 
0 
2 
4 
6 
8 
10
12
14
16
18 20
22
24 
2 wks after 
last study 
drug 
2 wks 
after 
WD1 
4 wks 
after 
WD2 
4 wks 
after 
WD3 
Informed consent b 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
TB screening (e.g., PPD c)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CXR d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TCZ infusions e, f 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs and 
temperature g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Height and weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Screening labs h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy (urine)  i, j 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Blood chemistry 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

Appendix 1  
Schedule of Assessments (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
111/Protocol WA28029, Version 3 
APPENDIX 1-A:  PART 1/RUN-IN PHASE (≤ 24 WEEKS) 
Part 1 Visits (Run-in Phase)  
Withdrawal Visits 
VISIT   
Screening 
Evaluation 1
Baseline 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11
12
13 
WD1a 
WD2a 
WD3a
WD4a
Weeks from Baseline 
for Part 1 ( ± 3 days)
≤ 4 weeks 
0 
2 
4 
6 
8 
10
12
14
16
18 20
22
24 
2 wks after 
last study 
drug 
2 wks 
after 
WD1 
4 wks 
after 
WD2 
4 wks 
after 
WD3 
Physical examination 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Anti-TCZ antibodies l  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
CXR = chest X-ray; ESR = erythrocyte sedimentation rate; HgbA1c = hemoglobin A1c; hsCRP = high-sensitivity C-reactive protein; PPD = purified protein 
derivative; Q2W = every 2 weeks; TB = tuberculosis; TCZ = tocilizumab; WD = withdrawal visit.  
a All 4 withdrawal visits to be performed after premature withdrawal from or on completion of Part 1 (and are not eligible for Part 2).  Patients 
who are entering Part 2 should successfully complete Screening Evaluation 2 before completing Part 1 WD1 and then transferring to Part 2.  
Patients who have fulfilled entry requirements for Part 2 Screening Evaluation 2 do not need to complete WD2, WD3, and WD4.  No 
infusion is given at withdrawal visits.  If a patient permanently discontinues study drug at any time during Part 1, Part 1 WD1 should be 
performed approximately 2 weeks after last infusion of study drug, followed by WD2 assessments 2 weeks later, followed by WD3 assessments 
4 weeks later, and WD4 4 weeks later.  
b The parent (or patient if he or she has reached the legal age of consent and if applicable at the site) must sign and date an Informed Consent 
Form before any study-related activities can occur.   
c PPD or equivalent (e.g., Quantiferon gold) must be interpreted based on local guidelines for immunosuppressed patients. 
d If a patient’s TB testing is positive at screening and the patient has not previously received TB treatment, then a chest radiograph is required 
at screening.  A chest radiograph obtained within 90 days of baseline can be utilized for screening purposes, if consistent with local practices.
e All assessments (safety, clinical, laboratory) except as noted should be completed prior to start of infusion.  If a patient has symptoms of 
anaphylaxis or serious hypersensitivity, or requires interruption of study drug because of symptoms of anaphylaxis or hypersensitivity 
(serious or non-serious), administration of TCZ must be permanently discontinued; a blood sample to assess anti-TCZ antibodies, TCZ PK 
and sIL-6R levels should be obtained at the time of the event and 6 weeks later. 
 

Appendix 1  
Schedule of Assessments (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
112/Protocol WA28029, Version 3 
f Patients will receive TCZ Q2W for ≤ 24 weeks until they experience a laboratory abnormality as specified in inclusion criteria 
(Section 4.1.1).  Following the occurrence and resolution of this laboratory abnormality, patients who have a successful screening evaluation 
(Screening Evaluation 2) and who fulfil all the Inclusion/Exclusion criteria for Part 2, may enter Part 2 of the study. 
g Vital signs must be taken pre-infusion, every 30 minutes during infusion, and 30 minutes after end of infusion (as stated in the main body 
of the protocol).  
h Screening laboratories include hepatitis B surface antigen, hepatitis C antibody, HgbA1c, hsCRP, fibrinogen, Epstein-Barr virus titer, 
varicella IgG testing, and ESR. 
i Urine pregnancy test for patients in Tanner stages ≥ 2 or above only or onset of menarche. 
j Dipstick urinalysis and pregnancy test on fresh voided urine sample.  May be performed at any visit at the investigator’s discretion for 
symptoms.  
l Samples for anti-TCZ antibodies, TCZ PK, and sIL-6R will be collected at baseline and WD1.  In addition to the scheduled samples listed for 
patients who withdraw because of anaphylaxis or serious or non-serious hypersensitivity reactions, a sample for assessment of anti-TCZ 
antibodies and PK (TCZ) and PD (sIL-6R) assessments will be drawn at the time of event and also at least 6 weeks after the last dose.   

Appendix 1  
Schedule of Assessments (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
113/Protocol WA28029, Version 3 
 
APPENDIX 1-B:  PART 2/MAIN STUDY 
Part 2 Visits (Main Study) 
Withdrawal Visits 
VISIT
Screening 
Evaluation 2 a Baseline b
2 
3 
4 
5 
6 
7 
8 
9 
Infusion 
Visits 
WD1 c 
WD2 c
WD3 c
WD4 c
Weeks from Baseline 
for Part 2
(± 3 days)
≤ 4 weeks  
0 
1 
2 
3 
6 
9 
10 
11 
12 
Q3W or 
Q4W d 
2 wks after 
last study 
drug 
2 wks 
after 
WD1 
4 wks 
after 
WD2 
4 wks 
after 
WD3 
Informed consent e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history f 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics g 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
TB screening (e.g., 
PPD) h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CXR i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TCZ infusions j, k, l 
 
x 
 
 
x 
x 
x 
 
 
x 
x 
 
 
 
 
Height/weight 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
 
 
x 
Physical examination 
x 
x 
 
 
x m 
x m 
x m 
 
 
x m 
x m 
x m 
x m 
x m 
x m 
Joint count 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
 
 
 
Patient/parent 
global (VAS) 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
 
 
 

Appendix 1  
Schedule of Assessments (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
114/Protocol WA28029, Version 3 
APPENDIX 1-B:  PART 2/MAIN STUDY 
Part 2 Visits (Main Study) 
Withdrawal Visits 
VISIT
Screening 
Evaluation 2 a Baseline b
2 
3 
4 
5 
6 
7 
8 
9 
Infusion 
Visits 
WD1 c 
WD2 c
WD3 c
WD4 c
Weeks from Baseline 
for Part 2
(± 3 days)
≤ 4 weeks  
0 
1 
2 
3 
6 
9 
10 
11 
12 
Q3W or 
Q4W d 
2 wks after 
last study 
drug 
2 wks 
after 
WD1 
4 wks 
after 
WD2 
4 wks 
after 
WD3 
Physician global (VAS) 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
 
 
 
CHAQ 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Screening 
laboratories n 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
Pregnancy (urine) o, p  
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
 
 
 
 
Blood chemistry 
x 
x q 
 
 
x q 
x 
x 
 
 
x 
x 
x q 
x 
x 
x 
Immunology profile 
(IgG, IgM, IgA) 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Urinalysis dipstick p 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Fibrinogen/D-Dimer 
 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
 
 
 
Lipid profile  
 
x q 
 
 
x q 
 
 
 
 
 
 
x q 
 
 
 
Acute phase reactants 
(hsCRP, serum ferritin, 
C4, C3, ESR) r 
 
x s  
x t  
x t 
x s  
x s 
x s 
x t  
x t  
x s 
x s  
x t 
 
 
 

Appendix 1  
Schedule of Assessments (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
115/Protocol WA28029, Version 3 
APPENDIX 1-B:  PART 2/MAIN STUDY 
Part 2 Visits (Main Study) 
Withdrawal Visits 
VISIT
Screening 
Evaluation 2 a Baseline b
2 
3 
4 
5 
6 
7 
8 
9 
Infusion 
Visits 
WD1 c 
WD2 c
WD3 c
WD4 c
Weeks from Baseline 
for Part 2
(± 3 days)
≤ 4 weeks  
0 
1 
2 
3 
6 
9 
10 
11 
12 
Q3W or 
Q4W d 
2 wks after 
last study 
drug 
2 wks 
after 
WD1 
4 wks 
after 
WD2 
4 wks 
after 
WD3 
PK/PD: TCZ, 
IL6 sIL-6R u, v 
 
x u, w 
x t, x
x t, x
x u, w
x u, w
x u, w
x t, x
x t, x 
x u 
x y, z 
x u 
 
 
 
Anti-TCZ 
antibodies l, v, s 
 
x s 
 
 
 
x s 
 
 
 
x s 
x y, z 
x s 
 
 
 
Vital signs and 
temperature aa 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
CHAQ = Childhood Health Assessment Questionnaire; CXR = chest X-ray; eCRF = electronic Case Report Form; ESR = erythrocyte sedimentation 
rate; hsCRP = high-sensitivity C-reactive protein; IL =  interleukin; JIA = juvenile idiopathic arthritis; PD = pharmacodynamic; PK = pharmacokinetic; 
PPD = purified protein derivative; Q3W = every three weeks; Q4W = every 4 weeks; sIL-6 = soluble interleukin-6; TB = tuberculosis; TCZ = tocilizumab; 
VAS = visual analogue scale; WD = withdrawal visit. 
a TCZ infusions may continue to be received during the Screening Evaluation 2, but there must be at least 10 days clear between the last TCZ 
infusion during screening and the first study TCZ infusion received at baseline.  
b Numbering for visits for Part 2 commence from baseline visit for Part 2. 
c Withdrawal visit:  All 4 withdrawal visits to be performed after premature withdrawal or when the patient completes Part 2.  No infusion is 
given at withdrawal visits.  If a patient permanently discontinues study drug at any time during the study, the first Withdrawal visit (WD1) 
should be performed approximately 2 weeks after last infusion of study drug, followed by WD2 assessments 2 weeks later, followed by WD3 
assessments 4 weeks later, followed by WD4 assessments 4 weeks later. Samples for anti-TCZ antibodies, TCZ PK, and sIL-6R will be 
collected at the WD1.  
 

Appendix 1  
Schedule of Assessments (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
116/Protocol WA28029, Version 3 
 
d Patients on Q3W who do not meet all requirements to switch to Q4W may continue on Q3W up to 52 weeks.  Patients on Q4W will 
remain on this dose until the end of Part 2 (up to 52 weeks). 
e The parent (or patient if he or she has reached the legal age of consent, and if applicable at the site) must sign and date an Informed Consent 
Form before any study related activities can occur. Informed Consent for Part 2 is not required for patients entering from Part 1.   
f Medical history to include information on prior immunization/vaccines.  Adverse events ongoing from Part 1 should be entered as an ongoing 
condition in the medical history for Part 2. 
g Demographics for Part 2 is not required for patients entering from Part 1.  
h  PPD (or equivalent, e.g., Quantiferon gold) must be interpreted based on local guidelines for immunosuppressed patients. TB screening does 
not need to be repeated for patients entering from Part 1.     
i If a patient’s TB testing is positive at screening and the patient has not previously received TB treatment, then a chest radiograph is 
required at screening. A chest radiograph obtained within 90 days of baseline can be utilized for screening purposes, if consistent with 
local practices. TB screening test and chest x-ray does not need to be repeated for patients entering from Part 1.     
j 
All assessments (safety, clinical, laboratory) except as noted should be completed prior to start of infusion.  If a patient has symptoms of 
anaphylaxis or serious hypersensitivity, or requires interruption of study drug because of symptoms of anaphylaxis or hypersensitivity 
(serious or non-serious), administration of TCZ must be permanently discontinued. A blood sample to assess for anti-TCZ antibodies, TCZ 
PK, and sIL-6R must be taken at the time of the event and 6 weeks later.   
k Patients must continue on Q3W dosing for a minimum of 5 consecutive infusions (at least 12 weeks).  After 5 consecutive Q3W infusions, if a 
patient experiences any of the laboratory abnormalities outlined in Section 3.1.2 and has maintained adequate disease control (JADAS ≤ 3.8 
and no fever attributable to sJIA), they will switch to Q4W dosing upon restarting treatment with TCZ.  Patients experiencing a JIA flare or 
fever attributable to sJIA will be withdrawn from the study at the discretion of the investigator. 
l For patients on Q4W dosing, please refer to Appendix 1-C for timing of these assessments.  
m Focused physical examination (examination may be limited to appropriate organ systems based on relevance to any ongoing adverse 
events).  Focused laboratory assessments may be appropriate depending on reason for discontinuation of study drug administration. 
n Screening labs include hepatitis B surface antigen, hepatitis C antibody, HgbA1c, hsCRP, fibrinogen, Epstein-Barr virus titer, varicella IgG 
testing and ESR.  
o Urine pregnancy test for patients in Tanner stages ≥ 2 or above only or onset of menarche. 
p Dipstick urinalysis, pregnancy test on fresh voided urine sample.  May be performed at any visit at the investigator’s discretion for symptoms.  
q Fasting labs for glucose and lipids should be obtained after minimum 8-hour fast. 

Appendix 1  
Schedule of Assessments (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
117/Protocol WA28029, Version 3 
r All samples taken pre-dose unless otherwise specified. ESR performed locally and required for the JIA flare assessment. 
s Pre-dose samples will be collected. 
t Can be obtained at any timepoint during the day that is convenient for patient and site unless the visit is designated as a fasting visit. 
u Pre-dose samples for PK (TCZ concentrations) and PD (IL-6, and sIL-6R concentrations) will be obtained from a single specimen obtained at 
indicated timepoints in Schedule of Assessments.  See laboratory manual for directions on handling of these specimens.  
v In addition to the scheduled samples listed, for patients who withdraw from Part 2 because of anaphylaxis or serious or non-serious 
hypersensitivity reactions, a sample for assessment of anti-TCZ antibodies and PK (TCZ) and PD (sIL-6R) will be drawn at the time of event 
and also at least 6 weeks after the last dose.  
w Post-dose PK/PD samples (obtained within 15 minutes following saline flush marking end of infusion) from opposite arm. 
x Home nursing may be used for collection of samples at non-dosing visits. 
y PK/PD and immunogenicity assessments for first 12 weeks of Q4W regimen are to be taken as specified in the Schedule of 
Assessments−PK/PD and immunogenicity assessments for Q4W regimen (Appendix 1-C).  
z After Week12, pre-dose PK/PD and immunogenicity samples to be taken at Weeks 24, 36, and 48 only for patients on Q3W. 
aa Vital signs must be taken pre-infusion, every 30 minutes during infusion, and 30 minutes after end of infusion (as stated in the main body 
of the protocol. 

Appendix 1  
Schedule of Assessments (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
118/Protocol WA28029, Version 3 
 
APPENDIX 1-C:  PK/PD AND IMMUNOGENICITY ASSESSMENTS FOR Q4W REGIMEN IN PART 2 
Part 2 Visit  
Weeks from first dosing of 
Q4W ( ± 3 days)
0 
1 
2 
3 
4 
8 
9 
10 
11 
12 
TCZ Infusion 
x 
 
 
 
x 
x 
 
 
 
x 
PK/PD: TCZ, IL-6, sIL-6R a 
x b,c 
x d 
x d 
x d 
x b,c 
x b,c 
x d 
x d 
x d 
x b 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Acute Phase Reactants 
(hsCRP, serum ferritin, C4, 
C3, ESR) 
x e 
x d,f 
x d,f 
x d,f 
x e 
xe 
x d,f 
x d,f 
x d,f 
x e 
Anti-TCZ Antibodies a 
x e 
 
 
 
 
x e 
 
 
 
x e 
ESR = erythrocyte sedimentation rate; hsCRP = high-sensitivity C-reactive protein; IL =  interleukin; JIA = juvenile idiopathic 
arthritis; PD = pharmacodynamic; PK = pharmacokinetic; Q4W = every 4 weeks; sIL-6 = soluble interleukin-6; sJIA = systemic 
Juvenile Idiopathic Arthritis; TCZ = tocilizumab. 
a In addition to the scheduled samples listed, for patients who withdraw from the study (Part 2) or who withdraw because of 
anaphylaxis or hypersensitivity reactions, a sample for assessment of anti-TCZ antibodies and PK (TCZ) and PD (sIL-6R) 
assessments will be drawn at the time of event and also at least 6 weeks after the last dose. 
b Pre-dose PK (TCZ concentrations) and PD (IL-6, and sIL-6R concentrations) will be obtained from a single specimen 
obtained at indicated timepoints in Schedule of Assessments for Q4W dosing. Anti-TCZ antibodies will be obtained from a 
separate specimen at indicated timepoints in Schedule of Assessments.  See laboratory manual for directions on handling of 
these specimens.  
c Post dose PK/PD samples (obtained within 15 minutes following saline flush marking end of infusion) from opposite arm. 
d Can be obtained at any timepoint during the day that is convenient for patient and site 
e Pre-dose samples will be collected. 
f Home nursing may be used for collection of samples at non-dosing visits. 
 

 
Tocilizumab—F. Hoffmann-La Roche Ltd 
119/Protocol WA28029, Version 3 
Appendix 2  
Childhood Health Assessment Questionnaire (CHAQ) 
(Example Only−Not for Use) 
 

Appendix 2  
Childhood Health Assessment Questionnaire 
(Example Only−Not for Use) (cont.)  
Tocilizumab—F. Hoffmann-La Roche Ltd 
120/Protocol WA28029, Version 3 
 

Appendix 2  
Childhood Health Assessment Questionnaire 
(Example Only−Not for Use) (cont.)  
Tocilizumab—F. Hoffmann-La Roche Ltd 
121/Protocol WA28029, Version 3 
 
References: 
Ruperto N, Martini A, for the Paediatric Rheumatology International Trials Organisation 
(PRINTO). Quality of life in juvenile idiopathic arthritis patients compared to healthy 
children. Clin Exp Rheumatol 2001; 19 (suppl.23):S1-S172. 
 
Ruperto N, Ravelli A, Pistorio A, et al., for the Paediatric Rheumatology International 
Trials Organisation (PRINTO): Cross-cultural adaptation and psychometric evaluation of 
the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health 
Questionnaire (CHQ) in 32 countries. Review of the general methodology. Clin Exp 
Rheumatol 2001; 19 (Suppl. 23): S1-9.

 
Tocilizumab—F. Hoffmann-La Roche Ltd 
122/Protocol WA28029, Version 3 
Appendix 3  
Definition of MAS (Macrophage Activation Syndrome) 
 
 
 
Recommendations: 
The aforementioned criteria are of value only in patients with active tocilizumab (sJIA). 
The thresholds of laboratory criteria are provided by way of example only. 
Please refer to Section 5.1.2.1 of the protocol for more detailed information on 
establishing the diagnosis of MAS within the context of tocilizumab (TCZ) administration. 
Comments:  
The clinical criteria are more useful as a classification criteria rather than diagnostic 
criteria because often they can occur late in the presentation. 
Other abnormal clinical features to include:  nonremitting high fever (different from the 
sJIA pattern), splenomegaly, generalized lymphadenopathy, and paradoxical 
improvement of signs and symptoms of arthritis. 

Appendix 3  
Definition of MAS (Macrophage Activation Syndrome) (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
123/Protocol WA28029, Version 3 
Other abnormal laboratory findings: anemia, falling Erythrocyte Sedimentation Rate, 
increased bilirubin, elevated liver enzymes, elevated LDH, hypertriglyceridemia, low 
sodium levels, decreased albumin, increase fibrin degradation products and 
hyperferritinemia. 
Reference  
Ravelli A, Magni-Mazoni S, Pistorio A, et al. Preliminary diagnostic guidelines for 
macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J 
Pediatr 2005;146:598-604.