Conditions: Juvenile Idiopathic Arthritis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 102
Healthy volunteers: no

Brief summary:
Primary Objective:

To describe the pharmacokinetic (PK) profile of sarilumab in participants aged 2-17 years with Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA) in order to identify the dose and regimen for adequate treatment of this population

Secondary Objective:

To describe the pharmacodynamic (PD) profile, the efficacy and the long-term safety of sarilumab in participants with pcJIA.

Detailed description:
For 73 participants enrolled in the dose-finding and second portions, the total study duration per participant was up to 166 weeks that consists of a 4- week screening, a 12-week core treatment phase, a 144-week extension phase, and a 6-week post-treatment follow-up. For 29 participants enrolled in the third portion, the total study duration per participant was up to 106 weeks that consists of a 4- week screening, a 12-week core treatment phase, a 84-week extension phase, and a 6-week post-treatment follow-up.

Arms:
arm 1: Participants received one of three ascending dose regimens of sarilumab by subcutaneous (SC) injection based on body weight. All the participants received the selected dose regimen once this was identified. Sarilumab was given during 12-week core treatment phase followed by an extension treatment phase (144 weeks for 73 participants enrolled in dose-finding and second portions and 84 weeks for approximately 29 participants enrolled in third portion)

Interventions: intervention 1: Sarilumab
Intervention descriptions: intervention 1: Pharmaceutical form:Solution Route of administration: Subcutaneous

Protocol document:
Prot_000.pdf: 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY 
Document
Country/countries 
impacted by 
amendment
Date, version
Amended Clinical Trial Protocol 3 
All 
Date: 12-Sep-2019, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 2 
All 
Date: 13-Dec-2018, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 1 
All 
Date: 06-Apr-2018, version 1 (electronic 2.0) 
Protocol Amendment 6 
All 
Date: 27-Jun-2018, version 2 (electronic 2.0) 
Amended Clinical Trial Protocol 2 (RU) 
Russia only 
Date: 21-Apr-2017, version 1 (electronic 2.0) 
Protocol Amendment 5 (RU) 
Russia only 
Date: 21-Apr-2017, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 2 (DE) 
Germany only 
Date: 03-Jan-2017, version 1 (electronic 3.0) 
Protocol Amendment 4 (DE) 
Germany only 
Date: 03-Jan-2017, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 1 (DE) 
Germany only 
Date: 20-Jul-2016, version 1 (electronic 1.0) 
Protocol Amendment 3 (DE) 
Germany only 
Date: 20-Jul-2016, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 1 (FR) 
France only 
Date: 15-Jul-2016, version 1 (electronic 1.0) 
Protocol Amendment 2 (FR) 
France only 
Date: 15-Jul-2016, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 1 (RU) 
Russia only 
Date: 08-Mar-2016, version 1 (electronic 1.0) 
Protocol Amendment 1 (RU) 
Russia only 
Date: 08-Mar-2016, version 1 (electronic 1.0) 
Clinical Trial Protocol 
 
Date: 14-Jan-2016, version 1 (electronic 1.0) 
Amended protocol 03 (12-Sep-2019)
This amended protocol (amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
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NAMES AND ADDRESSES OF
COORDINATING 
INVESTIGATOR
Name:
Address:
Tel:
Fax:
E-mail:
MONITORING TEAM’S 
REPRESENTATIVE
Name:
Address:
Tel:
Fax:
E-mail:
SPONSOR
Company:
Address:
OTHER EMERGENCY 
TELEPHONE NUMBERS
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CLINICAL TRIAL SUMMARY
COMPOUND: 
Sarilumab/SAR153191
STUDY No: DRI13925
TITLE
An Open-label, Sequential, Ascending, Repeated Dose-finding Study of 
Sarilumab, Administered with Subcutaneous (SC) Injection, in Children and 
Adolescents Aged 2 to 17 Years, with Polyarticular-course Juvenile Idiopathic 
Arthritis (pcJIA) Followed by an Extension Phase 
INVESTIGATOR/TRIAL LOCATION
Worldwide 
PHASE OF DEVELOPMENT
Phase 2b 
STUDY OBJECTIVE(S)
Primary objective:
To describe the pharmacokinetic (PK) profile of sarilumab in patients aged 2 to 
17 years with pcJIA in order to identify the dose and regimen for adequate 
treatment of this population. 
Secondary objectives:
To describe: 
x
The pharmacodynamic (PD) profile and the efficacy of sarilumab in patients 
with pcJIA. 
x
The long-term safety of sarilumab in patients with pcJIA. 
STUDY DESIGN
Design:  
Multicenter, open–label, two-phase study in pcJIA patients from 2 to 17 years (or 
country specified age requirement) of age: The two phases are: 
1)
A 12-week core treatment phase, split into 3 portions: 
x
A first sequential, ascending dose-cohort, dose-finding portion (hereafter 
referred to as “dose-finding portion”) in which up to 3 dose regimens will be 
investigated in two weight groups (Group A, patients ≥30 kg and ≤60 kg and 
Group B, patients <30 kg and ≥10 kg) in 6 evaluable patients per dose 
regimen weight group (around 36 patients in total). Patient enrollment will be 
staggered by weight group and dose regimen, starting with Group A and Dose 
Regimen 1 Cohort. 
x
A subsequent portion (hereafter referred to as “second portion”) where 
approximately 24 additional patients (12 in each weight group: patients ≥30 kg 
[Group A] and patients <30 kg and ≥10 kg [Group B]) will be enrolled directly to 
the selected dose regimen (identified based on the aggregate data from 
patients enrolled in the dose-finding portion) to achieve a total of 18 evaluable 
patients per weight group at this selected dose regimen. These patients will 
undergo the same 12-week core treatment phase assessments as patients 
recruited during the dose-finding portion. 
x
A third portion (hereafter referred to as “third portion”) where approximately 28 
additional patients (a cap of 70% of each weight group: patients ≥30 kg 
[Group A] and patients <30 kg and ≥10 kg [Group B]) will be enrolled directly to 
the selected dose regimen to achieve a total of approximately 100 treated 
patients for the entire study. These patients will undergo the same on-site visits 
during the12-week core treatment phase as patients recruited in the 
dose-finding and second portions; however, the patients in the third portion will 
not have the sarilumab PK sampling visits between Baseline and Week 2. 
The 12-week core treatment phase is from Visit 2 (baseline-Week 0) to the time that 
Visit 12 investigational medicinal product (IMP) is administered.  
 
 
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For the dose-finding and second portions, during the 12-week core treatment phase, 
patients in the lower weight group, (Group B: <30 kg and ≥10 kg) will be randomly 
assigned to the following sarilumab PK sampling Schedule 1 or 2, in order to 
minimize the amount of blood withdrawn and the number of visits while maintaining 
the evaluation of the primary endpoint:  
-
Schedule 1: Baseline, Day 3, Day 8, Week 2, Week 4, Week 8, and 
Week 12 
-
Schedule 2: Baseline, Day 5, Day 12, Week 2, Week 4, Week 8 and 
Week 12. 
2)
An extension phase: 
x
A 144-week extension for patients enrolled in the dose-finding and second 
portions: The IMP at Visit 12 is considered as the first IMP for the extension 
phase. Only patients who have reached a Juvenile Idiopathic Arthritis (JIA) 
American College of Rheumatology (ACR) 30 response at Visit 12 (Week 12) 
will be permitted to continue in the extension phase. Patients will continue on 
the same dose regimen of sarilumab they were assigned to receive in the 
12-week core phase of the study until the selected dose regimen is 
determined. Once the dose regimen is selected, patients who were not already 
on this dose regimen will have their dose regimen adjusted to the selected 
dose regimen, and will follow a new visit schedule with more frequent 
monitoring (for PK, safety, and efficacy) for the first 12 weeks compared to 
those patients who do not have their dose regimen adjusted.  
x
An 84-week extension for patients enrolled in the third portion. The IMP at 
Visit 12 is considered as the first IMP for the extension phase. 
3)
End-of-Treatment (EOT) and End-of-Study (EOS): 
x
For patients enrolled in the dose-finding and second portions: Patients who 
discontinue the study treatment prematurely will be assessed using the 
procedure for the End-of-Treatment (EOT) at Visit 27. These patients will be 
asked to return for the End-of-Study (EOS) assessment 6 weeks after the EOT 
visit (EOT + 6 weeks). For patients who prematurely discontinue the study 
treatment during the 12-week core treatment phase, there will be an additional 
sarilumab PK assessment 2 weeks after the EOT visit (EOT+ 2 weeks) and 
interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) will be measured 
at EOT visit. These patients will be asked to perform all the protocol scheduled 
visits and assessments except sarilumab administration until Visit 12.  
x
For patients enrolled in the third portion: Patients who discontinue the study 
treatment prematurely will be assessed using the procedure for the EOT at 
Visit 27 and will be asked to return for the EOS assessment 6 weeks after the 
EOT visit (EOT + 6 weeks). For patients who prematurely discontinue the 
study treatment during the 12-week core treatment phase, the IL-6 and sIL-6R 
will be measured at the EOT visit, and they will be asked to participate in all the 
protocol scheduled visits and assessments except sarilumab administration 
until Visit 12. 
Tested dose regimens: 
For each weight group, the 3 sequential ascending dose regimens to be tested 
were defined based on PK modeling with the following rationale:  
x
Dose Regimen 1: dose targeting PK exposures similar to sarilumab 150 mg 
once every other week (q2w), the lowest effective dose in adult patients with 
Rheumatoid Arthritis (RA) 
x
Dose Regimen 2: dose with targeted PK exposures similar to sarilumab 200 
mg q2w in adult patients with RA  
x
Dose Regimen 3: dose targeting PK exposures similar to sarilumab 150 mg 
once per week (qw), which yielded the highest exposures in chronic dosing 
studies in adult patients with RA. 
 
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Body weight 
Dose Regimen 1 
Dose 
Regimen 2 
Dose Regimen 3 
Group A 
≥30 kg and 
≤60 kg 
2 mg/kg q2w 
(6 patients) 
 
3 mg/kg q2w 
(6 patients) 
 
2 mg/kg qw 
(6 patients) 
 
Group B 
<30 kg and 
≥10 kg 
2.5 mg/kg q2w 
(6 patients) 
4 mg/kg q2w 
(6 patients) 
2.5 mg/kg qw 
(6 patients) 
Abbreviations: qw = once every week, q2w = once every other week. 
The dose (mg) to be administered to patients will be calculated at baseline. The 
dose and corresponding volume of drug product will remain the same throughout 
the course of the 12-week core treatment phase of the trial regardless of change 
in patient's body weight. In the extension phase, the patient’s weight will be 
measured at each visit and the dose will be adapted to the increase of weight 
only if the calculation shows a need for dose increase. The dose will be capped 
at 150 mg for Dose Regimens 1 and 3, and 200 mg for Dose Regimen 2, 
respectively. 
Rules for stepwise approach 
For permitting enrollment into Dose Regimen 1 Cohort for group B (<30 kg 
and ≥10 kg) 
Enrollment in Dose Regimen 1 Cohort for Group B (<30 kg and ≥10 kg), will be 
initiated after the review of available safety, efficacy, PK, and PD data for a 
minimum of 3 out of the 6 patients planned in that same tested dose regimen 
cohort in Group A (≥30 kg and ≤60 kg) who have completed at least 4 weeks of 
study treatment.  
For escalating the dose in a group 
The decision to initiate the next dose regimen cohort in the same weight group 
will be taken by the Dose Escalation Committee (DEC) after review of at least 
6 weeks of efficacy and safety data as well as the available PK and PD data for a 
minimum of 3 patients out of the 6 from the current dose regimen cohort in the 
weight Group A. 
Dose Regimen 3 Cohort in weight Group B will be initiated based on DEC 
decision after review of efficacy and safety as well as all available PK and PD 
data from Dose Regimen 1 and 2 Cohorts of Groups A and B.
For prematurely stopping enrollment in a dose regimen cohort weight 
group 
A dose regimen cohort for a weight group may be prematurely terminated after 
review of the 6-week data for at least 3 patients out of the 6 planned to be 
enrolled in that dose regimen cohort weight group if none of these patients have 
reached JIA ACR 30 response. All available efficacy, safety, PK, and PD data 
will be taken into account in making this decision.  
If a dose is declared to be ineffective, no additional patients will be enrolled in 
that dose regimen cohort weight group and, if there is no major safety concern, 
the next dose regimen cohort will be initiated immediately. Any patient that has 
been included in that dose regimen cohort group will have to discontinue from 
the study treatment and receive the standard of care treatment as per the 
Investigator’s clinical judgment. 
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Rules for dose regimen selection 
The selection of the dose regimen will be made by the DEC after review of 
sufficient Week 12 PK, PD, efficacy, and safety data from patients enrolled in the 
dose-finding portion of the study. 
STUDY POPULATION 
Main selection criteria
Inclusion criteria: 
x
Male and female patients aged ≥2 and ≤17 years (or country specified age 
requirement) at the time of the Screening visit 
x
Diagnosis of rheumatoid factor (RF)-negative or RF-positive polyarticular JIA 
subtype or oligoarticular extended JIA subtype according to the International 
League of Associations for Rheumatology (ILAR) 2001 JIA Classification 
Criteria with at least 5 active joints as per ACR definition for "active arthritis" at 
Screening 
x
Patient with an inadequate response to current treatment and considered as a 
candidate for a biologic disease modifying antirheumatic drug (DMARD) as per 
Investigator's judgment 
x
The patient (who has reached the legal age of consent based on local 
regulations) or the parent(s) or the legal guardian(s) sign and date the Ethics 
Committee (EC) approved written informed consent. The patient's assent 
should be obtained based on local guidelines, the patient's maturity and 
intellectual capacities of understanding the study associated information. 
Exclusion criteria: 
x
Body weight <10 kg or >60 kg for patients enrolled in the 3 ascending dose 
regimen cohorts, then body weight <10 kg for patients subsequently enrolled at 
the selected dose regimen cohorts 
x
Wheelchair-bound or bed-ridden 
x
Diagnosis of JIA subtypes except polyarticular RF-positive (RF+) or RF-
negative (RF-) JIA or extended oligoarticular juvenile idiopathic arthritis (oJIA) 
x
If nonsteroidal anti-inflammatory drugs (NSAIDs) (including cyclo-oxygenase-2 
inhibitors [COX-2]) taken, dose stable for <2 weeks prior to the Baseline visit 
and/or dosing prescribed outside of approved label 
x
If non-biologic DMARD taken, dose stable for <6 weeks prior to the Baseline 
visit or at a dose exceeding the recommended dose as per local labeling 
x
If oral glucocorticoid taken, dose stable for <2 weeks or dose exceeding 
equivalent prednisone dose 0.5 mg/kg/day (or 30 mg/day) within 2 weeks prior 
to Baseline 
x
Use of parenteral or intra-articular glucocorticoid injection within 4 weeks prior 
to Baseline 
x
Prior treatment with anti- IL-6 or IL-6 receptor (IL-6R) antagonist therapies, 
including but not limited to tocilizumab or sarilumab 
x
Treatment with any biologic treatment for pcJIA within 5 half-lives prior to the 
first dose of sarilumab as follows (the required off-treatment periods and 
procedures may vary according to local requirements): 
-
Etanercept: within 4 weeks  
-
Infliximab: within 8 weeks 
-
Adalimumab: within 15 weeks  
-
Anakinra: within 2 days 
-
Canakinumab: within 19 weeks 
-
Abatacept: within 10 weeks 
-
Rituximab or other cell-depleting agent: within 16 weeks or until total 
lymphocyte count and CD 19+ lymphocyte count are normalized, 
whichever is longer  
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-
Intravenous (IV) immunoglobulin (Ig): within 15 weeks. 
x
Treatment with a Janus kinase inhibitor within 4 weeks prior to the first dose of 
sarilumab; and treatment with growth hormone within 4 weeks prior to the first 
dose of sarilumab (the required off-treatment periods and procedures may vary 
according to local requirements) 
x
Treatment with any investigational biologic or non-biologic product within 8 
weeks or 5 half-lives prior to Baseline, whichever is longer 
x
Lipid lowering drug stable for less than 6 weeks prior to Screening 
x
Exclusion related to tuberculosis (TB):  
-
Active TB or a history of incompletely treated TB 
-
Purified Protein Derivative (PPD) or QuantiFERON-TB positive patients 
(no active disease) are excluded from the study, unless the following 
conditions are met: 
-
It is documented by a specialist that the patient has been adequately 
treated and can now start treatment with a biologic agent, in the medical 
judgment of the Investigator and/or infectious disease specialist 
-
No evidence of active TB infection indicated by the chest radiograph 
performed according to local guidance for the screening of TB infection 
prior to the study 
-
Suspected extrapulmonary TB infection 
-
Patients at high risk of contracting TB, such as close contact with 
individual with active or latent TB. 
x
Exclusion criteria related to past or current infection other than tuberculosis: 
-
History of invasive opportunistic infections, including but not limited to 
histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis 
jirovecii, aspergillosis despite resolution, or John Cunningham (JC) virus 
(progressive multifocal leukoencephalopathy) 
-
History of recurrent or active herpes zoster or reactivation or new onset 
of Epstein-Barr virus (EBV) or positive test for EBV within 2 months of the 
Screening (or at the Screening visit) 
-
Diagnosed non tuberculous mycobacterial infection based on clinical, 
radiological and microbiological evidence within 2 months of the 
Screening (or at the Screening visit) 
-
History of prior articular or prosthetic joint infection 
-
Fever (>38°C), or chronic, persistent, or recurring infection(s) requiring 
active treatment with antibiotics, antivirals, or antifungals within 4 weeks 
prior to the Screening visit or other frequent recurrent infections deemed 
unacceptable, as per the Investigator judgment 
-
Previous or at the Screening: hepatitis B surface antigen (HBs-Ag) 
positive, or total hepatitis B core antibody (HBc-Ab) positive; previous or 
at the Screening: Hepatitis C antibody positive 
-
Patients who had a positive test previously or at the Screening for human 
immunodeficiency virus (HIV) test or who are suspected to be positive for 
HIV. 
x
Any live, attenuated vaccine within 4 weeks prior to the Baseline visit, such as 
varicella-zoster, oral polio, rubella vaccines. Killed or inactive vaccine may be 
permitted based on the Investigator's judgment 
x
Prior or current history of malignancy, including lymphoproliferative diseases, 
other than adequately-treated carcinoma in-situ of the cervix, nonmetastatic 
squamous cell, or basal cell carcinoma of the skin, within 5 years prior to the 
Baseline visit 
x
Prior or current history of other significant concomitant illness (es) that, 
according to the Investigator's judgment, would adversely affect the patient's 
participation in the study. These include, but are not limited to, cardiovascular, 
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renal, neurological disorders (including demyelinating disease), active 
infectious diseases, endocrinological, gastrointestinal, hepatobiliary, metabolic, 
pulmonary (eg, severe asthma, cystic fibrosis), nonmalignant 
lymphoproliferative diseases, other lymphatic disease(s), autoimmune disease, 
psychiatric disorders, etc 
x
Patients with nonhealed/healing skin ulcers 
x
Surgery within 4 weeks prior to the Screening visit or with planned surgery 
during the course of the study 
x
History of a systemic hypersensitivity reaction, other than localized injection 
site reaction, to any biologic drug and known hypersensitivity to any constituent 
of the product 
x
History of inflammatory bowel disease, severe diverticulitis, or previous 
gastrointestinal perforation whatever the cause 
x
Uncontrolled diabetes mellitus, defined as glycosylated hemoglobin (HbA1c) 
≥9% at the Screening visit 
x
Conditions/situations such as: 
-
Patients with short life expectancy 
-
Conditions/concomitant diseases making patients non-evaluable for the 
efficacy endpoints, eg, patients with chronic pain caused by conditions 
other than JIA, eg, fibromyalgia 
-
Patients whose immediate family members are dependent (employee) of 
site/Investigator, and individuals who are institutionalized due to 
regulatory or legal order. 
x
Any of the following laboratory abnormalities at the Screening visit (identified 
by the central laboratory): 
 
 
 
 
 
 
 
 
 
 
 
 
 
x
Pregnant or breast-feeding female adolescent patients (refer to main body of 
protocol for details). 
Total expected number of patients
Assuming that 3 dose regimens will be tested and one of these 3 dose regimens 
will be selected, up to approximately 72 patients will be enrolled (to achieve 
approximately 60 evaluable patients) in the dose-finding and second portions. 
Approximately 28 additional patients will be enrolled in the third portion to 
achieve a total of approximately 100 treated patients for the entire study. 
Expected number of sites
Approximately 45 sites (additional sites could be opened). 
STUDY TREATMENT(s)
 
Investigational medicinal 
product(s)
Formulation:
Sarilumab, anti-interleukin 6 receptor alpha subunit (anti-IL-6R) monoclonal 
antibody.  
Vial: 175 mg/mL (2.7 mL filled with 2.0 mL extractible volume). 
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Route(s) of administration:
Route of administration: subcutaneous (SC).  
Injection sites: abdomen (alternated between the 4 quadrants), thighs, and upper 
arms lateral side (upper arm lateral side not appropriate for self-injection). 
Dose regimen:
Dose Regimen 1:  
x
Group A (≥30 kg and ≤60 kg): 2 mg/kg q2w 
x
Group B (<30 kg and ≥10 kg): 2.5 mg/kg q2w. 
Dose Regimen 2:  
x
Group A (≥30 kg and ≤60 kg): 3 mg/kg q2w 
x
Group B (<30 kg and ≥10 kg): 4 mg/kg q2w. 
Dose Regimen 3:  
x
Group A (≥30 kg and ≤60 kg): 2 mg/kg qw 
x
Group B (<30 kg and ≥10 kg): 2.5 mg/kg qw. 
Volumes for Dose Regimens 1 to 3 to be injected depending on patient’s weight 
at Baseline are further detailed in the protocol Appendix B. 
The dose regimen of the selected dose will be one of these 3 dose regimens, or 
an intermediate dose regimen based on DEC review of the sufficient Week 12 
PK, PD, efficacy, and safety data from the patients enrolled in the dose-finding 
portion of the study. 
The dose will be capped at 150 mg for Dose Regimens 1 and 3, and 200 mg for  
Dose Regimen 2, respectively. 
Noninvestigational medicinal 
product(s) (if applicable):
N/A 
Route(s) of administration:
N/A 
Dose regimen:
N/A 
ENDPOINT(S)
Primary endpoint: 
x
Sarilumab PK exposure (maximum serum concentration observed [Cmax] and 
area under the serum concentration versus time curve using the trapezoidal 
method during a dose interval [AUC0-W]), following the first dose, concentration 
observed before treatment administration during repeated dosing (Ctrough) from 
baseline to Week 12. 
Secondary endpoint(s):  
12-week core treatment phase 
x
Safety 
-
Adverse events (AEs), vital signs, physical examination, laboratory 
values 
-
Acceptability assessments (local tolerability).  
x
Efficacy  
-
Juvenile Idiopathic Arthritis ACR 30/50/70/90/100 response rate at 
Week 12 
-
Change from baseline in individual JIA ACR components at Week 12  
-
Juvenile Arthritis Disease Activity Score - 27 change from baseline at 
Week 12. 
x
Pharmacodynamics 
-
Changes in IL-6 associated biomarkers [eg, serum levels of high 
sensitivity C-reactive protein (hs-CRP), IL-6, total sIL-6R]. 
 
 
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Extension phase 
x
Safety  
-
Adverse events, vital signs, physical examination, laboratory values 
-
Acceptability assessments (local tolerability). 
x
Efficacy 
-
JIA ACR 30/50/70/90/100 response rate at Weeks 24 and 48, and every 
24 weeks up to the end of the study (EOS) 
-
Change from baseline in individual JIA ACR components at Weeks 24 
and 48, and every 24 weeks up to EOS 
-
Juvenile Arthritis Disease Activity Score – 27change from baseline at 
Weeks 24 and 48, and every 24 weeks up to EOS. 
STATISTICAL CONSIDERATIONS
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis populations: 
The efficacy population will consist of all included patients who receive at least 
1 dose of sarilumab. All patients should be followed at least to the end of the 12-
week core treatment phase and will be analyzed according to the treatment that 
they actually receive. 
The PK population will consist of all included patients who receive at least 1 dose 
of sarilumab and have at least one post-dose drug concentration. All patients will 
be analyzed according to the treatment that they actually receive. 
 
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The safety population will consist of all included patients who receive at least 
1 dose or part of a dose of sarilumab. All patients will be analyzed according to 
the treatment that they actually receive. 
Primary Analysis: 
 will be used to estimate sarilumab PK 
parameters and the effects of age, weight, and other intrinsic factors on these PK 
parameters. 
Analysis of efficacy endpoints 
Juvenile Idiopathic Arthritis ACR 30 response rates for each dose and weight 
group will be summarized by visit, and the mean (SD) of the JIA ACR component 
scores, PD parameters, and their changes from baseline calculated. 
Juvenile Idiopathic Arthritis ACR 50/70/90/100 will be summarized using the 
same primary approach as for ACR30. Overall score and change from baseline 
in JADAS-27 will be summarized by visit (including number, mean, and standard 
error, SD, median, minimum, and maximum) for each dose regimen cohort and 
weight group (if possible).  
  
 
 
Safety 
Treatment-emergent adverse events (TEAEs), treatment-emergent serious 
adverse events (SAEs), TEAEs leading to treatment discontinuation and 
treatment-emergent adverse events of special interest (AESIs) will be 
summarized for each treatment group based on Medical Dictionary for 
Regulatory Activities (MedDRA) coding of verbatim terms reported by 
Investigators. For laboratory parameters and vital signs, incidences of potentially 
clinically significant abnormality (PCSA) values, actual values and change from 
baseline will be summarized by treatment group. The number of patients with 
neutropenia will be summarized by maximum grade during the TEAE period for 
each treatment group. The group means of absolute neutrophils counts (ANC) 
with standard deviations will be displayed graphically over time. Similar analyses 
will be performed for ALT elevations and changes in serum lipids. 
Planned database lock date: 
The first database lock will occur once sufficient Week 12 data have been 
observed from the dose-finding portion of the study to allow a selection of a dose 
regimen for more detailed investigation. If the enrollments for weight Group B are 
not completed within a similar time frame as that for weight Group A, the dose 
selection on weight Group A will be done separately from the dose selection on 
weight Group B, ie, 2 separate data analyses will be needed. 
The second database lock will occur approximately 1 year from the time every 
patient enrolled in the dose-finding and second portions has received the 
selected dose regimen (either new enrolled patients or patients already in the 
extension phase). 
The third database lock will occur approximately 1 year from the time the last 
patient is enrolled in the third portion. 
The final database lock will occur approximately 4 weeks after the last patient 
has completed the EOS visit. 
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DURATION OF STUDY PERIOD (per 
patient) 
-
Total study duration of up to 166 weeks for patients enrolled in the dose-
finding and second portions and up to 106 weeks for patients enrolled in the 
third portion (per patient): 
x
Up to 4 weeks +3 days Screening (maximum 31 days) 
x
12 weeks core treatment phase 
x
Up to 144 weeks extension phase for patients enrolled in the dose-finding and 
second portions and up to 84 weeks extension phase for patients enrolled in 
the third portion 
x
6 weeks post-treatment follow-up. 
For all visits, a time frame of ±1 day for Dose Regimen 3 Cohort and ±3 days for 
Dose Regimen 1 and 2 Cohorts is acceptable using Day 1 as reference except 
for:  
x
For Visit 3 (Day 3), Visit 4 (Day 5) and Visit 5 (Day 8), no sample collection 
window is allowed where PK sampling occurs  
x
Visit 6 (Day 12) ±1 day for all applicable dose regimen cohorts 
x
Visit 7 (Week 2) ±1 day for all dose regimen cohorts 
x
Visit 8 (Week 4) ±2 days for Dose Regimen 1 and 2 Cohorts and ±1 day for 
Dose Regimen 3 Cohort. 
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1
FLOW CHARTS
1.1
GRAPHICAL STUDY DESIGN
1.1.1
Graphical study design for dose regimen cohorts: Group A: ≥30 kg and ≤60 kg for the dose-finding (first) portion and ≥30 kg for
patients enrolled once the selected dose regimen is identified (second and third portions); Group B: ≥10 kg and <30 kg
 
PD= pharmacodynamics, PK= pharmacokinetic, qw= once a week, q2w= once every other week.  
Notes: Enrollment in Group B (<30 kg and ≥10 kg) will initiate after the review of safety and available data from the first 3 out of the 6 patients planned in the first tested dose regimen in Group A (≥30 kg and ≤60 kg) 
who have completed at least 4 weeks of study treatment. 
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1.1.2
Study flow diagram
Abbreviations: EOS = end-of-study, EOT = end-of-treatment, PK = pharmacokinetic, V = visit, Wk = week
Notes: All patients must complete an end-of-treatment (EOT) visit (V27, Week 156 for dose-finding and second portions/Week 96 for third portion) at the completion of treatment (last IMP injection at 
Week 154/Week 94 for Dose Regimens 1 and 2 Cohorts and at Week 155 for Dose Regimen 3 Cohort) or at the time of early permanent treatment discontinuation (regardless of treatment phase). 
For a patient who discontinues study treatment prematurely during the 12-week core treatment phase, interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) will be measured at EOT visit. For patients in the 
dose-finding and second portions who discontinue study treatment prematurely during 12-week core treatment phase, an additional PK visit, 2 weeks after the EOT visit is required for blood sampling (V88).
All patients must complete a post-treatment follow-up visit (V28) 6 weeks after the EOT visit. However, patients discontinuing treatment prematurely during the core treatment phase should continue to return for the 
study visits as protocol scheduled without treatment administration through Week 12 (as per Food and Drug Administration (FDA) guidelines for missing data).
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Abbreviations: ADA = anti-drug antibody, ANA = antinuclear antibodies, BP = blood pressure, DNA = deoxyribonucleic acid, D = day, EBV = Epstein–Barr virus, EC = ethics committee, EOT = End-of-Treatment, 
ESR  = erythrocyte sedimentation rate, HbA1c = glycosylated hemoglobin, HIV = human immunodeficiency virus, hs-CRP= high sensitivity C-reactive protein, Ig = immunoglobulin, IVRS = Interactive Voice 
Response System, IL = interleukin, IMP = investigational medicinal product, JADAS = Juvenile Arthritis Disease Activity Score, JIA ACR = Juvenile Idiopathic Arthritis American College of Rheumatology, 
PK = pharmacokinetics, PPD = Purified Protein Derivative, SAE = serious adverse event, sIL-6R = soluble Interleukin-6 receptor, TB = tuberculosis, V = visit, Wk = week, yrs = years. 
a.
For patients who discontinue treatment during the 12-week core treatment phase (at or before Visit 12), there will be an additional sarilumab PK assessment 2 weeks after the EOT visit (EOT+2 weeks). For 
patients enrolled in the third portion, Visit 88 is not applicable. 
b.
Sarilumab PK sampling between Visit 2 and Visit 7 vary between patients: Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8), Visit 6 (Day 12) for Group A (≥30 kg); on visits and days of Visit 3 (Day 3), Visit 5 (Day 8) 
for Group B (<30 kg) schedule 1; on visits and days of visits: Visit 4 (Day 5), Visit 6 (Day 12) for Group B (<30 kg) schedule 2 (see Section 9.1.1 and flow chart Section 1.2.1 for sample collection schedule and 
Section 6.3.1 for visiting/dosing windows). Sarilumab PK sampling could be performed at home. A PK diary will be provided to capture date and time of sample collection. No sample collection window is allowed 
for Visit 3 (Day 3), Visit 4 (Day 5) and Visit 5 (Day 8). There is ±1 day window allowed for Visit 6 (Day 12). Please refer to Section 10.1.3 and Section 9.3.4 for the additional hematology test during the sarilumab 
PK sampling period. For patients enrolled in the third portion, Visits 3, 4, 5, and 6 are not applicable. However, an additional hematology test must be performed before the second sarilumab administration (see 
footnote “o” for details). 
c.
At the Investigators’ discretion laboratory tests mentioned in exclusion criterion E 24 may be repeated by central laboratory retesting between the Screening visit and the first IMP administration to ensure the 
patient meet eligibility with respect to exclusion criterion E 24. A locally approved specific consent form will be signed by patients who require Gilbert syndrome genetic testing (consent/assent must be obtained 
prior to performing this assessment and local regulations should be respected). 
d.
Prior to all screening assessments, the patient (if he/she has reached the legal age of consent based on the local regulations), the parent(s) or the legal guardian(s) must sign and date the EC approved written 
informed consent form. The patient, the parent(s) and the legal guardian(s) will receive information on the study objective(s) and procedures from the Investigator. Separate written consent forms should be 
obtained from the parent(s) or the legal guardian(s) who allows his/her child to participate in an optional saliva sample collection for pharmacogenomic study and give permission to the Sponsor to keep their 
left- over/unused blood samples for future research (see Section 10.1.1, Section 9.9, and Section 9.11). A separate (locally approved) informed consent form will be completed by any patients requiring genetic 
Gilbert disease testing as per local regulations. The signed assent forms should be obtained from the patient based on local regulations and his/her maturity of understanding the study information.  
e.
Home diary for IMP administration to be completed for IMP administered at home. 
f.
Complete physical examinations will be performed at Visit1 (Day -28 to Day -1, up to 31 days), Visit 2 (Day 1, Week 0), Visit 8 (Week 4), Visit 9 (Week 6), and Visit 12 (Week 12) including skin, nasal cavities, 
eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
g.
Optional: Based on the Investigator’s judgment, Epstein-Barr virus (EBV) titer including IgG and IgM may be performed at the Screening; based on the patient’s family and medical history and the Investigator’s 
judgment, hepatitis B surface antigen (HBs-Ag), hepatitis B surface antibody (HBs-Ab), total hepatitis B core antibody (HBc-Ab), and hepatitis C antibody (HCV-Ab) may be performed at the Screening. The HIV 
serology will be performed only based on the Investigator’s assessment for those HIV suspected patients. For Argentina and Germany only: Serology testing for hepatitis B and C and HIV have to be performed 
at Screening visit for all patients in order to screen corresponding exclusion criterion E 14. 
h.
Purified Protein Derivative (PPD) skin test should be performed in patients ≤5 years old prior to the Baseline Visit 2 (Day 1, Week 0). Patients should be evaluated within 48 to 72 hours after placement of the 
PPD skin test. For patients who fail to be evaluated within 72 hours, the skin test should be repeated. An assessment of the level of risk (TB contact and/or recent immigration from a country with a high 
prevalence of TB) vaccination history should be taken into consideration when defining the result of the skin tests. Refer to exclusion criteria E 13 for all the details. An interferon-gamma (IFN-r) release assay, 
QuantiFERON-TB test will be performed for patients >5 years old. (1) After the initial TB screening, if PPD or QuantiFERON result is negative, but clinical suspicion for TB is higher than moderate, the patient 
should be retested for TB at any time during the study based on the Investigator’s assessment. QuantiFERON-TB test will be considered in the younger group of patients (≤5 years) based on the local PPD 
availability, local regulation for TB screening and the Investigator’s judgment. 
i.
The chest X-ray may be performed for the patients only when deemed necessary based on the Investigator’s judgment or in line with local guideline for TB screening prior to initiating a biologic therapy for JIA 
patients who haven’t had a chest X-ray performed within 3 months prior to the Baseline Visit 2 (Day1, Week 0). 
j.
Investigational medicinal product to be administered once every other week for patients in Dose Regimen 1 and 2 Cohorts and once every week for patients in Dose Regimen 3 Cohort. Arrangements will be 
made for home nurses to administer IMP for Dose Regimen 3 Cohort patients for the intermediate visits (home administration if possible). Patients should be monitored for at least 30 minutes after IMP 
administration for any signs or symptoms of a hypersensitivity reaction. For Germany only: After the first IMP administration the patient has to be monitored for at least 1 hour to assess local tolerability. In the 
dose-finding and second portions, patients who do not achieve a JIA American College of Rheumatology (ACR) 30 by the end of the 12-week core treatment period will be discontinued from the study treatment 
to receive standard of care as per the Investigator’s clinical judgment. Juvenile Idiopathic arthritis ACR response, including JIA ACR30 response, will be provided by the Sponsor to Investigator to evaluate this 
criterion only after Visit 12. For patients completing the core treatment phase at Visit 12 (Week 12), but not continuing to the extension phase for reasons other than lack of JIA ACR30 response, there will be no 
IMP injection at Visit 12.  
k.
Investigational medicinal product will be dispensed to patients who are at the Dose Regimen 3 Cohort during the core treatment phase. 
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l.
Height will be measured using stadiometer at sites during the study. 
m.
Juvenile Idiopathic Arthritis ACR core set includes: global assessment of the severity of disease by the physician, global assessment of overall well-being by the patient or the parent(s)/guardian(s), number of 
joints with active arthritis (defined as swelling not due to deformity OR limitation of motion with either pain or tenderness or both), number of joints with limitation of motion, Childhood Health Assessment 
Questionnaire (CHAQ), hs-CRP (2,3,4). At the Screening, only number of joints with active arthritis and number of joints with limitation of motion will be assessed.  
n.
Juvenile Arthritis Disease Activity Score scoring is explained in Section 9.4.2. 
o.
Hematology (blood should be drawn PRIOR TO drug administration): Hemoglobin, hematocrit, red blood cell (RBC) count, and morphology (if RBC count is abnormal), white blood cell (WBC) differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, absolute neutrophil count (ANC). An additional hematology test must be performed at Visit 6 (Day 12±1 day) for Dose Regimens 1 
and 2 Cohorts in order to get the results before the second dose of sarilumab administration (Visit 7: Week 2, Day 15) or prior to or at Visit 5 (Day 8) for Dose Regimen 3 Cohort (not before Visit 4 [Day 5]) in 
order to get the results before second dose of sarilumab administration. For patients enrolled in the dose-finding and second portions, the additional hematology test can be done at the central laboratory or at the 
local laboratory to confirm the neutrophil count and platelet count before the second dose of sarilumab administration. For patients enrolled in the third portion without on-site Visit 6, the additional hematology test 
will be done at the local laboratory before the second dose of sarilumab administration, but no earlier than Day 12. If local laboratory is used, a central laboratory sample for hematology should still be drawn pre-
IMP administration at Visit 7 (Day 15, Week 2) as scheduled for Dose Regimens 1 and 2 Cohorts and Visit 5 (Day 8) for Dose Regimen 3 Cohort. For all patients, the Visit 2 (Day 1) and additional hematology 
laboratory assessment must be reviewed before the administration of the second dose of sarilumab at Visit 5 (Day 8) for Dose Regimen 3 Cohort patients or at Visit 7 (Week 2, Day 15) for Dose Regimens 1 and 
2 Cohort patients.  
p.
Chemistry (blood should be drawn BEFORE drug administration): Whole chemistry will be performed at the Screening visit, Baseline Visit 2 (Day1, Week 0) and Visit 12 (Week 12) or EOT only: sodium, 
potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, and creatinine clearance, glomerular filtration rate (using the modified Schwartz formula), calcium, phosphate, total protein, albumin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, and unconjugated bilirubin. At all other visits: only ALT, AST, ALP, total bilirubin, 
conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. 
q.
Fasting lipids (blood should be drawn BEFORE drug administration): Triglycerides (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol. Patients are required 
to fast at least 8 hours before the test.  
r.
Optional: HbA1c levels will be only measured based on the patient’s medical history and Investigator’s judgment. 
s.
Urinalysis dipstick: specific gravity, pH, glucose, blood, protein, nitrates, leukocyte esterase, bilirubin. If any parameter on the dipstick is abnormal, a urine sample should be sent to the central laboratory for 
testing. If positive for proteins, microscopic analysis is performed by central laboratory. 
t.
For females who have commenced menstruating, a serum pregnancy test is mandatory at the screening visit.  
u.
For females who have commenced menstruating, a urine pregnancy local test should be performed at Visit 2 (Week 0, Day 1), Visit 8 (Week 4), Visit 10 (Week 8), and Visit 12 (Week 12). The urine pregnancy 
test can be performed locally. The pregnancy status should be checked by urine pregnancy testing prior to exposure to the IMP and EOT. 
v.
Blood samples will be collected PRIOR TO IMP administration on the dosing days during the treatment period. If SAE occurs in a patient, blood samples should be collected for determination of sarilumab 
concentration and anti-drug antibody (ADA) assessment at or near the onset and completion of the occurrence of the event, if possible (see Section 9.1). In the dose-finding and second portions, if a patient 
discontinues study treatment prematurely during the 12-week core treatment phase, an additional PK Visit, 2 weeks after the EOT visit is required for blood sampling (Visit 88). 
w.
For patients who prematurely discontinue the study treatment during the core treatment phase, the IL-6 and total sIL-6R will be measured at the EOT assessment. 
x.
Parent(s) or legal guardian(s) must sign a separate informed consent form prior to optional saliva sample collection for phamacogenomic study. Samples are preferred to being collected at the Baseline Visit 2 
(Day 1, Week 0), but can be collected at any visit. The patient can also sign the informed consent form based on his/her age, local regulations, and his/her maturity of understanding the study information. The 
patient is still eligible to enroll in the study if he/she or his/her parent(s) or his/her legal guardian(s) do not wish him/her to participate in saliva sample collection. 
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1.2.2
Extension phase
In the dose-finding and second portions, only patients achieving at least a JIA ACR30 response at 
Week 12 will be permitted to continue to participate in the extension phase.
During the extension phase:
x
Patients who were enrolled to the selected dose regimen during the core treatment phase 
(either during the initial dose-finding portion or directly to the selected dose regimen in the
second portion) will continue on the selected dose regimen during the extension phase and 
will be followed-up as noted in Section 1.2.2.1)
x
Once the selected dose regimen has been determined, patients who were not assigned to 
the selected dose regimen will have their dose regimen adjusted to the selected dose 
regimen during the extension phase. Prior to dose adjustment, these patients will complete 
the assessments as noted in Section 1.2.2.1. After the dose regimen is determined, the 
patients will have their dose regimen adjusted to the selected dose regimen at the time of 
their next regular scheduled visit (according to Section 1.2.2.1), which will be considered 
as the first visit (Visit 101 [Week 0]) as shown in the flow chart in Section 1.2.2.2. These 
patients will then continue with the assessments as noted in Section 1.2.2.2. All patients 
will remain on treatment until they have received up to a total of 144 weeks of sarilumab 
exposure calculated from Visit 12. A table to determine when the last on-treatment visit 
should occur and the weeks between the last on-treatment visit, and the EOT visit based on 
when the patient was changed to the selected dose regimen is provided in Table 1. After 
the last on-treatment visit, patients will be scheduled for the EOT visit (Visit 27) and the 
EOS visit (Visit 28).
x
Patients who are enrolled in the third portion with the selected dose regimen will be 
followed-up as noted in Section 1.2.2.3.
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will be used for assessment at the next protocol-defined visit after the last IMP injection. Patients will be asked to return to the site for the EOS assessment 6 weeks after the EOT visit. There will be no IMP 
injection at the Visit 27 (Week 156).  
f.
Height will be measured using stadiometer at sites during the study. 
g.
Juvenile Idiopathic Arthritis American College of Rheumatology (JIA ACR) core set includes: global assessment of the severity of disease by the physician, global assessment of overall well-being by the 
patient or parent, number of joints with active arthritis (defined as swelling within the joint not due to deformity OR limitation of motion and with either pain, tenderness, or both), number of joints with limitation 
of motion, Childhood Health Assessment Questionnaire (CHAQ), and hs-CRP (2,3,4). If a patient discontinues prematurely before Week 96, hs-CRP must be performed by the central laboratory at EOT. 
h.
Juvenile Arthritis Disease Activity Score scoring is explained in Section 9.4.2. 
i.
Hematology (blood should be drawn PRIOR TO drug administration): Hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, absolute neutrophil count (ANC). If a patient discontinues prematurely before Week 96, the test must be performed by the 
central laboratory at EOT. 
j.
Chemistry (blood should be drawn BEFORE drug administration): ALT, AST, ALP, total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. Complete chemistry (refer to 
Section 9.3.4) should be done at Visit 27 EOT (Week 156). If a patient discontinues prematurely before Week 96, the test must be performed by the central laboratory at EOT. 
k.
Lipids (blood should be drawn BEFORE drug administration): Triglycerides (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol. Patients are required to 
fast at least 8 hours before the test. At EOT, the test will be performed only for patient who discontinues prematurely before Week 96 and must be performed by the central laboratory. 
l.
At EOT, the ANA/anti-dsDNA antibody test will be performed only for patient who discontinues prematurely before Week 96 and must be performed by the central laboratory.  
m.
For females who have commenced menstruating, urine pregnancy tests should be performed prior to exposure to the IMP at each scheduled visit and at the EOT. The urine pregnancy test could be 
performed locally. 
n.
Blood samples will be collected PRIOR TO IMP administration on the dosing days during the treatment period. If an SAE occurs in a patient, blood samples should be collected for determination of sarilumab 
concentration and anti-drug antibody (ADA) assessment at or near the onset and completion of the occurrence of the event, if possible (see Section 9.1).  
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e
Investigational medicinal product (IMP) to be administered q2w for patients in Dose Regimen 1 and 2 Cohorts and weekly for patients in Dose Regimen 3 Cohort. Patients should be monitored for at least 30 
minutes after IMP administration for any signs or symptoms of a hypersensitivity reaction. For patients who complete the extension phase, if the selected dose regimen is dosed once every other week (q2w), 
then the last IMP injection will occur 2 weeks before EOT if the selected dose regimen is dosed once a week (qw), then the last IMP injection will occur 1 week before EOT. Patients will have EOT 
assessment at the Visit 27 (Week 156). For patients who prematurely discontinue the study treatment during the extension phase, it will be preferable to have EOT assessment 2 weeks after the last IMP 
injection for Dose Regimen 1 and 2 Cohort patients and 1 week after the last IMP injection for Dose Regimen 3 Cohort patients. In case the patient is unable to meet the planned schedule, the EOT visit will 
be used for assessment at the next protocol-defined visit after the last IMP injection. Patients will be asked to return to the site for the EOS assessment 6 weeks after the EOT visit. There will be no IMP 
injection at the Visit 27 (Week 156). 
f
Height will be measured using stadiometer at sites during the study. 
g
Juvenile Idiopathic Arthritis ACR core set (Section 9.4.1) includes: global assessment of the severity of disease by the physician, global assessment of overall well-being by the patient or parent/legal 
guardian, number of joints with active arthritis defined as swelling within the joint not due to deformity, OR limitation of motion with either pain or tenderness, or both, number of joints with limitation of motion, 
Childhood Health Assessment Questionnaire (CHAQ), hs-CRP (2,3,4). If a patient discontinues prematurely before Week 96, hs-CRP must be performed by the central laboratory at EOT. 
h
Juvenile Arthritis Disease Activity Score scoring is explained in Section 9.4.2. 
i
Hematology (blood should be drawn PRIOR TO drug administration): Hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, absolute neutrophil count (ANC). If a patient discontinues prematurely before Week 96, the test must be performed by the central 
laboratory at EOT. 
j
Chemistry (blood should be drawn BEFORE drug administration): ALT, AST, ALP, total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. Complete chemistry (refer to Section 
9.3.4) should be done at Visit 27 EOT (Week 156). If a patient discontinues prematurely before Week 96, the test must be performed by the central laboratory at EOT. 
k
Lipids (blood should be drawn BEFORE drug administration): Triglycerides (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol. Patients are required to 
fast at least 8 hours before the test. At EOT, the test will be performed only for patient who discontinues prematurely before Week 96 and must be performed by the central laboratory. 
l
At EOT, the ANA/anti-dsDNA antibody test will be performed only for patient who discontinues prematurely before Week 96 and must be performed by the central laboratory. 
m For females who have commenced menstruating, urine pregnancy tests should be performed prior to exposure to the IMP at each visit (except Visits 102 [Week 2] and 103 [Week 6]) and at the EOT. The 
urine pregnancy test can be performed locally. 
n
Blood samples will be collected PRIOR TO IMP administration on the dosing days during the treatment period. If an SAE occurs in a patient, blood samples should be collected for determination of sarilumab 
concentration and anti-drug antibody (ADA) assessment at or near the onset and completion of the occurrence of the event, if possible (see Section 9.1). 
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Table 1 - Last on-treatment visit prior to EOT visit (V27) for patients
who change from a nonselected dose regimen to the selected dose regimen
Visit when the first dose 
adjustment occurs
Patient’s last on-treatment visit 
prior to V27 (EOT)
Weeks between patient’s last on-
treatment visit and EOT 
V13 (Week 16) 
V119 (Week 132) 
8 weeks 
V14 (Week 20) 
V119 (Week 132) 
4 weeks 
V15 (Week 24) 
V118 (Week 120) 
12 weeks 
V16 (Week 32) 
V118 (Week 120) 
4 weeks 
V17 (Week 40) 
V117 (Week 108) 
8 weeks 
V18 (Week 48) 
V116 (Week 96) 
12 weeks 
V19 (Week 60) 
V115 (Week 84) 
12 weeks 
V20 (Week 72) 
V114 (Week 72) 
12 weeks 
V21 (Week 84) 
V113 (Week 60) 
12 weeks 
V22 (Week 96) 
V112 (Week 48) 
12 weeks 
V23 (Week 108) 
V111 (Week 40) 
8 weeks 
V24 (Week 120) 
V109 (Week 24) 
12 weeks 
V25 (Week 132) 
V106 (Week 12) 
12 weeks 
V26 (Week 144) 
V105 (Week 8) 
4 weeks 
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h
Height will be measured using stadiometer at sites during the study. 
i
Juvenile Idiopathic Arthritis American College of Rheumatology (JIA ACR) core set includes: global assessment of the severity of disease by the physician, global assessment of overall well-being by the patient or 
parent, number of joints with active arthritis (defined as swelling within the joint not due to deformity OR limitation of motion and with either pain, tenderness, or both), number of joints with limitation of motion, 
Childhood Health Assessment Questionnaire (CHAQ), and hs-CRP (2, 3, 4). If a patient discontinues prematurely before Week 48, hs-CRP must be performed by the central laboratory at EOT. 
j
Juvenile Arthritis Disease Activity Score scoring is explained in Section 9.4.2. 
k
Hematology (blood should be drawn PRIOR TO drug administration): Hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, absolute neutrophil count (ANC). If a patient discontinues prematurely before Week 48, the test must be performed by the central 
laboratory at EOT. 
l
Chemistry (blood should be drawn BEFORE drug administration): ALT, AST, ALP, total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. Complete chemistry (refer to Section 9.3.4) 
should be done at Visit 27 EOT (Week 96 for third portion). If a patient discontinues prematurely before Week 48, the test must be performed by the central laboratory at EOT. 
m Lipids (blood should be drawn BEFORE drug administration): Triglycerides (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol. Patients are required to fast 
at least 8 hours before the test. At EOT, the test will be performed only for patient who discontinues prematurely before Week 48 and must be performed by the central laboratory. 
n
At EOT, the ANA/anti-dsDNA antibody test will be performed only for patient who discontinues prematurely before Week 48 and must be performed by the central laboratory. 
o
For females who have commenced menstruating, urine pregnancy tests should be performed prior to exposure to the IMP at each scheduled visit and at the EOT. The urine pregnancy test could be performed 
locally. 
p
Blood samples will be collected PRIOR TO IMP administration on the dosing days during the treatment period. If an SAE occurs in a patient, blood samples should be collected for determination of sarilumab 
concentration and anti-drug antibody (ADA) assessment at or near the onset and completion of the occurrence of the event, if possible (see Section 9.1). 
 
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2
TABLE CONTENTS
AMENDED CLINICAL TRIAL PROTOCOL 03 ..............................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................................................2 
DOCUMENT HISTORY...................................................................................................................................2 
OVERALL RATIONALE FOR THE AMENDMENT........................................................................................2 
1 
FLOW CHARTS.............................................................................................................................19 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................19 
1.1.1 
Graphical study design for dose regimen cohorts: Group A: ≥30 kg and ≤60 kg for the 
dose-finding (first) portion and ≥30 kg for patients enrolled once the selected dose regimen 
is identified (second and third portions); Group B: ≥10 kg and <30 kg..........................................19 
1.1.2 
Study flow diagram.........................................................................................................................20 
1.2 
STUDY FLOW CHARTS................................................................................................................21 
1.2.1 
12-week core treatment phase ......................................................................................................21 
1.2.2 
Extension phase.............................................................................................................................27 
1.2.2.1 
Flow chart for patients who remain on the current dose (selected dose regimen) from the 
dose-finding portion or recruited directly under the selected dose regimen in the second 
portion ............................................................................................................................................28 
1.2.2.2 
Flow chart for patients enrolled in the dose-finding portion who change to the selected 
dose regimen (during extension phase) ........................................................................................32 
1.2.2.3 
Flow chart for patients enrolled directly under the selected dose regimen in the third portion......38 
2 
TABLE CONTENTS ......................................................................................................................42 
3 
LIST OF ABBREVIATIONS ..........................................................................................................49 
4 
INTRODUCTION............................................................................................................................51 
4.1 
INTRODUCTION............................................................................................................................51 
4.2 
CLINICAL PROGRAM IN ADULT RHEUMATOID ARTHRITIS (RA)............................................52 
4.3 
STUDY RATIONALE......................................................................................................................54 
4.3.1 
Choice of the dose regimen ...........................................................................................................54 
4.3.2 
Study design ..................................................................................................................................56 
5 
STUDY OBJECTIVES ...................................................................................................................58 
5.1 
PRIMARY.......................................................................................................................................58 
5.2 
SECONDARY ................................................................................................................................58 
6 
STUDY DESIGN ............................................................................................................................59 
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6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................59 
6.1.1 
Tested dose regimens ...................................................................................................................60 
6.1.2 
Rules for the stepwise approach....................................................................................................61 
6.1.2.1 
For permitting enrollment into Dose Regimen 1 Cohort for Group B (<30 kg and ≥10 kg) ...........61 
6.1.2.2 
For escalating the dose in a group.................................................................................................61 
6.1.2.3 
For prematurely stopping enrollment in a dose regimen cohort weight group...............................61 
6.1.2.4 
Rules for dose regimen selection...................................................................................................62 
6.2 
STUDY COMMITTEES..................................................................................................................62 
6.2.1 
Data Monitoring Committee review for ensuring patients’ safety ..................................................62 
6.2.2 
Dose Escalation Committee review for dose selection..................................................................62 
6.3 
DURATION OF STUDY PARTICIPATION ....................................................................................62 
6.3.1 
Duration of study participation for each patient .............................................................................62 
6.3.2 
Determination of end of clinical trial (all patients) ..........................................................................63 
6.4 
INTERIM ANALYSIS......................................................................................................................63 
7 
SELECTION OF PATIENTS..........................................................................................................64 
7.1 
INCLUSION CRITERIA..................................................................................................................64 
7.2 
EXCLUSION CRITERIA ................................................................................................................64 
7.2.1 
Exclusion criteria related to study methodology ............................................................................64 
7.2.2 
Exclusion criteria related to the current knowledge of Sanofi compound ......................................67 
7.2.3 
Additional exclusion criteria during or at the end of Screening......................................................68 
8 
STUDY TREATMENTS .................................................................................................................69 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................69 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................70 
8.3 
BLINDING PROCEDURES............................................................................................................70 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................71 
8.5 
PACKAGING AND LABELING ......................................................................................................72 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................72 
8.7 
RESPONSIBILITIES ......................................................................................................................72 
8.7.1 
Treatment accountability and compliance......................................................................................73 
8.7.2 
Return and/or destruction of treatments ........................................................................................73 
8.8 
CONCOMITANT MEDICATION.....................................................................................................73 
8.8.1 
Prohibited medications...................................................................................................................73 
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8.8.2 
Corticosteroids ...............................................................................................................................74 
8.8.2.1 
Systemic parenteral and intra-articular corticosteroids..................................................................74 
8.8.2.2 
Oral corticosteroids ........................................................................................................................74 
8.8.2.3 
Intranasal - inhaled or topical corticosteroids ................................................................................74 
8.8.3 
Nonsteroidal anti-inflammatory drugs ............................................................................................75 
8.8.4 
Acetaminophen (paracetamol) and other analgesics ....................................................................75 
8.8.5 
Lipid lowering drugs .......................................................................................................................75 
8.8.6 
Cytochrome P450 enzyme substrates...........................................................................................75 
8.8.7 
Other concomitant treatment .........................................................................................................76 
8.8.7.1 
Topical anesthesia .........................................................................................................................76 
8.8.7.2 
Folic/folinic acid..............................................................................................................................76 
8.8.7.3 
Immunoglobulins............................................................................................................................76 
8.8.7.4 
Growth hormone/androgens ..........................................................................................................76 
8.8.7.5 
Iron .................................................................................................................................................76 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................77 
9.1 
PHARMACOKINETICS PRIMARY ENDPOINT ............................................................................77 
9.1.1 
Sampling time ................................................................................................................................77 
9.1.2 
Pharmacokinetics handling procedure...........................................................................................78 
9.1.3 
Bioanalytical method......................................................................................................................78 
9.1.4 
Pharmacokinetics parameters .......................................................................................................79 
9.2 
SECONDARY ENDPOINT(S)........................................................................................................79 
9.2.1 
12-week core treatment phase ......................................................................................................79 
9.2.2 
Extension part ................................................................................................................................80 
9.3 
SAFETY ENDPOINTS ...................................................................................................................80 
9.3.1 
Adverse events ..............................................................................................................................80 
9.3.2 
Vital signs.......................................................................................................................................81 
9.3.3 
Acceptability assessments (local tolerability).................................................................................81 
9.3.4 
Laboratory safety variables............................................................................................................81 
9.4 
EFFICACY ENDPOINTS ...............................................................................................................84 
9.4.1 
Juvenile idiopathic arthritis American college of rheumatology response .....................................84 
9.4.1.1 
Physician global assessment of disease activity ...........................................................................85 
9.4.1.2 
Patient/parent assessment of overall well-being ...........................................................................85 
9.4.1.3 
Childhood health assessment questionnaire .................................................................................85 
9.4.1.4 
Number of Joints with active arthritis and number of joints with limited motion ............................87 
9.4.1.5 
High sensitivity C-reactive protein..................................................................................................87 
9.4.2 
Juvenile arthritis disease activity Score .........................................................................................87 
9.5 
PHYSICAL EXAMINATION ...........................................................................................................88 
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9.6 
WEIGHT.........................................................................................................................................88 
9.7 
PHARMACODYNAMICS ...............................................................................................................88 
9.7.1 
Pharmacodynamics parameters ....................................................................................................88 
9.7.1.1 
Assessment methods.....................................................................................................................89 
9.7.1.2 
Assessment schedule ....................................................................................................................89 
9.8 
IMMUNOGENICITY .......................................................................................................................89 
9.9 
PHARMACOGENOMICS...............................................................................................................89 
9.10 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................90 
9.11 
FUTURE USE OF SAMPLES ........................................................................................................90 
10 
STUDY PROCEDURES ................................................................................................................91 
10.1 
VISIT SCHEDULE..........................................................................................................................91 
10.1.1 
Visit 1: Screening (Day -28 to Day -1, up to 31 days) for all patients ............................................91 
10.1.2 
Visit 2 Baseline (Day 1, Week 0) ...................................................................................................94 
10.1.3 
Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8), and Visit 6 (Day 12) .............................................95 
10.1.4 
Visit 7 (Week 2)..............................................................................................................................97 
10.1.5 
Visit 8 (Week 4)..............................................................................................................................98 
10.1.6 
Visit 9 (Week 6), Visit 10 (Week 8), Visit 11 (Week 10).................................................................99 
10.1.7 
Visit 12 (Week 12)........................................................................................................................100 
10.1.8 
Visit 88 - Pharmacokinetic (PK) Follow-up Visit (End-of-Treatment [EOT] + 2 Weeks) ..............102 
10.1.9 
Extension Phase ..........................................................................................................................102 
10.1.9.1 Patients who remain on the current dose (the selected dose regimen) or recruited directly 
under the selected dose regimen in the second portion..............................................................103 
10.1.9.2 Patients who change to the selected dose regimen ....................................................................105 
10.1.9.3 Patients enrolled directly under the selected dose regimen in the third portion ..........................106 
10.1.10 Visit 27: End-of-Treatment visit....................................................................................................108 
10.1.11 Visit 28 (End-of-Treatment [EOT] +6 weeks) End-of-Study Visit: Post-treatment follow-up .......109 
10.2 
DEFINITION OF SOURCE DATA................................................................................................110 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.....................................110 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) .........................110 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) .........................111 
10.3.3 
List of criteria for permanent treatment discontinuation...............................................................111 
10.3.4 
Handling of patients after permanent treatment discontinuation .................................................112 
10.3.5 
Procedure and consequence for patient withdrawal from study..................................................112 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................113 
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10.4.1 
Definitions of adverse events.......................................................................................................113 
10.4.1.1 Adverse event ..............................................................................................................................113 
10.4.1.2 Serious adverse event .................................................................................................................113 
10.4.1.3 Adverse event of special interest.................................................................................................114 
10.4.2 
General guidelines for reporting adverse events .........................................................................114 
10.4.3 
Instructions for reporting serious adverse events ........................................................................115 
10.4.4 
Guidelines for reporting adverse events of special interest.........................................................116 
10.4.4.1 Reporting of adverse events of special interest...........................................................................116 
10.4.5 
Guidelines for management of specific laboratory abnormalities ................................................118 
10.5 
OBLIGATIONS OF THE SPONSOR ...........................................................................................119 
10.6 
SAFETY INSTRUCTIONS ...........................................................................................................119 
10.6.1 
Infections......................................................................................................................................119 
10.6.2 
Liver function tests .......................................................................................................................120 
10.6.3 
Neutrophils ...................................................................................................................................120 
10.6.4 
Platelets .......................................................................................................................................120 
10.6.5 
Systemic hypersensitivity reactions/anaphylaxis .........................................................................121 
10.6.6 
Diverticulitis and Gastrointestinal Perforation ..............................................................................121 
10.6.7 
Management of dyslipidemia .......................................................................................................121 
10.6.8 
Acute renal failure ........................................................................................................................122 
10.7 
ADVERSE EVENTS MONITORING............................................................................................122 
11 
STATISTICAL CONSIDERATIONS............................................................................................123 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................123 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................125 
11.3 
ANALYSIS POPULATIONS.........................................................................................................126 
11.3.1 
Efficacy populations .....................................................................................................................126 
11.3.2 
Safety population .........................................................................................................................126 
11.3.3 
Pharmacokinetic, pharmacodynamics, and immunogenicity population .....................................126 
11.4 
STATISTICAL METHODS ...........................................................................................................127 
11.4.1 
Extent of study treatment exposure and compliance...................................................................127 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................127 
11.4.1.2 Compliance ..................................................................................................................................127 
11.4.2 
Analyses of efficacy endpoints.....................................................................................................127 
11.4.2.1 Analysis of primary efficacy endpoint(s) ......................................................................................128 
11.4.2.2 Analyses of secondary efficacy endpoints...................................................................................128 
11.4.2.3 Multiplicity considerations ............................................................................................................129 
11.4.3 
Analyses of safety data................................................................................................................129 
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11.4.4 
Analyses of pharmacokinetic and pharmacodynamics variables ................................................132 
11.4.5 
Pharmacodynamic and pharmacokinetic analysis.......................................................................132 
11.4.6 
Analysis of immunogenicity variables ..........................................................................................133 
11.5 
INTERIM ANALYSIS....................................................................................................................134 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................135 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................135 
12.2 
INFORMED CONSENT ...............................................................................................................135 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ............136 
13 
STUDY MONITORING.................................................................................................................138 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................138 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................138 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................138 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL
REQUEST....................................................................................................................................139 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................139 
14 
ADDITIONAL REQUIREMENTS.................................................................................................140 
14.1 
CURRICULUM VITAE..................................................................................................................140 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................140 
14.3 
CONFIDENTIALITY .....................................................................................................................140 
14.4 
PROPERTY RIGHTS...................................................................................................................141 
14.5 
DATA PROTECTION...................................................................................................................141 
14.6 
INSURANCE COMPENSATION..................................................................................................141 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................142 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................142 
14.8.1 
By the Sponsor.............................................................................................................................142 
14.8.2 
By the Investigator .......................................................................................................................143 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................143 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................143 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................144 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................145 
17 
APPENDICES..............................................................................................................................148 
APPENDIX A 
SUBCLASSIFICATION OF RHEUMATOID FACTOR (RF)-NEGATIVE, 
RHEUMATOID FACTOR (RF)-POSITIVE POLYARTICULAR AND OLIGOARTICULAR 
JUVENILE IDIOPATHIC ARTHRITIS (JIA)..................................................................................149 
APPENDIX B 
VOLUME TO BE ADMINISTERED AT EACH INJECTION ACCORDING TO BODY
WEIGHT.......................................................................................................................................150 
APPENDIX C 
DEFINITION OF EFFICACY AND JIA ACR 30/50/70/90/100...........................................154 
APPENDIX D 
SUBJECT’S AND PHYSICIAN’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY .....155 
APPENDIX E 
CHILDHOOD HEALTH ASSESSMENT QUESTIONNAIRE .............................................156 
APPENDIX F 
TANNER STAGES.............................................................................................................158 
APPENDIX G 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................160 
APPENDIX H 
ANAPHYLAXIS DEFINITION ............................................................................................164 
APPENDIX I 
LIST OF OPPORTUNISTIC INFECTIONS.........................................................................165 
APPENDIX J 
PROHIBITED LIVE (ATTENUATED) VACCINE LIST .......................................................166 
APPENDIX K 
COUNTRY SPECIFIC REQUIREMENTS .........................................................................167 
Requirements for Argentina ........................................................................................................................167 
Requirements for Germany.........................................................................................................................167 
Requirements for France.............................................................................................................................167 
Requirements for UK...................................................................................................................................167 
Requirements for Russia.............................................................................................................................168 
APPENDIX L 
PROTOCOL AMENDMENT HISTORY..............................................................................169 
Amended Clinical Trial Protocol 1 (RU) based on Protocol Amendment 1 (RU) ........................................169 
Amended Clinical Trial Protocol 1 (FR) based on Protocol Amendment 2 (FR) .........................................169 
Amended Clinical Trial Protocol 1 (DE) based on Protocol Amendment 3 (DE).........................................170 
Amended Clinical Trial Protocol 2 (DE) based on Protocol Amendment 4 (DE).........................................170 
Amended Clinical Trial Protocol 2 (RU) based on Protocol Amendment 5 (RU) ........................................172 
Amended Clinical Trial Protocol 1 based on Protocol Amendment 6 .........................................................172 
Amended Clinical Trial Protocol 2 ...............................................................................................................175 
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3
LIST OF ABBREVIATIONS
ACR:
American College of Rheumatology response criteria
ADA:
anti-drug antibody
AE:
adverse event 
AESI:
adverse event(s) of special interest
ALP:
alkaline phosphatase
ALT:
alanine aminotransferase 
ANA:
antinuclear antibody
ANC:
absolute neutrophil count 
anti-dsDNA:
anti-double stranded DNA
AST:
aspartate aminotransferase 
BP:
blood pressure
BUN:
blood urea nitrogen
CHAQ:
Childhood Health Assessment Questionnaire
COX-2:
cyclo-oxygenase-2 inhibitors 
CRF:
case report form
CRP:
C-reactive protein
CSR:
clinical study report
CYP:
cytochrome 
DMARD:
disease modifying antirheumatic drug 
DMC:
Data Monitoring Committee
DNA:
deoxyribonucleic acid 
EBV:
Epstein-Barr virus
e-CRF:
electronic case report form
EOS:
end-of-study
EOT:
end-of-treatment
ESR:
erythrocyte sedimentation rate
FDA:
Food and Drug Administration
GCP:
good clinical practice
HAQ-DI:
Health Assessment Questionnaire Disability Index
HBc-Ab:
hepatitis B core antibody 
HIV:
human immunodeficiency virus
HR:
heart rate
hs-CRP:
high sensitivity C-reactive protein
ICF:
informed consent form
ICH:
International Council for Harmonisation
IEC:
Independent ethics committee
IgG:
immunoglobulin G
IL-6:
Interleukin 6
IL-6R:
IL-6 receptor 
ILAR:
international league of associations for rheumatology
IMP:
investigational medicinal product
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IRB:
Institutional Review Board
IVRS:
interactive voice response system
IWRS:
interactive web response system
JADAS:
Juvenile Arthritis Disease Activity Score 
JAK:
Janus kinase
JIA:
juvenile idiopathic arthritis
LLOQ:
lower limit of quantification
mTSS:
modified total sharp score
MTX:
methotrexate
NIMP:
noninvestigational medicinal product
NSAID:
Non-steroidal anti-inflammatory drugs 
oJIA:
oligoarticular juvenile idiopathic arthritis
pcJIA:
polyarticular course of juvenile idiopathic arthritis
PD:
pharmacodynamic
PK:
pharmacokinetic
PopPK:
Population pharmacokinetic 
PPD:
Purified Protein Derivative 
q2w:
once every other week 
qw:
once a week
RA:
rheumatoid arthritis 
RF:
rheumatoid factor
SAE:
serious adverse event
SC:
subcutaneous
sIL-6R:
soluble interleukin-6 receptor
SUSAR:
suspected unexpected serious adverse reaction
TEAE:
treatment-emergent adverse event
TNF:
Tumor necrosis factor
ULN:
upper limit of normal
VAS:
visual analogue scale
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4
INTRODUCTION
4.1
INTRODUCTION
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood. It is 
defined by the International League of Associations for Rheumatology (ILAR) as arthritis of 
unknown etiology with onset before 16 years of age that persists for at least 6 weeks with other 
known conditions excluded (2,3,5,6,7). Juvenile idiopathic arthritis (JIA) comprises 7 subtypes 
categorized by age of onset, range, and disease characteristics in the first 6 months after onset as 
defined by the ILAR in 2001 (2).
Polyarticular course juvenile idiopathic arthritis (pcJIA), a subtype of JIA, affects at least 5 joints. 
Both large and small joints can be involved, and often in symmetric bilateral distribution, and 
often involving weight-bearing joints and small joints in the hands. Low grade fevers can 
accompany the arthritis. Presence of rheumatoid factor (RF) differentiates the 2 forms of pcJIA: 
RF-positive and RF-negative pcJIA:
Rheumatoid factor (RF)-positive pcJIA represents a relatively small proportion of all children and 
adolescents with JIA (3%-5%) but it is the only JIA subgroup resembling adult rheumatoid 
arthritis (RA), a deforming symmetrical polyarthritis, due to chronic synovial inflammation, 
articular cartilage loss and erosion of juxta-articular bone. Features of RF-positive pcJIA are the 
mean onset at age of 12 to 14 years, the marked female gender predominance (13:1 female/male 
ratio), symmetrical involvement of small and large joints, production of polyclonal IgM RF or 
antiCCP antibodies, genetic susceptibility (association with the HLA-DR4 allele), a clinical 
course marked by normocytic chronic anemia (reticuloendothelial block), and acute phase 
proteins (elevated ESR and C-reactive protein [CRP]) that rarely remits spontaneously, as well as 
elevated white blood cell count. The association with firm, mobile and nonpainful rheumatoid 
nodule formation is possible but rare. Laboratory findings are expected to be more severe than 
those associated with oligoarthritis. Long-term sequelae include joint subluxation (wrists and 
thumbs), joint contractures (proximal and distal interphalangeals, bone overgrowth of proximal 
interphalangeals, and finger deformities (eg, swan-neck or boutonniere deformities). 
Asymptomatic arthritis of the cervical spine, associated with decreased extension, can lead to 
subluxation, typically of C2 vertebrae on C3 and fusion of the posterior vertebral elements. 
Arthritis of the temporal-mandibular joint may also be asymptomatic and lead to micrognathia (2).
Rheumatoid factor (RF)-negative pcJIA presents at a younger age (in late childhood, 7 to 9 years) 
than RF-positive pcJIA and represents 11 to 28% of all children and adolescents with JIA. It may 
not be as destructive and persistent as RF-positive disease but does, by definition, involve 5 or 
more joints. Radiologic changes in RF-negative disease occur later than in RF-positive disease. 
Severe limitations in motion are usually accompanied by muscle weakness and decreased physical 
function.
Oligoarticular JIA (oJIA) (5,6,7), another subtype of JIA, is the most common subtype of juvenile 
arthritis, representing approximately 50% of all patients with JIA in the US and Western Europe. 
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Onset ranges from 1 to 5 years and peaks at 2 to 3 years. It is defined as an aseptic inflammatory 
synovitis that affects generally up to 4 joints (typically larger joints, such as knees, ankles, wrists) 
and is not associated with constitutional findings such as fever, weight loss, fatigue or systemic 
signs of inflammation. Nevertheless, if greater than 4 joints become affected after the first 
6 months of disease, it is designated as extended oligoarthritis in contrast to persistent oJIA that
features only up to 4 joints throughout the course of the disease. Children are often well-appearing 
despite ambulating with a limp. Oligoarticular JIA carries a risk for developing chronic anterior 
uveitis, especially when antinuclear antibodies (ANA) are present and disease onset is in early 
childhood. It is typically asymptomatic at onset and requires screening by ophthalmologic slit 
lamp examination. Chronic arthritis in a knee or ankle may lead to overgrowth of that limb with 
subsequent leg length discrepancy. Muscle atrophy, often of extensor muscles (eg, vastus lateralis, 
quadriceps when knee affected) and/or flexion contractures in the knees and, less commonly, the 
wrists are found. 
Please refer to Appendix A for Subclassification of RF-negative, RF-positive, polyarticular and 
oJIA. For the purpose of this study, extended oligoarticular, RF-positive and RF-negative 
polyarticular JIA will be referred to as polyarticularcourse (pcJIA).
Interleukin 6 (IL-6) is a key cytokine involved in the pathogenesis of RA and JIA causing 
inflammation, and joint destruction (8,9,10,11). The relevance of elevated IL-6 levels to disease 
mechanisms of polyarticular JIA (RF- and RF+ has been well documented in the medical-
scientific literature (12). Inhibition of IL-6 signaling through blockade of the IL-6 receptor (IL-
6R) was first demonstrated to be effective in pcJIA by tocilizumab, an intravenously 
administered, humanized monoclonal antibody (mAb) to the IL-6R (13,14). In the pcJIA studies 
that led to the approval of tocilizumab in this indication, the safety profile of tocilizumab appeared 
to be similar to that of the adult RA population.
Sarilumab is a recombinant human monoclonal antibody of the immunoglobulin G (IgG) isotype 
targeting the IL-6R α subunit (IL-6Rα). Sarilumab blinds the human IL-6Rα and has been 
demonstrated to inhibit IL-6 signaling.
 
Sarilumab may become an effective and safe therapeutic option for patients suffering from pcJIA. 
This study will evaluate the efficacy, safety, and pharmacokinetic (PK), pharmacodynamic (PD)
profiles of different doses of sarilumab administered to patients with pcJIA.
4.2
CLINICAL PROGRAM IN ADULT RHEUMATOID ARTHRITIS (RA)
The efficacy and safety of sarilumab, whether or not added to a nonbiologic disease modifying 
antirheumatic drug (DMARD), have been evaluated in adult patients with active RA. The dose 
regimens selected for the Phase 3 program in adults were 150 mg once every other week (q2w)
and 200 mg q2w. These selected dose regimens added to methotrexate (MTX) in patients who are 
MTX inadequate responders, showed clinically relevant and statistically significant (p<0.0001) 
improvements compared with placebo in all 3 co-primary efficacy endpoints: signs and symptoms 
American College of Rheumatology response criteria, ACR20, physical function (Health 
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Assessment Questionnaire Disability Index, [HAQ-DI]), and radiographic progression (Van der 
Heijde modified total Sharp score, vdH-mTSS]) in the double-blind, placebo-controlled, 
SARIL-RA-MOBILITY (EFC11072) study:
x
Improvement in signs and symptoms of RA at 24 weeks as measured by the ACR20 
(proportion of patients achieving an ACR20 response: 58.0% for the sarilumab 
150 mg q2w group, 66% for the sarilumab 200 mg q2w group, and 33% for the placebo 
group).
x
Improvement in physical function, as measured by the change from baseline in the 
HAQ-DI at Week 16 (-0.54 for the sarilumab 150 mg q2w group, -0.58 for the sarilumab 
200 mg q2w group, and -0.30 for the placebo group).
x
Inhibition of progression of structural damage at Week 52, as measured by the change 
from baseline in them TSS (0.90 for the sarilumab 150 mg q2w group, 0.25 for the 
sarilumab 200 mg q2w group, and 2.78 for the placebo group).
The improvements in the ACR20 response and HAQ-DI were maintained up to Week 52 (End-of-
Treatment [EOT]). The sarilumab 200 mg q2w group had a reduction of approximately 90% in 
the radiographic progression that was assessed by the mTSS, compared to the placebo group. 
Another phase 3 efficacy and safety study, SARIL-RA-TARGET (EFC10832) enrolled total 
546 patients into three treatment groups, placebo (181), sarilumab 150 mg q2w (181) and 
sarilumab 200 mg q2w (184). Both doses of sarilumab showed clinically relevant and statistically 
significant improvements compared with placebo in 2 co-primary endpoints:
x
Improvement in signs and symptoms of RA at 24 weeks as measured by the ACR20 
response at Week 24 (the proportion of patients achieving an ACR20 response: 56% for 
the sarilumab 150 mg q2w group, 61% for the sarilumab 200 mg q2w group, and 34% for 
the placebo group p<0.0001)
x
Improvement in physical function, as measured by the change from baseline in HAQ-DI at 
Week 12. The results demonstrated statistically significant difference in favor of sarilumab 
in HAQ-DI change from baseline at Week 12 in the sarilumab 200 mg q2w and 150 mg 
q2w dose groups (-0.21 and -0.20 units), compared to placebo, with p-values of 0.0004 
and 0.0007, respectively. 
The safety profile in SARIL-RA-MOBILITY was consistent with the anticipated effects of IL-6
inhibition. There was a higher incidence of treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), and TEAEs leading to withdrawal in the sarilumab treatment groups 
compared to placebo. The incidences of treatment-emergent SAEs in the sarilumab treatment 
groups were higher compared to placebo (for 100 patient years, there were 18.7, 16.8, and 12.9 
events in the 200 mg q2w, 150 mg q2w, and placebo treatment groups, respectively). Infections 
were the most frequently reported SAEs (for 100 patient years, there were 4.7, 3.0, and 3.3 
patients and 6.0, 3.8, and 3.9 events in the 200 mg q2w, 150 mg q2w, and placebo treatment 
groups, respectively), generally involving the respiratory tract or skin/soft tissue. In the sarilumab 
treated groups compared to placebo, there were decreases in neutrophil count, elevation in alanine 
aminotransferase (ALT), elevation in serum LDL-cholesterol and injection site reactions (ie, 
erythema, pain). No notable differences have been observed with regards to loss or lack of 
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efficacy or hypersensitivity reactions, including systemic and local, between those patients who 
were anti-drug antibody (ADA)-positive and ADA-negative. 
The safety profile of sarilumab observed in SARIL-RA-TARGET (EFC10832) was consistent 
with that observed for MOBILITY and other RA studies in the phase 3 registration program.
Based on the safety profile of tocilizumab (an approved IL-6R inhibitor) and other biological 
DMARDs, potential important risks to be considered with sarilumab administration are 
tuberculosis and clinically significant opportunistic infections, complications of 
diverticulitis/gastrointestinal perforations, anaphylaxis, clinical consequences of immunogenicity, 
clinical consequences of thrombocytopenia, malignancy, and demyelinating disorders. In addition, 
clinical consequences of laboratory abnormalities which may occur due to sarilumab 
administration (eg, serious infection secondary to neutropenia) are considered an important 
potential risk.
Based on the experience to date from the sarilumab clinical development program, the potential 
important risks associated with sarilumab administration are non-opportunistic infections, 
neutropenia, elevation in lipids, elevation in liver transaminase, and injection site reactions 
(ie, erythema, pain). 
From the results of the sarilumab RA development program in adult patients, the two selected 
dose regimens of sarilumab for the phase 3 program were recognized efficacious with an 
acceptable safety profile by Health Agencies worldwide including the Food and Drug 
Administration (FDA) in the US and the European Medicines Agency (EMA) in Europe who 
approved them for the treatment of adult RA. The recommended dose regimen in US and EU is 
200 mg q2w that is to be reduced to 150 mg q2w for management of neutropenia, 
thrombocytopenia, and elevated liver enzymes. These 3 dose regimens served as an appropriate 
reference for the evaluation of sarilumab in pediatric patients with polyarticular course and 
systemic juvenile idiopathic arthritis (pcJIA and sJIA). For complete information regarding the 
preclinical and clinical evaluation of sarilumab to date, see the Clinical Investigator’s Brochure 
(Edition 13, 28 February 2017).
4.3
STUDY RATIONALE
4.3.1
Choice of the dose regimen
This study targets children and adolescents aged 2 to 17 (or country specified age requirement) 
with pcJIA, a JIA subset that resembles adult RA. In this pediatric population, 3 dose regimens of 
sarilumab are planned to be tested. 
 Population pharmacokinetic (PopPK) analyses in 
adult RA patients showed that age, gender, and race did not affect the PKs of sarilumab. Weight 
was found to impact sarilumab exposure with higher exposure observed in patients with lower 
weight. 
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Due to differential growth rates in young children, there is a much larger variability in body size 
for children than for adults. In addition, since body weight has an important effect on the 
clearance of monoclonal antibodies; a weight-adjusted dosage may be required for patients of 
different weights in order to achieve relatively comparable drug exposure from a recommended 
fixed dose regimen in adults. 
Sarilumab at doses of 150 mg q2w, 200 mg q2w, and 150 mg once a week (qw) all demonstrated 
improvements in endpoints of RA disease activity with the safety profile anticipated for an IL-6R
antagonist. The published literature suggests that exposures that are efficacious in adult RA are 
likely to be efficacious in pcJIA. Therefore, Dose 1 for this pcJIA study has been chosen to yield 
an exposure similar to 150 mg q2w (the lowest efficacious dose) observed in the adult RA 
program. Dose 2, the second dose level to be evaluated in this study, has been predicted to achieve 
an exposure comparable to the sarilumab 200 mg q2w dose observed in the adult RA program.
Dose 3, the third dose level to be evaluated in this study, has been predicted to achieve an 
exposure comparable to the sarilumab 150 mg qw dose observed in the adult RA program, the 
highest dose level tested in the adult program that also demonstrated better improvement in signs 
and symptoms of RA compared to placebo and had an acceptable safety profile.
The approximate equivalents of a 150 mg or 200 mg dose for a 75 kg adult RA patient are 
2 mg/kg or 3 mg/kg, respectively. 
. The PK target for the pediatric population was 
comparable exposure to that observed in adult RA patients for dosing regimens of 150 mg q2w or 
200 mg q2w. 
In addition, in sarilumab program in adult RA, the dose regimen that provided the highest 
exposure, ie, 150 mg qw was received by more than 300 patients including about 30% patients for 
one year.
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4.3.2
Study design
This multi-center Phase 2b study has been designed to determine the appropriate dose and 
regimen for adequate treatment of patients with pcJIA disease based on PK, PD, safety, and 
efficacy evaluation of the 3 sarilumab dose regimens tested in the study. With the ethical concern 
to not expose these children to a noneffective dose for a too long period due to the potential 
severity and chronicity of the disease, the open-label sequential ascending repeat-dose design was 
preferred to a double-blind, placebo-controlled, parallel arms design. 
The 12-week core treatment phase of the study comprises 3 portions. The first portion is a
dose-finding portion that follows a multiple ascending dose design. Within a dose regimen cohort, 
treatment will initiate in the higher weight group A (≥30 kg and ≤60 kg), as these children are 
older. Dosing will commence in the lower weight group B (<30 kg and ≥10 kg) after reviewing 
PK, PD, efficacy, and safety data from the first dose regimen tested in group A. The duration of 
the core treatment period (12 weeks) is consistent with the generally accepted time period 
required to assess the clinical effect of a biological therapy for JIA.
The proposed stepwise evaluation of different sarilumab doses in the dose-finding portion of the 
12-week core treatment phase of the study, starting with the lowest effective dose that had an 
acceptable safety profile observed in the adult RA program, is appropriate to ensure a balance of 
the potential efficacy and safety considerations for the first dose of sarilumab to be assessed in the 
pediatric population in this study. This adaptive sequential design will minimize the exposure of 
children to an ineffective or unsafe dose with rules for prematurely stopping a dose regimen 
cohort for lack of efficacy and the stepwise approach for evaluating each dose regimen cohort 
before allowing next one. The third dose may be evaluated in this study, after review of the PK, 
PD, and clinical safety/efficacy data from the prior dose regimen cohorts, if it is determined that 
another dose regimen may allow for further optimization of the benefit-risk balance for this study 
population.
After completing the investigation of the ascending dose regimen cohorts in the dose-finding
portion of the 12-week core treatment phase, one dose regimen will be selected by the Dose 
Escalation Committee (DEC) and additional patients will be enrolled at the selected dose regimen
(second portion of the core treatment phase) to obtain 18 evaluable patients per weight group with 
that selected dose regimen in order to provide sufficient precision for PK parameters and PK-PD 
relationship assessments. Those patients will undergo the same assessments as patients recruited 
in the dose-finding portion.
Additionally, after completing the enrollment of dose-finding and second portions, a third portion 
where approximately 28 additional patients will be enrolled directly to the selected dose regimen 
to achieve a total of approximately 100 treated patients for the entire study as per a health 
authority recommendation. These patients will undergo the same on-site visits during the 12-week 
core treatment phase as patients recruited in the dose-finding and second portions; however, the
patients in the third portion will not have the sarilumab PK sampling visits between Baseline and 
Week 2.
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An additional treatment period in the extension phase will allow collection of long-term safety 
and clinical response data for sarilumab in pcJIA patients. This extension phase is up to 
144 weeks for patients enrolled in the dose-finding and second portions and up to 84 weeks for 
patients enrolled in the third portion. Patients enrolled in the dose-finding portion who are already 
in the extension phase at time of dose regimen selection and who did not receive the selected dose 
regimen will have their dose regimen adjusted to the selected dose.
To minimize the amount of blood collected, Group B patient (<30 kg and ≥10 kg) in the 
dose-finding and second portions will be randomized to 1 of 2 different sarilumab PK sample 
collection schedules. The PK analyses will integrate these sampling schedules to describe the PK 
profile of sarilumab (see Section 9.1). No PK sample collection is planned between Baseline and 
Week 2 for patients enrolled in the third portion. Total volume of blood withdraw for the study 
will not exceed 3% of the total blood volume during a period of 4 weeks and not exceed 1% of the 
total blood volume at any single time (16).
Furthermore, the planned frequent assessments control risk to study participants.
Lastly, the post-treatment follow-up period of 6 weeks after the last treatment visit for TEAEs, 
sarilumab PK and PD assessments is appropriate taking into account the observed PK profiles in 
the adult RA program.
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5
STUDY OBJECTIVES
5.1
PRIMARY
The primary objective of this study is to describe the PK profile of sarilumab in patients aged 2 to 
17 years with pcJIA in order to identify the dose and regimen for adequate treatment of this 
population.
5.2
SECONDARY
The secondary objectives are to describe:
x
The PD profile and the efficacy of sarilumab in patients with pcJIA.
x
The long-term safety of sarilumab in patients with pcJIA.
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6
STUDY DESIGN
6.1
DESCRIPTION OF THE PROTOCOL
DRI13925 is a multinational, multicenter, open-label, 2-phase study in children and adolescents, 
aged 2 to 17 years (or country specified age requirement), with pcJIA who have inadequate 
response to or who are intolerant to standard therapy and who will receive SC injections of 
sarilumab administrated q2w or qw. The 2 phases are as follows:
1. A 12-week core treatment phase, split into 3 portions:
x
A first sequential, ascending dose-cohort, dose-finding portion in which up to 3 dose 
regimens will be investigated in two weight groups: patients ≥30 kg and ≤60 kg (Group A) 
and patients <30 kg and ≥10 kg (Group B) in 6 evaluable patients per dose and weight 
group (around 36 patients in total). Patient enrollment will be staggered by weight group 
and dose regimen, starting with Group A (≥30 kg and ≤60 kg) and Dose Regimen 1 Cohort.
x
A subsequent portion where approximately 24 additional patients (12 in each weight 
group: ≥30 kg [Group A] and patients <30 kg and Ӌ10 kg [Group B]) will be enrolled 
directly to the selected dose regimen (identified based on the aggregate data from patients 
enrolled in the dose-finding portion) to achieve a total of 18 evaluable patients per weight 
group at this selected dose regimen. These patients will undergo the same 12-week core 
treatment assessments as patients recruited during the dose-finding portion.
x
A third portion where approximately 28 additional patients (a cap of 70% in each weight 
group: patients ≥30 kg [Group A] and patients <30 kg and ≥10 kg [Group B]) will be 
enrolled directly to the selected dose regimen to achieve a total of approximately 
100 treated patients for the entire study. These patients will undergo the same on-site visits 
during the 12-week core treatment phase as patients recruited in the dose-finding and 
second portions; however, the patients in the third portion will not have the sarilumab PK 
sampling visits between Baseline and Week 2.
The 12-week core treatment phase is from Visit 2 (Baseline-Week 0) to the time that Visit 12
investigational medicinal product (IMP) is administrated. During the 12-week core treatment 
phase, for the dose-finding and second portions, patients in the lower weight group (Group B:
<30 kg and ≥10 kg) will be randomly assigned to the following sarilumab PK sampling 
Schedule 1 or 2 (Section 9.1.1) in order to minimize the amount of blood withdrawn and the 
number of visits while maintaining the evaluation of the primary endpoint:
-
Schedule 1: Baseline, Day 3, Day 8, Week 2, Week 4, Week 8, and Week 12 
-
Schedule 2: Baseline, Day 5, Day 12, Week 2, Week 4, Week 8, and Week 12.
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2. An extension phase:
x
A 144-week extension for patients enrolled in the dose-finding and second portions: The 
IMP at Visit 12 is considered as the first IMP for the extension phase. Only patients who 
have reached a JIA ACR30 response at Visit 12 (Week 12) will be permitted to continue in 
the extension phase. Patients will continue on the same dose regimen of sarilumab they 
were assigned to receive in the 12-week core treatment phase of the study until the 
selected dose regimen is determined. Once the dose regimen is selected, patients who were 
not already on this dose regimen will have their dose regimen adjusted to the selected dose 
regimen and will follow a new visit schedule with more frequent monitoring (for PK, 
safety, and efficacy) for the first 12 weeks compared to those patients who do not have 
dose regimen adjusted (Section 1.2.2.2).
x
An 84-week extension for patients enrolled in the third portion. The IMP at Visit 12 is 
considered as the first IMP for the extension phase.
3. End-of-Treatment (EOT) and End-of-Study (EOS): 
x
For patients enrolled in the dose-finding and second portions: Patients who discontinue the 
study treatment prematurely will be assessed using the procedure for the EOT at Visit 27. 
These patients will be asked to return for the end-of-study (EOS) assessment 6 weeks after 
the EOT visit (EOT + 6 weeks). For patients who discontinue the study treatment during 
the 12-week core treatment phase, there will be an additional sarilumab PK assessment 2 
weeks after the EOT visit (EOT + 2 weeks) and IL-6 and soluble interleukin-6 receptor
(sIL-6R) will be measured at EOT visit. These patients will be asked to perform all the 
protocol scheduled visits and assessments except sarilumab administration until Visit 12.
x
For patients enrolled in the third portion: Patients who discontinue the study treatment 
prematurely will be assessed using the procedure for the EOT at Visit 27 and will be asked 
to return for the EOS assessment 6 weeks after the EOT visit (EOT + 6 weeks). For 
patients who prematurely discontinue the study treatment during the 12-week core 
treatment phase, the IL-6 and sIL-6R will be measured at the EOT visit, and they will be 
asked to participate in all the protocol scheduled visits and assessments except sarilumab
administration until Visit 12.
6.1.1
Tested dose regimens
For each weight group, to the 3 sequential ascending dose regimens to be tested were defined 
based on PK modeling with the following rationale: 
x
Dose Regimen 1: dose targeting PK exposures similar to sarilumab 150 mg q2w, the 
lowest effective dose in adult patients with RA
x
Dose Regimen 2: dose with targeted PK exposures similar to sarilumab 200 mg q2w in 
adult patients with RA 
x
Dose Regimen 3: dose targeting PK exposures similar to sarilumab 150 mg qw, which 
yielded the highest exposures in chronic dosing studies in adult patients with RA.
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Table 2 - Dose by body weight and dose regimen
Body weight
Dose Regimen 1
Dose Regimen 2
Dose Regimen 3
Group A 
≥30 kg and ≤60 kg 
2 mg/kg q2w 
(6 patients) 
3 mg/kg q2w 
(6 patients) 
2 mg/kg qw 
(6 patients) 
Group B 
<30 kg and ≥10 kg 
2.5 mg/kg q2w 
(6 patients) 
4 mg/kg q2w 
(6 patients) 
2.5 mg/kg qw 
(6 patients) 
Abbreviations: qw = once every week, q2w = once every other week. 
The dose (mg) to be administered to patients will be calculated at the Baseline. The dose and 
corresponding volume of drug product will remain the same throughout the course of the 
12- week core treatment phase of the trial regardless of change in patient's body weight. In the 
extension phase, the patient’s weight will be measured at each visit and the dose will be adapted 
to the increase of weight only if the calculation shows a need for dose increase. The dose will be 
capped at 150 mg for Dose Regimen 1 and 3, and 200 mg for Dose Regimen 2, respectively. 
Volumes of sarilumab to be injected for Dose Regimens 1 to 3 are presented in Appendix B.
6.1.2
Rules for the stepwise approach
6.1.2.1
For permitting enrollment into Dose Regimen 1 Cohort for Group B (<30 kg and 
≥10 kg)
Enrollment in the first Dose Regimen Cohort Group B (<30 kg and ≥10 kg), will initiate after the 
review of safety, efficacy, and available PK/PD and efficacy data for a minimum of 3 out of the 
6 patients planned in that same tested Dose Regimen Cohort in Group A (≥30 kg and ≤60 kg) who 
have completed at least 4 weeks of study treatment.
6.1.2.2
For escalating the dose in a group
The decision to initiate the next dose regimen cohort in the same weight group will be taken by 
the DEC and will depend on the data review of at least 6 weeks of efficacy and safety data as well 
as the available PK and PD data for a minimum of 3 patients out of the 6 from the current dose 
regimen cohort in the weight Group A.
Dose Regimen 3 Cohort in weight Group B will be initiated based on DEC decision after review 
of efficacy and safety as well as the available PK, and PD data from Dose Regimen 1 and 2
Cohorts of Groups A and B.
6.1.2.3
For prematurely stopping enrollment in a dose regimen cohort weight group
A dose regimen cohort for a weight group may be prematurely terminated after review of the 
6-week data for at least 3 patients out of the 6 planned to be enrolled in that dose regimen cohort 
weight group if none of these patients have reached JIA ACR 30 response. The decision will be 
taken by the DEC who will consider all available efficacy, safety, PK, and PD data and confirm 
the current dose regimen to be ineffective.
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If a dose is declared to be ineffective, no additional patients will be enrolled in that dose regimen 
cohort weight group and, if there is no major safety concern, the next dose regimen cohort will be 
initiated immediately. Any patient that has been included in that dose regimen cohort weight
group will have to discontinue from the study treatment and receive the standard of care treatment 
as per the Investigator’s clinical judgment. 
6.1.2.4
Rules for dose regimen selection
The decision about the selected dose regimen will be made by the DEC after review of sufficient 
Week 12 PK, PD, efficacy, and safety data from the patients enrolled in the dose-finding portion 
of the study.
6.2
STUDY COMMITTEES
6.2.1
Data Monitoring Committee review for ensuring patients’ safety
The Data Monitoring Committee (DMC) will be composed of independent pediatric 
rheumatologists who are not participants in the sarilumab pediatric clinical studies, are not 
sponsor employees, and do not have any conflict of interest with regard to study outcomes. The 
DMC will monitor patient safety by conducting formal reviews of accumulated safety data. The 
DMC will also review efficacy, PK, and PD data to evaluate the benefit-risk profile of sarilumab. 
The DMC members’ responsibilities and the process for data review are described in the DMC 
charter.
6.2.2
Dose Escalation Committee review for dose selection
The DEC is composed of sponsor representatives who will review the study data on a continuous 
basis as well as between dose regimen cohorts. The DEC will decide the appropriate course of 
action for the study, such as continuation to the next dose regimen cohort or modifications to the 
protocol. 
DEC member responsibilities and the process for dose escalation decisions are described in the
DEC charter.
6.3
DURATION OF STUDY PARTICIPATION
6.3.1
Duration of study participation for each patient
Total duration of study (per patient) is expected to be up to 166 weeks for patients enrolled in the
dose-finding and second portions and up to 106 weeks for patients enrolled in the third portion:
x
Up to 4 weeks + 3 days screening (up to 31 days)
x
12-week core treatment phase
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x
Up to 144-week extension phase for patients enrolled in the dose-finding and second 
portions and up to 84-week extension phase for patients enrolled in the third portion
x
6-week post-treatment follow-up.
For all visits, a time frame of ±3 days for Dose Regimen 1 and 2 Cohorts and ±1 day for Dose 
Regimen 3 Cohort is acceptable using Day 1 as reference except for 
x
For Visit 3 (Day 3), Visit 4 (Day 5) and Visit 5 (Day 8), no visit window is allowed where 
PK sampling occurs
x
Visit 6 (Day 12) ±1 day for all applicabledose regimen cohorts
x
Visit 7 (Week 2) ±1 day for all dose regimen cohorts
x
Visit 8 (Week 4) ±2 days for Dose Regimen 1 and 2 Cohorts and ±1 day for Dose 
Regimen 3 Cohort.
6.3.2
Determination of end of clinical trial (all patients)
The end of the clinical trial in all participating sites is reached when the last patient last visit is 
completed per protocol. The last patient last visit will occur at Visit 28/EOS for all patients who 
complete the open-label extension period of the study.
6.4
INTERIM ANALYSIS
Refer to Section 11.5 for details on interim analyses.
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7
SELECTION OF PATIENTS
7.1
INCLUSION CRITERIA
I 01.
Male and female patients aged ≥2 and ≤17 years (or country specified age requirement) at 
the time of the Screening visit 
I 02.
Diagnosis of RF-negative or RF-positive polyarticular JIA subtype or oJIA subtype 
according to the ILAR 2001 JIA Classification Criteria (2) with at least 5 active joints per 
ACR definition for “active arthritis” at Screening (Appendix A)
I 03.
Patient with an inadequate response to current treatment and considered as a 
candidate for a biologic DMARD as per Investigator’s judgment 
I 04.
The patient who has reached the legal age of consent, or the parent(s) or the legal 
guardian(s) sign and date the Ethic Committee approved written informed consent. The 
patient’s assent should be obtained based on local guidelines and the patient’s maturity and 
intellectual capabilities of understanding the study associated information. In cases 
involving emancipated or mature minors with adequate decision-making capacity, or when 
otherwise permitted by law, a signed informed consent will be obtained directly from the 
parent(s) or the legal guardian(s).
7.2
EXCLUSION CRITERIA
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following three sub-sections:
7.2.1
Exclusion criteria related to study methodology
E 01. Body weight <10 kg or >60 kg for patients enrolled in the 3 ascending dose regimen 
cohorts, then body weight <10 kg for patients subsequently enrolled at the selected dose 
regimen cohorts
E 02. Wheelchair-bound or bed-ridden
E 03. Diagnosis of JIA subtypes except polyarticular RF-positive (RF+) or RF-negative (RF-)
JIA or extended oJIA
E 04. If non-steroidal anti-inflammatory drugs (NSAIDs) (including cyclo-oxygenase-2
inhibitors [COX-2]) taken, dose stable for less than 2 weeks prior to the Baseline visit 
and/or dosing prescribed outside of approved label
E 05. If nonbiologic DMARD taken, dose stable for less than 6 weeks prior to the Baseline visit 
or at a dose exceeding the recommended dose as per local labeling
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E 06. If oral glucocorticoid taken, dose stable for <2 weeks or dose exceeding equivalent 
prednisone dose 0.5 mg/kg/day (or 30 mg/day) within 2 weeks prior to Baseline
E 07. Use of parenteral or intra-articular glucocorticoid injection within 4 weeks prior to 
Baseline
E 08. Prior treatment with anti-IL-6 or IL-6R antagonist therapies, including but not limited to 
tocilizumab or sarilumab
E 09. Treatment with any biologic treatment for pcJIA within 5 half-lives prior to the first dose 
of sarilumab as follows (the required off-treatment periods and procedures may vary 
according to local requirements):
-
Etanercept: within 4 weeks 
-
Infliximab: within 8 weeks 
-
Adalimumab: within 15 weeks 
-
Anakinra: within 2 days 
-
Canakinumab: within 19 weeks 
-
Abatacept: within 10 weeks 
-
Rituximab or other cell-depleting agent: within 16 weeks or until total lymphocyte 
count and CD 19+ lymphocyte count are normalized, whichever is longer
-
Intravenous Ig: within 15 weeks 
E 10. Treatment with a Janus kinase (JAK) inhibitor within 4 weeks prior to the first dose of 
sarilumab; and treatment with growth hormone within 4 weeks prior to the first dose of 
sarilumab (the required off-treatment periods and procedures may vary according to local 
requirements)
E 11. Treatment with any investigational biologic or non-biologic product (Appendix J) within 
8 weeks or 5 half-lives prior to Baseline, whichever is longer
E 12. Lipid lowering drug stable for less than 6 weeks prior to Screening
E 13. Exclusion related to tuberculosis:
x
Active TB or a history of incompletely treated TB
x
Purified Protein Derivative (PPD) or QuantiFERON-TB positive patients (no active 
disease) are excluded from the study unless the following conditions are met:
-
It is documented by a specialist that the patient has been adequately treated and can 
now start treatment with a biologic agent, in the medical judgment of the Investigator 
and / or infectious disease specialist
-
No evidence of active TB infection indicated by the chest radiograph performed 
according to local guidance for the screening of TB infection prior to the study
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-
Suspected extrapulmonary TB infection
-
Patients at high risk of contracting TB, such as close contact with individual with 
active or latent TB
E 14. Exclusion criteria related to past or current infection other than tuberculosis:
-
History of invasive opportunistic infections, including but not limited to 
histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis jirovecii, 
aspergillosis despite resolution, or John Cunningham virus (progressive multifocal 
leukoencephalopathy [PML]).
-
History of recurrent or active herpes zoster or reactivation or new onset of Epstein-
Barr virus (EBV) or positive test for EBV within 2 months of the screening (or at the 
Screening visit)
-
Diagnosed nontuberculous mycobacterial infection based on clinical, radiological and 
microbiological evidence within 2 months of the screening (or at the Screening visit)
-
History of prior articular or prosthetic joint infection
-
Fever (>38°C), or chronic, persistent, or recurring infection(s) requiring active 
treatment with antibiotics, antivirals, or antifungals within 4 weeks prior to the 
Screening visit or other frequent recurrent infections deemed unacceptable, as per the 
Investigator judgment
-
Previous or at the Screening: hepatitis B surface antigen (HBs-Ag) positive, or total 
hepatitis B core antibody (HBc-Ab) positive; previous or at the Screening: Hepatitis C 
antibody (HCV-Ab) positive
-
Patients who had a positive test previously or at the Screening for human 
immunodeficiency virus (HIV) test or who are suspected to be positive for HIV
E 15. Any live attenuated vaccine within 4 weeks prior to the Baseline visit, such as 
varicella-zoster, oral polio, rubella vaccines (Appendix J). Killed or inactive vaccine may 
be permitted based on the Investigator’s judgment
E 16. Prior or current history of malignancy, including lymphoproliferative diseases, other than 
adequately-treated carcinoma in-situ of the cervix, nonmetastatic squamous cell, or basal
cell carcinoma of the skin, within 5 years prior to the Baseline visit
E 17. Prior or current history of other significant concomitant illness(es) that, according to the 
Investigator’s judgment, would adversely affect the patient’s participation in the study. 
These include, but are not limited to, cardiovascular, renal, neurological disorders 
(including demyelinating disease), active infectious diseases, endocrinological, 
gastrointestinal, hepatobiliary, metabolic, pulmonary (eg, severe asthma, cystic fibrosis), 
nonmalignant lymphoproliferative diseases, other lymphatic disease(s), autoimmune 
disease, psychiatric disorders, etc. 
E 18. Patients with nonhealed/healing skin ulcers
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E 19. Surgery within 4 weeks prior to the Screening visit or with planned surgery during the 
course of the study
E 20. History of a systemic hypersensitivity reaction, other than localized injection site reaction, 
to any biologic drug and known hypersensitivity to any constituent of the product
E 21. History of inflammatory bowel disease, severe diverticulitis, or previous gastrointestinal 
perforation whatever the cause
E 22. Uncontrolled diabetes mellitus, defined as glycosylated hemoglobin (HbA1c) ≥9% at the 
Screening visit
E 23. Conditions/situations such as
-
Patients with short life expectancy
-
Conditions/concomitant diseases making patients non-evaluable for the efficacy 
endpoints, eg, patients with chronic pain caused by conditions other than JIA, 
eg, fibromyalgia
-
Patients whose immediate family members are dependent (employee) of 
site/Investigator, and individuals who are institutionalized due to regulatory or legal 
order.
7.2.2
Exclusion criteria related to the current knowledge of Sanofi compound
E 24. Any of the following laboratory abnormalities at the Screening visit (identified by the 
central laboratory):
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E 25. Female adolescent patients of childbearing potential, unwilling to use, if adequate for age,
an effective method of contraception (eg, birth control pills, double-barrier contraception, 
etc) during treatment and for up to at least 3 months following the last dose (as defined in 
the informed consent form (ICF) and/or in a local protocol addendum/amendment), and/or 
who are unwilling or unable to be tested for pregnancy;
Notes: Abstinence may be a possible option depending on local rules and/or regulations;
however, if a female patient is abstinent but becomes sexually active during the course of 
the study, she must be willing to use an effective method of contraception. Sexual 
counseling will be provided for adolescent patients.
E 26. Positive pregnancy test at Screening or Baseline
E 27. Breast-feeding female adolescent patients.
7.2.3
Additional exclusion criteria during or at the end of Screening
E 28. Patient/parent/legal guardians who has withdrawn consent before enrollment
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8
STUDY TREATMENTS
8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S)
Investigational Medicinal Product
Sarilumab, anti-IL-6R mAb (anti-interleukin 6 receptor alpha subunit monoclonal antibody).
Formulation
Sarilumab drug product will be provided at 175 mg/mL in an aqueous buffered vehicle, pH 6.0. It 
will be supplied in a 5 mL vial filled by 2.7 mL of sarilumab with an extractable volume of 
2.0 mL.
Route(s) of administration:
Sarilumab will be administered subcutaneously in the abdomen or thigh when self-injections or 
also in upper arm (lateral side) by a professional or a non-professional caregiver. It is preferred 
that SC injection sites be alternated between the 4 quadrants of the abdomen (except the navel or 
waist area) or the thigh (front and side). 
For patients receiving Dose Regimens 1 or 2 (q2w), injections will be performed by a professional 
caregiver at the site during the 12-week core treatment phase of the study. For patients receiving 
Dose Regimen 3 (weekly injections), arrangements must be made for qualified site personnel or 
home nurse to administer IMP for the doses that are not scheduled to be given at the study site. 
For the extension phase of the study, if the patients or the parent(s) or the legal guardian(s) or the 
caregiver(s) are willing and able to perform the injections, the home injection will be permitted. In 
those cases, the training will be required and provided to prepare and administer IMP starting at 
Visit 10 (Week 8) at the core treatment phase. This training must be documented in the patients’ 
study file. The patients or the parent(s) or the legal guardian(s) or the caregiver(s) are allowed to 
administer the injections under observation/supervision by the Investigator(s) or the delegate(s) 
at Visit 10 (Week 8), Visit 11 (Week 10), and Visit 12 (Week 12) before the allowance for home 
injection at the extension treatment phase. 
On days when the patient has a study visit, the IMP will be administered following clinical 
procedures and blood collection. Diaries will be provided to record information pertaining to these 
injections; these diaries will be kept as source data in the patients’ study file. If the caregiver is 
unable or unwilling to administer IMP, arrangements must be made for qualified site personnel to 
administer IMP for the doses that are not scheduled to be given at the study site.
Dose regimen
Sarilumab should be administered q2w or qw. However, the sarilumab administration window of 
±3 days for Dose Regimen 1 and 2 Cohorts, and ±1 day for Dose Regimen 3 Cohort is permitted 
per protocol to accommodate exceptional circumstances, eg, laboratory test result pending, 
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ongoing adverse event (AE), patient scheduling difficulty except the Visit 5 (Day 8). There is no 
administration window at Visit 5 (Day 8). There will be only ±1 day of administration window for 
patients enrolled in all dose cohorts at Visit 7 (Week 2) and ±1 day of administration window for 
Dose Regimen 3 Cohort or ±2 for Dose Regimen 1 and 2 Cohorts at Visit 8 (Week 4).
Note that an overdose (accidental or intentional) with the IMP is defined as at least twice the dose 
during an interval of less than 11 days for q2w administrations and less than 6 days for weekly 
administration (see Section 10.4.4.1).
The following sarilumab dose is to be administered q2w or qw:
Dose Regimen 1:
x
Group A (≥30 kg and ≤60 kg): 2 mg/kg q2w
x
Group B (<30 kg and ≥10 kg): 2.5 mg/kg q2w.
Dose Regimen 2:
x
Group A (≥30 kg and ≤60 kg): 3 mg/kg q2w
x
Group B (<30 kg and ≥10 kg): 4 mg/kg q2w.
Dose Regimen 3:
x
Group A (≥30 kg and ≤60 kg): 2 mg/kg qw
x
Group B (<30 kg and ≥10 kg): 2.5 mg/kg qw.
Dose modification
The dose (mg) to be administered to patients will be calculated at Baseline. The dose and 
corresponding volume of drug product will remain the same throughout the course of the 12-week 
core treatment phase of the trial regardless of change in patient's body weight. In the extension 
phase, the patient’s weight will be measured at each visit and the dose will be adapted to the 
increase of weight only if the calculation shows a need for dose increase. The dose will be capped 
at 150 mg and 200 mg for Dose Regimen 1 and 3 and Dose Regimen 2, respectively. Volumes to 
be injected depending on patient’s weight are further detailed in Appendix B.
8.2
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S)
Not applicable.
8.3
BLINDING PROCEDURES
Not applicable.
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8.4
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP
The list of randomized treatment kit numbers will be generated centrally by Sanofi. The IMPs are 
packaged in accordance with this list. Patients will be assigned a treatment kit by an interactive 
voice response system (IVRS) or an interactive web response system (IWRS).
Patients who meet the entry criteria will be included and will be dispensed the treatment kits 
within 2 weight groups (Group A: ≥30 kg and ≤60 kg for patients enrolled during the dose-finding
portion and ≥30 kg for patients enrolled during the second and the third portions; Group B: 
<30 kg and ≥10 kg for all 3 portions).
x
For the dose-finding and second portions, the planned ratio of enrollments for the 2 weight 
groups is 1:1.
x
For the third portion, there is no pre-specified enrollment ratio for the 2 weight groups, but
each weight group will be capped at 70% (ie, 20 patients). As a result, the most 
unbalanced enrollments by weight group possible would be 20 versus 8 patients in the
third portion.
Patients who meet exclusion criteria may be rescreened once during the open screening period of 
the study. A different patient identification will be issued. There is no requirement for a waiting 
period between the screen failure and the rescreening. The IVRS/IWRS report will flag rescreened 
patients. Patients that are rescreened will be required to sign a new consent form (if the patient has 
reached the legal age) or by parents or legal guardians. Visit 1 procedures must be repeated 
(except chest X-ray).
At the Screening Visit 1 (Day-28 to D-1, up to 31 days), the site staff will contact the IVRS/IWRS 
to obtain a patient number for each patient who gives informed consent. Each patient will be 
allocated a patient number associated with the center and allocated in chronological order in each 
site.
At the Baseline Visit 2 (Week 0, Day 1), after confirming the patient is eligible for entry into the 
treatment period, the site staff will contact the IVRS/IWRS in order to receive the first treatment 
allocation kit number. To minimize the amount of blood withdrawn and the number of visits while 
maintaining the evaluation of the primary endpoint, for Group B (<30 kg and ≥10 kg, lighter 
weight group), patients will be randomly assigned to sarilumab PK sampling schedule 1 or 2 (only 
applicable for patients in the the dose-finding and second portions) (see Section 9.1.1 for the 
detailed sarilumab PK sampling schedule). At subsequent visits during the treatment period, the 
site staff will call IVRS to obtain the next treatment kit number. A confirmation fax/e-mail will be 
sent to the site after each assignment. 
An included patient is defined as a patient who is registered and assigned a treatment kit number. 
The IMP will also be recorded and tracked on the center IMP inventory forms.
Details of the IVRS/IWRS procedures will be provided to sites in the IVRS/IWRS site manual.
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8.5
PACKAGING AND LABELING
The IMP will be provided in patient treatment kits containing labeled vials. The content of the 
labeling is in accordance with the local regulatory specifications and requirements. One kit 
contains one vial. The patients will be provided sufficient kits until the next site visit. Additional 
treatment kits, to provide medication to patients under circumstances, such as a damaged kit, will 
be allocated by IVRS when a “replacement treatment call” is made to IVRS.
8.6
STORAGE CONDITIONS AND SHELF LIFE
The study medication should be kept refrigerated between 2oC and 8oC at the site or at home. 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures and providing proper storage instructions to patients.
Control of IMP storage condition, especially control of temperature (eg, refrigerated storage) and 
the information on in-use stability and instruction for handling the compounds provided by Sanofi 
should be managed according to the rules provided by the Sponsor. 
The IMP may be supplied from the site to the patient via a sponsor-approved courier company 
where allowed by local regulations and approved by the patient.
8.7
RESPONSIBILITIES
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements.
The IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is
maintained.
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure.
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards.
Under no circumstances will the Investigator supply IMP to a third party allow the IMP to be used 
other than as directed by this clinical trial protocol, or dispose of IMP in any other manner.
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8.7.1
Treatment accountability and compliance
Measures taken to ensure and document treatment compliance and IMP accountability include:
x
Proper recording of treatment kit number or packaging number as required on appropriate 
electronic case report form (e-CRF) page for accounting purposes
x
All medication treatment kits (whether empty or unused) are returned by the patient at 
each visit when a treatment dispensing is planned
x
The completed home injection diary (returned to the site at each visit), returned treatment 
kit boxes and any unused and used vials will be used for drug accountability purposes 
x
The study coordinator tracks treatment accountability/compliance by diary and by 
counting the number of used treatment kits and fills in the appropriate page of the patient 
treatment log
x
The monitor in charge of the study then checks the data entered on the IMP administration 
page by comparing them with the IMP that has been retrieved and the patient treatment log 
form.
8.7.2
Return and/or destruction of treatments
All partially used or unused treatment kits will be retrieved by the Sponsor or destroyed at study 
site. A detailed treatment log of the returned IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy the unused IMP, used or partially used kits unless the Sponsor provides written 
authorization.
8.8
CONCOMITANT MEDICATION
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
All medication taken during the study should be recorded on the corresponding pages of the 
patient e-CRF.
8.8.1
Prohibited medications
The use of any biologic DMARDs, including but not limited to etanercept, adalimumab, 
infliximab, anakinra, canakinumab, rilonacept, abatacept, rituximab, tocilizumab, and any 
biologic DMARDs that may become approved during the study is not authorized throughout the 
study treatment and until 6 weeks following the EOT visit. If any of these treatments are used, the 
patient should be discontinued from the study treatment and will be asked to perform the 
scheduled visits and assessments up to EOS visit. (See exclusion criterion E 09 in Section 7.2 for 
biologic DMARDs off-treatment period).
Treatment with new non-biologic DMARDs should not be initiated during the study. Existing 
non-biologic DMARDs, such as MTX should be kept at a stable dose unless the patient develops 
an AE.
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Administration of any live (attenuated) vaccine (Appendix J) is contraindicated until 4 weeks 
following the last dose of IMP administration 
Treatment with anti-IL-6 or IL-6R antagonist therapies, including but not limited to tocilizumab 
or sarilumab (E 08).
Treatment with a JAK inhibitor (such as tofacitinib) (E 10).
8.8.2
Corticosteroids
8.8.2.1
Systemic parenteral and intra-articular corticosteroids
Patients should not receive systemic parenteral glucocorticoids and/or intra-articular 
glucocorticoid injections (within 4 weeks prior to Baseline), and should not be initiated on new 
corticosteroids (either systemic or intra-articular) for JIA-related complaints during the 12-week 
core treatment phase of the study. In the extension period, intra-articular glucocorticoid injections 
are permitted as clinically indicated for JIA disease flares, if Investigator considers potential 
benefit outweighs risk of such injection. 
8.8.2.2
Oral corticosteroids
Oral steroids may be increased at any time for flare. Oral corticosteroids are permitted if not 
exceeding 0.5 mg/kg/day (or 30 mg/day) oral prednisone or equivalent at stable dose for at least 
2 weeks prior to the Baseline visit.
No change is permitted during the 12-week core treatment phase unless the patient develops an 
AE (excluding worsening JIA). The dose may be tapered during the extension phase as per the 
Investigator’s recommendations. 
If the patient develops an AE for a condition not related to pcJIA that requires a corticosteroid 
dose modification (eg, increase, or decrease of current concomitant oral prednisone or equivalent), 
or the introduction of a new oral steroid medication, the dosage modification and AE must be 
recorded on the patient e-CRF. Furthermore, if this AE occurs during the 12-week core treatment 
phase, the Sponsor must be notified at the time of the steroid dose modification (eg, within one 
working day) to verify that the patient can continue to participate in the study.
Glucocorticoid tapering is allowed during the extension phase as per the Investigator’s judgment.
8.8.2.3
Intranasal - inhaled or topical corticosteroids
Intranasal, inhaled, or topical corticosteroids as per label are authorized, as needed throughout the 
course of the study.
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8.8.3
Nonsteroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAID) and COX-2 are permitted if taken at a stable 
dose for at least 2 weeks prior to Baseline. The dose used should be in accordance with the 
approved dose in the country in which the study is conducted. No change is permitted during the 
12-week core treatment phase, unless the patient develops an AE (generally requiring a lowering 
or discontinuation of NSAID/COX-2 treatment). Patients should not be initiated on new 
NSAIDs/COX-2 during their participation in the 12-week core treatment phase.
8.8.4
Acetaminophen (paracetamol) and other analgesics
Acetaminophen (paracetamol):
Normal release acetaminophen (not extended release) may be used for pain as required. 
Acetaminophen use should be limited to ≤80 mg/kg every 24 hours. Specific attention should be 
paid to co-administration of hepatotoxic drugs.
Other analgesics:
Narcotic or non-narcotic analgesics (with no anti-inflammatory properties) for JIA pain relief are 
permitted based on Investigator judgment that there is insufficient JIA pain relief with stable 
maintenance NSAIDs. As limited treatment for inter-current pain, all analgesics (with no 
anti-inflammatory properties) are allowed.
These analgesics, including acetaminophen, should be avoided within 6 hours of efficacy 
assessments, including physical function and quality of life assessments.
8.8.5
Lipid lowering drugs
Lipid lowering drugs are permitted. Dose should be stable for at least 6 weeks prior to Screening.
Anti-IL-6 drugs, including sarilumab are known to increase serum cholesterol levels and this 
effect will be closely monitored during the study. If, during the study, patients are found to have 
significant increase in cholesterol levels, then the dose of concomitant lipid lowering drug(s) 
should be adjusted as per local guidelines. A referral to a specialist should be considered when 
dyslipidemia is difficult to manage.
8.8.6
Cytochrome P450 enzyme substrates
In vitro studies demonstrate that IL-6 reduces cytochrome (CYP)1A2, CYP2C9, CYP2C19, and 
CYP3A4 enzyme expression; Sarilumab or tocilizumab, which antagonize IL-6, may normalize 
the formation of CYP450 enzymes. As a result, the therapeutic effect of drugs that are 
metabolized by these CYP450 isoforms may decrease when RA patients start receiving sarilumab. 
CYP450 substrates with a narrow therapeutic index should be monitored in patients that enter the 
open-label core treatment phase and the extension study. Some examples of CYP450 substrates 
with a narrow therapeutic index that require therapeutic monitoring (PD and/or drug 
concentration) include: warfarin, cyclosporine, theophylline, digoxin, antiepileptics like 
carbamazepine (Carbatrol®, Tegretol®), divalproex (Depakote®), phenytoin (Dilantin®), or 
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valproic acid (Depakene®); or antiarrhythmics, like disopyramide (Norpace®), procainamide 
(Procan®, Pronestyl®), or quinidine (Quinidex®, Quin-Release Quin-G®).
8.8.7
Other concomitant treatment
8.8.7.1
Topical anesthesia
Topically applied anesthetic creams or pad are permitted based on local guidelines for blood 
withdrawals and will be used for sarilumab injections only if necessary or based on local 
guideline.
For Germany only: pain prevention is permitted for all patients and is mandatory for patients aged 
6 to 11 years old. 
8.8.7.2
Folic/folinic acid
Patients receiving MTX during the study must receive at least the minimum recommended dose of 
folic acid or folinic acid weekly as per local standard of care.
8.8.7.3
Immunoglobulins
Administration of IV Ig is not permitted during the study or within 15 weeks prior to Baseline.
For active varicella infection (chickenpox) or significant exposure to varicella-zoster infection in a 
patient without history of chickenpox (varicella IgG titer available from Screening),
varicella-zoster Igs can be given at the discretion of the Investigator.
8.8.7.4
Growth hormone/androgens
Growth hormone/androgens are not permitted within 4 weeks prior to the Baseline visit, or during 
the entire study.
8.8.7.5
Iron
Iron may be administered to the patients determined to be anemic at Screening based on the 
opinion of the Investigator that the anemia is likely due to anemia of chronic inflammation or iron 
deficiency and iron is likely to be beneficial and there is no contraindication to its use.
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9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT
9.1
PHARMACOKINETICS PRIMARY ENDPOINT
The primary endpoint is: sarilumab PK exposure (maximum serum concentration observed [Cmax]
and area under the serum concentration versus time curve using the trapezoidal method during a 
dose interval [AUC0-W]), following the first dose, concentration observed before treatment 
administration during repeated dosing (Ctrough) from baseline to Week 12.
9.1.1
Sampling time
For Group A patients (≥30 kg), blood for sarilumab PK sampling will be collected at Visit 2* 
(Day 1, prior to IMP administration), Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8), Visit 6 
(Day 12), Visit 7 (Week 2)*, Visit 8 (Week 4)*, Visit 10 (Week 8)*, and Visit 12 (Week 12)*.
For Group B patients (<30 kg and ≥10 kg) enrolled in the dose-finding and second portions, in 
order to minimize the amount of blood withdrawn, patients will be randomly assigned to 
sarilumab PK sampling schedule 1 or 2 with the following time points:
x
Schedule 1: Visit 2* (Day 1), Visit 3 (Day 3), Visit 5 (Day 8)**, Visit 7 (Week 2)*, Visit 8
(Week 4)*, Visit 10 (Week 8)*, Visit 12 (Week 12)*
x
Schedule 2: Visit 2* (Day 1), Visit 4 (Day 5), Visit 6 (Day 12), Visit 7 (Week 2)*, Visit 8
(Week 4)*, Visit 10 (Week 8)*, Visit 12 (Week 12)*.
The sampling schedule for blood collection in 12-week core treatment phase and the extension 
phases can be found in the study flow charts (see Section 1.2.1 and Section 1.2.2, respectively). 
For patients for whom the dose will be adjusted to the selected dose regimen, additional PK 
sampling will be collected for 12 weeks. The sampling schedule for blood collection in these 
patients can be found in the study flow chart in Section 1.2.2.2.
For patients enrolled in the third portion, the PK sampling visits, ie, Visits 3, 4, 5, and 6 are not 
applicable during the core treatment phase. The sampling schedule for blood collection in these 
patients during the extension phase can be found in the study flow chart in Section 1.2.2.3.
If an SAE occurs in a patient, blood samples should be collected for determination of sarilumab 
concentration and ADA formation at or near the onset and completion of the occurrence of the 
event, if possible. For patients who discontinue the study treatment prematurely during the core 
treatment phase (at or before Visit 12) in the dose-finding and second portions, an additional 
sarilumab PK assessment will be received 2 weeks after the planned EOT assessment (3 weeks 
after the last IMP injection for Dose Regimen 3 Cohort patients or 4 weeks after the last IMP 
injection [for Dose Regimen 1 and 2 Cohort patients]). These patients will be asked to return for
the EOS assessment 6 weeks after the EOT assessment. The date of the sample collection should 
be recorded in the patient e-CRF. For early treatment discontinuation patients, blood samples 
should be collected at the EOS Visit if possible (see flow chart Section 1.2).
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Notes: 
The nominal sampling times for blood collection on Visit 3 (Day 3), Visit 4 (Day 5) and Visit 5
(Day 8) represent 48, 96, and 168 hours post-dose, respectively. 
* On dosing days, PK samples should be collected prior to IMP administration for all 
3 dose regimen cohorts
**On dosing days, PK samples should be collected prior to IMP administration for Dose 
Regimen 3 Cohort.
9.1.2
Pharmacokinetics handling procedure
It is extremely important to collect all blood samples as close to the protocol specified days as 
possible (see Section 9.1.1 and study flow chart Section 1.2 for sampling schedule). The reasons 
for any missed or lost blood samples should be documented. Special procedures for collection, 
storage and shipping of serum are described in separate operational manuals.
Table 3 - Sample handling procedure for sarilumab and anti-sarilumab antibody
Sample type
Functional Sarilumab
Anti-sarilumab antibody
Matrix 
Serum 
Serum 
Blood sample volume 
0.5 ml 
0.5 mLa 
Anticoagulant 
None 
None 
Blood handling 
procedures 
See operation manual 
See operation manual 
Storage conditions 
erum hipment 
Conditions 
9 months at -20ºC or below 
80ºC (preferred) 
In dry ice 
24 months at -20ºC or below 
80ºC (preferred) 
In dry ice 
 
a
For a study visit with blood collection for both pharmacokinetics and anti-sarilumab antibody samples (eg, Baseline Visit 2), it is 
recommended to draw 1 mL of blood. The serum will be split equally into 2 aliquots to obtain one PK serum aliquot and one anti-sarilumab 
antibody serum aliquot. 
9.1.3
Bioanalytical method
The serum levels of functional sarilumab and anti-sarilumab antibodies will be determined using 
validated bioanalytical methods. 
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Table 4 - Summary of bioanalytical method for sarilumab and anti-sarilumab antibody
Bioanalysis 
Functional sarilumab 
Anti-sarilumab antibody 
Matrix 
Serum 
Serum 
Analytical technique 
ELISA 
Electrochemiluminescence 
Assay volume 
Variable 
Variable 
Site of bioanalysis 
Regeneron 
Regeneron 
Abbreviation: ELISA = enzyme-linked immunosorbent assay 
9.1.4
Pharmacokinetics parameters
A population PK model will be developed using 
 to describe the 
PK profile of sarilumab. The following pharmacokinetic parameters will be calculated, using the 
PopPK model for functional Sarilumab in serum. The PK parameters will include, but may not be 
limited to the following listed in Table 5.
Table 5 - List of pharmacokinetic parameters and definitions
Cmax 
Maximum serum concentration observed 
Ctrough 
Concentration observed before treatment administration during repeated dosing 
tmax 
Time to reach Cmax 
AUC0-t 
Area under the serum concentration versus time curve calculated using the trapezoidal method during a dose 
interval (W) 
9.2
SECONDARY ENDPOINT(S)
9.2.1
12-week core treatment phase
The following parameters will be analyzed in 12-week open-label core treatment phase:
x
Safety
-
Adverse events (AEs), vital signs, physical examination, laboratory values
-
Acceptability assessments (local tolerability) (see Section 9.3.3)
x
Efficacy
-
Juvenile Idiopathic Arthritis ACR30/50/70/90/100 response rate at Week 12
-
Change from baseline in individual JIA ACR components at Week 12
-
Juvenile Arthritis Disease Activity Score (JADAS)-27 change from baseline at Week 
12 (see Section 9.4.2)
x
Pharmacodynamics
-
Changes in IL-6 associated biomarkers (eg, serum levels of high sensitivity C-reactive
protein [hs-CRP], IL-6, total sIL-6R).
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9.2.2
Extension part
x
Safety
-
Adverse events, vital signs, physical examination, laboratory values
-
Acceptability assessments (local tolerability) (see Section 9.3.3)
x
Efficacy
-
Juvenile Idiopathic Arthritis ACR 30/50/70/90/100 response rate at Weeks 24, 48, and 
every 24 weeks up to the EOS
-
Change from baseline in JIA ACR components at Weeks 24, 48, and every 24 weeks 
up to the EOS
-
Juvenile Arthritis Disease Activity Score-27 change from baseline at Weeks 24, 48, 
and every 24 weeks up to the EOS.
9.3
SAFETY ENDPOINTS
9.3.1
Adverse events
Adverse events (AEs), SAEs, adverse events of special interest (AESI), AE that lead to IMP 
discontinuation and death will be collected from the time of informed consent signature and then 
at each visit until the EOS. The study specific and general safety criteria are detailed in Section
10.4. To assure the continuing safety of patients in this study, an Independent Data Monitoring 
Committee will be responsible for reviewing the safety data on a periodic basis throughout the 
course of the study as outlined in Section 6.2.
Safety Observations
x
The Investigator should take all appropriate measures to ensure the safety of the patients. 
Notably, he/she should follow up the outcome of SAEs/AESI until clinical recovery is 
complete and laboratory results have returned to normal or until progression has been 
stabilized or death. In all cases, this may imply that observations will continue beyond the 
last planned visit per protocol, and that additional investigations may be requested by the 
Sponsor
x
For patients who discontinue the study treatment during the 12-week core treatment phase, 
these patients will be assessed using the procedure planned for the EOT visit for Visit 27 
(Week 156) followed by an additional sarilumab PK assessment 2 weeks after the EOT 
assessment (the additional PK assessment is only applicable for patients enrolled in the
dose-finding and second portions). These patients will be asked to return for the EOS 
assessment 6 weeks after the EOT assessment. These patients will be asked to perform the 
protocol scheduled visits and assessments except sarilumab administration until Visit 12.
x
For patients who discontinue the study treatment during the extension treatment phase, 
these patients will be assessed using the procedure planned for the EOT at Visit 27 (Week 
156 for dose-finding and second portions/Week 96 for third portion). These patients will 
be asked to return for the EOS assessment 6 weeks after the EOT assessment. 
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In case of any SAE/AESI brought to the attention of the Investigator at any time after the EOS for 
the patient, and considered by him/her to be caused by the investigational product with a 
reasonable possibility, this should be reported to the Sponsor (see Section 10.4.1.2 and 
Section 10.4.1.3 for details).
9.3.2
Vital signs
Vital signs include temperature, blood pressure (BP), and heart rate (HR). Please refer Section
1.2.1 and Section 1.2.2 for vital sign time points for patients in the 12-week core treatment phase
and extension phase, respectively.
Body temperature
Body temperature must be collected using the same method for a given patient. Any fever (body 
temperature ≥38°C) should be recorded as an AE and the Investigator should perform all 
investigations necessary to rule out infection.
Blood pressure
Blood pressure will be measured at each scheduled assessment visit using the same 
well-calibrated apparatus. Both systolic and diastolic BP should be recorded after the patient has 
been in a relaxed, semi-supine or supine position for at least 2 minutes. The same arm (the right 
arm is recommended) should be used to measure BP throughout the study. At each visit requiring 
BP measurement, two measurements should be taken at the same position at least 1 minute apart 
(17).
9.3.3
Acceptability assessments (local tolerability)
The patient acceptability (local tolerability) will be evaluated after each IMP injection either at the 
site or at home. The patients should be monitored at least 30 minutes. The following parameters 
will be evaluated: presence or absence of bruising, erythema swelling, warmth, burning, stinging, 
itching, hive formation, pain, induration, mass, discoloration, inflammation and other. In case of 
any local reaction, the event should be followed up until it resolved. Please refer Section 10.4.2
and Section 10.4.3 for AE or SAE (if applicable) reporting.
For Germany only: After the first IMP administration the patient has to be monitored for at least 
1 hour to assess local tolerability.
9.3.4
Laboratory safety variables
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry) 
and urinalysis. Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables.
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Blood will be taken at the study site or at home by qualified personnel. If the blood sample is 
taken on a day of IMP administration, then blood will be sampled before administration of the 
IMP. Both central and local laboratories will be used for sample assessments and analysis. 
Blood sampling limits, as determined by regulatory guidelines, should be followed with these and 
any other blood testing during the study. To avoid exceeding blood sample limits, a suggested 
prioritization of tests is provided to Investigators for reference in the laboratory manual.
The following laboratory tests will be performed at designated visits specified in the study flow 
charts (Section 1.2)
x
Hematology including hemoglobin, hematocrit, red blood cell count and morphology (if 
red blood cell count is abnormal), white blood cell count (WBC) differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) including absolute neutrophil count 
(ANC) and platelet count will be performed at Visit 1 (Day-28 to Day-1, up to 31 days), 
the Baseline Visit 2 (Week 0, Day 1), Visit 7 (Week 2), Visit 8 (Week 4), Visit 9 (Week 
6), Visit 10 (Week 8), Visit 11 (Week 10), and Visit 12 (Week 12) during the initial core 
treatment phase and at designated visits during the extension phase (see Section 1.2.2)
x
In order to check how the patient’s blood cells react on the first dose of study medication, 
for patients enrolled in the dose-finding and second portions, an additional hematology test 
must be performed at Visit 6 (Day 12±1 Day) for Dose Regimen 1 and 2 Cohort patients in 
order to get results before the second dose of sarilumab injection (Visit 7: Week 2, Day 
15). For Dose Regimen 3 Cohort patients, an additional hematology test should be 
performed prior to or at Visit 5 (Day 8) but no earlier than Visit 4 (Day 5) and the results 
need to be reviewed prior to the second sarilumab injection at Visit 5 (Day 8). The 
additional hematology test can be done at the central laboratory or at the local laboratory 
to confirm that the ANC and platelet count are not within the protocol-defined limits for 
temporary or permanent discontinuation of study drug. For patients enrolled in the third
portion without on-site Visit 6, the additional hematology test will be done at the local 
laboratory before the second dose of sarilumab administration, but no earlier than Day 12.
If local laboratory is used, a central laboratory sample for hematology should still be 
drawn pre-IMP administration at Visit 7 (Day 15, Week 2) as scheduled for Dose Regimen
1 and 2 Cohorts and Visit 5 (Day 8) for Dose Regimen 3 Cohort.
x
Complete chemistry profiles will be performed only at the Visit 1 (Day -28 to Day -1, up 
to 31 days), Baseline Visit 2 (Week 0, Day 1), and Visit 12 (Week 12) during the initial 
core treatment phase and at designated visits during the extension phase (see 
Section 1.2.2).
-
Complete chemistry includes: Sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen (BUN), creatinine and creatinine clearance, glomerular filtration rate (using 
the modified Schwartz formula), calcium, phosphate, total protein, albumin, ALT,
AST, alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, and 
unconjugated bilirubin
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-
At Visit 7 (Week 2), Visit 8 (Week 4), Visit 9 (Week 6), Visit 10 (Week 8), and 
Visit 11 (Week 10) during the initial core treatment phase and at designated visits 
during the extension phase (see Section 1.2.2) only an abbreviated chemistry profile 
(ALT, AST, ALP, total bilirubin, conjugated bilirubin, unconjugated bilirubin, and 
albumin) will be measured.
Fasting lipids including total cholesterol, high density lipoprotein cholesterol, low density 
lipoprotein cholesterol, and triglycerides will be tested at Visit 1 (Day-28 to Day -1, up to 
31 days), Visit 8 (Week 4), Visit 12 (Week 12) during the initial core treatment phase and at 
designated visits during the extension phase (Section 1.2.2). Patients are required to fast at least 8 
hours before the test.
The HbA1c evaluation will only be performed at the Screening based on the patient’s medical 
history and the Investigator’s judgment.
x
High sensitivity C-reactive protein (hs-CRP) will be evaluated at Visit 1 (Day -28 to 
Day -1, up to 31 days), the Baseline Visit 2 (Week 0, Day 1), Visit 7 (Week 2), Visit 8 
(Week 4), Visit 9 (Week 6), Visit 10 (Week 8), Visit 11 (Week 10), Visit 12 (Week 12)
during the initial core treatment phase and at designated visits during the extension phase 
(see Section 1.2.2).
Blood samples for ANA/anti double-stranded deoxyribonucleic acid (dsDNA) antibody 
will be collected at the Baseline Visit 2 (Week 0, Day 1), Visit 12 (Week 12) during the 
initial core treatment phase and at designated visits during the extension phase (see 
Section 1.2.2).
Erythrocyte sedimentation rate (ESR) will be measured at Visit 2 (Week 0, Day 1), and 
Visit 12 (Week 12) during the initial core treatment phase and at designated visits during 
the extension phase (see Section 1.2.2).
Pregnancy test: For females who have commenced menstruating, a serum pregnancy test 
should be performed at the Screening and the urine pregnancy test should be tested locally 
at Visit 2 (Week 0, Day 1), Visit 8 (Week 4), Visit 10 (Week 8), and every visit from 
Visit 12 (Week 12)  to Visit 27 EOT (Week 156 for dose-finding and second
portions/Week 96 for third portion).
x
Optional: Based on patient’s family and medical history, the Investigator’s judgment, EBV 
IgG and IgM, hepatitis B and C screening: HBs-Ag, hepatitis B surface antibody (HBs-
Ab), total hepatitis B core antibody (HBc-Ab), and hepatitis C antibody (HCV-Ab) may be 
performed at the Screening Visit 1 (Day -28 to Day -1, up to 31 days). The HIV serology 
may be performed only based on the Investigator’s assessment for those HIV suspected 
patients. Some tests defined as optional may be required according to local regulations. 
For Argentina and Germany only: Serology testing for hepatitis B and C and HIV have to 
be performed at Screening visit for all patients in order to screen corresponding exclusion 
criterion E 14.
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x
Purified Protein Derivative (PPD) test for patient ≤5 years old or QuantiFERON-TB test 
for patient >5 years is required to be completed prior to the Baseline Visit 2 (Day 1,
Week 0). QuantiFERON-TB test will be considered in the younger group of patients 
(≤5 years old) based on the local PPD availability, local regulation for PPD screening and 
the Investigator’s judgments. 
Patients with PPD tests should be evaluated within 48 to 72 hours after placement of the 
PPD skin test (for patients who fail to be evaluated within 72 hours, the skin test should be 
repeated). An assessment of the level of risk (TB contact and/or recent immigration from a 
country with a high prevalence of TB) should be taken into consideration when defining 
the result of the skin tests. Refer to exclusion criteria E 13. The TB test should be 
performed at Visit 18 (Week 48), Visit 22 (Week 96), and Visit 26 (Week 144, not 
applicable for the third portion), approximately 1, 2, and 3 years, respectively after the 
patient is enrolled in the study. Tuberculosis risk assessment will be done at every visit 
throughout the study. 
x
Urine analysis including specific gravity, pH, glucose, blood, protein, nitrites, leukocyte 
esterase and bilirubin, will be performed at the Screening Visit 1 (Day-28 to Day-1, up to 
31 days) using a dipstick. If any parameter on the dipstick is abnormal, a urine sample
should be sent to the central laboratory for testing. For any abnormal dipstick result, 
microscopic analysis will be performed by central laboratory.
9.4
EFFICACY ENDPOINTS
9.4.1
Juvenile idiopathic arthritis American college of rheumatology response
The JIA ACR rating scale to assess signs and symptoms will be used in this study (refer to 
Section 1.2).
The JIA ACR 30/50/70/90/100 response is defined as a patient with 3 of 6 core set variables 
improved by at least 30%/50%/70%/90%/100% from baseline with no more than 1 of the 
remaining variables worsened by more than 30% Appendix C. The JIA ACR core set includes 
6 variables:
x
Physician global assessment of disease activity 
x
Patient/parent assessment of overall well-being 
x
Functional ability determined by Childhood Health Assessment Questionnaire (CHAQ)
x
Number of joints with active arthritis (0-71 joints)
x
Number of joints with limitation of motion (0-67 joints)
x
High sensitivity C-reactive protein.
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During the 12-week core treatment phase, JIA ACR disease core set will be evaluated at every site 
visit except Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8), and Visit 6 (Day 12). During the 
extension phase (for patients who remain on the current dose (selected dose regimen), the JIA 
ACR core set will be assessed periodically at Weeks 24, 48, 72, 96 (EOT for third portion), 120
(not applicable for third portion), 144 (not applicable for third portion), and EOT (Week 156 for 
dose-finding and second portions/Week 96 for third portion). For patients who change to the 
selected dose regimen during the extension phase, please refer to Section 1.2.2.2.
9.4.1.1
Physician global assessment of disease activity
Physician’s global assessment of disease activity will be performed at Screening, at Baseline prior 
to IMP administration and at each designated site visit until the EOT visit. The Investigator will 
be requested to rate the patient’s disease activity on an anchored 100 mm horizontal visual 
analogue scale (VAS) where 0 is considered the best disease activity and 100 the worst 
(see Appendix D).
9.4.1.2
Patient/parent assessment of overall well-being
Patient/parent assessment of overall well-being will be measured on a 100 mm horizontal VAS at 
Screening, at Baseline prior to dosing and at each designated site visit until the EOT visit. The 
patient or the same parent or the same guardian should be requested to complete the form to 
ensure the consistency (see Appendix D)
9.4.1.3
Childhood health assessment questionnaire
The CHAQ is an interview or self-administered instrument for children ≥8 and 
parent/proxy-administered for children younger than 8 years of age. The CHAQ is a generic 
measure of health status in children ages 1 to 19 years of age. The Spearman’s correlation 
coefficient between Disability Index scores from questionnaires administered to parents and those 
administered to other children (>8 years) was 0.84 (n = 29; p<0.001), demonstrating that parents 
can accurately report for their children. The face validity of the instrument was evaluated by a 
group of 20 health professionals and parents of 22 healthy children. The assessment consists of 43 
items in total and takes approximately 10 minutes to complete. The CHAQ questionnaire will be 
completed before IMP dosing and at subsequent time points (as per guidance provided by the 
health economics and outcomes research department). The recall period is 1 week (18). In this 
case, the actual date of the CHAQ questionnaire will be recorded in the e-CRF.
The median CHAQ scores corresponding to mild, mild-to-moderate and moderate disability 
reported in the development of the CHAQ were 0.13, 0.63, and 1.75 respectively (19).
In order to eliminate discrepancies which could be introduced by growth and development, 
parents are asked to note only those difficulties due to illness (eg, if child unable to do an activity 
because too young, mark response as “not applicable”). Response options assessing difficulty are 
based on a 5 point Likert scale (0 = Without Any Difficulty, 1 = with some Difficulty, 2 = With 
MUCH difficulty, 3 = Unable to do and 4 = Not Applicable). 
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Part 1 of the CHAQ is the Disability Index which contains 41 items assessing ability to function 
in daily life. The following 8 subscales/domains: 1. Dressing and Grooming, 2. Arising, 3. Eating, 
4. Walking, 5. Hygiene, 6. Reach, 7. Grip, and 8. Activities. For each domain: (a) ratings of the 
degree to which daily functions are difficult to perform (items 6-9, 12-13, 16-18, 21-22, 34-38,
41-44, 47-51, and 54-58); (b) require use of special aides or devices (item 24-27, 60-62) and (c) 
require assistance from another person (items 29-30, 64-65) are assessed. 
x
To calculate the CHAQ-DI each domain score is first calculated:
-
The question with the highest response determines the score for that functional area
-
If aids or devices are used or help is needed to complete tasks in a certain area, a 
minimum score of 2 is recorded for the corresponding functional area
-
The 8 subscales/domains are averaged to calculate a mean score which is the Disability 
Index (with range of 0-3).
Lower disability index scores indicate better than health status/better healthier related quality of 
life/less signs and symptoms while higher disability index scores indicate worse health 
status/worse HRQL/more signs and symptoms (18, 20).
The minimal clinical important improvement in CHAQ-disability index is a reduction in score of 
0.13. The minimal clinical important deterioration in the CHAQ-disability index is a median 
change score of 0.75 (19).
Part 2 of the CHAQ is the Discomfort Index while Part 3 of the CHAQ is the Health Status 
measure; both are measured on separate 15-cm scales. 
The CHAQ-Discomfort Index is determined by the severity of pain in the past week, rated on a 
VAS (with anchors of “0 no pain” and “100 very severe pain”). 
x
To calculate the CHAQ-discomfort index (item 67)
-
Measure the distance from the left end of the VAS in item 67 to the respondent’s mark 
and multiply by 0.2 Range is 0.3. The Discomfort Index score can be rescaled to a 
0-100 scale. 
The Part 3 of the CHAQ Health Status score measure the patient’s or parent’s global assessment 
of illness. 
x
To calculate the CHAQ Health Status score (item 69)
-
Measure the distance from the left end of the VAS in item 69 to the respondent’s mark 
and multiply by 0.2 Range is 0-3. The Health Status score can be rescaled to a 
0-100 scale, see Appendix E.
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9.4.1.4
Number of Joints with active arthritis and number of joints with limited motion
An active joint is defined as joint with
x
Swelling within join not due to deformity, OR
x
Limitation of motion with either pain or tenderness
Seventy-one joints will be assessed for active disease by counting the number of the joints with 
swelling not due to deformity OR limitation of motion with either pain or tenderness or both (21,
22).
Cervical spine (counts as 1 joint), Temporomandibular (2 joints, R and L side), Sternoclavicular 
(2 joints), Acromioclavicular (2 joints), Shoulder (2 joints), Elbow (2 joints), Wrist (2 joints), 
Metacarpophalangeal (10 joints total, 5 on each side), Proximal interphalangeal (10 joints total, 
5 on each side), Distal interphalangeal (8 joints total, 4 on each side), Hip (2 joints), Knee 
(2 joints), Ankle (2 joints), Subtalar (2 joints), Tarsometatarsal (2 joints), Metatarsophalangeal 
(10 joints, 5 on each side), and Foot interphalangeal (10 joints, 5 on each side) total 71 joints. 
Sixty-seven joints will be examined for limitation of motion are the same as those examined for 
active disease except the sternoclavicular (n = 2) and acromioclavicular (n = 2). A formal count of 
the joints will be performed by a trained assessor. Joint tenderness is defined as pain induced by 
the pressure of the joints, exerted by the assessor’s thumb and index finger.
9.4.1.5
High sensitivity C-reactive protein
High sensitivity C-reactive protein (hs-CRP) will be evaluated at Visit 1 (Day-28 to Day -1, up to 
31 days), the Baseline Visit 2 (Week 0, Day 1), Visit 7 (Week 2), Visit 8 (Week 4), Visit 9 
(Week 6), Visit 10 (Week 8), Visit 11 (Week 10), Visit 12 (Week 12) during the initial core 
treatment phase and at designated visits during the extension phase (see Section 1.2.2). High 
sensitivity C-reactive protein levels are directly correlated with IL-6R activity. It is expected that 
active dose regimens will have a dramatic lowering effect on CRP levels.
9.4.2
Juvenile arthritis disease activity Score
The JADAS includes 4 measures: 
x
Physician global assessment of disease activity measured on a 10-cm VAS where 0 = no
activity and 10 = maximum activity
x
Parent/patient global assessment of well-being, measured on a 10-cm VAS where 0 = very 
well and 10 = very poor
x
Count of joints with active disease 
x
Erythrocyte sedimentation rate (ESR) normalized to a 0-10 scale according to the 
following formula: 
-
[ESR (mm/hour)-20]/10
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-
Before making the calculation, ESR value <20 mm/hour converted to 0 and ESR 
values >120 mm/hour were converted to 120. 
The JADAS will be calculated as the simple linear sum of the scores of its 4 components. (23).
The JADAS-27 includes the following joints: cervical spine, elbows, wrists, metacarpophalangeal 
joints (from first to third), proximal interphalangeal joints, hips, knees, and ankles. The JADAS 
was found to be a valid instrument for assessment of disease activity in JIA and is potentially 
applicable in standard clinical care, observational studies and clinical trials (23). JADAS-27 will 
be calculated at Visit 12 (Week 12) during the initial core treatment phase and at designated visits 
during the extension phase (see Section 1.2.2).
9.5
PHYSICAL EXAMINATION
A complete physical examination will be performed at the Screening Visit 1 (Day -28 to Day -1,
up to 31 days), Visit 2 (Day 1, Week 0), Visit 8 (Week 4), Visit 9 (Week 6), and Visit 12 
(Week 12) during the initial core treatment phase and at designated visits during the extension 
phase (see Section 1.2.2). Any clinically significant abnormalities should be reported in the 
patient e-CRF as medical history if observed at Visit 1 (Day -28 to Day -1, up to 31 days) and 
reported as an AE if observed at Visit 2 (Day 1, Week 0) and during subsequent visits. Any 
clinically significant physical examination abnormality known at the Screening visit should be 
reported as medical history and not an AE. Clinically significant abnormalities or worsening from 
Baseline reported after the Screening visit should be reported as AEs.
9.6
WEIGHT
Weight should be taken with the patient wearing undergarments or very light clothing (without 
outerwear or accessories) and no shoes and with an empty bladder. Weight is to be determined to 
nearest 0.1 kg.
The same scale is recommended to be used throughout the study. Weight will be collected at the 
Screening Visit 1 (Day -28 to Day -1, up to 31 days), Baseline Visit 2 (Day 1, Week 0), Visit 12
(Week 12), and every visit during the extension phase except for some visits for patients who 
change to the selected dose regimen (no assessment done at Visit 102 (Week 2) and Visit 104 
(Week 6) for patients who changed to selected dose regimen).
9.7
PHARMACODYNAMICS
9.7.1
Pharmacodynamics parameters
Pharmacodynamic effects of sarilumab will be assessed through measurement of the following 
biomarkers: hs-CRP, IL-6, total sIL-6R.
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9.7.1.1
Assessment methods
The sample handling procedure for total sIL-6R and IL-6 is summarized in Table 6. Special 
procedures for collection, storage and shipping of serum are described in separate operational 
manuals. The sample procedure for hs-CRP is described in Section 9.4.1.5 and Section 9.3.4.
Table 6 - Summary of handling procedures for total sIL-6R and IL-6
Sample type
sIL-6R
IL-6
Blood sample volume 
0.5 ml 
0.5 mL 
Anticoagulant 
NONE 
None 
handling procedures 
Aliquot split 
Refer to Lab Manual 
One aliquot 
Refer to Lab Manual 
One aliquot 
Storage conditions 
Shipment Conditions 
 -70oC (if not available, -20oC) 
In dry ice 
-70oC (if not available, -20oC) 
In dry ice 
Abbreviations: IL = interleukin, sIL-6R = soluble interleukin-6 receptor. 
9.7.1.2
Assessment schedule
The sampling schedule for blood collection can be found in the study flow chart (see Section 1.2).
IL-6 and total sIL-6R will be measured at the Baseline Visit 2 (Week 0) and Visit 12 (Week 12). 
For patients who discontinue the study treatment prematurely during the core treatment phase, the
IL-6 and total sIL-6R will be measured at the EOT assessment.
9.8
IMMUNOGENICITY
Immunogenicity of sarilumab will be assessed through measurement of anti-sarilumab antibodies
(ADA). Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. The sampling schedule for blood collection can be found in the study flow 
charts (see Section 1.2).
9.9
PHARMACOGENOMICS
Parent(s) or legal guardian(s) will be required to sign a separate ICF for (optional) saliva sample 
collection. The DNA samples for the genomic research will be double-coded as defined by the 
International Council for Harmonisation (ICH) guideline E15. DNA samples may be stored for up 
to 15 years after the final date of the clinical study report (CSR) and may be used for research 
purposes. For saliva sampling collection, please refer to the Laboratory Manual.
The purpose of the genomic analyses is to identify genomic associations with clinical or 
biomarker response to target modulation, disease prognosis and progression, or other clinical 
outcome measures. These data may be used or combined with data collected from other studies to 
identify genomic markers that may predict response and elucidate mechanisms of disease. 
Analyses may include sequence determination or single nucleotide polymorphism studies of 
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candidate genes and surrounding genomic regions. Genome-wide studies, including (but not 
limited to) single nucleotide polymorphism analyses, genomic sequencing, and transcriptome 
sequencing may also be performed. If indicated, genomic analyses may also be performed to 
identify markers associated with toxicity.
Patients are still eligible to enroll in the study if they and their parents or legal guardians do not 
wish to participate in the pharmacogenomic sample collection.
9.10
APPROPRIATENESS OF MEASUREMENTS
The pharmacokinetic and pharmacodynamics assessments used in this study are standard for the 
evaluation of the anti-IL-6. The efficacy and safety assessments used in this study are appropriate
for the evaluation of DMARD in patients with pcJIA.
9.11
FUTURE USE OF SAMPLES
Any unused or left-over serum samples collected for drug concentration or ADA measurements 
may be stored and used for exploratory biomarker research related to pcJIA, inhibition of the 
IL-6Rα pathway with an antibody, treatment response (PD and or predictive), to investigate 
unexpected AEs, or to identify markers associated with toxicity. Samples may be stored up to 
15 years after the date of the CSR or based on local regulation. 
The decision for unused or left-over serum samples retention is entirely voluntary. The patient/the 
parent(s)/guardian(s) will be required to sign a separate consent form for the future use of 
samples. If the patients or the parent(s) or the guardian(s) do not wish to keep the unused or 
left-over serum samples, this will not have an effect on the patient’s participation in the main 
study and will not affect the quality of his/her care.
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10
STUDY PROCEDURES
10.1
VISIT SCHEDULE
It is preferred that all study visits take place in the morning when fasting blood samples are 
required. A non fasting condition could overestimate LDL/triglycerides value which will affect 
notification of related AEs/AESIs. To permit reliable results, fasting status for at least 8 hours is 
required for each visit at which fasting lipids laboratory tests will be performed. If the test is
performed centrally, both the duration of fasting and the reason of no fasting will be reported in 
central laboratory data base.
For all visits, a time frame of ±1 day for Dose Regimen 3 Cohort and ±3 days for Dose Regimen 1
and 2 Cohorts is acceptable using Day 1 as reference except for: 
x
Visit 3 (Day 3), Visit 4 (Day 5), and Visit 5 (Day 8), no visit window is allowed where PK 
sampling occurs
x
Visit 6 (Day 12) ±1 day for all applicable dose regimen cohorts
x
Visit 7 (Week 2) ±1 day for all dose regimen cohorts
x
Visit 8 (Week 4) ±2 days for Dose Regimen1 and 2 Cohorts; and ±1 day for Dose 
Regimen 3 Cohort.
The previous laboratory testing needs to be reviewed by the Investigator or Investigator’s 
designee based on local guidelines before IMP administration and dispense. The results of the 
evaluation will be recorded on the appropriate e-CRF pages. 
Patients who discontinue the study treatment prematurely will be assessed using the procedure 
planned for the EOT (Visit 27) These patients will be asked to return for the EOS assessment 6 
weeks after the EOT visit (Visit 28/EOT+ 6 weeks). For patients who discontinue the study 
treatment during the 12-week core treatment phase (at or before Week 12), there will be an 
additional PK assessment 2 weeks after the EOT visit (Visit 88/EOT + 2 weeks) (the additional
PK assessment is only applicable for patients in the dose-finding and second portions). For 
patients who discontinue the study treatment permanently during the 12-week core treatment 
phase, these patients should return for the protocol scheduled visits for the planned assessments 
without study medication administration until Visit 12. 
Screening Period (Day -28 to Day -1 + 3 days, maximum up to 31 days)
10.1.1 Visit 1: Screening (Day -28 to Day -1, up to 31 days) for all patients
Prior to all screening assessments, the patient (if he/she has reached the legal age of consent based 
on local guidelines), the parent(s) or the legal guardian(s) must sign and date the Ethics 
Committee approved ICF. The patient assent should be obtained depending on his/her maturity of 
understanding study associated information. All patients, parent(s), and the legal guardian(s) will 
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receive information on the study objective(s) and procedures from the Investigator. Separated 
ICFs should be obtained for patients who are going to participate in the optional saliva sample 
collection for genomic analysis and agree to keep left-over blood samples for future research. A 
separate (locally approved) ICF will be completed by any patients requiring genetic Gilbert 
disease testing as per local regulations.
Although the screening assessments for this study are grouped under the heading of a single visit 
in this protocol, it is possible for them to be performed over more than 1 site visit if necessary, as 
long as the Screening visit window prior to the Baseline Visit 2 (Day 1) is respected. 
Patients who fail screening for exclusion criteria such as concomitant medications, required 
drug-specific discontinuation periods or laboratory abnormalities, may be rescreened for study 
eligibility 1 additional time. The site has first to contact IVRS to declare the patient as screen 
failure and then contact IVRS again to re screen the patient (see Section 8.4).
Laboratory retesting is allowed during the Screening visit without sending a screen failure notice 
to IVRS for rescreening if the result of the corresponding retest is expected during the screening
period in the following conditions:
x
Blood sample issues, (eg, sample clot, hemolysis, indeterminate results received from 
central laboratory)
x
Laboratory result does not reflect the patient’s condition, or if this retest is medically 
justified as per Investigator judgment
x
At the Investigator’s discretion laboratory tests mentioned in exclusion criterion E 24 may 
be repeated by central laboratory retesting between the Screening visit and the first IMP 
administration to ensure the patient meet eligibility with respect to exclusion criterion 
E 24. A locally approved specific consent form will be signed by patients who require 
Gilbert syndrome genetic testing (consent/assent must be obtained prior to performing this 
assessment and local regulations should be respected).
The Screening visit will include the following procedures and assessments (see Section 1.2) in the 
study flow chart. The following items will then be checked and recorded:
x
Call IVRS for notification of Screening and assign a patient number
x
Interview to collect patient demographic information (including race and ethnicity), 
previous medical and surgical history. Medical history should include in particular JIA 
history, in order to confirm (a) the diagnosis; (b) the patient’s intolerance or inadequate 
response to the current treatment and/or non-biologic DMARD
x
Assess eligibility by review of inclusion/exclusion criteria. Patients who do not meet these 
inclusion/exclusion criteria should not continue the Screening process
x
Review prior and concomitant medications including biologic and non-biologic DMARDs 
such as MTX (see Section 8.8.1). Record duration of treatment, dosage, date and reason 
for discontinuation, the period between the last treatment date with a biologic DMARD 
and JAK kinase inhibitor treatment (see E 10 and Section 8.8.1)
x
Collect the vaccination history
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x
Record vital signs including body temperature, BP, and HR
x
Record weight (kg) and height (cm)
x
Check Tanner stage (see Appendix F) and menstruation status for female patients
x
Inquire regarding AEs/SAEs 
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up.
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, gastrointestinal, lymphatic examinations, complete 
neurological examinations, and musculoskeletal systems. 
-
If abnormal clinically significant already known report medical history
-
If new abnormal clinically significant (discover at Visit 1) report AE
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity. Any abnormalities should be recorded and 
documented in prior medical/surgical history
x
Collect fasting blood for hematology (see Section 9.3.4), chemistry (including sodium, 
potassium, chloride, bicarbonate, BUN, creatinine, creatinine clearance, glomerular 
filtration rate, calcium, phosphate, total protein, albumin, ALT, AST, ALP, total bilirubin, 
conjugated bilirubin, unconjugated, and bilirubin), fasting lipids, HbA1c (based on the 
Investigator’s judgment), hepatitis B and C, EBV and HIV serology (based on medical 
history and the Investigator’s judgment), hs-CRP, and serum pregnancy test for female 
patients who have commenced menstruating (see Section 9.3.4 and the study flow chart 
Section 1.2)
For Argentina and Germany only: Serology testing for hepatitis B and C and HIV have to 
be performed at Screening visit for all patients in order to screen corresponding exclusion 
criteria E 14
x
Perform PPD tuberculin skin test for patients ≤5 years or QuantiFERON-TB Gold for 
patients >5 years. PPD or QuantiFERON-TB is required to be completed prior to the 
Baseline Visit 2 (Day 1, Week 0). Purified Protein Derivative (PPD) results must be 
evaluated within 48 to 72 hours after placement of the PPD skin test (for patients who fail 
to be evaluated within 72 hours, the skin test should be repeated). An assessment of the 
level of risk (TB contact and/or recent immigration from a country with a high prevalence 
of TB) should be taken into consideration when defining the result of the skin tests. Refer 
to exclusion criteria E 13 for the details
x
Chest X-ray: may be performed for the patients only when deemed necessary based on the 
Investigator’s judgment or in line with local guideline for TB screening prior to initiating a 
biologic therapy for JIA patients who haven’t had chest X-ray performed within 3 months 
prior to the Baseline Visit 2 (Day 1, Week 0)
x
Obtain urine for urinalysis (dipstick). If any parameter on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for testing. If positive for proteins, 
microscopic analysis is performed by central laboratory
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x
Schedule the appointment for Visit 2 Baseline (Day1, Week 0) for patients who meet all 
the inclusion criteria and none of the exclusion criteria.
Core Treatment Period (Visit 2 [Day 1, Week 0] ~ Visit 12 [Week 12]; up to 12 Weeks)
10.1.2 Visit 2 Baseline (Day 1, Week 0)
x
Reconfirm eligibility by reviewing of inclusion/exclusion criteria with particular attention 
to exclusion criteria (see Section 7.2) and concomitant medication use (see Section 8.8)
x
Call IVRS to inform the Baseline Visit 2 (Day 1, Week 0) and get the treatment kit 
number(s) assigned to each patient along with the dose volume to be administered. For 
Group B patients in the dose-finding and second portions, in order to minimize the amount 
of blood withdrawn, patients will be randomly assigned to sarilumab PK sampling 
schedule 1 or 2 (see Section 9.1.1)
x
Remind parent(s) and legal guardian(s) to sign a separate ICF for optional saliva sample 
collection for genomic studies and left-over blood samples for future research (see 
Section 9.9 and Section 9.11)
x
Inquire regarding AEs/SAE
x
Record concomitant medications use with start date and dose in the patient’s e-CRF 
x
Record vital signs including body temperature, BP, and HR
x
Record weight (kg) and height (cm) 
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears 
respiratory, cardiovascular, gastrointestinal, lymphatic, neurological systems, and 
musculoskeletal systems.
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity. Any abnormalities should be recorded and 
documented in prior medical/surgical history (ensure JADAS-27 joints are included)
x
Complete the physician global assessment of disease activity
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and (parent or guardian)/patient assessment of overall well-
being. All questionnaires should be documented in the subject’s study file. Each VAS 
score should be copied on the patient’s e-CRF
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up.
x
Collect blood for hematology (see Section 9.3.4), complete chemistry (including sodium, 
potassium, chloride, bicarbonate, BUN, creatinine, creatinine clearance, calcium, 
phosphate, total protein, albumin, ALT, AST, ALP, total bilirubin, conjugated bilirubin, 
and unconjugated bilirubin; see Section 9.3.4), hs-CRP, ESR, RF, ANA, anti-double
stranded DNA (anti-dsDNA)
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x
Collect blood samples for serum sarilumab and antibodies to sarilumab, IL-6, and 
total sIL-6R (see Section 9.1 and the study flow chart Section 1.2)
x
Collect optional saliva sample (as appropriate). This is optional. The samples are 
preferably collected at the Baseline Visit 2 (Day 1), however it may be collected at any 
time during the study
x
Perform urine pregnancy test locally for the female patients who have commenced 
menstruation
x
Dispense the IMP to those patients who are at the Dose Regimen 3 Cohort for home 
injection
x
Provide home diary to Dose Regimen3 Cohort patients to record information pertaining to 
injections performed at home (date, time, injection location, and any problems) at each 
intermediate on-site visit. The completed diary will be reviewed at the next scheduled 
visit. In case sarilumab PK sampling is performed at home during the core treatment phase
(Visit 3, Visit 4, Visit 5 and Visit 6) a PK diary will be provided to collect real date and 
time of the samples. This PK diary should be delivered by the site to the nurse/qualified 
personnel, completed by the nurse/qualified personnel then returned to the site. This PK 
diary will be reviewed at each visit when applicable
x
Administer the IMP
-
Patients should be monitored for at least 30 minutes after IMP administration for any 
signs or symptoms of a hypersensitivity reaction
-
For Germany only: After the first IMP administration the patient has to be monitored 
for at least 1 hour to assess local tolerability
x
Check local tolerability (see Section 9.3.3)
x
Schedule the appointment for Visit 3 (Day 3) for blood sample collection or Visit 4 
(Day 5) depending the PK schedule (only applicable for dose-finding and second portions)
x
Schedule the appointment for Visit 7 (Week 2), and ask the patient to come in fasting 
condition and instruct for performing an additional hematology test locally before Visit 7,
but no earlier than Day 12 in order to get results prior to the second dose of sarilumab 
administration to confirm that the ANC and platelet counts are not within the 
protocol-defined limits for temporary or permanent discontinuation of study drug (only 
applicable for third portion)
10.1.3 Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8), and Visit 6 (Day 12)
For patients enrolled in the third portion, Visits 3, 4, 5, and 6 are not applicable.
Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8), and Visit 6 (Day 12) are serum PK sample 
collection visits (see flow chart Section 1.2) with no visit window permitted for Visit 3 (Day 3), 
Visit 4 (Day 5), and Visit 5 (Day 8). There is ±1 day window allowed for Visit 6 (Day 12). In case 
the patient is unable to have the blood collection at the site, a home nurse should be arranged to 
collect the blood at home and the IMP should be brought for patients who are at Dose Regimen 3 
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Cohort for injection at Visit 5 (Day 8). All the blood collection, storage, and shipment conditions 
should be strictly followed. Concomitant medications and AEs/SAEs will be inquired at these 
visits. 
x
For Group A, sample collection at Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8), and 
Visit 6 (Day 12) for patients in Dose Regimen 1, 2, and 3 Cohorts
x
For Group B, in order to minimize the amount of blood withdrawn, patients will be 
randomly assigned to sarilumab PK sampling schedule 1 or 2 with the following time 
points (see Section 9.1.1):
-
Schedule 1: Visit 3 (Day 3), Visit 5 (Day 8)
-
Schedule 2: Visit 4 (Day 5), Visit 6 (Day 12).
Visit 3 (Day 3)
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF
x
Sarilumab PK sampling will be performed for Group A patients and for Group B patients 
who are in Schedule 1.
Visit 4 (Day 5):
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF
x
Sarilumab PK sampling will be performed for Group A patients and for Group B patients 
who are in Scheduled 2
x
An additional hematology test will be performed for Dose Regimen 3 Cohort patients prior 
to or at Visit 5 (Day 8) but no earlier than Visit 4 (Day 5) and the results need to be 
reviewed prior to the second sarilumab injection at Visit 5 (Day 8) to confirm that the 
ANC and platelet count are not within the protocol-defined limits for temporary or 
permanent discontinuation of study drug. 
Visit 5 (Day 8): 
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF
x
The Visit 2 (Day 1) hematology laboratory assessment and the additional hematology test 
results must be reviewed before the administration of the second dose of sarilumab 
injection at Visit 5 (Day 8) for Dose Regimen 3 Cohort patients 
x
Sarilumab PK sampling will be performed for Group A patients and for Group B patients 
who are in Schedule 1
x
For the Dose Regimen 3 Cohort patient who used local laboratory for the additional 
hematology test, a central laboratory sample for hematology should still be drawn pre-IMP 
administration and preferred at Visit 5 (Day 8)
x
Investigational medicinal product administration and local tolerability check for Dose 
Regimen 3 Cohort patients at Visit 5 (Day 8)
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Visit 6 (Day 12)
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF
x
Sarilumab PK sampling will be performed for Group A patients and for Group B patients 
who are in Schedule 2
x
An additional hematology test must be performed at Visit 6 (Day 12 ±1 Day) for patients 
in the Dose Regimen 1 and 2 Cohorts in order to get results before the second dose of 
sarilumab administration (Visit 7; Week 2, Day 15) to confirm that the ANC and platelet 
count are not within the protocol-defined limits for temporary or permanent 
discontinuation of study drug.
10.1.4 Visit 7 (Week 2)
The Visit 2 (Day 1) hematology laboratory assessment and the test results for additional 
hematology test performed prior to the second sarilumab administration for Dose Regimen 1 and 
2 Cohort patients must be reviewed before the second dose of sarilumab injection scheduled at 
Visit 7 (Day 15, Week 2) to confirm that the ANC and platelet count are not within the protocol-
defined limits for temporary or permanent discontinuation of study drug. If a local laboratory was 
used for the additional hematology test at Visit 6 (Day 12 ±1 Day), a central laboratory sample for 
hematology should be drawn pre-IMP administration at this visit as scheduled for Dose Regimen
1 and 2 Cohorts.
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF 
x
Inquire regarding AEs/SAEs
x
Check home diary/compliance for Dose Regimen 3 Cohort patients
x
Provide home diary to Dose Regimen 3 Cohort patients to record information pertaining to 
injections performed at home (date, time, injection location, and any problems) at each 
intermediate on-site visit. The completed diary will be reviewed at the next scheduled visit
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity
x
Complete the physician global assessment of disease activity
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and (parent or guardian)/patient assessment of overall 
well-being. All questionnaires should be documented in the subject’s study file. Each VAS
score should be copied on the patient’s e-CRF
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up
x
Collect blood for hematology (see Section 9.3.4), chemistry including ALT, AST, ALP, 
total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin 
x
Collect blood samples for hs-CRP and serum sarilumab (see Section 9.1 and the study 
flow chart Section 1.2)
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x
Call IVRS to register the visit and get the treatment kit number(s) assigned to each patient 
along with the dose volume to be administered
x
Dispense the IMP to those patients who are at the Dose Regimen 3 Cohort for home 
injection
x
Administer the IMP
-
Patients should be monitored for at least 30 minutes after each IMP administration for 
any signs or symptoms of a hypersensitivity reaction
x
Check local tolerability (see Section 9.3.3)
x
Schedule the appointment for Visit 8 (Day 29, Week 4) and request the patient to come in 
fasting condition.
10.1.5 Visit 8 (Week 4)
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF 
x
Inquire regarding AEs/SAEs
x
Check home diary/compliance for Dose Regimen 3 Cohort patients
x
Record vital signs including body temperature, BP and HR
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, gastrointestinal, lymphatic examinations, complete 
neurological examinations, and musculoskeletal systems.
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity.
x
Provide home diary to Dose Regimen 3 Cohort patients to record information pertaining to 
injections performed at home (date, time, injection location, and any problems) at each 
intermediate on-site visit. The completed diary will be reviewed at the next scheduled visit
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and (parent or guardian)/patient assessment of overall well-
being. All questionnaires should be documented in the subject’s study file. Each VAS 
score should be copied on the patient’s e-CRF
x
Complete the physician global assessment of disease activity
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up
x
Collect blood for hematology (see Section 9.3.4), chemistry including ALT, AST, ALP, 
total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin, fasting lipid, and 
hs-CRP
x
Collect blood samples for serum sarilumab (see Section 9.1 and the study flow chart 
Section 1.2)
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x
Perform urine pregnancy test locally for female patients who have commenced 
menstruating
x
Call IVRS to register the visit and get the treatment kit number(s) assigned to each patient 
along with the dose volume to be administered
x
Dispense the IMP to those patients who are at the Dose Regimen 3 Cohort for home 
injection
x
Administer the IMP
-
Patients should be monitored for at least 30 minutes after IMP administration for any 
signs or symptoms of a hypersensitivity reaction.
x
Check local tolerability (see Section 9.3.3)
x
Schedule the appointment for Visit 9 (Week 6).
10.1.6 Visit 9 (Week 6), Visit 10 (Week 8), Visit 11 (Week 10)
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF 
x
Inquire regarding AEs/SAEs
x
Check home diary/IMP compliance 
x
Provide home diary to Dose Regimen 3 Cohort patients to record information pertaining to
injections performed at home (date, time, injection location, and any problems) at each 
intermediate on-site visit. The completed diary will be reviewed at the next scheduled visit
x
Record vital signs including body temperature, BP and HR at Visit 10 (Week 8)
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears 
respiratory, cardiovascular, gastrointestinal, lymphatic, neurological systems, and 
musculoskeletal systems at Visit 9 (Week 6)
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and (parent or guardian)/patient assessment of overall well-
being. All questionnaires should be documented in the subject’s study file. Each VAS 
score should be copied on the patient’s e-CRF
x
Complete the physician global assessment of disease activity
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up
x
Collect blood for hematology (see Section 9.3.4), chemistry including ALT, AST, ALP, 
total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin 
x
Collect blood for hs-CRP at Visit 9 (Week 6), Visit 10 (Week 8), and Visit 11 (Week 10)
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x
Collect blood samples for serum sarilumab at Visit 10 (Week 8) (see Section 9.1 and the 
study flow chart Section 1.2)
x
Perform urine pregnancy test locally for females who have commenced menstruating at 
Visit 10 (Week 8)
x
Call IVRS to register the visit and get the treatment kit number(s) assigned to each patient 
along with the dose volume to be administered
x
Dispense the IMP to those patients who are at the Dose Regimen 3 Cohort for home 
injection
x
Administer the IMP
-
For those patients or parents or caregivers who are willing and able to perform 
injections for the patients, the Investigator or delegate will provide the training 
regarding to preparation and injection of IMP starting from Visit 10 (Week 8). This 
training must be documented in the patient’s study file. The patient or the 
parent(s)/guardian(s) or the caregiver(s) is allowed to administer the IMP for the
patient under the supervision of the Investigator or his/her delegate at Visit 10 
(Week 8), Visit 11 (Week 10) and Visit 12 (Week 12) during the core treatment phase. 
For the subsequent administrations at the extension phase, the patient or the 
parent(s)/guardian(s) or the caregiver(s) will be allowed to administer the IMP at home 
and will record information linked to this injection in the diary at the intermediate on-
site visits
-
If the patient or the parent(s)/guardian(s) or the caregiver(s) who are unable or who are 
unwilling to administer IMP, arrangements must be made for a qualified site personnel 
and/or professional caregiver to administer IMP for the patient
-
Patients should be monitored for at least 30 minutes after IMP administration for any 
signs or symptoms of a hypersensitivity reaction
x
Check local tolerability (see Section 9.3.3)
x
Schedule the appointment for the next visit and request the patient to come in fasting 
condition for Visit 12 (Week 12).
10.1.7 Visit 12 (Week 12)
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF 
x
Inquire regarding AEs/SAEs
x
Record vital signs including body temperature, BP and HR
x
Record patient weight (kg) and height (cm)
x
Check Tanner stage (see Appendix F) and menstruation status for female patients
x
Check home diary/compliance for Dose Regimen 3 Cohort patients
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x
Provide home diary to all dose regimen cohort patients to record information pertaining to 
injections performed at home (date, time, injection location, and any problems) at each 
intermediate on-site visit. The completed diary will be reviewed at the next scheduled visit
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears 
respiratory, cardiovascular, gastrointestinal, lymphatic, neurological systems, and 
musculoskeletal systems
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity (ensure JADAS -27 joints are included)
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and (parent or guardian)/patient assessment of overall well-
being. All questionnaires should be documented in the subject’s study file. Each VAS 
score should be copied on the patient’s e-CRF
x
Complete the physician global assessment of disease activity
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up
x
Collect blood for hematology (see Section 9.3.4), complete chemistry (including sodium, 
potassium, chloride, bicarbonate, BUN, glomerular filtration rate, creatinine, creatinine 
clearance, calcium, phosphate, total protein, albumin, ALT, AST, ALP, total bilirubin, 
conjugated bilirubin, and unconjugated bilirubin), fasting lipid, hs-CRP, ESR, ANA, and 
anti-dsDNA
x
Collect blood samples for serum sarilumab and antibodies to sarilumab, IL-6 and 
total sIL-6R (see Section 9.1 and the study flow chart Section 1.2)
x
Perform urine pregnancy test locally for female patients who have commenced 
menstruating 
x
Call IVRS to register the visit and get the treatment kit number(s) assigned to each patient 
along with the dose volume to be administered
x
Dispense the IMP to those patients who will continue the treatment in the extension phase. 
x
Administer the IMP for patients who are going to enter the extension treatment phase. 
-
Patients should be monitored for at least 30 minutes after IMP administration for any 
signs or symptoms of a hypersensitivity reaction
x
Check local tolerability (see Section 9.3.3)
x
Schedule the appointment for the next visit, ie, Visit 13 (Week 16) for patients in the 
dose-finding and second portions
x
Schedule the appointment for the next visit, ie, Visit 15 (Week 24) for patients in the third 
portion
x
Patients who discontinue the study treatment prematurely will be assessed using the 
procedure planned for the EOT Visit (Visit 27). These patients will be asked to return for 
an additional PK assessment 2 weeks after the EOT (the additional PK assessment is only 
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applicable for patients in the dose-finding and second portions) and EOS assessment 
planned for Visit 28, 6 weeks after the EOT visit. Schedule the appointment for the next 
PK assessment and EOS visit for those study discontinuation patients, as applicable. 
Patients discontinuing treatment prematurely during the core treatment phase should 
continue to return for the study visits as protocol scheduled except the IMP administration.  
10.1.8 Visit 88 - Pharmacokinetic (PK) Follow-up Visit (End-of-Treatment [EOT] + 2 Weeks)
Visit 88 is an additional sarilumab PK assessment visit and this visit is not applicable for patients 
enrolled in the third portion.
In the dose-finding and second portions, if a patient discontinues the study treatment prematurely 
during the core treatment phase (at or before Week 12), the patient is required to have a PK 
follow-up visit 2 weeks after the EOT assessment. 
x
Record all concomitant medication use with start date and dose in the patient’s e-CRF 
x
Inquire regarding AEs/SAEs
x
Collect blood samples for serum sarilumab (see Section 9.1 and the study flow chart 
Section 1.2).
10.1.9 Extension Phase
In the dose-finding and second portions, only patients achieving at least a JIA ACR30 response at 
Week 12 will be permitted to continue to participate in the extension phase. During the extension 
phase:
x
Patients who were enrolled to the selected dose regimen during the core treatment phase 
(either during the initial dose-finding portion or directly to the selected dose regimen in the
second portion) will continue on the selected dose regimen during the extension phase and 
will be followed-up as noted in (Section 1.2.2.1)
x
Once the selected dose regimen has been determined, patients who were not assigned to 
the selected dose regimen will have their dose regimen adjusted to the selected dose 
regimen during the extension phase. Prior to dose adjustment, these patients will complete 
the assessments as noted in Section 1.2.2.1. After the dose regimen is determined, the 
patients will have their dose regimen adjusted to the selected dose regimen at the time of 
their next regular scheduled visit (according to Section 1.2.2.1), which will be considered 
as the first visit (Visit 101 [Week 0]) as shown in the flow chart in Section 1.2.2.2. These 
patients will then continue with the assessments as noted in Section 1.2.2.2. All patients 
will remain on treatment until they have received up to a total of 144 weeks of sarilumab 
exposure calculated from Visit 12. A table to determine when the last on-treatment visit 
should occur and the weeks between the last on-treatment visit, and the EOT visit based on 
when the patient was changed to the selected dose regimen is provided in Table 1. After 
the last on-treatment visit, patients will be scheduled for the EOT visit (Visit 27) and the 
EOS visit (Visit 28).
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x
Patients who are enrolled in the third portion with the selected dose regimen will be 
followed-up as noted in Section 1.2.2.3.
10.1.9.1 Patients who remain on the current dose (the selected dose regimen) or recruited 
directly under the selected dose regimen in the second portion
For additional information on the procedures for patients who remain on the current dose (or who 
are recruited directly under the selected dose regimen [second portion]), see the flow chart in 
Section 1.2.2.1.
10.1.9.1.1Visit 13 (Week 16), Visit 14 (Week 20), Visit 15 (Week 24), Visit 16 (Week 32), Visit 17 
(Week 40), Visit 18 (Week 48), Visit 19 (Week 60), Visit 20 (Week 72), Visit 21 (Week 
84), Visit 22 (Week 96), Visit 23 (Week 108), Visit 24 (Week 120), Visit 25 (Week 132), 
and Visit 26 (Week 144)
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF 
x
Inquire regarding AEs/SAEs
x
Check home diary/compliance
x
Provide home diary. All patients or their parents or guardians will record information 
pertaining to injections performed at home (date, time, injection location, and any 
problems)
x
Record vital signs including body temperature, BP, and HR
x
Record weight (kg)
x
Record patient height at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72), 
Visit 22 (Week 96), Visit 24 (Week 120), and Visit 26 (Week 144)
x
Check Tanner stage and menstruation status at Visit 15 (Week 24), Visit 18 (Week 48),
Visit 20 (Week 72), Visit 22 (Week 96), Visit 24 (Week 120), and Visit 26 (Week 144)
(see Appendix F)
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears 
respiratory, cardiovascular, gastrointestinal, lymphatic, neurological systems, and 
musculoskeletal systems at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72),
Visit 22 (Week 96), Visit 24 (Week 120), and Visit 26 (Week 144)
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity (ensure JADAS -27 joints are included) at 
Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72), Visit 22 (Week 96), Visit 24 
(Week 120), and Visit 26 (Week 144)
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and (parent or guardian)/patient assessment of overall 
well-being at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72), Visit 22
(Week 96), Visit 24 (Week 120), and Visit 26 (Week 144). All questionnaires should be 
documented in the subject’s study file. Each VAS score should be copied on the patient’s 
e-CRF
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x
Complete the physician global assessment of disease activity at Visit 15 (Week 24),
Visit 18 (Week 48), Visit 20 (Week 72), Visit 22 (Week 96), Visit 24 (Week 120), and 
Visit 26 (Week 144)
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up
x
Perform PPD tuberculin skin test for patients ≤5 years or QuantiFERON-TB test for 
patients >5 years at Visit 18 (Week 48); Visit 22 (Week 96), and Visit 26 (Week 144). 
QuantiFERON-TB test will be considered in the younger group of patients
(≤5 years) based on the local PPD availability, local regulation for PPD screening, and the 
Investigator’s judgments
x
Collect blood for hematology (see Section 9.3.4), chemistry including ALT, AST, ALP, 
total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin
x
Collect blood for fasting lipids at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 
72), and Visit 22 (Week 96).
x
Collect blood for hs-CRP at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72),
Visit 22 (Week 96), Visit 24 (Week 120), and Visit 26 (Week 144)
x
Collect blood for ESR at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72), 
Visit 22 (Week 96), Visit 24 (Week 120), and Visit 26 (Week 144)
x
Collect blood for ANA/anti-dsDNA at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 
(Week 72), and Visit 22 (Week 96)
x
Collect blood samples for serum sarilumab, antibodies to sarilumab at Visit 15 (Week 24), 
Visit 18 (Week 48), Visit 20 (Week 72) Visit 22 (Week 96), Visit 24 (Week 120) (see
Section 9.1 and the study flow chart Section 1.2)
x
Perform urine pregnancy test locally for female patients who have commenced 
menstruating for each visit 
x
Call IVRS to register the visit and get the treatment kit number(s) assigned to each patient 
along with the dose volume to be administered
x
Dispense the IMP
x
Administer the IMP 
-
During the course of the extension phase (starting at Visit 12), the IMP injection dose 
can be adjusted. Refer Appendix B for injection volume based on the patient’s weight
-
Patients should be monitored for at least 30 minutes after IMP administration for any 
signs or symptoms of a hypersensitivity reaction
x
Check local tolerability (see Section 9.3.3)
x
Schedule the appointment for the next visit and request patients to come in a fasting 
condition at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72), Visit 22 
(Week 96), Visit 24 (Week 120), Visit 26 (Week 144), and Visit 27 EOT (Week 156).
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10.1.9.2 Patients who change to the selected dose regimen
For additional information on the procedures for patients who change to the selected dose 
regimen, see the flow chart in Section 1.2.2.2.
In this section, “Day” means “Day at this dose,” and “Week” means “Week at this dose.”
10.1.9.2.1Visit 101 (Week 0), Visit 102 (Week 2), Visit 103 (Week 4), Visit 104 (Week 6), 
Visit 105 (Week 8), and Visit 106 (Week 12)
x
Tanner stage and menstruation status at Visit 101 (Week 0) 
x
Review the previous visit’s hematology laboratory assessment before the administration of 
the dose of sarilumab
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF
x
Inquire regarding AEs/SAE
x
Record vital signs including body temperature, BP, and HR
x
Record weight (kg) at Visit 101 (Week 0), Visit 103 (Week 4), Visit 105 (Week 8), and 
Visit 106 (Week 12)
x
Record height (cm) at Visit 101 (Week 0)
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears 
respiratory, cardiovascular, abdominal, lymphatic, neurological systems, and 
musculoskeletal systems at Visit 101 (Week 0), Visit 104 (Week 6), and Visit 106 
(Week 12)
x
Call IVRS to register the visit and get the treatment kit number(s) assigned to each patient 
along with the dose volume to be administered
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity. Any abnormalities should be recorded and 
documented in prior medical/surgical history (ensure JADAS -27 joints are included)
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and parent/patient assessment of overall well-being. All 
questionnaires should be documented in the subject’s study file. Each VAS score should 
be copied on the patient’s e-CRF
x
Complete the physician global assessment of disease activity
x
Perform a tuberculosis risk assessment. In case of suspicion of TB, refer the patient to a 
specialist for a complete examination and additional work-up
x
Purified Protein Derivative tuberculin skin test for patients ≤5 years or QuantiFERON-TB 
test for patients >5 years at Visit 101 (Week 0) 
x
Collect blood for hematology and complete chemistry profile (see Section 9.3.4) at Visit 
101 (Week 0), Visit 102 (Week 2), Visit 103 (Week 4), Visit 105 (Week 8), and Visit 106 
(Week 12)
x
Collect blood for fasting lipids at Visit 101 (Week 0), Visit 103 (Week 4), and Visit 106 
(Week 12)
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x
Collect blood for hs-CRP from Visit 101 to Visit 106.
x
Collect blood for ESR, ANA/anti-dsDNA antibody at Visit 101 (Week 0) and Visit 106 
(Week 12)
x
Collect blood samples for serum sarilumab (see Section 9.1 and the study flow chart in 
Section 1.2.2.2) at Visit 101 (Week 0), Visit 102 (Week 2), Visit 103 (Week 4), Visit 105 
(Week 8), and Visit 106 (Week 12)
x
Collect blood samples for antibodies to sarilumab (see Section 9.1 and the study flow chart 
in Section 1.2.2.2) at Visit 101
x
Perform local urine pregnancy test for the female patients who have commenced 
menstruation prior to exposure to the IMP at each visit (except Visits 102 [Week 2] and 
104 [Week 6])
x
Dispense the IMP
x
Provide home diary for IMP/compliance
x
Administer the IMP
-
Patients should be monitored for at least 30 minutes after IMP administration for any 
signs or symptoms of a hypersensitivity reaction
x
Check local tolerability (see Section 9.3.3)
x
Schedule the appointment for the next visit
10.1.9.2.2Visit 107 (Week 16), Visit 108 (Week 20), Visit 109 (Week 24), Visit 110 (Week 32), 
Visit 111 (Week 40), Visit 112 (Week 48), Visit 113 (Week 60), Visit 114 (Week 72) 
Visit 115 (Week 84), Visit 116 (Week 96), Visit 117 (Week 108), Visit 118 (Week 120), 
and Visit 119 (Week 132)
For detailed information on the procedures for patients who change to the selected dose regimen,
see the flow chart in Section 1.2.2.2.
10.1.9.3 Patients enrolled directly under the selected dose regimen in the third portion
For detailed information on the procedures for patients who are recruited directly under the 
selected dose regimen in the third portion, see the flow chart in Section 1.2.2.3.
10.1.9.3.1Visit 15 (Week 24), Visit 16.1 (Week 36), Visit 18 (Week 48), Visit 19 (Week 60), 
Visit 20 (Week 72), Visit 21 (Week 84)
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF
x
Inquire regarding AEs/SAEs
x
Check home diary/compliance
x
Provide home diary. All patients or their parents or guardians will record information 
pertaining to injections performed at home (date, time, injection location, and any 
problems)
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x
Record vital signs including body temperature, BP, and HR
x
Record weight (kg)
x
Record patient height at Visit 15 (Week 24), Visit 18 (Week 48), and Visit 20 (Week 72)
x
Check Tanner stage and menstruation status at Visit 15 (Week 24), Visit 18 (Week 48),
and Visit 20 (Week 72) (see Appendix F)
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears 
respiratory, cardiovascular, gastrointestinal, abdominal, lymphatic, neurological systems, 
and musculoskeletal systems at Visit 15 (Week 24), Visit 18 (Week 48), and Visit 20
(Week 72)
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity (ensure JADAS -27 joints are included) at 
Visit 15 (Week 24), Visit 18 (Week 48), and Visit 20 (Week 72)
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and (parent or guardian)/patient assessment of overall 
well-being at Visit 15 (Week 24), Visit 18 (Week 48), and Visit 20 (Week 72). All 
questionnaires should be documented in the subject’s study file. Each VAS score should 
be copied on the patient’s e-CRF
x
Complete the physician global assessment of disease activity at Visit 15 (Week 24),
Visit 18 (Week 48), and Visit 20 (Week 72)
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up
x
Perform PPD tuberculin skin test for patients ≤5 years or QuantiFERON-TB test for 
patients >5 years at Visit 18 (Week 48); QuantiFERON-TB test will be considered in the 
younger group of patients (≤5 years) based on the local PPD availability, local regulation 
for PPD screening, and the Investigator’s judgments
x
Collect blood for hematology (see Section 9.3.4), chemistry including ALT, AST, ALP, 
total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin
x
Collect blood for fasting lipids at Visit 15 (Week 24) and Visit 18 (Week 48)
x
Collect blood for hs-CRP at Visit 15 (Week 24), Visit 18 (Week 48), and Visit 20 
(Week 72)
x
Collect blood for ESR at Visit 15 (Week 24), Visit 18 (Week 48), and Visit 20 (Week 72)
x
Collect blood for ANA/anti-dsDNA at Visit 15 (Week 24) and Visit 18 (Week 48)
x
Collect blood samples for serum sarilumab, antibodies to sarilumab at Visit 15 (Week 24), 
Visit 18 (Week 48), Visit 20 (Week 72) (see Section 9.1 and the study flow chart 
Section 1.2)
x
Perform urine pregnancy test locally for female patients who have commenced 
menstruating for each visit
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x
Call IVRS to register the visit and get the treatment kit number(s) assigned to each patient 
along with the dose volume to be administered
x
Dispense the IMP
x
Administer the IMP
-
During the course of the extension phase (starting at Visit 12), the IMP injection dose 
can be adjusted. Refer Appendix B for injection volume based on the patient’s weight
-
Patients should be monitored for at least 30 minutes after IMP administration for any 
signs or symptoms of a hypersensitivity reaction
x
Check local tolerability (see Section 9.3.3)
x
Schedule the appointment for the next visit and request patients to come in a fasting 
condition at Visit 15 (Week 24), Visit 18 (Week 48)
Visits 13, 14, 16, 17, 22, 23, 24, 25, and 26 are not applicable for patients enrolled in the third 
portion.
10.1.10 Visit 27: End-of-Treatment visit
Visit 27 (EOS) will be Week 156 for patients enrolled in the dose-finding and second portions and 
Week 96 for patients enrolled in the third portion.
x
Record all concomitant medications used with start date and dose in the patient’s e-CRF 
x
Inquire regarding AEs/SAEs
x
Record vital signs including body temperature, BP and HR
x
Record patient weight (kg) and height (cm)
x
Check Tanner stage and menstruation status for female patients (see Appendix F)
x
Check home diary/compliance 
x
Perform a complete physical examination including skin, nasal cavities, eyes, ears 
respiratory, cardiovascular, gastrointestinal, lymphatic, neurological systems, and 
musculoskeletal systems
x
Perform the joint count assessments to note JIA disease manifestations (articular and 
extra-articular) and assess disease activity (ensure JADAS -27 joints are included) 
x
Ask the patient/parent(s)/guardian(s) to complete relevant questionnaires: functional 
ability determined by CHAQ and (parent or guardian)/patient assessment of overall 
well-being. All questionnaires should be documented in the subject’s study file. Each VAS 
score should be copied on the patient’s e-CRF
x
Complete the physician global assessment of disease activity
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up
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x
Collect blood for hematology (see Section 9.3.4) and complete chemistry (including 
sodium, potassium, chloride, bicarbonate, BUN, glomerular filtration rate, creatinine, 
creatinine clearance, calcium, phosphate, total protein, albumin, ALT, AST, ALP, 
total bilirubin, conjugated bilirubin, and unconjugated bilirubin; see Section 9.3.4)
x
The IL-6 and total sIL-6R will be measured for patients who discontinue the study 
treatment prematurely during the core treatment phase
x
Collect blood for hs-CRP, ESR, serum sarilumab, and antibodies to sarilumab 
x
Collect blood for fasting lipids and ANA/anti-dsDNA only for patients who discontinue
prematurely before Week 96 (for the dose-finding and second portion)/Week 48 (for the 
third portion)
x
Perform urine pregnancy test for female patients who have commenced menstruating
x
Call IVRS to notify the patient’s status (EOT) 
x
There is no IMP administration at this visit
x
Check local tolerability (for patients who change to the selected dose; see Section 9.3.3)
x
Schedule the appointment for the post-treatment follow-up visit of Visit 28 (EOT +
6 weeks).
Post-treatment safety follow-up (Visit 28; 6 weeks after EOT assessment, EOT+6 weeks)
10.1.11 Visit 28 (End-of-Treatment [EOT] +6 weeks) End-of-Study Visit: Post-treatment 
follow-up
x
Record all concomitant medications use with start date and dose in the patient’s e-CRF 
x
Inquire regarding AEs/SAEs
x
Record vital signs including body temperature, BP and HR
x
Record patient weight (kg)
x
Check Tanner stage (see Appendix F) and menstruation status for female patients
x
Perform a tuberculosis risk assessment. In case of suspicion of tuberculosis, refer the 
patient to a specialist for a complete examination and additional work-up
x
Collect blood for serum sarilumab and antibodies to sarilumab 
x
Call IVRS to notify the patient’s status (study completion).
Note: Post-treatment follow-up visit is also applied at 6 weeks after EOT visit for those patients 
who permanently discontinue the study treatment.
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10.2
DEFINITION OF SOURCE DATA
Source data is all information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents. Source documents are 
original documents, data and records such as hospital records, clinic and office charts, laboratory 
notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, etc. 
All evaluations that are reported in the e-CRF must be supported and identified by appropriate 
source documentation related but not limited to:
x
Patient chart
x
Number of joints with active arthritis 
x
Number of joints with limitation of motion 
x
Physician’s global assessment of disease activity
x
Parent/patients assessment of overall well-being
x
Childhood Health Assessment Questionnaire
x
Home injection diaries (if applicable), serum sarilumab diary (when samples are collected 
at home) and patients user instruction
x
Laboratory assessment including chest X-ray 
x
The e-CRF will be verified against the source documentation to ensure that all data are 
captured accurately.
10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the CRF. In any case, the 
patient should remain in the study as long as possible.
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)
Temporary treatment discontinuation decided by the Investigator corresponds to more than 
one injection not administered to the patient. 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. For laboratory abnormalities, Investigator will refer to Appendix G for the stopping rules.
Re-initiation of treatment with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met (refer to Section 7.1 and 
Section 7.2).
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For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the CRF (see Appendix G for the stopping rules).
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s)
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
A temporary discontinuation of IMP that is greater than 31 days could be considered permanent if 
a significant impact on the efficacy has been identified.
10.3.3 List of criteria for permanent treatment discontinuation
The patient or the parent(s) or the legal guardian(s) may withdraw the patient from treatment with 
the IMP if they decide to do so at any time and irrespective of the reason. Based on the 
Investigator’s judgment, the patient could be discontinued from the study treatment once his/her 
condition requires the treatment with prohibited medications (starting new DMARDs, significant 
increase in glucosteroids or considering other biologic therapy, etc). All efforts should be made to
document the reasons for treatment discontinuation and this should be documented in the e-CRF.
Investigational medicinal product will be permanently discontinued in case of the following 
events (refer to Section 10.6 for details):
x
Clinical significant infections such as opportunistic infections (see Appendix I) or active 
tuberculosis 
-
The diagnosis of tuberculosis can be made either on symptoms or on a chest 
radiograph suggestive of active tuberculosis. Patients should be referred to appropriate 
medical specialists and whenever possible, skin PPD test or blood QuantiFERON-TB 
test should be performed and the results should be recorded in the e-CRF
-
Culture positive for non-TB mycobacteria
-
The patient is at risk through close contact with a person with active tuberculosis and 
the patient refuses to undergo tuberculosis evaluation
x
Symptoms of systemic hypersensitivity or anaphylactic reactions
x
Significant laboratory abnormalities
-
ALT >5 x ULN or ALT >3 x ULN with concomitant total bilirubin >2 x ULN (unless 
patient with documented Gilbert’s Syndrome)
-
neutrophil count <1000/mm3 (Grade 3 or 4 neutropenia) with evidence of infection
-
platelet count <50 000/mm3, or platelet count <100 000/mm3 with evidence of 
bleeding
x
Acute renal failure (refer to Appendix G)
x
Pregnancy in female participant
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x
Use of any biologic DMARDs other than IMP
x
Any AEs, per Investigator’s judgment that may jeopardize the patient’s safety.
Any abnormal laboratory value that is close to the values described in Appendix G should be 
immediately rechecked for confirmation. No dose will be given until the results of the 
confirmation laboratory tests are received. No decision by the Investigator or Sponsor should be 
made to permanently discontinue the IMP for the concerned patient until the results of the 
confirmation laboratory test are received.
10.3.4 Handling of patients after permanent treatment discontinuation
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of early termination visit and the post-treatment visit, or up to recovery or 
stabilization of any AE to be followed-up as specified in this protocol, whichever comes last.
Patients discontinuing treatment prematurely before 12 weeks should continue to be followed 
according to the study flow chart, with the exception of treatment dispensing and administration. 
An additional PK sampling is required 2 weeks after the EOT assessment.
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure for the EOT visit, including a sample for determination of sarilumab 
concentration (bound and functional) and antibodies to sarilumab, if appropriate. The patients will 
be asked to return for the EOS assessments 6 weeks after the EOT assessment. This EOS visit will 
be applicable to all the patients in both the core treatment phase and the extension phase.
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed.
10.3.5 Procedure and consequence for patient withdrawal from study
The patients or parent(s) or the guardian(s) may withdraw the patient from the study before study 
completion if they decide to do so, at any time and irrespective of the reason.
If possible, the patients are assessed using the procedure for the End-of-Treatment visit including 
serum sarilumab (PK) level and anti-sarilumab antibodies evaluation. 
For patients who fail to return to the site, the Investigator should make the best effort to recontact 
the patient (eg, contacting patient’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status. 
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter).
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. Patients who have withdrawn from the study cannot be re-entered 
(treated) in the study. Their inclusion and treatment numbers must not be reused. 
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If possible, the patients should be assessed using the procedures defined above.
The patient/parent(s)/guardian(s) who withdraw consent should be explicitly asked about the 
contribution of possible AEs. Preferably the patient should withdraw consent in writing and, if the 
patient or the parent(s)/guardian(s) refuses or is physically unavailable, the site should document 
and sign the reason for the patient’s failure to withdraw consent in writing. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented.
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING
10.4.1 Definitions of adverse events
10.4.1.1 Adverse event
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.
10.4.1.2 Serious adverse event
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
x
Results in death, or
x
Is life threatening, or
Note: The term “life threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.
x
Requires inpatient hospitalization or prolongation of existing hospitalization, or
x
Results in persistent or significant disability/incapacity, or
x
Is a congenital anomaly/birth defect
x
Is a medically important event
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above.
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Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is not 
intended to be exhaustive:
x
Intensive treatment in an emergency room or at home for:
-
Allergic bronchospasm 
-
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc)
-
Convulsions (seizures, epilepsy, epileptic fit, absence, etc)
x
Development of drug dependence or drug abuse
x
Alanine aminotransferase >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT 
increase >10 x ULN (unless patient with documented Gilbert’s Syndrome)
x
Suicide attempt or any event suggestive of suicidality
x
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling)
x
Bullous cutaneous eruptions
x
Cancers diagnosed during the study or aggravated during the study 
x
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study
x
Suspected transmission of an infectious agent: if any suspected transmission of an 
infectious agent via a medicinal product (eg, product contamination).
10.4.1.3 Adverse event of special interest
An AESI is an AE (serious or non serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor are required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added or removed 
during a study. AESIs will be flagged in the database using search criteria (see Section 10.4.4 for 
AESI reporting).
10.4.2 General guidelines for reporting adverse events
x
All AEs, regardless of seriousness or relationship to IMP/NonIMP, spanning from the 
signature of the ICF until the EOS as defined by the protocol for that patient, are to be 
recorded on the corresponding page(s) or screen(s) of the e-CRF.
x
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP.
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x
The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor.
x
Patients who experience an ongoing SAE or an AESI at the pre-specified study end-date, 
should be followed until resolution, stabilization, or death and related data will be 
collected.
x
When treatment is prematurely discontinued, the patient’s observations will continue until 
the EOS as defined by the protocol for that patient.
x
Laboratory results and vital sign values are to be recorded as AEs only if: 
-
Associated with symptoms, and/or 
-
Requiring either corrective treatment or consultation, and/or 
-
Leading to IMP discontinuation or modification of dosing, and/or 
-
Fulfilling a seriousness criterion, and/or 
-
Defined as an AESI.
10.4.3 Instructions for reporting serious adverse events
In the case of occurrence of an SAE, the Investigator must immediately:
x
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay.
x
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and e-mail address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document
provided to the Sponsor. For laboratory results, include the laboratory normal ranges.
x
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc.) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification.
x
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work.
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Any SAE brought to the attention of the Investigator at any time after the EOS for the patient and 
considered by him/her to be caused by the IMP with a reasonable possibility, should be reported 
to the monitoring team.
10.4.4 Guidelines for reporting adverse events of special interest
10.4.4.1 Reporting of adverse events of special interest
For AESIs, the Sponsor will be informed immediately (ie, within 24 hours), as per the SAE 
notification instructions described in Section 10.4.3 and Table 7 even if not fulfilling a seriousness 
criterion, using the corresponding pages in the e-CRF (to be sent) or screens in the e-CRF. The 
following is the list for AESIs for this study: 
x
Clinically significant infections including:
-
Opportunistic infections (refer to Appendix I) (Note: Candidiasis – only systemic 
and/or extensive mucocutaneous cases of candidiasis) 
-
Active/latent tuberculosis or initiation of medications for suspected tuberculosis
x
Anaphylaxis fulfilling the criteria in the Appendix H
x
Gastrointestinal 
-
Perforation
-
Diverticulitis
x
The following laboratory abnormalities:
-
Alanine aminotransferase increase leading to permanent discontinuation
-
Grade 4 neutropenia (>10 days after the initial IMP administration) or any neutropenia 
leading to permanent discontinuation
-
Thrombocytopenia leading to permanent discontinuation
x
Pregnancy (adolescent):
-
Pregnancy occurring in a female patient included in the clinical trial (as well as 
pregnancy occurring in a female partner of a male subject entered in a study with IMP) 
will be recorded as an AESI in all cases and reported to the sponsor immediately 
(within 24 hours of knowledge). It will be qualified as an SAE only if it fulfills the 
SAE criteria.
-
In the event of pregnancy in a female participant, IMP should be discontinued. 
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined, or as permitted 
according to applicable local regulations.
x
Symptomatic overdose with IMP
-
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
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dose during an interval of less than 11 days for q2w administrations and less than 6 
days for weekly administration. Symptomatic overdose is defined as an AESI and 
reported the sponsor immediately (within 24 hours of knowledge), following the same 
process as described for the SAEs. The circumstances (ie, accidental or intentional) 
should be clearly specified in the verbatim and symptoms, if any, entered on separate 
AE forms. Overdose without symptoms should be reported as an AE.
Table 7 - Summary of adverse event reporting instructions
Event category
Reporting 
timeframe
Specific events in this category
Case report form completion
 
 
 
AE form 
Safety 
complementary 
form 
Other 
specific 
forms 
Adverse Event 
(non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
All Serious 
Adverse Events 
Expedited (within 
24 hours of 
knowledge) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
As 
needed 
for select 
AESI 
AESI  
Expedited (within 
24 hours of 
knowledge) 
The following AE defined in Section 10.4.4.1 
 
 
 
 
 
x
Clinically significant infections including: 
-
Opportunistic infections (see list in 
Appendix I) (Note: Candidiasis – 
only systemic candidiasis and 
extensive cases) 
Yes 
Yes 
Yes 
 
 
-
Active/latent TB or initiation of 
medications for suspected TB 
 
 
 
 
 
x
Anaphylaxis fulfilling the criteria in 
Appendix H 
Yes 
Yes 
Yes 
 
 
x
Gastrointestinal perforation and 
diverticulitis 
Yes 
Yes 
No 
 
 
x
ALT increase leading to permanent 
discontinuation 
Yes 
Yes 
Yes 
 
 
x
Grade 4 neutropenia (>10 day after the 
initial IMP administration) or any 
neutropenia leading to permanent 
discontinuation 
Yes 
Yes 
Yes 
 
 
x
Thrombocytopenia leading to 
permanent discontinuation 
Yes 
Yes 
Yes 
 
 
x
Pregnancy of a female adolescent 
patient/or partner of a male adolescent 
patient participating in the study 
Yes 
Yes 
Yes 
 
 
x
Symptomatic overdose with IMP 
Yes 
Yes 
Yes 
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Event category
Reporting 
timeframe
Specific events in this category
Case report form completion
 
 
 
AE form 
Safety 
complementary 
form 
Other 
specific 
forms 
Adverse Event 
(non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Any laboratory, 
vital sign 
abnormality (non-
SAE) other than 
those specifically 
listed in another 
section that is: 
symptomatic, 
requiring 
corrective 
treatment or 
consultation, 
leading to IMP 
discontinuation or 
dose 
modification. 
Routine 
Report specific abnormality 
Yes 
No 
No 
Abbreviations: AE = adverse event, AESI = adverse event of special interest, ALT = alanine aminotransferase, IMP = investigational 
medicinal product, SAE = serious adverse event, TB = tuberculosis 
Reminder: Safety Complementary Forms should be completed for all SAEs and AESIs. 
10.4.5 Guidelines for management of specific laboratory abnormalities
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix G. Evaluation and management of these laboratory abnormalities may include, but are 
not limited to those listed in the appendices. Investigators should assess the patient clinically and 
further evaluate the patient with assessments beyond those listed the appendices, if needed, 
according to his/her best clinical judgment as well.
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 
x
Neutropenia
x
Thrombocytopenia
x
Alanine aminotransferase increase
x
Acute renal insufficiency
NOTE: In some clinical trials these laboratory abnormalities can be considered as AESIs 
(see Section 10.4.4.1).
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10.5
OBLIGATIONS OF THE SPONSOR
During the course of the study, the Sponsor will report in an expedited manner:
x
All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction [SUSAR]), to the Health Authorities, Institutional 
Review Boards/Independent Ethics Committees (IRBs/IECs) as appropriate and to the 
Investigators
x
All SAEs that are expected and at least reasonably related to the IMPs to the Health 
Authorities, according to local regulations.
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected (eg, arthralgia related to RA).
Any other AE not listed as an expected event in the Investigator’s brochure or in this protocol will 
be considered unexpected.
For safety, the Sponsor will report to the Health Authorities of any SUSAR and reasonably 
associated with the use of the IMP according to either the judgment of the Investigator and/or the 
Sponsor. 
The Sponsor will report all safety observations made during the conduct of the trial in the CSR.
10.6
SAFETY INSTRUCTIONS
10.6.1 Infections
Biologics including tumor necrosis factor (TNF) antagonists and tocilizumab (another IL-6R
antagonist similar to sarilumab) have been associated with an increased risk of infection, 
including black box warnings for serious infections leading to hospitalization or death. In Phase 2 
sarilumab studies in adults, the most commonly reported TEAEs were infections (mostly 
nonserious upper respiratory and urinary tract infections). In the ongoing phase 3 program, 
clinically significant infections including life threatening sepsis, have been reported, some notably 
associated with minor trauma. As a precautionary measure, Investigators should carefully follow 
any signs of infection with particular care to identify potential infective complications in immune-
suppressed individuals where superficial skin wounds or abrasions may lead to serious infections 
including necrotizing fasciitis and/or sepsis.
Any infection should be reported by the Investigator as an AE and a corresponding e-CRF form 
should be filled in. If possible, culture should be performed to identify the type of infection. The 
type of infection should be listed in the e-CRF form. Treatment with antibiotics, if any, should be 
recorded including the route of administration. Clinically significant infections including 
opportunistic infections are AESIs and should be reported accordingly (Section 10.4.4.1). The 
IMP should be discontinued in case of suspicion of a clinically significant infection and a 
complete diagnosis work-up should be performed. 
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Tuberculosis assessment: sarilumab is a biologic treatment that may induce immunosuppression, 
increasing the risk of reactivation of latent TB. A special warning of the increased risk of TB is 
included in the label of TNF inhibitors and tocilizumab. As a precautionary measure, patients at 
risk for TB will be excluded from the study. For inclusion, patient with a past history of TB could 
be included only if there is a documented confirmation medically validated by the Investigator 
that the patient was adequately treated and does not meet any of the TB-related exclusion criteria. 
x
A clinical examination and history will be performed at every visit to assess any signs and 
symptoms of TB or contact with a patient with active TB. 
x
Purified Protein Derivative (PPD) skin test or QuantiFERON-TB blood test will be 
performed at the Screening visit and can be repeated at any time during the course of the 
studies in case of suspicion of TB (Refer to E 13 for the details)
x
In case of suspicion of TB, the Investigator must refer the patient to a specialist for a 
complete examination. The IMP should be discontinued until TB is ruled out.
Chest X-ray: A standard posterior-anterior chest X-ray (lateral view is also recommended but not 
required) may be recommended when deemed necessary based on the Investigator’s judgment or 
in line with local guidelines for TB screening prior to initiating a biologic therapy for JIA patients 
who haven’t had a chest X-ray performed within 3 months prior to Baseline.
10.6.2 Liver function tests
Please refer to Section 10.4.4 for LFT abnormalities to be reported as AESI. 
The Sponsor relies on the Investigator’s judgment for adapting concomitant medication in case of 
LFT abnormalities.
In the present protocol, in order to closely follow liver function tests, assessment of ALT, AST, 
ALP, and bilirubin (total, conjugated) are performed per specifications on the study flow charts 
(sec flow chart Section 1.2 and Appendix G for the general guidance for the follow-up of ALT 
elevation).
10.6.3 Neutrophils
For all patients, a hematology test must be performed and the results must meet eligibility criteria 
prior to the enrolment. 
For all subsequent visits, in order to prevent the administration of IMP in patients at risk for 
severe neutropenia, the hematology test will be performed and the results will be reviewed. Please 
refer to Appendix G for guidance on the follow-up of neutropenia and refer to Section 10.4.4.1
criteria for reporting neutropenia as AESI or SAE.
10.6.4 Platelets
For all patients, a hematology test must be performed and the results must meet eligibility criteria
prior to the enrolment. 
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For all subsequent visits, in order to prevent the administration of IMP in patients at risk for 
thrombocytopenia, the hematology test will be performed and the results will be reviewed. Please 
refer to Appendix G for guidance on the follow-up of thrombocytopenia and refer to 
Section 10.4.4.1 criteria for reporting thrombocytopenia as AESI or SAE.
10.6.5 Systemic hypersensitivity reactions/anaphylaxis
Severe systemic hypersensitivity reactions (in rare cases, fatal anaphylaxis) have been reported 
with biologics. Infrequent, mild to moderate, systemic hypersensitivity reactions have been 
observed with sarilumab. The patient should be monitored for 30 minutes after the IMP injection 
when given at the study site. Also patient should be advised, when IMP is administered at home, 
to self-monitor for potential signs and symptoms that may suggest a hypersensitive reaction for 
30 minutes after administration. Any problems should be documented in the patient’s home diary 
or in the medical notes and reported as AE. In case of systemic hypersensitivity reaction, the IMP 
should be discontinued and those events meeting seriousness criteria (eg, hospitalization, life 
threatening); see Section 10.4.1.2 should be reported as SAEs. Appendix H defines clinical criteria 
for diagnosing anaphylaxis. If clinical criteria for anaphylaxis are met, appropriate treatment 
should be administered immediately and the event should be reported as a SAE.
For Germany only: After the first IMP administration the patient has to be monitored for at least 
1 hour to assess tolerability.
10.6.6 Diverticulitis and Gastrointestinal Perforation
The Investigator should pay particular attention to gastrointestinal symptoms such as, but not 
limited to, abdominal pain, hemorrhage, or unexplained change in bowel habits with fever to 
assure that the diagnosis is not missed and that the conditions are managed appropriately to avoid 
the complication of perforation. If necessary, the patient should be referred to a specialist.
Corticosteroid use or prior history of diverticulitis is known to increase the risk of gastrointestinal 
perforations. The Investigator should be aware of this potential risk and monitor any sign of 
diverticulitis.
Gastrointestinal perforation is an AESI to be reported as SAE (see Section 10.4.3 and 
Section 10.4.4.1) Confirmed gastrointestinal ulceration without perforation and diverticulitis 
should be reported as AESI (Section 10.4.3).
10.6.7 Management of dyslipidemia
Patients treated with tocilizumab have been observed to have increased elevations of all lipid
parameters, including low density lipoprotein (LDL) cholesterol. A similar finding has been 
observed for sarilumab. The potential for dyslipidemia in pcJIA patients treated with IL-6R 
antagonists is unknown. Patients who are found to have dyslipidemia during the course of the 
study should refer National Cholesterol Education Program (NCEP) Expert Panel Report on 
Blood Cholesterol levels in Children and Adolescents and refer to applicable local guideline for 
the standard care of treatment (24).
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10.6.8 Acute renal failure
Sarilumab is not known to be associated with a clinically significant effect on renal function.
10.7
ADVERSE EVENTS MONITORING
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR.
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11
STATISTICAL CONSIDERATIONS
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11.2
DISPOSITION OF PATIENTS
Screened patients are defined as patients meeting the inclusion criteria and having a signed 
informed consent/assent (as applicable). 
Included patients consist of all patients with a signed ICF who have had a treatment kit number 
allocated and recorded in the IVRS/IWRS database, regardless of whether the treatment kit was 
used.
For patient study status, the total number of patients in each of the following categories will be 
presented in the CSR using a flowchart diagram or summary table:
x
Screened patients
x
Screen failure patients 
x
Included patients 
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x
Included but not treated patients
x
Included and treated patients
x
Patients completing the initial 12-week core treatment phase
x
Patients completing the study treatment per protocol
x
Patients who did not complete the study treatment period as per protocol
x
Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation
x
Patients entering the extension phase
x
Status at last study contact.
11.3
ANALYSIS POPULATIONS
11.3.1 Efficacy populations
The efficacy population consists of all included patients who receive at least 1 dose of sarilumab. 
All patients should be followed at least to the end of the 12-week study treatment period and will 
be analyzed according to the treatment that they actually receive.
11.3.2 Safety population
Safety population: the included population who actually received at least 1 dose or part of a dose 
of the IMP, analyzed according to the treatment actually received.
In addition: 
x
Patients for whom it is unclear whether they took the study medication will be included in 
the safety population according to the assigned treatment.
x
In case a patient receives 1 or more incorrect doses of sarilumab other than the one 
assigned, the dose regimen allocation for as-treated analysis will be the dose regimen in
which he/she was treated for the longest duration.
11.3.3 Pharmacokinetic, pharmacodynamics, and immunogenicity population
The PK population will consist of all patients in the safety population with at least one post-dose, 
nonmissing serum concentration value. The PD population will consist of all patients in the safety 
population with at least one post-dose biomarker assessment. The ADA population will consist of 
all patients in the safety population with at least one post-dose, evaluable ADA sample. Patients 
will be analyzed according to the treatment actually received.
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11.4
STATISTICAL METHODS
11.4.1 Extent of study treatment exposure and compliance
The extent of IMP exposure and compliance will be assessed and summarized by actual IMP dose 
regimen, overall and within each weight group, using the safety population.
11.4.1.1 Extent of investigational medicinal product exposure
The extent of IMP exposure will be assessed by the duration of IMP exposure, and actual dose 
information.
The duration of sarilumab exposure is defined as: last dose date - first dose date+ 14 days for 
Dose Regimens 1 and 2 (+ 7 days for Dose Regimen 3). These calculations are regardless of 
unplanned intermittent discontinuations. Duration of IMP exposure will be summarized 
descriptively as a quantitative variable (number, mean, SD, median, minimum, and maximum) 
and by categories. Additionally, the cumulative duration of treatment exposure, defined as the 
sum of patients’ duration of treatment exposure and expressed in patient years, will be provided.
11.4.1.2 Compliance
A given administration will be considered noncompliant if the patient did not take the planned 
dose of IMP as required by the protocol. No imputation will be made for patients with missing or 
incomplete data.
Percentage of compliance for a patient will be defined as the number of administrations that the 
patient was compliant divided by the total number of administrations that the patient was planned 
to take on or before the last dose date during the treatment epoch. 
Treatment compliance percentages will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum), along with a summary of the percentage 
of patients whose compliance is <80%. In addition, patients with the wrong dose will be 
summarized.
Overdose is defined as administering 2 or more sarilumab doses in less than 11 calendar days for 
q2w dosing and in less than 6 calendar days for qw dosing. Symptomatic overdose will be 
reported as an AESI. More generally, dosing irregularities will be listed.
11.4.2 Analyses of efficacy endpoints
See Section 9.3.4. Efficacy is considered as secondary in this study. Efficacy data will be 
summarized descriptively. The approach to handle the dose-adjustment in the efficacy analyses 
will be detailed in the statistical analysis plan.
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11.4.2.1 Analysis of primary efficacy endpoint(s)
Analysis of JIA ACR30 response is provided in this study section.
Patients achieving JIA ACR30 response for each dose regimen cohort, overall, and by weight 
group will be summarized by visit using counts, proportions and 95% CIs. All observed data, 
while the patient remains on treatment will be included in this analysis. No missing data will be 
imputed. Additionally, for the summaries on the JIA ACR 30 responses during the 12-week core
treatment phase, several different approaches will be used for the handling of treatment 
discontinuations and missing data.
Non responder imputation:
In general, number of joints with active arthritis, number of joints with limited range of motion, 
and at least 3 of the remaining 4 ACR components at Baseline and a time point are required to 
determine responder status. 
In this method of missing data handling, the data collected after treatment discontinuation will be 
set to missing. No imputation of missing post baseline values will be performed. Responder status 
will be determined using available data and patients will automatically become non responders for 
all time points beyond the time point they discontinued study treatment or for which there is 
insufficient data.
LOCF approach: 
In this method of missing data handling, the missing data will be imputed using the LOCF 
procedure from the point of treatment discontinuation for all 6 ACR components for all visits post 
that point. Responder status will be determined using the imputed data.
In this approach, patients with insufficient data after imputation (ie, number of joints with active 
arthritis, number of joints with limited range of motion, and at least 3 of the remaining 4 ACR 
components) at baseline and a time point will be considered as non responders at that time point.
As observed including post discontinuation follow-up:
All observed data up to Week 12, including those collected after treatment discontinuation, will be 
included in this analysis. No missing data will be imputed.
Subgroup analyses:
No additional subgroup summaries are planned for the efficacy.
11.4.2.2 Analyses of secondary efficacy endpoints
Juvenile idiopathic arthritis ACR30 core set variable scores and changes from baseline for each 
dose regimen cohort and weight group will be summarized by visit using means, standard errors, 
and corresponding 95% CIs. Juvenile idiopathic arthritis ACR30 response using ESR instead of 
hs-CRP will be summarized using the same methods as for the primary efficacy endpoint.
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ACR50/70/90/100 will be summarized using the approaches as described above for ACR30.
Overall score and change from baseline in JADAS-27 will be summarized by visit (including 
number, mean, and standard error, SD, median, minimum, and maximum) for each dose regimen 
cohort and weight group (if possible).
11.4.2.3 Multiplicity considerations
No formal hypothesis testing will be performed in this study.
11.4.3 Analyses of safety data
Safety data will be summarized descriptively. The summary of safety results will be presented by 
dose regimen. Further subdivision by weight group will be performed only for selected parameters 
given the small sample size. Additional methods including the approach to handle the dose-
adjustment in safety analyses, safety analyses by time periods, and the exposure-adjusted analyses 
on safety events will be detailed in the statistical analysis plan.
The safety analysis will be based on the reported AEs and other safety information, such as 
clinical laboratory data, vital signs, etc. Safety and acceptability assessments (local tolerability) 
are the primary objectives of the extension parts of the studies (see Section 9.3).
All safety analyses will adhere to Sanofi “Guideline for the Analysis and Reporting of Safety Data 
from Clinical Trials.”
Observation period 
The observation period will be divided into 5 epochs: Screening, Treatment in core period, 
Treatment in extension period, Follow-up, and Post-study (defined below):
x
The Screening epoch is defined as the time from the signed informed consent date up to 
the time prior to the first dose of IMP.
x
The Core-treatment epoch is defined as the time from the first dose of IMP to last dose in 
the core treatment phase + 13 days (or + 6 days for patients on weekly dosing), or first 
dose of IMP in the extension period for patients who enter the extension phase.
x
The Extension treatment epoch is defined as the time from first dose of IMP in extension 
period to last dose of IMP in extension period + 13 days (or + 6 days for patients on 
weekly dosing). Only patients who enter the extension period have the Extension 
treatment epoch.
x
The Follow-up treatment epoch is defined as the time from the EOT epoch (ie, the end of 
core-treatment epoch for patients not entering in the extension period; or the end of the 
extension treatment epoch for patients who enter the extension period) to last dose of 
IMP + 60 days.
x
The Post-study epoch is defined as the time after the last dose of IMP + 60 days. The 
rationale of having “last dose of IMP + 60 days” as the end of follow-up epoch is to 
capture the events observed within approximately 5 half-lives of the last IMP.
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The entire TEAE period includes the core treatment, extension treatment (only applicable for 
patients who enter the extension), and follow-up epochs. The TEAE period in the core treatment 
phase includes core-treatment epoch for patients who enter the extension, and includes 
core-treatment and follow-up epochs for patients not entering the extension.
All safety analyses will be performed on the safety population, unless otherwise specified, using 
the following common rules:
x
The baseline value is defined as the last available value prior to the first dose of the study 
medication.
x
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests and vital signs.
x
The PCSA criteria will determine which patients had at least 1 PCSA during the TEAE 
period, taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.
x
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the TEAE period by dose 
regimen on the safety population.
x
For quantitative safety parameters based on laboratory measurements, descriptive statistics 
will be used to summarize results and change from baseline values by visit and dose 
regimen. Summaries will include the endpoint value. The endpoint value is commonly 
defined as the value collected at the same day/time of the last dose of investigational 
product. If this value is missing, this endpoint value will be the closest one prior to the last 
dose intake.
x
Analyses of the safety variables will be essentially descriptive and no systematic 
between-group testing is planned.
Adverse events 
Adverse event incidence tables will present the number (n) and percentage (%) of patients in each 
dose regimen cohort experiencing an AE by primary system organ class (SOC; sorted by 
internationally agreed SOC order), high-level group term (HLGT), high-level term (HLT) and 
preferred term (PT) sorted in alphabetical order. Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each dose regimen.
All treatment-emergent AESIs will be summarized by AESI category and PT, showing 
number (%) of patients, sorted by decreasing incidence of PT within each AESI category (see
Section 10.4.4.1).
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Death
The incidence of death, if applicable, will be generated on the safety population 
Number (%) of patients who died by study period (on-treatment, during follow-up or post-study):
x
Death in included but not treated patients 
x
TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT, and by primary SOC and PT, 
showing number (%) of patients sorted by internationally agreed order of SOC and 
alphabetic order of HLGT, HLT, and PT for the 4-level summary. 
Clinical laboratory evaluations
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all laboratory variables (laboratory values and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each post baseline time point, endpoint) by 
dose regimen. This section will be organized by biological function.
The incidence of PCSAs and abnormal laboratory values at any time during the TEAE period will 
be summarized by biological function and dose regimen.
For lipids, the NCEP APTIII classification will be used for the baseline.
The incidence of neutropenia, thrombocytopenia, and lymphopenia by maximal grade will be 
summarized.
Hepatic disorders
The liver function tests (LFTs), namely AST, ALT, ALP, and total bilirubin are used to assess 
possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by dose regimen for each parameter. The 
proportion of patients with PCSA values at any post baseline visit may be displayed by duration 
of exposure for each dose regimen cohort. 
A graph of the distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3x ULN for ALT and 
a horizontal line corresponding to 2x ULN for total bilirubin.
The normalization (to <1 ULN) or return to baseline (in case of baseline is >ULN) of elevated 
LFTs will be summarized by categories of elevation (>3 ULN, >5 ULN, >10 ULN, >20 ULN for 
ALT and AST; >1.5 ULN for ALP; and >1.5 ULN and >2 ULN for total bilirubin) with the 
following categories of normalization: 1) normalized on-treatment; 2) continued into extension 
study (for initial analysis of 12-week core treatment phase); 3) normalized after last dose; 
4) last value not normal. The labs measured during the post-study period will be considered in the 
analysis of normalization. Note that a patient is counted only once under the maximum elevation 
category.
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Vital signs
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all vital signs variables (vital signs values and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each post baseline time point, endpoint) by 
dose regimen. The average of the two systolic blood pressure (SBP) and the two diastolic blood 
pressure (DBP) readings for a patient at a particular visit will be used for analysis.
The incidence of PCSAs at any time during the TEAE period will be summarized by dose 
regimen.
11.4.4 Analyses of pharmacokinetic and pharmacodynamics variables
Pharmacokinetic (PK) analyses will be performed using the PK population via pooling all 
available data.
Serum trough concentrations of functional sarilumab will be summarized using descriptive 
statistics (including number, arithmetic and geometric means, standard deviation, standard error of 
the mean (SEM), CV, minimum, median, and maximum) by dose, overall and by weight group, 
for each visit. The samples will be considered non eligible for these analyses if the previous 
dosing time is <11 days or >17 days before the sampling time for q2w regimens; <5 days or >9 
days before the sampling time for qw regimens. Concentrations below the lower limit of 
quantification (LLOQ) will be set to zero for samples at predose (Week 0). Other concentrations 
below LLOQ will be replaced by LLOQ/2. Semi log plots of concentration over time will also be 
provided (no value at time 0). Serum concentrations of functional sarilumab will be summarized 
using descriptive statistics mentioned above by immunogenicity status for each dose at each visit 
(see Section 9.1 and Section 9.7).
A PopPK model will be developed using 
 to describe the PK 
profile of sarilumab. A PopPK model will be used to estimate population and individual PK 
parameters, the sources of PK variability and assess the influence of covariates on PK parameters. 
The potential covariates to be evaluated in the PopPK analysis include 
The predicted individual sarilumab PK exposure (Cmax and AUC0-τ) following the first 
dose will be summarized using descriptive statistics by dose and weight group. PopPK results 
may be presented in a separate document from the CSR.
Serum concentrations of IL-6, total sIL-6Rα and hs-CRP will be summarized using descriptive 
statistics (including number, arithmetic and geometric means, standard deviation, standard error of 
the mean [SEM], CV, minimum, median, and maximum) by dose and weight group for each visit 
(Section 9.1 and Section 9.7).
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11.4.6 Analysis of immunogenicity variables
At each sample time, the result of the ADA assay will be categorized as either positive or 
negative, and in the case of a positive result will be further characterized as either neutralizing or 
non-neutralizing.
ADA-positive patient is defined as a patient with at least 1 treatment-emergent or 
treatment-boosted ADA-positive sample during the TEAE period, where
x
Treatment-emergent ADA-positive patient is defined as a patient with non-positive assay 
(meaning negative or missing) response at baseline but with a positive assay response 
during the TEAE period
x
Treatment-boosted ADA-positive patient is defined as a patient with a positive ADA assay 
response at baseline and with at least a 4-fold increase in titer compared to baseline during 
the TEAE period.
ADA-negative patient is defined as a patient without a treatment-emergent or treatment-boosted 
ADA-positive sample during the TEAE period.
ADA prevalence and titer
The following summary will be provided based on the ADA population:
x
Number (%) of patients with an ADA-positive sample at baseline
-
Number (%) of neutralizing antibody
-
Number (%) of non-neutralizing antibody
-
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) 
of the titer for the baseline ADA-positive patients
x
Number (%) of patients with an ADA-negative sample at baseline.
ADA incidence and titer
The following summary will be provided based on the ADA population during the TEAE period:
x
Number (%) of ADA-negative patients
x
Number (%) of ADA-positive patients
-
Number (%) of patients with neutralizing antibody
-
Number (%) of patients with non-neutralizing antibody
x
Number (%) of treatment-emergent ADA-positive patients
-
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) 
of the peak post baseline titer for treatment-emergent ADA-positive patients
x
Number (%) of treatment-boosted ADA-positive patients
-
Number (%) of patients with neutralizing antibody
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-
Number (%) of patients with non-neutralizing antibody.
In addition, number (%) of patients with ADA-positive or negative response at each visit will be 
summarized by dose.
ADA and PK
By visit descriptive summary of serum concentration of sarilumab will be provided by ADA 
patient classification (positive or negative) for each dose regimen.
Scatter plots of serum concentration versus visit will also be provided by ADA classification 
(positive or negative) and dose regimen.
11.5
INTERIM ANALYSIS
Ongoing review of safety data will be performed by an independent DMC (Section 6.2). The 
timing of DMC reviews will be detailed in the DMC charter. An internal DEC will review 
accumulating safety, PK, PD, and efficacy data, according to the timing and rules described in 
Section 6.1.2.
The first formal interim analysis will be performed once sufficient Week 12 data have been 
observed from the dose-finding portion of the study to allow a selection of a dose regimen for 
more detailed investigation. If the enrollments for Weight Group B are not completed within a 
similar time frame as that for weight Group A, the dose selection for weight Group A will be done 
separately from the dose selection for weight Group B, ie, two separate data analyses will be 
needed.
The second interim analysis will be performed approximately 1 year from the time every patient 
enrolled in the dose-finding and second portions has received the selected dose regimen (either 
new enrolled patients or patients already in the extension phase). Only patients enrolled in the 
dose-finding and second portions will be included in this interim analysis.
The third interim analysis will occur approximately 1 year from the time the last patient is
enrolled in the third portion.
The final database lock will occur approximately 4 weeks after the last patient has completed the 
EOS visit.
The primary objective is PK estimation and there is no formal hypothesis testing, thus there are no
statistical implications for the summary and reporting of the final data at the conclusion of the 
extension.
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12
ETHICAL AND REGULATORY CONSIDERATIONS
12.1
ETHICAL AND REGULATORY STANDARDS
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Sub-investigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, in particular the Declaration of Helsinki as amended in 1996 for clinical trials with 
medicinal products in the EU, and the ICH guidelines for good clinical practice (GCP), all 
applicable laws, rules and regulations.
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Sub-investigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the ICH guidelines for GCP, all applicable laws, rules and regulations. This 
clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later than 
21 days after the first patient enrollment, in compliance with applicable regulatory requirements 
and with Sanofi public disclosure commitments.
12.2
INFORMED CONSENT
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient who is 
≥6 years and parent(s) or legal guardian(s) of all pertinent aspects of the clinical trial including 
the written information giving approval/favorable opinion by the Ethics Committee (IRB/IEC). 
All patient(s)/parent(s)/legal guardian(s) should be informed to the fullest extent possible about 
the study, in language and terms they are able to understand.
It is the responsibility of the Investigator or designee (if acceptable by local regulations) to obtain 
written informed assent from each patient ≥6 years of age (or above an age determined by the 
IRB/IEC and in according with the local regulations and requirements) and written informed 
consent from each patient’s parent(s) or legal guardian(s) prior to the patient’s participation in the 
study. The written informed consent should be signed and dated by the patient’s parent(s) or legal 
guardian(s) and the same Investigator or designee. 
Local law must be observed in deciding whether 1 or both parents/guardians consent is required. 
If only 1 parent or guardian signs the consent form, the Investigator must document the reason the 
other parent or guardian did not sign. The patient may also be required to sign and date the ICF as 
determined by the IRB/IEC and in accordance with the local regulations and requirements. 
x
Patient(s)/parent or legal guardian(s) who can write but cannot read will have the 
assent/consent form read to them before writing their name on the form
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x
Patients/parent or legal guardian who can understand but who can either write nor read 
will have the informed assent/consent form read to them in presence of an impartial 
witness, who will sign and date the assent/consent form to confirm that informed consent 
was given.
The original assent/consent form must be retained by the Investigator as part of the patient’s study 
record and a copy of the signed assent/consent form must be given to the patient/patient’s 
parent(s) or legal guardian(s). 
The patient’s general practitioner (family doctor) if any and if the parents/legal guardian and 
patient agree will be informed by the Investigator of the patient’s participation in this study. 
Information regarding the study treatment will be sent to the family doctor.
The informed assent/consent form used by the Investigator must be reviewed and approved by the 
Sponsor prior to submission to the appropriate Ethics Committee (IRB/IEC) for 
approval/favorable opinion. In relation with the population of patients exposed in the trial, 
ie, pediatric/minor patients, the IRB/IEC should ensure proper advice from specialists with 
pediatrics expertise (competent in the area of clinical, ethical, and psychosocial problems in the 
field of pediatrics) according to national regulations. A copy of the IRB/IEC-approved 
assent/consent form and documentation of approval must be provided to sponsor before initiation 
of the study.
In relation with the population of patients exposed in the trial, ie, pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialists with pediatrics expertise (competent in the 
area of clinical, ethical, and psychosocial problems in the field of pediatrics) according to national 
regulations.
If new safety information results in significant changes in the risk/benefit assessment, the ICF
must be reviewed and updated appropriately. All study patients and their parents or legal 
guardian(s) must be informed of the new information and provide their written assent (if 
applicable) or consent if they wish the patient to continue in the study. The original signed revised 
assent/consent form must be maintained in the patient’s study record and a copy must be given to 
the patient’s parent(s) or legal guardian(s). If the race/ethnic origin of the patients will be 
collected in the clinical trial, the scientific justification should be specified in Section 14.5.
A locally approved specific consent form will be signed by patients who require Gilbert syndrome 
genetic testing (consent must be obtained prior to performing this assessment and local 
regulations should be respected).
12.3
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party a 
copy of the written and dated approval/favorable opinion signed by the Chairman with IRB/IEC 
composition.
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The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s Brochure, Investigator’s curriculum vitae, 
etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion.
Investigational medicinal product (IMP) will not be released at the study site and the Investigator 
will not start the study before the written and dated approval/favorable opinion is received by the 
Investigator and the Sponsor.
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC.
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.
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13
STUDY MONITORING
13.1
RESPONSIBILITIES OF THE INVESTIGATOR(S)
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives.
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred.
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Sub-investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The 
Sub-investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information.
13.2
RESPONSIBILITIES OF THE SPONSOR
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial.
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data.
13.3
SOURCE DOCUMENT REQUIREMENTS
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
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Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the CRFs (eg, patient's medical file, appointment 
books, original laboratory records). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules).
13.4
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL
REQUEST
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data.
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF.
The computerized handling of the data by the Sponsor when available in the e-CRF may generate 
additional requests (DRF) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be managed through the 
e-CRF. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.
13.5
USE OF COMPUTERIZED SYSTEMS
Computerized systems anticipated for use during the different steps of the study are listed below. 
New computerized systems may be established and the obsolete system may be deleted:
x
For Screening and inclusion activities, IVRS/IWRS
x
For data management activities, e-CRF (Rave Medidata)
x
For statistical activities, SAS
x
For pharmacovigilance activities, AWARE
x
For monitoring activities,  IMPACT
x
For medical writing activities, Vault RIM.
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14
ADDITIONAL REQUIREMENTS
14.1
CURRICULUM VITAE
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial.
14.2
RECORD RETENTION IN STUDY SITES
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents.
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial.
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required.
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation.
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a
mutually agreed upon designee.
14.3
CONFIDENTIALITY
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor.
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics Committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality.
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial.
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The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account.
14.4
PROPERTY RIGHTS
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor.
The Investigator shall not and shall cause the delegated Investigator staff/Sub-investigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights.
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor.
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial.
As the case may be, the Investigator and/or the Sub-investigators shall provide all assistance
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents.
14.5
DATA PROTECTION
x
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations.
x
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party.
x
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations.
Subject race or ethnicity will be collected in this study because these data are required by several 
regulatory authorities (eg, on African-American population for FDA). Also, race/ethnicity data 
will be used as covariates in PopPK analysis as described in Section 11.4.5.
14.6
INSURANCE COMPENSATION
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
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obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.
14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities.
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information.
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents.
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection.
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections.
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor.
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections.
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE
14.8.1 By the Sponsor
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 
x
The information on the product leads to doubt as to the benefit/risk ratio
x
Patient enrollment is unsatisfactory
x
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon
x
Noncompliance of the Investigator or Sub-investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP
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x
The total number of patients are included earlier than expected.
In any case the Sponsor will notify the Investigator of its decision by written notice.
14.8.2 By the Investigator
The Investigator may terminate his/her participation upon thirty days' prior written notice if the 
study site or the Investigator for any reason becomes unable to perform or complete the clinical 
trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements.
14.9
CLINICAL TRIAL RESULTS
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator.
14.10 PUBLICATIONS AND COMMUNICATIONS
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval.
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve months of the completion of this study at all sites, the Investigator shall 
have the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s).
The Sponsor has the right at any time to publish the results of the study.
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15
CLINICAL TRIAL PROTOCOL AMENDMENTS
All appendices attached hereto and referred to herein are made part of this clinical trial protocol.
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol.
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons.
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be recollected if necessary.
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16
BIBLIOGRAPHIC REFERENCES
1. IGRA Expert Committee, Centers for Disease Control and Prevention (CDC). Updated 
guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis 
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League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second 
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College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: 
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quality of life in juvenile idiopathic arthritis. Arthritis Rheum. 2009 15;61(3):393-9.
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interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin 
Invest. 1989;83:585-92.
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12. Mangge H, Kenzian H, Gallistl S, Kaulfersch W, Beaufort F, Muntean W, et al. Serum 
cytokines in juvenile rheumatoid arthritis. Correlation with conventional inflammation  
parameters and clinical subtypes. Arthritis Rheum. 1995;38(2):211-20.
13. Maddison P, Woo P, Glass D, Breedveld FC. Oxford textbook of rheumatology. Oxford: 
Oxford University Press; 2004.
14. Brunner H, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, et al. Efficacy and safety of 
tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a 
phase 3, randomized, double-blind withdrawal trial. Ann Rheum Dis. 2015;74(6):1110-17.
15. FDA. Tocilizumab, Clinical Pharmacology Review; BLA125276/22, supplement 22; Oct 15, 
2010.
16. European Medicines Agency. Ethical considerations for clinical trials on medicinal products 
conducted with the paediatric population. Recommendations of the ad hoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to good clinical 
practice in the conduct of clinical trials on medicinal products for human use London: 
European Medicines Agency. 2008.
17. Thomas G. Pickering, MD, DPhil; John E. Hall, PhD; Lawrence J. Appel, MD; et al. 
Recommendations for blood pressure measurement in humans and experimental animals: part 
1: blood pressure measurement in humans: a statement for professionals from the 
Subcommittee of Professional and Public Education of the American Heart Association 
Council on High Blood Pressure Research. 2005;111(5):697-716.
18. Gurkirpal S, Balu H A, James FF, Donald PG. Measurement of Health Status in Children with 
Juvenile Rheumatoid Arthritis. Arthritis Rheum. 1994;37(12);1761-69.
19. Dempster H1, Porepa M, Young N, Feldman BM. The Clinical Meaning of Functional 
Outcome Scores in Children With Juvenile Arthritis. Arthritis Rheum. 2001;44(8);1768-74.
20. Klepper S. Exercise and Fitness in Children With Arthritis : Evidence of Benefits for Exercise 
and Physical Activity. Arthritis Rheum. 2003 June 15:49(3);435-43.
21. Bazso A, Consolaro A, Niccolino R, Pistorio A, Viola S, Magni-Manzoni S. Development and 
Testing of Reduced Joint Counts in Juvenile Idiopathic Arthritis. J Rheumatol. First Release 
2008, 2009;36(1):183-90.
22. Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ,  Dewitt EM. American 
College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: 
Initiation and Safety Monitoring of Therapeutic Agents for the Treatment of Arthritis and 
Systemic Features; Arthritis Care Res (Hoboken). 2011;63(4):465-82.
23. Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni̺Manzoni S, Filocamo G et al. 
Development and validation of a composite disease activity score for juvenile idiopathic 
arthritis. Arthritis Rheum. 2009; 61(5):658-66.
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24. NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents; National 
Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on 
Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992 March 1;89(3);495-
501.
25. Zhang X, Morcos PN, Saito T, Terao K. Clinical pharmacology of tocilizumab for the 
treatment of systemic juvenile idiopathic arthritis. Expert Rev Clin Pharmacol. 2013;6(2):123-
37.
26. Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample 
size when designing pediatric pharmacokinetics studies. J Clin Pharmacol. 
2012;52(10):1601̻06.
27. De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized 
trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 
2012;367(25):2385-95.
28. De Benedetti F, Ruperto N, Baildam E, Burgos-Vargas R, Horneff G, Huppertz HI, et al. A14: 
Neutropenia with tocilizumab treatment is not associated with increased infection risk in 
patients with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2014;66(S3):S23-4.
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17
APPENDICES
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Appendix A
Subclassification of rheumatoid factor (RF)-negative, rheumatoid 
factor (RF)-positive polyarticular and oligoarticular juvenile 
idiopathic arthritis (JIA)
JIA subtypes
Clinical 
features 
defined by 
ILAR 
Classification
Exclusion 
criteria 
(footnote a)
Frequency
(% of total JIA)*
Onset (yrs)
Mean-range
Outcome
RF-negative 
pcJIA (5,7,6)  
- Affects 5 or 
more joints in 
the first 6 
months of 
disease.  
- Tests for RF 
negative 
- Tendosynovitis, 
uveitis, 
vasculitis 
a, b, c, d, e 
15% 
7-9 yrs 
Two peaks:  
- early: 1-3 yrs 
- later: 6-12 yrs 
- 10% 
destructive joint 
disease 
RF-positive pcJIA (5) 
ANA 
- ILAR Affects 
oJIA5 pcJIA or 
more joints in 
the first 6 
months of 
disease.  
- Tests for 
RFpositive twice 
at least 2 
months apart 
- Tenosynovitis, 
rheumatoid 
nodules, 
vasculitis, 
Sjögren’s 
syndrome 
a, b, c, e 
5% 
12-14 yrs 
10 - 18 yrs 
- Like adult RA 
- Seen in late 
childhood 
- Severe 
destructive joint 
disease 
oJIA (5,7,6) 
x
Persistent 
 
 
x
Extended
 
- Affects no more 
than 4 joints 
throughout the 
disease course 
 
- Affects more 
than 4 joints 
after the first 
6 months 
a, b, c, d, e 
50% 
2-3 yrs 
 
1-5 yrs 
- Young age 
onset 
- Chronic uveitis, 
especially 
ANA+ 
- Leg length 
discrepancy 
 
- Destructive 
joint disease 
- Therapy as for 
pcJIA 
a. Psoriasis or history of psoriasis in patients or first-degree relatives.  
b. Arthritis in HLA B27 positive males beginning after the age of 6 years;  
c. Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter's syndrome, acute anterior uveitis, or 
history of 1 of these disorders in first-degree relatives;  
d. Presence of IgM rheumatoid factor on at least 2 occasions at least 3 months apart;  
e. Presence of systemic JIA in patients. 
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Appendix B
Volume to be administered at each injection according to body 
weight
Notes:
1) Volume to be administrated at each injection during 12-week core treatment 
phase will be calculated based on Baseline (Visit 2) body weight and will be 
maintained during all 12-week core treatment phase.
2) Volume to be administrated during the extension treatment phase will be 
adjustable by body weight measured at each visit in case of weight increase and if 
the calculation shows a need for dose increase.
3) If the selected dose regimen is one from the 3 predefined dose regimens, the 
patients subsequently enrolled at or changed to the selected dose regimen will use 
the corresponding dose in the tables below.
4) If the selected dose regimen is an intermediate dose, corresponding tables will be 
provided to the Investigators.
B.1 Patient in high weight group (Group A): Patients ≥30 kg and ≤60 kg for 
dose-finding portion and ≥30 kg for additional patients in the second portion
x Dose Regimen 1 and 3 Cohorts
Dose Regimen 1 Cohort (2 mg/kg q2w) and Dose Regimen 3 Cohort 
(2 mg/kg qw)
Body weight (kg)
Volume per injection (mL)
Corresponding dose (mg)
≥30 and <33
0.35
61.25
≥33 and <37.5
0.40
70
≥37.5 and <42
0.45
78.75
≥42 and <46.5
0.50
87.5
≥46.5 and <50.5
0.55
96.25
≥50.5 and <55 
0.60
105
≥55 and <59.5
0.65
113.75
≥59.5 and <64
0.70
122.5
≥64 and <68
0.75
131.25
≥68 and <72.5
0.80
140
≥72.5 
0.85 (cap injection volume)
148.75 (cap under 150 mg)
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x
Dose Regimen 2 Cohort
Dose Regimen 2 Cohort (3 mg/kg q2w)
Body weight (kg)
Volume per injection (mL)
Corresponding dose (mg)
≥30 and <31
0.50
87.5
≥31 and <34
0.55
96.25
≥34 and <37
0.60
105
≥37 and <39.5
0.65
113.75
≥39.5 and <42.5
0.70
122.5
≥42.5 and <45 
0.75
131.25
≥45 and <48.5
0.80
140
≥48.5 and <51.5
0.85
148.75
≥51.5 and <54.5
0.90
157.5
≥54.5 and <57
0.95
166.25
≥57 and <63
1.00
175
≥63 
1.1 (cap injection volume)
192.5 (cap under 200 mg)
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B.2 Patient in low weight group (Group B): <30 kg and ≥10 kg
x
Dose Regimens 1 and 3 Cohorts
Dose Regimen 1 Cohort (2.5 mg/kg q2w) and Dose Regimen 3 Cohort 
(2.5 mg/kg qw)
Body weight (kg)
Volume per injection (mL)
Corresponding dose (mg)
≥10 and <12.5
0.15
26.25
≥12.5 and <16
0.20
35
≥16 and <19.5
0.25
43.75
≥19.5 and <23
0.30
52.5
≥23 and <26.5
0.35
61.25
≥26.5 and <30
0.40
70
For patients who grow over 30 kg, the following injection 
volume will be followed
≥30 and <37.5
0.40
70
≥37.5 and <42
0.45
78.75
≥42 and <46.5
0.50
87.5
≥46.5 and <50.5
0.55
96.25
≥50.5 and <55
0.60
105
≥55 and <59.5
0.65
113.75
≥59.5 and <64
0.70
122.5
≥64 and <68
0.75
131.25
≥68 and <72.5
0.80
140
≥72.5
0.85 (cap injection volume)
148.75 (cap under 150 mg)
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x
Dose Regimen 2 Cohort
Dose Regimen 2 Cohort (4 mg/kg q2w)
Body weight (kg)
Volume per injection (mL)
Corresponding dose (mg)
≥10 and <12.5
0.25
43.75
≥12.5 and <14.5
0.30
52.5
≥14.5 and <16.5
0.35
61.25
≥16.5 and <19
0.40
70
≥19 and <21
0.45
78.75
≥21 and <23.5
0.50
87.5
≥23.5 and <25.5
0.55
96.25
≥25.5 and <27.5
0.60
105
≥27.5 and <30
0.65
113.75
For patients who grow over 30 kg, the following injection                      
volume will be followed
≥30 and <39.5
0.65
113.75
≥39.5 and <42.5
0.70
122.5
≥42.5 and <45
0.75
131.25
≥45 and <48.5
0.80
140
≥48.5 and <51.5
0.85
148.75
≥51.5 and <54.5
0.90
157.5
≥54.5 and <57
0.95
166.25
≥57 and <60.5 
1.00
175
≥60.5 and <63
1.00
175
≥63
1.1 (cap injection volume)
192.5 (cap under 200 mg)
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Appendix C
Definition of Efficacy and JIA ACR 30/50/70/90/100
In the dose-finding and second portions, patients who do not achieve a JIA ACR30 by the end of 
the 12-week core treatment phase should be discontinued from the study treatment to receive 
standard of care as per the Investigator’s clinical judgment. Assessment for lack of efficacy may 
be initiated after the patient has received at least six weeks of study treatments.
The definition for improvement in JIA [ACR Pediatric 30 criteria (Pedi30)] defines ≥3/6 core set 
variables improved ≥30% from baseline with no more than 1/6 worsened by ≥30% (3, 22)
The definition for improvement in JIA [ACR Pediatric 50 criteria (Pedi50)] defines ≥3/6 core set 
variables improved ≥50% from baseline with no more than 1/6 worsened by ≥30% 
The definition for improvement in JIA [ACR Pediatric 70 criteria (Pedi70)] defines ≥3/6 core set 
variables improved ≥70% from baseline with no more than 1/6 worsened by ≥30% 
The definition for improvement in JIA [ACR Pediatric 90 criteria (Pedi90)] defines ≥3/6 core set 
variables improved at least 90% from baseline with no more than 1/6 worsened by ≥30% 
The definition for improvement in JIA [ACR Pediatric 100 criteria (Pedi100)] defines ≥3/6 core 
set variables improved ≥100% from baseline with no more than 1/6 worsened by ≥30% 
ACR JIA Core Set Includes:
x
Physician global assessment of disease activity - Visual Analogue Scale (VAS) 
x
Parent or patient assessment of overall well-being
x
Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI)
x
Number of joints with active arthritis
x
Number of joints with limited range of motion
x
Index of inflammation: hs-CRP.
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Appendix D
Subject’s and Physician’s Global Assessment of Disease Activity
SUBJECT’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY
Considering all the ways that your arthritis affects you, rate how you are doing on the following 
scale by placing a vertical mark on the line:
Very well
Very poor 
0 mm
100 mm
PHYSICIAN’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY
Place a vertical mark on the line rating your patient’s current activity level
Not active
Very active 
0 mm
100 mm
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Appendix E
Childhood Health Assessment Questionnaire
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Reference: 
Marshall WA, Tanner JM (February 1970). "Variations in the pattern of pubertal changes in 
boys". Arch. Dis. Child. 45 (239): 13–23. doi:10.1136/adc.45.239.13. PMC 2020414. PMID 
5440182.
Marshall WA, Tanner JM (June 1969). "Variations in pattern of pubertal changes in girls". Arch. 
Dis. Child. 44 (235): 291–303. doi:10.1136/adc.44.235.291. PMC 2020314. PMID 5785179.
Encyclopedia of Children’s Health; Puberty: w.healthofchildren.com/P/Puberty.html
Source: http://www.ncbi.nlm.nih.gov/books/NBK138588/table/annexh.t1/?report=objectonly
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Appendix G
General Guidance for the follow-up of laboratory abnormalities by Sanofi
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Appendix H
Anaphylaxis definition
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.”
(Adapted from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, 
et al. Second symposium on the definition and management of anaphylaxis: Summary report—
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol 2006; 117: 391-7)
Clinical criteria for diagnosing anaphylaxis
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Appendix I
List of opportunistic infections
x
Aspergillosis 
x
Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along Mississippi and Ohio Rivers) 
x
Candidiasis - systemic or extensive mucocutaneous cases 
x
Coccidioides immitis (endemic south-western US and Central and South America) 
x
Paracoccidiodomycosis 
x
Cryptococcus 
x
Cytomegalovirus 
x
Herpes Simplex (severe/disseminated) 
x
Herpes Zoster 
x
Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-Ohio-Mississippi river basins) 
x
Listeriosis 
x
Infection with mycobacterium avium and other non-tuberculosis mycobacteria 
x
Pneumocystis pneumonia (PCP) 
This list is indicative and not exhaustive.
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Appendix J
Prohibited live (attenuated) vaccine list
Chickenpox (Varicella) 
Intranasal influenza 
Measles (Rubeola) 
Measles-mumps-rubella (MMR) combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (Vaccinia) 
Shingles (Herpes zoster) 
Bacille Calmette-Guerin 
Yellow fever 
Note: This list is indicative and not exhaustive.
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Appendix K
Country specific requirements
Country specific requirements are included in the body of the protocol.
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
ECG parameters 
Ref. : Rijnbeek P.R. et al., 
Eur Heart J 2001; Davignon 
A. et al., Ped Cardiol 
1979/1980; Semizel E.et al., 
Cardiol Young 2008; Mulberg 
AE et al. Pediatric Drug 
Development Concepts and 
applications. John Wiley & 
sons, Inc. 2009 
HR 
Birth/0 to 27 days old 
(Neonates) 
d90 bpm and decrease from baseline t20 bpm 
t190 bpm and increase from baseline t20 bpm 
 
28 days/1 month to 23 
months old (Infants) 
d80 bpm and decrease from baseline t20 bpm 
t175 bpm and increase from baseline t20 bpm 
24 months/2 years to <6 
years old (Children) 
d75 bpm and decrease from baseline t20 bpm 
t140 bpm and increase from baseline t20 bpm 
6 to <12 years old (Children) 
d50 bpm and decrease from baseline t20 bpm 
t120 bpm and increase from baseline t20 bpm 
12 to 16/18 years old 
(Adolescents) 
d50 bpm and decrease from baseline t20 bpm  
t120 bpm and increase from baseline t20 bpm 
PR 
Birth/0 to 27 days old 
(Neonates) 
t120 ms 
 
28 days/1 month to 23 
months old (Infants) 
t140 ms 
24 months/2 years to <6 
years old (Children) 
t160 ms 
6 to <12 years old (Children) 
t170 ms 
12 to 16/18 years old 
(Adolescents) 
t180 ms 
QRS 
Birth/0 to 27 days old 
(Neonates) 
t85 ms 
 
28 days/1 month to 23 
months old (Infants) 
t85 ms 
2 to <6 years old (Children) 
t95 ms 
6 to <12 years old (Children) 
t100 ms 
12 to 16/18 years old 
(Adolescents) 
t110 ms 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
QTc  
Birth/0 to <12 years old  
(Neonates, Infants, Children) 
 
 
 
 
 
 
 
Absolute values (ms)  
Borderline: 431-450 ms  
Prolonged*: >450 ms  
Additional: ≥500 ms 
 
AND 
 
Increase from baseline  
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms 
To be applied to QTcF 
 
*QTc prolonged and 
'QTc>60 ms are the PCSA 
to be identified in individual 
subjects/patients listings. 
 
12 to 16/18 years old 
(Adolescents) 
 
Borderline: 431-450 ms (Boys); 451-470 ms (Girls) 
Prolonged*: >450 ms (Boys); >470 ms (Girls) 
Additional: ≥500 ms 
 
AND 
 
Increase from baseline  
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms  
Vital Signs 
Ref. : Kidney Disease 
Outcomes Quality Initiatives 
(KDOQI) Guideline 13; 1996; 
The fourth report on the 
diagnosis, evaluation, and 
treatment of high blood 
pressure in children and 
adolescents, Pediatrics 2004; 
Bowman E & Fraser S 
Neonatal Handbook 2012;  
Mulberg AE et al. Pediatric 
Drug Development Concepts 
and applications. John Wiley 
& sons, Inc. 2009; Pediatric 
respiratory rates 
http://www.health.ny.gov/ 
SBP  
 
Birth/0 to 27 days old 
(Neonates) 
d60 mmHg and decrease from baseline t20 
mmHg  
t85mHg and increase from baseline t20 mmHg 
Based on definition of 
Hypertension as average 
SBP or DBP ≥ 95th percentile 
for gender, age, and height 
on ≥ 3 occasions 
28 days/1 month to 23 
months old (Infants) 
d70 mmHg and decrease from baseline t20 
mmHg  
t98 mmHg and increase from baseline t20 
mmHg 
24 months/2 years to <6 
d70 mmHg and decrease from baseline t20 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
years old (Children) 
mmHg  
t101mHg and increase from baseline t20 mmHg 
6 to <12 years old (Children) 
d80 mmHg and decrease from baseline t20 
mmHg  
t108 mmHg and increase from baseline t20 
mmHg 
12 to 16/18 years old 
(Adolescents) 
d90 mmHg and decrease from baseline t20 
mmHg  
t119mmHg and increase from baseline t20 
mmHg 
DBP 
  
 
Birth/0 to 27 days old 
(Neonates) 
d34 mmHg and decrease from baseline t10 
mmHg  
t50mHg and increase from baseline t10 mmHg 
 
28 days/1 month to 23 
months old (Infants) 
d34 mmHg and decrease from baseline t10 
mmHg  
t54mHg and increase from baseline t10 mmHg 
24 months/2 years to <6 
years old (Children) 
d34 mmHg and decrease from baseline t10 
mmHg  
t59mHg and increase from baseline t10 mmHg  
6 to <12 years old (Children) 
d48 mmHg and decrease from baseline t10 
mmHg  
t72mHg and increase from baseline t10 mmHg  
12 to 16/18 years old 
(Adolescents) 
d54 mmHg and decrease from baseline t10 
mmHg  
t78mHg and increase from baseline t10 mmHg  
Orthostatic 
hypotensio
n 
All age ranges 
SBP : St — Su ≤ - 20 mmHg  
DBP : St — Su ≤ - 10 mmHg  
 
Temperatur
e 
All age ranges 
Rectal, ear or temporal artery: >100.4 °F/38.0 °C 
Oral or pacifier: >99.5 °F/37.5 °C 
Axillary or skin infrared: >99 °F/37.2 °C 
Ear temperature not accurate 
below 6 months of age 
Respiratory 
rate 
Birth/0 to 27 days old 
(Neonates) 
< 30 per minutes  
> 60 per minutes 
Based on normal range 
 
28 days/1 month to 23 
months old (Infants) 
< 24 per minutes  
> 40 per minutes 
24 months/2 years to <6 
years old (Children) 
< 22 per minutes  
> 34 per minutes 
6 to <12 years old (Children) 
< 18 per minutes  
> 30 per minutes 
12 to 16/18 years old 
(Adolescents) 
< 12 per minutes  
> 20 per minutes 
Sa02 
All age ranges 
<95 % 
 
Weight 
All ranges 
>5 % weight loss from baseline 
 
Based on identification of 
trends in the child’s growth 
with a series of visits 
WHO Multicentre Reference 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Study Group, 2006; Center 
for Disease Control. Growth 
chart 2007 
Clinical Chemistry  
Ref Molleston JP et al. JPGN 
2011; Moritz et al., Pediatrics 
1999; Moritz et al., Pediatr 
Nephrol 2005 ; Sedlacek et 
al., Seminars in Dialysis 
2006) Gong G et al. Clinical 
Biochemistry 2009; 
Masilamani et al. Arch Dis 
Children 2012; Mulberg AE 
et al. Pediatric Drug 
Development Concepts and 
applications. John Wiley & 
sons, Inc. 2009 
ALT/SGPT 
All age ranges 
>3 ULN 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Based on normal ranges: 6 
to 50 U/L (0-5 days), 5 to 45 
U/L (1-19 years)  
AST/SGOT 
All age ranges 
>3 ULN 
By distribution analysis: 
>3 ULN    
>5 ULN   
>10 ULN  
>20 ULN 
Based on normal ranges: 35 
to 140 U/L (0-5 days), 15 to 
55 U/L (1-9 years), 5 to 45 
U/L (10-19 years) 
Alkaline 
Phosphatas
e 
All age ranges 
≥1.5 ULN 
Based on normal ranges: 
145 to 420 U/L (1-9 years), 
130 to 560 U/L (10-11 years), 
200 to 495 U/L (Boys 12-13 
years), 105 to 420 U/L (Girls 
12-13 years), 130 to 525 U/L 
(Boys 14-15 years), 70 to 
130 U/L (Girls 14-15 years), 
65 to 260 U/L (Boys 16-19 
years), 50 to 130 U/L (Girls 
16-19 years) 
Total 
Bilirubin 
All age ranges 
≥1.3 ULN 
CF = mg x 1.7 = μmol 
Based on normal ranges: <6 
mg/dL (Term 0-1 day), <8 
mg/dL (Term 1-2 days), <12 
mg/dL (Term 3-5 days), <1 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
mg/dL (Term >5 days) 
Conjugated 
Bilirubin 
All age ranges 
>35% Total Bilirubin and TBILI≥1.3 ULN 
CF = mg x 1.7 = μmol 
Based on normal range: 0 to 
0.4 mg/dL  
ALT and 
Total 
Bilirubin 
All age ranges  
ALT ≥ 3 ULN and Total Bilirubin ≥ 2 ULN 
 
CPK 
All age ranges 
≥3 ULN 
 
Creatinine 
Birth/0 to <6 years old 
(Neonates, Infants, Children) 
>53 μmol/L or 0.6 mg/dL   
CF = mg x 8.8 = μmol 
Based on normal ranges: 
<0.6 mg/dL (0-1 year), 0.5 
to 1.5 mg/dL (1 to 16/18 
years) 
6 years to <12 years old 
(Children) 
>90 μmol/L or 1.1mg/dL 
12 years to 16/18 years old 
(Adolsecents) 
>132μmol/L or 1.5mg/dL 
Creatinine 
Clearance 
All age ranges 
50 % of normal  
<60 ml/min/1.73m2 (After 1 year old) 
Based on GFR Bedside 
Schwartz Formula 
Based on normal ranges: 20 
to 50 (<8 days), 25 to 80 (8 
days to 1 month), 30 to 90 
(1-6 months), 40 to 115 (6-12 
months), 60 to 190 (12-23 
months), 90 to 165 (2-12 
years), 80-120 (After 12 
years)  
Uric Acid  
All age ranges 
<2.0 mg/dL or 119 μmol/L 
>8.0 mg/dL or 476 μmol/L  
CF = mg x 5.95 = μmol 
Based on normal ranges: 2.4 
to 6.4 mg/dL  
Blood Urea 
Nitrogen 
(BUN) 
Birth/0 to 27 days old 
(Neonates) 
≥4.3 mmol/L or 12 mg/dl 
CF = g x 16.66 = mmol 
Based on normal ranges: 3 
to 12 mg/dL (NN; 5 to 18 
mg/dL (other classes of age) 
28 days/1 month to 16/18 
years old (Infants, Children, 
Adolescents) 
≥6.4 mmol/L or 18 mg/dl 
Chloride 
All age ranges 
≤80 mmol/L or 80 mEq/L 
≥115 mmol/L or 115 mEq/L 
CF = 1 
Based on normal range: 98 
to 106 
Sodium 
All age ranges 
≤129 mmol/L or 129 mEq/L 
≥150 mmol/L or 150 mEq/L 
CF = 1 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Based on normal range : 134 
to 146 
Potassium 
Birth/0 to 27 days old 
(Neonates) 
≤3.0 mmol/L or 3.0 mEq/L 
≥7.0 mmol/L or 7.0 mEq/L 
CF = 1 
Based on normal ranges: 3.0 
to 7.0 (NN); 3.5 to 6.0 
(Infants); 3.5 to 5.0 (>Infants) 
28 days/1 month to 23 
months old (Infants) 
≤3.5 mmol/L or 3.5 mEq/L 
≥6.0 mmol/L or 6.0 mEq/L 
24 months/2 years to 16/18 
years old (Children, 
Adolescents) 
≤3.5 mmol/L or 3.5 mEq/L 
≥5.5 mmol/L or 5.5 mEq/L 
Bicarbonat
e 
All age ranges 
≤16 mmol/L or 16 mEq/L 
≥30 mmol/L or 30 mEq/L 
CF = 1 
Based on normal range: 18 
to 26 
Calcium 
total 
All age ranges 
≤2.0 mmol/L or 8.0 mg/dL 
≥2.9 mmol/L or 11.6 mg/dL 
CF = mg x 0.025 = mmol 
Based on normal range: 8.4 
to 10.9 mg/dL 
Calcium 
ionized 
All age ranges 
≤1.0 mmol/L or 4.0 mg/dL 
≥1.4 mmol/L or 5.6 mg/dL 
CF = mg x 0.025 = mmol 
Based on normal range: 4.0 
to 5.1 mg/dL 
Total 
Cholesterol 
All age ranges  
>6.20 mmol/L or 240 mg/dL 
CF = g x 2.58 = mmol 
Based on normal ranges: 45 
to 182 mg/dL (1-3 years), 
109 to 189 mg/dL (4-6 
years), 126 to 191 mg/dL 
(Boys 6-9 years), 122 to 209 
mg/dL (Girls 6-9 years), 130 
to 204 mg/dL (Boys 10-14 
years), 124-217 mg/dL (Girls 
10-14 years), 114 to 198 
mg/dL (Boys 15-19 years), 
125 to 212 mg/dL (Girls 14-
19 years) 
Triglyceride
s 
All age ranges 
>4.0 mmol/L or 350 mg/dL 
After >12 hours of fast) 
CF = g x 1.14 = mmol 
Based on normal ranges: 30 
to 86 mg/dL (Boys 0-5 
years), 32 to 99 mg/dL (Girls 
0-5 years), 31-108 mg/dL 
(Boys 6-11 years), 35 to 114 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
mg/dL (Girls 6-11 years), 36 
to 138 mg/dL (Boys 12-15 
years), 43 to 138 mg/dL 
(Girls 12-15 years), 40 to 163 
mg/dL (Boys 16-19 years), 
40-128 mg/dL (Girls 16-19 
years) 
Lipasemia 
All age ranges 
>2 ULN 
Based on normal ranges: 3 
to32 U/L (1-18 years) 
Amylasemi
a 
All age ranges 
>2 ULN 
Based on normal ranges: 10 
to 30 U/L (NN), 10 to 45 U/L 
(1-18 years) 
Glucose 
All age ranges 
Hypoglycaemia <2.7 mmol/L or 50 mg/dL 
Hyperglycaemia >7 mmol/L or 120 mg/dL (fasted 
after >12 hours of fast); >10.0 mmol/L or 180 
mg/dL (unfasted) 
CF = g x 5.55 = mmol 
Based on normal ranges: 50 
to 90 mg/dL (NN), 60 to 100 
mg/dL (Child) 
CRP 
All age ranges 
>2 ULN or 
>10 mg/L (if ULN not provided) 
Based on normal ranges: <6 
mg/L 
Hematology 
Common Terminology 
Criteria for Adverse Events 
v3.0 (CTCAE), 2006 ; 
Division of Microbiology and 
Infectious Diseases Pediatric 
Toxicity Tables, 2007 ; 
Division of AIDS Table for 
Grading the Severity of Adult 
and Pediatric Adverse 
Events, 2004; Mulberg AE et 
al. Pediatric Drug 
Development Concepts and 
applications. John Wiley & 
sons, Inc. 2009; Family 
Practice Notebook, LLC, 
2012; Tietz NW et al. Clinical 
Guide to Laboratory Testing, 
3rd edition 1995 
WBC 
Birth/0 to 27 days old 
(Neonates) 
<4.0 GIGA/L or 4,000 /mm3 
>25.0 GIGA/L or 25,000 /mm3 
To be used if no differential 
count available 
Based on normal ranges: 
9,000 to 30,000 /mm3 (birth), 
9,400 to 38,000 /mm3 (0-1 
28 days/1 month to 23 
months old (Infants) 
<4.0 GIGA/L or 4,000 /mm3 
>20.0 GIGA/L or 20,000 /mm3 
24 months/2 years to <6 
years old (Children) 
<3.0 GIGA/L or 3,000 /mm3 
>16.0 GIGA/L or 16,000 /mm3 
6 to <12 years old (Children) 
<5.0 GIGA/L or 5,000 /mm3 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
>17.0 GIGA/L or 17,000 /mm3 
day), 5,000 to 21,000 /mm3 
(1 day-1 month), 6,000 to 
17,500 /mm3 (1 month-2 
years), 5,000 to 17,000 /mm3 
(2-6 years), 4,500 to 15,500 
/mm3 (6-11 years), 4,500 to 
13,500 /mm3 (11-18 years) 
12 to 16/18 years old 
(Adolescents) 
<4,5 GIGA/L or 5,000 /mm3 
>13.5 GIGA/L or 17,000 /mm3 
Lymphocyt
es (ALC) 
Birth/0 to 27 days old 
(Neonates) 
<1.2 GIGA/L or 1,200 /mm3 
>17.0 GIGA/L or 17,000 /mm3 
Based on normal ranges: 
2,000 to 11,500 /mm3 (0-1 
days), 2,000 to 17,000 /mm3 
(2 days-1 month), 3,000 to 
13,500 /mm3 (1 month-2 
years), 1,500 to 9,500 /mm3 
(2-6 years), 1,500 to 8,000 
/mm3 (6-10 years), 1,200 to 
5,200 /mm3 (10-18 years) 
28 days/1 month to 23 
months old (Infants) 
<2.0 GIGA/L or 2,000 /mm3 
>13.5 GIGA/L or 13,500 /mm3 
24 months/2 years to <6 
years old (Children) 
<1.0 GIGA/L or 1,000 /mm3 
>9.5 GIGA/L or 9,500 /mm3 
6 to <12 years old (Children) 
<1.0 GIGA/L or 1,000 /mm3 
>8.0 GIGA/L or 8,000 /mm3 
12 to 16/18 years old 
(Adolescents) 
<0.6 GIGA/L or 600 /mm3 
>6.0 GIGA/L or 6,000 /mm3 
Absolute 
Neutrophil 
Count 
(ANC) 
Birth/0 to 27 days old 
(Neonates) 
<4.0 GIGA/L or 4,000 /mm3 (1 day old) 
<1.5 GIGA/L or 1,500 /mm3 (2-7 days old) 
<1.25 GIGA/L or 1,250 /mm3 (>7 day-1 month 
old) 
> 1 ULN 
Based on normal ranges: 
5,000 to 28,000 /mm3 (0-1 
day), 1,000 to 10,000 (1 day-
1 month), 1,000 to 8,500 (1-
12 months), 1,500 to 8,500 
(1 to 6 years), 1,500 to 8,000 
(6 to 10 years), 1;800 to 
8,000 (10 to 18 years)  
28 days/1 month to 23 
months old (Infants) 
<1.0 GIGA/L or 1,000/mm3 (1-3 months) 
<1.2 GIGA/L or 1,200 /mm3 (3-24 months) 
> 1 ULN 
24 months/2 years to <6 
years old (Children) 
<1.2 GIGA/L or 1,200 /mm3 
> 1 ULN 
6 to <12 years old (Children) 
<1.2 GIGA/L or 1,200 /mm3 
> 1 ULN 
12 to 16/18 years old 
(Adolescents)  
<1.2 GIGA/L or 1,200 /mm3 
> 1 ULN 
Eosinophils 
All age ranges 
>0.5 GIGA/L or 500 /mm3  
Or >ULN if ULN >0.5 GIGA/L or 500 /mm3 
Based on normal ranges: 0 
to 500 /mm3 (0-1 month), 0 
to 300 /mm3 (1 month-18 
years) 
Hemoglobi
n 
Birth/0 to 27 days old 
(Neonates) 
< 86 mmol/L or 12.0 g/dL or any decrease > 0.31 
mmol/L or 2 g/dL 
CF = g x 1.55 = mmol 
Based on normal ranges: 15 
to 20 g/dL (0-3 days), 12.5 to 
18.5 g/dL (1-2 weeks), 10.0 
to 13.0 g/dL (1-6 months), 
10.5 to 13.0 g/dL (7 months-
2 years), 11.5 to 13.0 g/dL 
(2-5 years), 11.5 to 14.5 (5-8 
years), 12.0 to 15.2 g/dL (13-
18 years)   
28 days/1 month to 23 
months old (Infants) 
< 1.40 mmol/L or 9.0 g/dL or any decrease > 0.31 
mmol/L or 2 g/dL 
24 months/2 years to <16/18 
years old (Children, 
Adolescents) 
< 1.55 mmol/L or10.0 g/dL or any decrease > 
0.31 mmol/L or 2 g/dL 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Hematocrit 
Birth/0 to 27 days old 
(Neonates) 
< 0.39 l/l or 40 % 
> 0.61 l/l or 47 % 
CF = % x 0.01 = l/l 
Based on normal ranges: 45 
to 61 % (0-3 days), 39 to 57 
% (1-2 weeks), 29 to 42 % 
(1-6 months), 33 to 38 % (7 
months-2 years), 34 to 39 % 
(2-5 years), 35 to 42 % (5-8 
years); 36 to 47 % (13-18 
years) 
28 days/1 month to 23 
months old (Infants) 
< 0.29 l/l or 29 % 
> 0.42 l/l or 42 % 
24 months/2 years to <16/18 
years old (Adolescents) 
< 0.32 l/l or 32 % 
> 0.47 l/l or 47 % 
Platelets 
All age ranges 
<100 GIGA/L or 100,000 /mm3 
> 700 GIGA/L or 700,000 /mm3 
Based on normal ranges: 
250,000 to 450,000 /mm3 
(NN); 300,000 to 700,000 
/mm3 (1-6 months), 250,000 
to 600,00 /mm3 (7 months-2 
years), 250,000 to 550,000 
/mm3 (2-12 years), 150,000 
to 450,000 /mm3 (13-18 
years) 
Urinalysis 
Patel HP, Pediatr Clin N Am, 
2006 
Ketonuria 
All age ranges 
Presence 
Semi-quantitative methods 
Glycosuria 
All age ranges 
Presence 
Semi-quantitative methods 
Hematuria 
All age ranges 
> 1+ 
Semi-quantitative methods 
Proteinuria 
All age ranges 
> 1+ 
Semi-quantitative methods 
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Week 
Target daya
PK 
ADA 
W0 
1 
Day≤1 
Day≤1 
D3 
3 
2≤Day<4 
 
D5 
5 
4≤Day<7 
 
D8 
8 
7≤Day<10 
 
D12 
12 
10≤Day<14 
 
W2 
15 
14≤Day<22 
 
W4 
29 
22≤Day<43 
 
W8 
57 
43≤Day<71 
 
W12 
85 
71≤Day<127 
2≤Day<127 
W24 
169 
127≤Day<253 
127≤Day<253 
W48 
337 
253≤Day<421 
253≤Day<421 
W72 
505 
421≤Day<589 
421≤Day<589 
W96 
673 
589≤Day<757 
589≤Day<757 
W120 
840 
757≤Day<967 
757≤Day<967 
W156 
1092 
Dayb≥967 
Dayb≥967 
EOT+2 
n.a. 
Dayc≥2 
n.a. 
Follow-up  
n.a.
Dayd≥2
Dayd≥2
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Week 
Target daya
PK 
ADA 
a Based on days relative to the reference day (ie, the date of first dose of sarilumab). 
b Excluding the measurements at the end of study follow-up visit (ie, per protocol, 6 weeks after end of treatment visit) and at V88 for PK. 
c Only applicable to patients who d/c the study during the core treatment phase or not going to enter the extension phase - includes only the 
measurement(s) at V88 (ie, per protocol, 2 weeks after end of treatment visit). 
d Includes only the measurement(s) at the end of study follow-up visit V28 (ie, per protocol, 6 weeks after end of treatment visit). 
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Week 
Target 
daya
 
 
 
 
 
) 
lipids 
ANA/Anti-ds 
DNA antibody 
Vital signs 
(Temperature 
[pcJIA], HR, BP) 
Vital signs 
(Weight) 
Vital signs 
(Height) 
W0 
1 
 
 
Day≤1 
Day≤1 
Day≤1 
Day≤1 
Day≤1 
D3 
3 
 
 
 
 
 
 
 
D5 
5 
 
 
 
 
 
 
 
D8 
8 
 
 
 
 
 
 
 
D12 
12 
 
 
 
 
 
 
 
W2 
15 
 
 
 
 
 
 
 
W4 
29 
 
 
2≤Day<57 
 
2≤Day<43 
 
 
W6 
43 
 
 
 
 
 
 
 
W8 
57 
 
 
 
 
43≤Day<71 
 
 
W10 
71 
 
 
 
 
 
 
 
W12 
85 
 
 
57≤Day<127 
2≤Day<127 
71≤Day<99 
2≤Day<99 
2≤Day<127 
W16 
113 
 
 
 
 
99≤Day<127 
99≤Day<127 
 
W20 
141 
 
 
 
 
127≤Day<155 
127≤Day<155 
 
W24 
169 
 
 
127≤Day<253 
127≤Day<253 
155≤Day<196 
155≤Day<196 
127≤Day<253 
W32 
225 
 
 
 
 
196≤Day<253 
196≤Day<253 
 
W40 
253 
 
 
 
 
253≤Day<309 
253≤Day<309 
 
W48 
337 
 
 
253≤Day<421 
253≤Day<421 
309≤Day<379 
309≤Day<379 
253≤Day<421 
W60 
421 
 
 
 
 
379≤Day<463 
379≤Day<463 
 
W72 
505 
 
 
421≤Day<589 
421≤Day<589 
463≤Day<547 
463≤Day<547 
421≤Day<589 
W84 
589 
 
 
 
 
547≤Day<631 
547≤Day<631 
 
W96 
673 
 
 
589≤Day<757 
589≤Day<757 
631≤Day<715 
631≤Day<715 
589≤Day<757 
W108 
756 
 
 
 
 
715≤Day<799 
715≤Day<799 
 
W120 
840 
 
 
757≤Day<925 
757≤Day<925 
799≤Day<883 
799≤Day<883 
757≤Day<925 
W132 
924 
 
 
 
 
883≤Day<966 
883≤Day<966 
 
W144 
1008 
 
 
925≤Day<1051 
925≤Day<1051 966≤Day<1051 
966≤Day<1051 
925≤Day<1051 
W156 
1092 
 
 
Day≥1051 
Day≥1051 
Dayb≥1051 
Dayb≥1051 
Day≥1051 
Follow-
up  
n.a. 
 
 
n.a. 
n.a. 
Dayc≥2 
Dayc≥2 
n.a. 
a Based on days relative to the date of first dose of sarilumab. 
b Excluding the measurements at the end of study follow-up visit (ie, per protocol, 6 weeks after end of treatment visit). 
c Includes only the measurement(s) at the end of study follow-up visit V28 (ie, per protocol, 6 weeks after end of treatment visit). 
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