Clinical trial NCT03600805
Conditions: Giant Cell Arteritis
Sponsor: Sanofi
Start date: 2018-11-20; Completion date: 2020-11-24
Enrollment: 83 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate the efficacy of sarilumab in participants with giant cell arteritis (GCA) as assessed by the proportion of participants with sustained remission for sarilumab compared to placebo, in combination with a corticosteroid (CS) tapering course.

Secondary Objective:

* To demonstrate the efficacy of sarilumab in participants with GCA compared to placebo, in combination with CS taper with regards to:
* Clinical responses (such as responses based on disease remission rates, time to first disease flare) over time.
* Cumulative CS (including prednisone) exposure.
* To assess the safety (including immunogenicity) and tolerability of sarilumab in participants with GCA.
* To measure sarilumab serum concentrations in participants with GCA.
* To assess the effect of sarilumab on sparing glucocorticoid toxicity as measured by glucocorticoid toxicity index (GTI).

Detailed description:
Study duration per participant was approximately 82 weeks, including an up to 6-week screening period, 52-week treatment period, and 24-week follow-up period.

Arms: arm 1: Participants received sarilumab-matching placebo as subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone/prednisone-matching placebo tapering oral daily doses for 52 weeks. arm 2: Participants received sarilumab-matching placebo as SC injection q2w up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone-matching placebo from Week 26 up to Week 52. arm 3: Participants received sarilumab 150 milligrams (mg) as SC injection q2w up to 52 weeks along with prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone-matching placebo from Week 26 up to Week 52. arm 4: Participants received sarilumab 200 mg as SC injection q2w up to 52 weeks along with prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone-matching placebo from Week 26 up to Week 52.
Interventions: intervention 1: Sarilumab SAR153191 intervention 2: Sarilumab matching placebo intervention 3: Prednisone intervention 4: Prednisone matching placebo
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection Route of administration: subcutaneous intervention 2: Pharmaceutical form: solution for injection Route of administration: subcutaneous intervention 3: Pharmaceutical form: tablets or capsules Route of administration: oral administration intervention 4: Pharmaceutical form: capsules Route of administration: oral administration

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002579 VERSION N°16.0 (31-JUL-2017) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 01 
COMPOUND: Kevzara ®/Sarilumab (SAR153191) 
A randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of sarilumab in patients with giant cell arteritis 
STUDY NUMBER: EFC15068 
Version Number: 
1 
EudraCT: 
2017-002988-18 
IND Number(s): 
100632 
WHO universal trial number: 
U1111-1200-2184 
Date: 
12-Sep-2018
Total number of pages: 
150 
NCT03600805


Amended Clinical Trial Protocol No. 01  
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EFC15068 - sarilumab 
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Page 2 
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 
 
 
 


Amended Clinical Trial Protocol No. 01  
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/Countries 
impacted by amendement 
Date, version 
Amended Clinical Trial Protocol 01 
All 
12-Sep-2018, version 1 (electronic 2.0) 
Original Protocol 
All 
09-Feb-2018, version 1 (electronic 4.0) 
AMENDMENT PROTOCOL 01 (12-Sep-2018) 
This amended protocol (Amendment 01) is considered to be non-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 because it neither significantly impacts the safety or physical/mental integrity 
of participants nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the changes implemented in the protocol amendment is to address several 
comments raised by the European Regulatory Authorities during the initial protocol review.  


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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Clinical Trial 
Summary –
Statistical 
Consideration AND 
Section 11.1 
Determination of 
sample size 
More details on the power calculations were 
added. 
The assumed treatment effects used for 
the power calculations were added for 
clarity. 
 
Section 4.1 Benefit 
and Risk 
assessment 
This sub-section related to benefit and risk 
assessment was created. 
This sub-section of benefit and risk 
assessment was created to address a 
specific request from the European 
Regulatory Authorities and to align it with 
the current protocol template of the 
Sponsor. 
Section 8.4 
Methods of 
assigning patients 
to treatment group 
More details about the randomization procedure 
(blocked randomization schedule) were added. 
Additional detail was added to this section 
to provide clarity on the randomization 
procedure, particularly pertaining to the 
blocked randomization and stratification 
process employed in the study. 
Section 11.4.2.1 
Analysis of primary 
efficacy endpoint(s) 
The non-inferiority test between Sarilumab 200 
mg q2w arm and the placebo with 52 week taper 
arm was removed. 
Based on the results from the GiACTA 
study, the non-inferiority test is deemed as 
unnecessary and thus removed from the 
protocol 
Section 11.4.2.3 
Multiplicity 
considerations 
The hierarchical testing approach including the 
testing sequence for the secondary endpoints 
were clarified. 
Details on the hierarchical testing 
sequence for the secondary endpoints 
were added for clarification to address a 
specific request from the European 
Regulatory Authorities. 
 


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CLINICAL TRIAL SUMMARY 
 
COMPOUND: Sarilumab 
STUDY No.: EFC15068  
TITLE 
A randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of sarilumab in patients with giant cell arteritis. 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
Phase 3 
STUDY OBJECTIVE(S) 
 
Primary objective: 
 
To evaluate the efficacy of sarilumab in patients with giant cell 
arteritis (GCA) as assessed by the proportion of patients with 
sustained remission at Week 52 for sarilumab compared to 
placebo, in combination with a 26-week corticosteroid (CS) 
tapering course. 
Secondary objective(s): 
 
To demonstrate the efficacy of sarilumab in patients with GCA 
compared to placebo, in combination with (either 26- or 
52-week) CS taper with regards to: 
- 
Clinical responses (such as responses based on disease 
remission rates, time to first disease flare) over time. 
- 
Cumulative CS (including prednisone) exposure. 
 
To assess the safety (including immunogenicity) and tolerability 
of sarilumab in patients with GCA. 
 
To measure sarilumab serum concentrations in patients with 
GCA. 
 
To assess the effect of sarilumab on sparing glucocorticoid 
toxicity as measured by glucocorticoid toxicity index (GTI). 
Other objectives: 
 
To assess the effect of sarilumab on physician assessment of 
disease activity as measured by a visual analogue scale 
(MD-VAS). 
 
To assess the effect of sarilumab compared with placebo, in 
combination with a 26-week CS taper as on a variety of patient 
reported outcome (PRO) concepts including fatigue (FACIT-
Fatigue), health status (EuroQol five-dimensional three-level 
questionnaire [EQ-5D-3L], and Short form-36 [SF-36v2]), 
physical functioning (health assessment questionnaire disability 
index [HAQ-DI]), including pain (visual analogue scale) and 
patient assessment of disease activity (visual analogue scale). 
 
To assess the impact of erythrocyte sedimentation rate 
(ESR)/C-reactive protein (CRP) levels on remission status.  
 
To characterize the disease activity of GCA patients while on 
steroid taper or sarilumab treatment in a subset of patients 
using comprehensive approaches to evaluate circulating 
immune cell types. 
 
To characterize the disease activity of GCA patients while on 
steroid taper or sarilumab treatment by evaluating circulating 
proteins, genetics and gene expression in consenting patients. 


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STUDY DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled 
52-week study with a 24-week post-treatment follow up phase, evaluating 
the efficacy and safety of sarilumab in patients with GCA.  
Patients with GCA (new onset or refractory [eg, disease relapse] GCA 
defined as below) will be randomized to 4 parallel treatment groups with 
sarilumab 200 mg every 2 weeks (q2w), 150 mg q2w, or placebo q2w 
plus 26 week prednisone taper, or placebo with standardized prednisone 
taper of 52 weeks at a ratio of 2:1:1:2 as described below. Randomization 
will be stratified by the starting dose of prednisone at baseline 
(<30 mg/day or ≥30 mg/day).  
 
Treatment Group A: sarilumab 200 mg q2w with a 26 week taper 
of CS. 
 
Treatment Group B: sarilumab 150 mg q2w with a 26 week 
taper of CS. 
 
Treatment Group C: sarilumab matching placebo q2w with a 
26 week taper of CS. 
 
Treatment Group D: sarilumab matching placebo q2w with a 
52 week taper of CS. 
Patients will be dosed with prednisone between 20 to 60 mg/day at the 
time of randomization (baseline) and initiate taper according to the 
protocol defined schedule. Patients will have up to 7 weeks to taper down 
to prednisone dose of 20 mg/day following randomization. If, for example, 
the patient is randomized on 20 mg prednisone per day, the patient will 
start the blinded, standardized prednisone taper 1-week after 
randomization. For other patients randomized on higher prednisone 
doses, upon reaching prednisone of 20 mg/day, patients will be initiated 
on a blinded, standardized taper of prednisone of up to 26 weeks or up to 
52 weeks from time of randomization.  
The protocol will aim to enroll at least 30% of new onset patients, 
therefore, the Sponsor will reserve the possibility to cap enrolment of 
refractory patients to ≤70% of total patients randomized.  
For the management of predefined neutropenia, thrombocytopenia and 
alanine aminotransferase increases, study drug(sarilumab or matching 
placebo) must be temporarily withheld, and may be reduced to sarilumab 
150 mg q2w (for patients randomized to the 200 mg q2w arm only) based 
on Investigator judgment. The request for dose reduction will be 
managed via IRT and the sarilumab dose prior to and following the dose 
reduction will remain blinded to site and Sponsor (for patients in the 
sarilumab 150 mg or sarilumab matching placebo groups, there will be 
only a sham dose reduction to maintain the blind). 
During the course of study, for patients in need of rescue therapy as per 
Investigator judgment, CS should be the agent of first choice. Patients 
may continue subcutaneous (SC) administration of sarilumab or matching 
placebo only if CS is used as rescue therapy. If the patients remain 
symptomatic despite CS rescue therapy, then other treatment options 
including nonbiological immunosuppressive drugs may be used and the 
patient must be discontinued from the study treatment and considered a 
nonresponder. 
All patients who prematurely and permanently discontinue study 
medication will be asked to return to the site for study assessments as 
per protocol until end of study (EOS) evaluation. 


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STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
 
Diagnosis of GCA classified according to the following criteria: 
- 
Age >50 years 
- 
History of ESR ≥50 mm/hour (or CRP >25 mg/L) 
- 
Presence of at least one of the following: Unequivocal 
cranial symptoms of GCA (new onset localized headache, 
scalp or temporal artery tenderness, ischemia-related 
vision loss, or otherwise unexplained mouth or jaw pain 
upon mastication) or symptoms of polymyalgia (defined as 
shoulder and/or hip girdle pain associated with 
inflammatory stiffness). 
- 
Presence of at least one of the following: Temporal artery 
biopsy revealing features of GCA; Evidence of large-
vessel vasculitis by angiography or cross-sectional 
imaging (angiography, computed tomography angiography 
[CTA], magnetic resonance angiography [MRA], or 
positron emission tomography-computed tomography 
[PET-CT], ultrasound).  
 
New onset active disease or refractory active disease 
according to the following criteria: 
- 
New onset active disease is defined as: Diagnosis within 
6 weeks of baseline. 
- 
Refractory active disease is defined as: Diagnosis 
>6 weeks before baseline and previous treatment with 
≥40 mg/day prednisone (or equivalent) for at least 
2 consecutive weeks at a time. This includes patients who 
have achieved remission in the past but have a flare in the 
disease again or patients who have not been able to 
achieve complete remission since diagnosis of GCA. 
 
At least one of the following symptoms of GCA within 6 weeks 
of baseline: 
- 
Unequivocal cranial symptoms of GCA (such as new onset 
localized headache, scalp or temporal artery tenderness, 
ischemia-related vision loss, or otherwise unexplained 
mouth or jaw pain upon mastication). 
- 
Unequivocal symptoms of polymyalgia rheumatica (PMR) 
(defined as shoulder and/or hip girdle pain associated with 
inflammatory stiffness). 
- 
Other features judged by the Investigator to be consistent 
with GCA or PMR flares (ie, new or worsened extremity 
claudication, fever not associated with infection). 
 
Either ESR ≥30 mm/hour or CRP ≥10 mg/L within 6 weeks of 
baseline. 
 
Receiving or able to receive prednisone 20 to 60 mg/day for the 
treatment of active GCA. 
Note: Sites that will consider inclusion of patients in the study using 
ultrasound as part of screening and diagnostic process for relevant 
disease status confirmation should only employ this method following 
completion of certification by the Sponsor (details of the ultrasound 
certification process are found in the manual). 


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Exclusion criteria: 
 
Organ transplantation recipient (except corneas, unless it is 
within 3 months prior to baseline visit). 
 
Major ischemic event, unrelated to GCA, within 12 weeks of 
screening.  
 
Prior treatment with any of the following: 
- 
Janus kinase (JAK) inhibitor within 4 weeks of baseline. 
- 
Alkylating agents including cyclophosphamide within 
6 months of baseline. 
- 
Tumor necrosis factor (TNF) inhibitors within 2 to 8 weeks 
of, or less than at least 5 half-lives have elapsed prior to, 
baseline, whichever is longer. 
- 
Abatacept within 8 weeks of baseline. 
- 
Anakinra within 1-week of baseline. 
 
Therapeutic failure with biological Interleukin 6/(R) (IL-6/(R) 
antagonist. 
 
Evidence of serious, uncontrolled concomitant disease (eg, 
cardiovascular, respiratory, hepatic, renal, endocrine, etc,). 
Total expected number of patients 
Approximately 360 
STUDY TREATMENT(s) 
 
Investigational medicinal product-1 
Formulation: 
 
Route(s) of administration: 
Dose regimen: 
Sarilumab or placebo. 
Single-use prefilled glass syringes of sarilumab 200 mg, sarilumab 
150 mg or matching placebo for sarilumab. 
Subcutaneous (SC) route, in abdomen or thigh, or upper arm. 
Sarilumab 200 mg, sarilumab 150 mg or matching placebo is to be 
administered q2w. 
Investigational medicinal product-2: 
Formulation: 
Route(s) of administration: 
Dose regimen 
Prednisone or placebo 
Over-encapsulated tablets/tablets/capsule  
Oral 
During the open-label prednisone period: 
 
Prednisone once a day with dose level from 20 to 60 mg 
depending on the starting prednisone dose at randomization 
During the double-blind prednisone period: 
 
Prednisone and/or matching placebo, once a day with dose 
level as per the prednisone protocol defined tapering regimen. 
Noninvestigational medicinal 
product(s):  
The chosen rescue therapy, including CS, as per Investigator judgment. 
ENDPOINT(S) 
 
Primary endpoint:  
Proportion of patients achieving sustained remission at Week 52. 
Sustained remission at Week 52 is defined by having met all of the 
following parameters: 
 
Achievement of disease remission no later than Week 12.  
AND 


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 
Absence of disease flare from Week 12 through Week 52.  
AND 
 
Normalization of CRP (to <10 mg/L, with an absence of 
successive elevations to ≥10 mg/L) from Week 12 through 
Week 52. 
AND 
 
Successful adherence to the prednisone taper from Week 12 
through Week 52. 
Disease remission is defined as resolution of signs and symptoms of 
GCA, and normalization of CRP (<10 mg/L). 
Note: A single CRP elevation (≥10 mg/L) is not considered absence of 
remission unless CRP remained elevated (≥10 mg/L) at the next study 
visit. 
Flare is defined as either 1) recurrence of signs and symptoms 
attributable to active GCA plus an increase in CS dose due to GCA, or 2) 
elevation of ESR attributable to active GCA plus an increase in CS dose 
due to GCA.  
Increase in CS dose is defined as: 
 
Any dose increase during the protocol defined steroid taper. 
 
Reinitiation of prednisone therapy after the protocol defined 
taper has been completed.  
Secondary endpoint(s): 
Efficacy: 
 
Summary of components of the sustained remission composite 
measure at Week 52. 
 
Total cumulative CS (including prednisone) dose over 
52 weeks. 
 
Proportion of patients achieving disease remission at  2. 
 
Time to first GCA flare. 
 
Glucocorticoid toxicity index (GTI) (total score and domain-
specified component scores) 
Safety: 
 
Adverse events (AEs), laboratory values (including antidrug 
antibody [ADA], vital signs. 
Pharmacokinetic: 
 
Concentrations of sarilumab in serum. 
Pharmacodynamic: 
 
Changes in ESR and CRP over time. 
 
Changes of IL-6 level and soluble IL-6 receptor. 
 
Changes in markers of inflammation and disease activity over 
time as assessed in circulating immune cell types, circulating 
proteins and gene expression changes. 
Other efficacy endpoints: 
 
Physician global assessment of disease activity - visual analog 
scale (MD-VAS). 


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 
PROs (changes from baseline for the following): 
- 
EuroQol 5 dimension questionnaire; 3-level version 
(EQ-5D-3L) - index score and visual analogue scale score.  
- 
Short-form 36-item questionnaire (SF-36v2) - domain 
scores, and physical and mental component summary 
scores 
- 
Functional assessment of chronic illness therapy fatigue 
scale (FACIT-fatigue) - total score. 
- 
Health Assessment Questionnaire Disability Index 
(HAQ-DI) - total score, pain score, patient global 
impression score 
ASSESSMENT SCHEDULE 
The study will consist of the following visits: 
 
Visit 1 (D -42 - D -1): Screening 
 
Visit 2 (D1): Baseline, randomization, first study drug 
administration 
 
Visit 2 to 12 (D1-Week 52): on treatment (double-blind phase) 
 
Visit 12 (Week 52): End of Treatment (EOT) visit (last sarilumab 
or matching placebo administration at Week 50) 
 
Visit 13 (Week 58): 6 weeks post-treatment follow up visit 
 
Visit 14 (Week 76): EOS visit 
Patient’s CS tapering period may vary (maximum of 52 weeks) 
depending on the dose of daily prednisone at the time of randomization. 
At screening and baseline visits, a physical examination to assess 
disease activity and general health will be performed. Patients will be 
assessed for active or latent tuberculosis (TB) at baseline and during the 
study. Laboratory tests includes hematology, chemistry, lipids, glucose, 
insulin, antinuclear antibodies (ANA), glycosylated hemoglobin A1c 
(HbA1c), urinalysis, human immunodeficiency virus (HIV), Hepatitis B and 
C, serum and plasma for biomarkers and a 12-lead electrocardiogram 
(ECG). A serum pregnancy test for women of child bearing potential 
(WOCBP) will be obtained at screening as well.  
Blood samples for circulating proteins (serum and plasma) and for 
deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) will be collected 
from each consenting patient, by signing off the additional research 
program part (optional) included in the main informed consent forms. 
Safety assessments are done at each study visit and include AEs, 
serious adverse events (SAEs) and adverse events of special interest 
(AESIs) including but not limited to neutropenia, thrombocytopenia, 
elevations in hepatic enzymes leading to permanent discontinuation and 
TB, and potential opportunistic infections. 
A dual assessor approach will be required in order to maintain the blind 
during the double-blind treatment period with sarilumab, placebo, and 
prednisone. Efficacy Assessor should be a rheumatologist or other skilled 
GCA assessor and may be the Principal Investigator; they will be 
responsible for completing the overall evaluation and management of 
GCA disease activity. The Safety Assessor should be a physician; they 
will be responsible for assessing and managing any safety concerns of 
the patient during the course of the study including access to the patient’s 
laboratory data and AEs, performing assessments related to GTI. The 


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Safety Assessor cannot be the Efficacy Assessor. Patients and 
Investigators must respect the visit schedule per study flow chart. If a visit 
date is changed, the next visit should take place according to the original 
schedule. 
Blood samples in a subset of patients will be collected to evaluate 
circulating immune cell phenotype. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: Based on the results from GiACTA, a 
trial that evaluated the safety and efficacy of tocilizumab (another IL-6 
receptor antagonist similar to sarilumab) in patients with GCA, it is 
expected that the sustained remission rate at Week 52 (ie, the primary 
endpoint) will be approximately 14% for Group C (placebo + 26 week 
taper), approximately 18% for Group D (placebo + 52 week taper), and 
approximately 54% for sarilumab 200 mg q2w. A slightly lower sustained 
remission rate of approximately 50% is assumed for sarilumab 150 mg 
q2w. The proposed sample sizes will provide at least 90% overall power 
for all the 4 between-group comparisons (between 200 mg q2w and 2 
placebo groups, and between 150 mg q2w and 2 placebo groups) on the 
primary endpoint. All tests will be performed at 0.01 significance level 
(2-sided). 
Analysis population: The primary efficacy analysis population will 
be the intent-to-treat (ITT) population, which consists of all randomized 
patients. All patients will be analyzed according to the treatment to which 
they are randomized. 
The safety population will include all randomized patients who have 
received at least one dose of the study medication. All patients will be 
analyzed according to the treatment they have actually received. 
Primary analysis: The rate of sustained remission at Week 52 will 
be analyzed using a Cochran-Mantel-Haenszel test stratified by any 
randomization strata. A significance level of 0.01 will be used, and the 
primary comparison will be between the sarilumab 200 mg q2w arm and 
the placebo arm with 26-week taper. 
Analysis of secondary endpoints: Other binary endpoints will 
be analyzed using the same approach. The cumulative prednisone dose 
will be analyzed using a nonparametric van Elteren test stratified by 
baseline prednisone dose. Time to event analysis will use Kaplan-Meier 
estimates and a log-rank test. 
DURATION OF STUDY PERIOD (per 
patient)  
Total duration of study per patient is expected to be approximately 82 
weeks: 
 
Up to 6 weeks screening period. 
 
52 weeks treatment period (sarilumab or placebo, double-blind 
phase). 
 
24 weeks post-treatment follow up period. 


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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
Patients will be randomized to 4 groups with the ratio of 2:1:1:2               *Patients experiencing a disease flare may be rescued with open-label 
                                                                                                                                              treatment as per Investigator judgment during the study treatment period. 
6 weeks 
screening 
V1 
W4 
V4 
W2 
 V3 
D1
V2 
W8 
V5 
W24
V9 
W52
V12 
EOT 
W12 
V6 
W16
V7 
52 weeks 
Double blind period*  
R 
6 weeks  
follow up 
W58 
V13 
W40
V11 
W32
V10 
Treatment Group A: Sarilumab 200 mg q2w with 26 wk corticosteroid taper   N=120 
Treatment Group B: Sarilumab 150 mg q2w with 26 wk corticosteroid taper  N=60 
Treatment Group C: Sarilumab matching placebo with 26 wk corticosteroid taper 
N=60 
Treatment Group D: Sarilumab matching placebo with 52 wk corticosteroid taper 
N=120 
W20
V8 
W76 
V14 
EOS 
Post medication follow up 
 


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1.2 
STUDY FLOW CHART 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
V11 
V12 
(EOT) 
V13  
V14 (EOS) 
DAY 
D -42 to D -
1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85 (±3) 
D113 (±3) 
D141 (±3) 
D169 (±3) 
D225 (±3) 
D281 (±3) 
D365 (±3) 
D407 (±3) 
D532 (±3)  
WEEK 
 
Wk 0 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 52 
Wk 58 
Wk 76 
Eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriaa 
Xa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical/smoking/alcohol 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family cardiovascular history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Targeted physical examinationb 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
Confirm eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Call IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial treatment kit assignment 
(IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administrationc 
 
X 
X 
X 
X 
X 
X 
X 
Xd 
Xd 
Xd 
X 
 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense patient diary (for study 
medications) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Compliance/review patient diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
V11 
V12 
(EOT) 
V13  
V14 (EOS) 
DAY 
D -42 to D -
1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85 (±3) 
D113 (±3) 
D141 (±3) 
D169 (±3) 
D225 (±3) 
D281 (±3) 
D365 (±3) 
D407 (±3) 
D532 (±3)  
WEEK 
 
Wk 0 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 52 
Wk 58 
Wk 76 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature, heart rate, blood 
pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCA clinical assessments 
(including disease flare) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PROse 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Physician Global Assessment 
(MD-VAS) 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
GTI Assessment (excluding 
Bone Density assessment) 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
Bone density assessmentf 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE recording 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
QuantiFERON® 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-rayg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
 
Chemistryi 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
 
ANA 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 


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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
V11 
V12 
(EOT) 
V13  
V14 (EOS) 
DAY 
D -42 to D -
1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85 (±3) 
D113 (±3) 
D141 (±3) 
D169 (±3) 
D225 (±3) 
D281 (±3) 
D365 (±3) 
D407 (±3) 
D532 (±3)  
WEEK 
 
Wk 0 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 52 
Wk 58 
Wk 76 
Fasting lipids j, k/fasting glucose, 
fasting insulinj 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
 
HbA1c 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
 
CRPl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ESRl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysism 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virologyn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testo 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sarilumabj 
 
X 
X 
X 
 
X 
X 
 
Xp 
 
 
X 
X 
 
Anti-drug antibodyj 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Genotyping and biomarkersj,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers-IL-6 and sIL-6R 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Blood for circulating immune cell 
phenotypingq 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
Future Use of Samples for 
Circulating proteins (serum/ 
plasma)r (optional) 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 


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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
V11 
V12 
(EOT) 
V13  
V14 (EOS) 
DAY 
D -42 to D -
1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85 (±3) 
D113 (±3) 
D141 (±3) 
D169 (±3) 
D225 (±3) 
D281 (±3) 
D365 (±3) 
D407 (±3) 
D532 (±3)  
WEEK 
 
Wk 0 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 52 
Wk 58 
Wk 76 
DNAs (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RNAs (optional) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
AE = Adverse event; ANA = Antinuclear antibodies; CRP = C-reactive protein; D = Day; DNA = Deoxyribonucleic acid; ECG = Electrocardiogram; EOT = End of treatment; EOS = End of study; EQ-5D-3L = EuroQol 
five-dimensional three-level questionnaire; ESR = Erythrocyte sedimentation rate; FACIT-Fatigue = Functional assessment of chronic illness therapy fatigue scale; GCA = Giant cell arteritis; GTI = Glucocorticoid 
toxicity index; HAQ-DI = Health assessment questionnaire disability index; HbA1c = Hemoglobin A1c; HBsAg = Hepatitis B surface antigen; HBcore Ab = Hepatitis B core antibodies; HCV = Hepatitis C virus; IL = 
Interleukin; IMP = Investigational medicinal product; IRT = Interactive response technology; MD-VAS = Physician global assessment of disease activity- visual analog scale; MRI = Magnetic resonance imaging; Pain 
VAS = Pain visual analog scale; PROs = Patient reported outcomes; Pt-VAS = Patient global assessment of disease activity – visual analog scale; RNA = Ribonucleic acid; SAE = Serious adverse event; SF-36v2 = 
Short form 36 version 2; TB = Tuberculosis; V = Visit; Wk = Week. 
a If ultrasound is being used as a diagnostic tool of GCA, the image needs to be submitted to the central reader for confirmation of eligibility. 
b Targeted physical examination: head, eyes, ears, neck and throat, skin, respiratory, cardiovascular, neurologic, lymphatic examinations and abdominal examination. 
c Last administration of sarilumab is at Week 50. 
d Where the visit interval exceeds 4 weeks, interim shipments of IMP to patients home may be performed using direct to patient (DTP) shipping (according to local regulations and logistics), in order to provide the 
patient with only 4 weeks IMP at a time in order to minimize compliance errors. 
e Patient Reported Outcomes include EQ-5D-3L, FACIT-Fatigue, SF-36v2, HAQ-DI (including Pain VAS and Pt-VAS). 
f 
Bone mineral density assessment must be performed during baseline if not already available within 12 weeks prior to screening visit. A ±2 week time window is allowed at baseline visit and -2 week time window 
is allowed at EOT visit. 
g Posterior-Anterior chest X-ray must be performed during screening if not already available within 12 weeks prior to screening visit.  
A standard PA chest X-ray (lateral view is also recommended but not required) is required during the screening period if no chest imaging (X-ray, Computed Tomography [CT], MRI) is available within the previous 
12 weeks of V1 that clearly documents the exclusion of TB (or >12 weeks, if appropriate according to local guidelines and requirements for screening of active TB). In countries for which a specific approval 
procedure for the X-ray is required by a different committee than the local ethics committee/Institutional review board (EC/IRB), a chest MRI between V1 and V2 can be performed.  
h Hematology (blood to be drawn before drug administration): Hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential, platelet count, 
absolute neutrophil count (ANC). 
i 
Chemistry(blood to be drawn before drug administration): Sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine and creatinine clearance, calcium, phosphate, total protein, albumin, 
alanine aminotransferase (ALT) (SGPT), aspartate aminotransferase (AST) (SGOT), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated bilirubin, lactate dehydrogenase (LDH), uric 
acid. 
j 
Blood to be drawn before drug administration. 
k Lipids: Triglycerides (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol.  
l 
CRP and ESR results will be blinded to Investigator (except screening and baseline). ESR kits will be provided by the central laboratory while the test will be performed locally at the site, results will be blinded to 
Investigator and staff directly involved in management of study patient, except safety assessor. 
m Urinalysis dipstick: specific gravity, pH, glucose, ketones, blood, protein, nitrite, leukocytes, urobilinogen and 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. 


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n Human immunodeficiency virus antibodies (a separate local Informed Consent may need to be obtained if applicable); Hepatitis B: HBsAg, total HB core Ab, Hep B Surface Antibody, and Hep B viral DNA (if 
necessary); Hepatitis C: HCV-antibodies. 
o In women of child-bearing potential. 
p Additional sample is to be drawn 4-7 days after Wk 24 dosing. 
q Immune cell phenotyping may be performed in only a subset of patients as determined by IRT system. 
r 
Future use Samples (for consented patients only). 
s Pharmacogenetic Research Informed Consent for collecting and sequencing DNA and RNA samples has to be obtained before any sampling. One DNA (at baseline) and RNA sample (predose) for sequencing 
sampling time point at baseline and V3 are needed. 
 


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2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 01 ....................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
1 
FLOW CHARTS ............................................................................................................................. 12 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 12 
1.2 
STUDY FLOW CHART .................................................................................................................. 13 
2 
TABLE OF CONTENTS ................................................................................................................ 18 
2.1 
LIST OF TABLES ........................................................................................................................... 24 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 25 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 27 
4.1 
BENEFIT AND RISK ASSESSMENT ............................................................................................ 29 
5 
STUDY OBJECTIVES ................................................................................................................... 31 
5.1 
PRIMARY ....................................................................................................................................... 31 
5.2 
SECONDARY ................................................................................................................................ 31 
5.3 
OTHER ........................................................................................................................................... 31 
6 
STUDY DESIGN ............................................................................................................................ 32 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 32 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 33 
6.2.1 
Duration of study participation for each patient ............................................................................. 33 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 33 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 33 
6.4 
STUDY COMMITTEES .................................................................................................................. 33 
6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS ............................. 34 
7 
SELECTION OF PATIENTS .......................................................................................................... 35 
7.1 
INCLUSION CRITERIA .................................................................................................................. 35 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 36 


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7.2.1 
Exclusion criteria related to study methodology ............................................................................ 36 
7.2.2 
Exclusion criteria related to the current knowledge of Sanofi compound ...................................... 37 
8 
STUDY TREATMENTS ................................................................................................................. 41 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 41 
8.1.1 
Sarilumab or matching placebo: .................................................................................................... 42 
8.1.2 
Prednisone or matching placebo: .................................................................................................. 43 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 45 
8.3 
BLINDING PROCEDURES ............................................................................................................ 45 
8.3.1 
Methods of blinding ........................................................................................................................ 45 
8.3.1.1 
Blinding of IMP ............................................................................................................................... 45 
8.3.1.2 
Blinding of non investigational medicinal product .......................................................................... 46 
8.3.2 
Randomization code breaking during the study ............................................................................. 46 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 46 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING ............................. 47 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 48 
8.7 
RESPONSIBILITIES ...................................................................................................................... 48 
8.7.1 
Treatment accountability and compliance...................................................................................... 48 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 49 
8.8 
LIST OF FORBIDDEN AND PERMITTED CONCOMITANT MEDICATIONS............................... 49 
8.8.1 
Steroids .......................................................................................................................................... 50 
8.8.2 
Nonsteroidal anti-inflammatory drugs and analgesics ................................................................... 50 
8.8.3 
Treatment of dyslipidemia .............................................................................................................. 50 
8.8.4 
Glucocorticoid-induced osteopenia/osteoporosis prevention and treatment ................................. 50 
8.8.5 
CYP substrates .............................................................................................................................. 51 
8.8.6 
Anti-platelet therapy ....................................................................................................................... 51 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 52 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 52 
9.1.1 
Primary efficacy endpoint ............................................................................................................... 52 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 53 
9.2.1 
Secondary efficacy endpoints ........................................................................................................ 53 
9.2.1.1 
Components of the sustained remission composite measure at Week 52 .................................... 53 
9.2.1.2 
Total cumulative corticosteroid (including prednisone) dose over 52 weeks................................. 53 
9.2.1.3 
Time to first GCA flare.................................................................................................................... 54 
9.2.1.4 
Glucocorticoid toxicity index and components ............................................................................... 54 


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9.2.2 
Safety endpoints ............................................................................................................................ 54 
9.2.2.1 
Adverse events .............................................................................................................................. 54 
9.2.2.2 
Laboratory safety variables ............................................................................................................ 55 
9.2.2.3 
Chest X-ray .................................................................................................................................... 55 
9.2.2.4 
Vital signs ....................................................................................................................................... 56 
9.2.2.5 
Physical examination ..................................................................................................................... 56 
9.2.2.6 
Electrocardiogram variables .......................................................................................................... 56 
9.3 
OTHER EFFICACY ENDPOINTS .................................................................................................. 57 
9.3.1 
Clinical outcome assessments ....................................................................................................... 57 
9.3.1.1 
Patient-reported outcomes ............................................................................................................. 57 
9.3.1.2 
Clinician-reported outcomes .......................................................................................................... 58 
9.4 
PHARMACODYNAMICS ............................................................................................................... 58 
9.4.1 
Pharmacodynamic variables .......................................................................................................... 58 
9.4.2 
Pharmacokinetics and antidrug antibodies .................................................................................... 59 
9.4.2.1 
Sampling time ................................................................................................................................ 59 
9.4.2.2 
Sample handling procedure ........................................................................................................... 59 
9.4.2.3 
Bioanalytical method ...................................................................................................................... 59 
9.4.2.4 
Pharmacokinetics parameters ....................................................................................................... 60 
9.4.3 
Pharmacogenetic assessment ....................................................................................................... 60 
9.4.3.1 
Optional stored DNA and RNA samples ........................................................................................ 60 
9.5 
FUTURE USE OF SAMPLES ........................................................................................................ 60 
9.5.1 
Serum and plasma for future biomarker analysis (circulating proteins) ......................................... 61 
9.6 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 61 
10 
STUDY PROCEDURES ................................................................................................................ 62 
10.1 
INDEPENDENT EFFICACY AND SAFETY ASSESSORS ........................................................... 62 
10.2 
VISIT SCHEDULE .......................................................................................................................... 63 
10.2.1 
Visit 1: Screening from Day -42 to Day -1 ..................................................................................... 63 
10.2.2 
Double blind period (52 weeks) ..................................................................................................... 65 
10.2.2.1 Visit 2/Baseline visit (Day 1, Week 0) ............................................................................................ 65 
10.2.2.2 Visit 3 (Day 15 ±3, Week 2) ........................................................................................................... 66 
10.2.2.3 Visit 4-11 (Day 29 ±3, Week 4 to Day 281±3, Week 40) ............................................................... 67 
10.2.2.4 Visit 12/End of Treatment (Day 365 ±3, Week 52) ........................................................................ 68 
10.2.3 
Post-treatment follow up period (24 weeks) .................................................................................. 69 
10.2.3.1 Visit 13 (Day 407 ±3, Week 58) ..................................................................................................... 69 
10.2.3.2 Visit 14/End of study (Day 532 ±3, Week 76) ................................................................................ 69 
10.3 
DEFINITION OF SOURCE DATA .................................................................................................. 70 
10.4 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 70 


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10.4.1 
Temporary treatment discontinuation with investigational medicinal product................................ 70 
10.4.2 
Permanent treatment discontinuation with investigational medicinal product(s) ........................... 72 
10.4.3 
List of criteria for permanent treatment discontinuation ................................................................. 72 
10.4.4 
Handling of patients after permanent treatment discontinuation ................................................... 73 
10.4.5 
Procedure and consequence for patient withdrawal from study .................................................... 73 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 74 
10.5.1 
Definitions of adverse events ......................................................................................................... 74 
10.5.1.1 Adverse event ................................................................................................................................ 74 
10.5.1.2 Serious adverse event ................................................................................................................... 74 
10.5.1.3 Adverse event of special interest ................................................................................................... 75 
10.5.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities ....................................................................................................................................... 76 
10.5.3 
General guidelines for reporting adverse events ........................................................................... 76 
10.5.4 
Instructions for reporting serious adverse events .......................................................................... 77 
10.5.5 
Guidelines for reporting adverse events of special interest ........................................................... 78 
10.5.6 
Guidelines for management of specific laboratory abnormalities .................................................. 78 
10.5.7 
Guidelines for reporting product complaints (IMP) ........................................................................ 78 
10.6 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 78 
10.7 
SAFETY INSTRUCTIONS ............................................................................................................. 79 
10.7.1 
Infections ........................................................................................................................................ 79 
10.7.2 
Liver function tests ......................................................................................................................... 80 
10.7.3 
Neutrophils ..................................................................................................................................... 81 
10.7.4 
Platelets ......................................................................................................................................... 82 
10.7.5 
Systemic hypersensitivity reactions/anaphylaxis ........................................................................... 82 
10.7.6 
Diverticulitis and gastrointestinal perforation ................................................................................. 82 
10.7.7 
Management of dyslipidemia ......................................................................................................... 83 
10.7.8 
Acute renal failure .......................................................................................................................... 83 
10.8 
ADVERSE EVENTS MONITORING .............................................................................................. 83 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 84 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 84 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 84 
11.3 
ANALYSIS POPULATIONS ........................................................................................................... 85 
11.3.1 
Efficacy populations ....................................................................................................................... 85 
11.3.1.1 Intent–to-treat population ............................................................................................................... 85 
11.3.2 
Safety population ........................................................................................................................... 85 


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11.3.3 
Pharmacokinetic analysis population ............................................................................................. 85 
11.3.4 
Antidrug antibody (ADA) population............................................................................................... 86 
11.4 
STATISTICAL METHODS ............................................................................................................. 86 
11.4.1 
Extent of study treatment exposure and compliance ..................................................................... 86 
11.4.1.1 Extent of investigational medicinal product exposure .................................................................... 86 
11.4.1.2 Compliance .................................................................................................................................... 86 
11.4.2 
Analyses of efficacy endpoints ....................................................................................................... 87 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................ 87 
11.4.2.2 Analyses of secondary efficacy endpoints ..................................................................................... 87 
11.4.2.3 Multiplicity considerations .............................................................................................................. 87 
11.4.3 
Analyses of safety data .................................................................................................................. 88 
11.4.3.1 Analysis of adverse event data ...................................................................................................... 89 
11.4.3.2 Analysis of laboratory data ............................................................................................................. 89 
11.4.3.3 Analysis of the vital signs data ....................................................................................................... 91 
11.4.3.4 Analysis of antidrug antibody data ................................................................................................. 91 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 92 
11.4.5 
Analyses of patient reported outcomes.......................................................................................... 92 
11.5 
INTERIM ANALYSIS ...................................................................................................................... 92 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 94 
12.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 94 
12.2 
INFORMED CONSENT ................................................................................................................. 94 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................... 95 
13 
STUDY MONITORING................................................................................................................... 96 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 96 
13.2 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 96 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 96 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST ...................................................................................................................................... 97 
13.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 97 
14 
ADDITIONAL REQUIREMENTS ................................................................................................... 98 
14.1 
CURRICULUM VITAE.................................................................................................................... 98 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................... 98 
14.3 
CONFIDENTIALITY ....................................................................................................................... 98 


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14.4 
PROPERTY RIGHTS ..................................................................................................................... 99 
14.5 
DATA PROTECTION ..................................................................................................................... 99 
14.6 
INSURANCE COMPENSATION .................................................................................................... 99 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 100 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 100 
14.8.1 
By the Sponsor ............................................................................................................................. 100 
14.8.2 
By the Investigator ....................................................................................................................... 101 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 101 
14.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 101 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 102 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 103 
17 
APPENDICES .............................................................................................................................. 105 
APPENDIX A 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 106 
APPENDIX B 
STANDARDIZED CORTICOSTEROID-TAPER REGIMEN DURING STUDY 
TREATMENT PERIOD ................................................................................................................ 109 
APPENDIX C 
COMPOSITE GLUCOCORTICOID TOXICITY INDEX ..................................................... 115 
APPENDIX D 
SPECIFIC LIST FOR GLUCOCORTICOID TOXICITY INDEX ......................................... 122 
APPENDIX E 
FACIT FATIGUE SCALE (VERSION 4) (PAPER VERSION)* .......................................... 126 
APPENDIX F 
EUROQOL QUESTIONNAIRE (EQ-5D-3L) (PAPER VERSION)* .................................... 127 
APPENDIX G 
SF-36 (VERSION 2) (PAPER VERSION)* ........................................................................ 130 
APPENDIX H 
HEALTH ASSESSMENT QUESTIONNAIRE (HAQ-DI) (PAPER VERSION)* ................. 136 
APPENDIX I 
PHYSICIAN’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY (PAPER 
VERSION)* .................................................................................................................................. 139 
APPENDIX J 
GCA BIOMARKER OBJECTIVES ..................................................................................... 140 
APPENDIX K 
PROCEDURE FOR COLLECTION, HANDLING, STORAGE, AND SHIPMENT OF 
SAR153191 SPECIMENS FOR PHARMACOGENETIC SAMPLES ........................................... 142 
APPENDIX L 
GENERAL GUIDANCE FOR THE FOLLOW UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 143 
APPENDIX M 
LIST OF OPPORTUNISTIC INFECTIONS ....................................................................... 147 


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APPENDIX N 
DEFINITION OF ANAPHYLAXIS ...................................................................................... 148 
APPENDIX O 
COUNTRY-SPECIFIC REQUIREMENTS ......................................................................... 149 
APPENDIX P 
PROTOCOL AMENDMENT HISTORY ............................................................................. 150 
2.1 
LIST OF TABLES 
Table 1 - Summary of investigational medicinal products ............................................................................. 41 
Table 2 - Summary of bioanalytical methods for functional sarilumab and antidrug antibody ...................... 59 
Table 3 - Sample size determination ............................................................................................................. 84 
 


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3 
LIST OF ABBREVIATIONS 
 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
BP: 
blood pressure 
CRFs: 
case report forms 
CRP: 
C-reactive protein 
CS: 
corticosteroid 
DMARDs: 
disease modifying anti rheumatic drugs 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EOS: 
end of study 
EOT: 
End of Treatment 
EQ-5D-3L: 
EuroQol five-dimensional three-level questionnaire 
ESR: 
Erythrocyte sedimentation rate 
FACIT-Fatigue: functional assessment of chronic illness therapy fatigue scale 
GCA: 
giant cell arteritis 
GTI: 
glucocorticoid toxicity index 
HAQ-DI: 
health assessment questionnaire disability index 
HbA1c: 
Hemoglobin A1c 
HR: 
heart rate 
IB: 
investigator’s brochure 
ICH: 
International Conference on Harmonisation 
IEC: 
independent ethics committee 
Ig: 
immunoglobulins 
IL-6: 
Interleukin 6 
IRB: 
institutional review board 
IRT: 
interactive response technology 
LDL: 
low-density lipoprotein 
LFT: 
liver function test 
mAb: 
monoclonal antibody 
Max: 
maximum 
MD-VAS: 
physician global assessment of disease activity- visual analog scale 
Min: 
minimum 
NIMP: 
noninvestigational medicinal product 
PD: 
pharmacodynamics 
PFS: 
prefilled syringe 
PK: 
pharmacokinetics 
PMR: 
polymyalgia rheumatica 


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PRO: 
patient reported outcome 
q2w: 
every 2 Weeks 
RA: 
rheumatoid arthritis 
RNA: 
ribonucleic acid 
SAA: 
serum amyloid A 
SAE: 
serious adverse event 
SC: 
subcutaneous 
SD: 
standard deviation 
SF-36v2: 
short form 36 version 2 
sIL-6R: 
soluble IL-6 receptor 
TB: 
tuberculosis 
TBI: 
tuberculosis infection 
TEAEs: 
treatment-emergent AEs 
ULN: 
upper limits of normal 
WOCBP: 
woman of child-bearing potential 
 


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4 
INTRODUCTION AND RATIONALE 
Giant cell arteritis (also known as temporal arteritis; GCA) is a chronic, immune-mediated, 
systemic inflammatory vasculitis that affects medium-sized and large vessels. It is one of the most 
common types of vasculitis, and usually affects individuals older than 50 years and has a 
prevalence that ranges from 24 to 280 cases per 100 000 persons in Western countries (1, 2). The 
vascular involvement can be widespread and variable, including the cranial vascular beds, aorta 
and primary and secondary branches of the aorta, such as the subclavian and axillary arteries. 
Clinical manifestations of GCA are indicative of the site of vessel affected, such as headaches, 
scalp tenderness, jaw claudication and vision loss that are characteristic of cranial vascular 
involvement while disease involving the subclavian and axillary arteries may manifest as 
claudication, abnormal pulses and blood pressures (BP), paresthesias, etc in the affected extremity 
(3). Histologically, all layers of the vessel walls are involved at affected sites, consisting of 
granulomatous inflammatory infiltrate of activated CD4+ T-cells, macrophages and giant cells. 
Diagnosis involves a typical constellation of clinical signs/symptoms (eg, headaches, visual 
disturbances, jaw claudication) and corroborating laboratory abnormalities (eg, elevated acute 
phase reactants) and radiographic or histological evidence of vasculitis (3, 4, 5). 
The precise cause of GCA is unknown. Both the adaptive and innate immune responses have been 
implicated in the pathogenesis of GCA. It is hypothesized that dysregulation of the innate and 
adaptive immune response leads to abnormal activation of dendritic cells which attract and 
activate CD4+ T-cells and macrophages to the vessel wall, which then release proinflammatory 
cytokines that are responsible for the cascade of inflammatory activities and injuries to the vessels 
that are characteristics of GCA (4, 5, 6). As a result of the stress and injury, the innate immune 
system produces the acute-phase systemic response through a cascade of signals where 
interleukin-6 (IL-6) plays a critical role (7, 8). 
Interleukin 6 (IL-6) is a pleiotropic cytokine produced by T-cells, B-cells, macrophages, 
endothelial cells, and fibroblasts upon different stimuli. The IL-6 pathway is located at the 
intersection of the innate and adaptive immune systems and, if down-regulated, has the potential 
to inhibit inflammatory responses. In GCA patients, IL-6 is up-regulated within inflamed arteries 
and its concentration in the peripheral circulation is elevated compared to healthy controls, serum 
IL-6 levels mirror disease activity and decline with adequate corticosteroid (CS) treatment. It has 
been speculated that IL-6R blockade may ameliorate vascular inflammation through several 
mechanisms. Recent reports from the evaluation of tocilizumab as a therapy for GCA, including a 
randomized, double-blind, placebo-controlled trial, suggest that blockade of the IL-6 signaling 
pathway is effective for the treatment of GCA (9, 10, 11). 
The current standard of care for GCA, CS therapy, is a suboptimal treatment strategy. Although 
high dose CSs have generally been effective for the treatment of acute disease and control of 
inflammation, usually a year or more of coritcosteroid (CS) therapy is required for maintenance of 
remission or control of disease activity (3, 12, 13, 14). More than 85% of patients suffer from 
CS-related side effects, which are associated with substantial toxicities, and the elderly 
population, such as those diagnosed with GCA, are especially at risk for the toxicities associated 
with long term CS use. In addition, there is a high rate (over 50%) of relapse or flare of the 


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disease when CS is tapered (13, 15) and persistently active vascular inflammation despite ongoing 
CS therapy has been demonstrated in animal models and confirmed in patients who lack overt 
clinical symptoms. Aside from CS, there are limited highly effective treatment options for GCA. 
Thus, there remains a high unmet medical need for effective treatment that can maintain remission 
of GCA and spare patients the toxicities of CSs. Tocilizumab, an IL-6R antagonist, has been 
shown to be effective for the treatment of GCA in open-label treatment and in recent double-
blind, placebo-controlled studies (9, 10, 11) and has received recent approval for the treatment of 
GCA in both the US and Europe. 
Sarilumab, a human immunoglobulin (Ig) IgG1 monoclonal antibody (mAb), targets the IL-6R 
and inhibits IL-6 signaling. In this study, GCA patients will be treated with sarilumab. Sarilumab 
has been evaluated for the treatment of patients with moderate to severe active rheumatoid 
arthritis (RA) and has demonstrated superior efficacy compared to placebo when administered on 
background disease modifying antirheumatic drugs (DMARDs), and superior efficacy compared 
to another biologic (adalimumab) when administered as monotherapy with an acceptable safety 
profile consistent with this class of therapy. Sarilumab may be an effective and safe therapy for 
the treatment of patients with active GCA and sparing patients the toxicities associated with 
chronic CS therapy. To this end, the current proposed study will evaluate the efficacy and safety 
of sarilumab in patients with active GCA. 
The efficacy and safety of sarilumab have been evaluated in Phase 2 and 3 studies of the RA 
clinical development program across different segments of the RA populations. Patients with 
sarilumab treatment showed clinically relevant and significant improvements compared with 
placebo or active comparator either in combination with methotrexate (MTX) or csDMARDs or 
as monotherapy, respectively.  
In addition to clinical development for RA, sarilumab has also been studied in patients with 
ankylosing spondylitis and noninfectious uveitis. Overall, the safety observations from these 
studies were consistent with what has been observed in patients with RA.  
The primary dose of sarilumab for this study/indication (ie, 200 mg subcutaneous [SC] every 
2 weeks [q2w]) and a second dose (150 mg SC q2w) are selected based largely on the aggregate 
data from the sarilumab RA clinical development program. 
Five different doses of sarilumab were evaluated in a Phase 2 placebo-controlled dose-ranging 
study in patients with RA, EFC11072 Part A: 100 mg q2w, 150 mg q2w, 100 mg once a week 
(qw), 200 mg q2w, and 150 mg qw. In this study, the effect on free soluble IL6R-alpha (sIL6Rα) 
and C-reactive protein (CRP) levels and on efficacy endpoints related to signs and symptoms of 
RA was apparent at doses of 150 mg q2w or above. A plateau was reached for pharmacodynamics 
(PD) biomarkers and endpoints at the 200 mg q2w dose, with a further increase in exposure by 
2.7-fold (at 150 mg qw) providing, a marginal change in the responses. Therefore, the 200 mg 
q2w dose delivered sarilumab concentrations near target saturation. In addition, evaluation of the 
PD effects on RA biological markers of disease activity and inflammation, which are similar to 
those found in GCA patients, revealed that reduction of CRP and/or serum amyloid A (SAA) 
levels to a normal range was apparent at sarilumab trough concentrations of 1 mg/L or above. 
More patients treated with sarilumab 200 mg q2w compared to 150 mg q2w showed trough levels 
at or exceeding 1 mg/L throughout the dosing interval (86% versus 61%). In addition to the 


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commonly observed, elevated acute phase reactants, such as erythrocyte sedimentation rate (ESR) 
and CRP, circulating levels of IL-6 are significantly elevated in GCA patients (40 to 50 pg/mL) 
compared to healthy controls (16, 17), and these levels are generally higher than those observed in 
established RA patients, which range from 21 to 36 pg/mL in circulation. Therefore, based on 
available pharmacokinetic (PK)/PD data from the RA clinical development program and the 
higher levels of IL-6 in GCA patients, the 200 mg q2w dose is more likely to be the effective dose 
for the treatment of GCA. 
Although both the 200 mg q2w and 150 mg q2w doses have demonstrated robust clinical efficacy 
in the RA clinical development program with suppression of biological markers of disease and 
inflammation similar to those found in GCA patients with an acceptable safety profile, the higher 
dose has a generally more favorable efficacy response (refer Investigator’s Brochure [IB] for 
additional details). Consequently for the treatment of patients with moderate to severe RA, the 
approved starting dose of sarilumab is 200 mg q2w with the option to decrease to 150 mg q2w for 
laboratory abnormalities. Therefore, the sarilumab 200 mg q2w dose is selected for evaluation in 
this study and for the primary comparison while a second dose of sarilumab 150 mg q2w is added 
to provide additional information on efficacy and safety in GCA patients. 
4.1 
BENEFIT AND RISK ASSESSMENT 
The available aggregate nonclinical and clinical data from the sarilumab development program in 
RA have demonstrated a potent anti-inflammatory effect and significant clinical benefit for 
patients with active RA via blockade of the IL-6 signaling pathway, which is also thought to play 
a key role in the pathogenesis of GCA. Therefore, treatment of GCA patients with sarilumab may 
lead to clinical benefits as observed in patients with active RA.  This likely benefit with sarilumab 
is further supported by the pivotal GiACTA trial (a phase 3 study which evaluated efficacy and 
safety of tocilizimab in GCA patients [9]) that resulted in the approval of a similar IL-6 inhibitor, 
tocilizumab, for the treatment of GCA. Because of the similarity of sarilumab to tocilizumab and 
a study design that mirrors the successful GiACTA trial, it is expected that the current study will 
demonstrate a similar efficacy for sarilumab in GCA. Sarilumab is already approved for the 
treatment of rheumatoid arthritis in multiple countries.   
Based on the safety profile of sarilumab available to date and other biological DMARDs, 
important identified risks include serious infections, neutropenia and hypersensitivity reactions; 
important potential risks to be considered with sarilumab administration, consistent with this class 
of therapy, include laboratory abnormalities and the potential clinical consequences, such as 
thrombocytopenia and the potential risk of bleeding, clinically evident hepatic injury with 
elevated hepatic transaminases, and lipid abnormalities and potential increased risk of major 
adverse cardiovascular event (MACE). Other potential important risks include increased risk of 
malignancy and gastrointestinal perforation. Various risk mitigation strategies are either built into 
the eligibility criteria (Section  7.1 and Section 7.2) to exclude those with conditions that may 
jeopardize their safety or into other sections of the protocol (Section 10.4 and Section 10.7) for 
monitoring and management of certain risks/adverse events (eg, neutropenia, thrombocytopenia, 
liver transaminase elevation, etc). 


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Based upon the overall safety and efficacy data of the sarilumab program in RA, the 
comparability of sarilumab to tocilizumab and the positive GiACTA trial, the benefit/risk 
assessment favors the study of sarilumab in patients with GCA. More detailed information about 
the known and expected benefits and risks and reasonably expected adverse events of sarilumab 
may be found in the Investigator’s Brochure. 


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5 
STUDY OBJECTIVES 
5.1 
PRIMARY  
To evaluate the efficacy of sarilumab in patients with GCA as assessed by the proportion of 
patients with sustained remission at Week 52 for sarilumab compared to placebo, in combination 
with a 26-week CS tapering course.   
5.2 
SECONDARY  
 To demonstrate the efficacy of sarilumab in patients with GCA compared to placebo, in 
combination with (either 26 or 52 weeks) CS tapering course with regards to: 
- 
Clinical responses (such as responses based on disease remission rates, time to first 
disease flare) over time.  
- 
Cumulative CS (including prednisone) exposure. 
 To assess the safety (including immunogenicity) and tolerability of sarilumab in patients 
with GCA. 
 To measure sarilumab serum concentrations in patients with GCA. 
 To assess the effect of sarilumab on sparing glucocorticoid toxicity as measured by 
glucocorticoid toxicity index (GTI). 
5.3 
OTHER 
 To assess the effect of sarilumab on physician assessment of disease activity as measured 
by a visual analogue scale (MD-VAS). 
 To assess the effect of sarilumab compared with placebo, in combination with a 26-week 
CS taper as on a variety of patient reported outcome (PRO) concepts including fatigue 
(FACIT-Fatigue), health status (EuroQol five-dimensional three-level questionnaire 
[EQ-5D-3L], Short form 36 version 2 [SF-36v2]), physical functioning (health assessment 
questionnaire disability index [HAQ-DI]), including pain (visual analogue scale) and 
patient assessment of disease activity (visual analogue scale). 
 To assess the impact of ESR/CRP levels on remission status. 
 To characterize the disease activity of GCA patients while on steroid taper or sarilumab 
treatment in a subset of patients using comprehensive approaches to evaluate circulating 
immune cell types.  
 To characterize the disease activity of GCA patients while on steroid taper or sarilumab 
treatment by evaluating circulating proteins, genetics and gene expression in consenting 
patients. 


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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a multicenter, randomized, double-blind, placebo-controlled 52-week Phase 3 study with a 
24-week post-treatment follow up phase, evaluating the efficacy and safety of sarilumab in 
patients with GCA.  
Approximately 360 patients with GCA (new onset or refractory [eg, disease relapse] GCA) who 
meet the entry criteria will be randomized to 4 parallel treatment groups with sarilumab 200 mg 
q2w, 150 mg q2w, or placebo q2w plus 26-week prednisone taper, or placebo q2w with 52-week 
standardized prednisone taper at a ratio of 2:1:1:2 as described below. The protocol will aim to 
enroll at least 30% of new onset patients, therefore, the Sponsor will reserve the possibility to cap 
enrolment of refractory patients to ≤70% of total patients randomized. Randomization will be 
stratified by the starting dose of prednisone at baseline (<30 mg/day or ≥30 mg/day). 
 Treatment Group A: sarilumab 200 mg q2w with a 26-week taper of CS. 
 Treatment Group B: sarilumab 150 mg q2w with a 26-week taper of CS. 
 Treatment Group C: sarilumab matching placebo q2w with a 26-week taper of CS. 
 Treatment Group D: sarilumab matching placebo q2w with a 52-week taper of CS. 
It is important to optimize CS treatment prior to randomization to minimize the risk of adverse 
sequelae from GCA. Patients will be dosed with prednisone between 20 to 60 mg/day at the time 
of randomization (baseline) and initiate taper according to the protocol defined schedule. Patients 
will be initiated on a standardized taper of prednisone from the time of randomization. The taper 
will initially be open label; patients will have between 1 to 7 weeks to taper prednisone dose to 
20 mg/day following randomization. 
The further tapering of prednisone once a dose of 20 mg/day is achieved will be done in a blinded 
manner. To achieve the appropriate daily dose during this phase, patient will receive a 
combination of prednisone and/or placebo to prednisone depending on the assigned treatment 
group and associated taper regimen. 
The total tapering period (open label plus double blind prednisone) will be between 46 weeks to 
52 weeks depending on the initial prednisone dose at randomization.  
At each site visit, the patient’s disease will be assessed to determine whether the patient can 
adhere to the protocol defined prednisone taper schedule. 
During the course of study, for patients in need of rescue therapy as per Investigator judgment, CS 
should be the agent of first choice. Patients may continue SC administration of sarilumab or 
matching placebo only if CS is used as rescue therapy. If the patients remain symptomatic despite 
CS rescue therapy, then other treatment options including nonbiological immunosuppressive 


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drugs may be used and the patient must be discontinued from the study treatment and considered a 
nonresponder.  
If the patient or Investigator decides to discontinue the administration of blinded sarilumab 
injections, then the patient will be asked to return to the site for study assessments as per protocol 
until end of study (EOS) evaluation, unless the patient cannot or does not wish to continue the 
assessments, in which case an early withdrawal visit and safety follow up should be performed. It 
is recommended that patients complete Visit 13, if possible. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
Total duration of study participation for each patient is up to 82 weeks:  
 Up to 6 weeks screening period. 
 52-week treatment period (sarilumab or placebo, double-blind phase). 
 24-weeks post treatment follow up period. 
6.2.2 Determination of end of clinical trial (all patients) 
The last patient last visit will occur when the last patient has completed the 24-week follow up 
period (EOS). The end of the clinical trial is defined as the last patient’s last visit. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned.  
Primary analysis at Week 52 will be conducted after the final patient has completed the 
double-blind treatment period and all data have been verified. 
Patients will continue into the 24-week posttreatment follow up period with the database lock 
occurring after the last patient has completed the EOS visit. 
6.4 
STUDY COMMITTEES 
Central review and certification of diagnostic ultrasounds 
If ultrasound is used to diagnose GCA and determine patient eligibility, the ultrasound images 
will be centrally reviewed by an expert rheumatologist (from a group of expert rheumatologists) 
specialized in the performance and interpretation of diagnostic ultrasounds of the vasculitis in 
order to confirm the diagnosis. Additionally, the same group of expert rheumatologists will also 
serve to help certify the sites who wish to have the option of using ultrasound in the diagnosis of 
GCA for their patients. 


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6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS 
EFC15068 has been designed as a 52-week, double-blind, placebo-controlled, randomized, 
comparator study with a 24-week posttreatment follow up phase, to evaluate the efficacy and 
safety of sarilumab in patients with GCA. The 52-week study treatment duration reflects the 
standard duration of corticosterioid therapy required to ensure sustained remission for patients 
with GCA (hence, the primary endpoint of sustained remission is at Week 52). This duration of 
treatment is consistent with that in published interventional studies in GCA (11, 18). 
Approximately 360 patients who have either newly diagnosed GCA or have refractory active 
GCA, will be enrolled and randomized into 4 different arms to receive either sarilumab 200 mg 
q2w with 26-week prednisone taper (Group A) or sarilumab 150 mg q2w (Group B) with 26-week 
prednisone taper or sarilumab matching placebo with prednisone taper periods of either 26 weeks 
(Group C) or 52 weeks (Group D) in the ratio of 2:1:1:2. 
The 26-week taper is selected to demonstrate that sarilumab can enable patients to taper off CS 
earlier rather than the usual prolonged taper of 52 weeks with CS alone. The ability to taper off of 
CS rapidly (26 weeks taper period as opposed to the usual tapering regimen of a year or more) 
while maintaining disease remission would represent an important clinically meaningful benefit. 
The 52-week taper mimicks the usual care with CS and serves as a calibrator arm. Therefore, the 
primary comparison will be between Group A (sarilumab 200 mg q2w) and Group C (placebo 
sarilumab) where a 26 week taper of CS regimen will be used in both arms. Group B will evaluate 
a second dose of sarilumab (150 mg q2w) also with a 26 week taper of CS. Group D will evaluate 
the effect of placebo sarilumab with a 52-week taper of CS that reflects usual care, and will serve 
as a calibrator for further benefit risk assessment.  
The Weeks 12 to 52 period assesses the “sustainability” of the remission that should be achieved 
by Week 12 as this is the anticipated timepoint where most patients should have achieved 
remission in usual care with steroids. After completion of the 52-week, double-blind, 
placebo-controlled treatment period, patients will be followed for another 24 weeks to assess the 
durability of the treatment response. 


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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Diagnosis of GCA classified according to the following criteria: 
- 
Age ≥50 years. 
- 
History of ESR ≥50 mm/hour (or CRP >25 mg/L). 
- 
Presence of at least one of the following: Unequivocal cranial symptoms of GCA (new 
onset localized headache, scalp or temporal artery tenderness, ischemia-related vision 
loss, or otherwise unexplained mouth or jaw pain upon mastication) or symptoms of 
polymyalgia (defined as shoulder and/or hip girdle pain associated with inflammatory 
stiffness). 
- 
Presence of at least one of the following: Temporal artery biopsy revealing features of 
GCA; Evidence of large-vessel vasculitis by angiography or cross-sectional imaging 
(angiography, computed tomography angiography [CTA], magnetic resonance 
angiography [MRA] or positron emission tomography-computed tomography 
[PET-CT], ultrasound).  
Note: For countries where local EC does not approve an angiography, CTA or PET-CT or 
for which a specific approval procedure for angiography, CTA or PET-CT is required by a 
different committee than the local EC/IRB, patients may be enrolled using temporal artery 
biopsy or ultrasound. 
Note: Sites that will consider inclusion of patients in the study using ultrasound as part of 
screening and diagnostic process for relevant disease status confirmation should only 
employ this method following completion of certification by the sponsor (details of the 
ultrasound certification process are found in the manual). 
I 02. New onset active disease or refractory active disease according to the following criteria: 
- 
New onset active disease is defined as: 
 Diagnosis within 6 weeks of baseline. 
- 
Refractory active disease is defined as: 
 Diagnosis >6 weeks before baseline and previous treatment with ≥40 mg/day 
prednisone (or equivalent) for at least 2 consecutive weeks at a time. This includes 
patients who have achieved remission in the past but have a flare in the disease 
again or patients who have not been able to achieve complete remission since 
diagnosis of GCA. 


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I 03. At least one of the following symptoms of GCA within 6 weeks of baseline. 
- 
Unequivocal cranial symptoms of GCA (new onset localized headache, scalp or 
temporal artery tenderness, ischemia-related vision loss, or otherwise unexplained 
mouth or jaw pain upon mastication). 
- 
Unequivocal symptoms of polymyalgia rheumatica (PMR) (defined as shoulder and/or 
hip girdle pain associated with inflammatory stiffness). 
- 
Other features judged by the Investigator to be consistent with GCA or PMR flares (ie, 
new or worsened extremity claudication, fever not associated with infection).  
I 04. Either ESR ≥30 mm/hour or CRP ≥10 mg/L within 6 weeks of baseline must be present. 
I 05. Receiving or able to receive prednisone 20 to 60 mg/day for the treatment of active GCA.  
I 06. Signed written informed consent. 
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 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Organ transplantation recipient (except corneas, unless it is within 3 months prior to 
baseline visit). 
E 02. Major ischemic event, unrelated to GCA, within 12 weeks of screening. 
E 03. Any prior use of the following therapies, for the treatment of GCA: 
- 
Janus kinase (JAK) inhibitor (eg, tofacitinib) within 4 weeks of baseline.  
- 
Cell-depletion agents (eg, anti CD20) without evidence of recovery of B cells to 
baseline level. 
- 
Abatacept within 8 weeks of baseline. 
- 
Anakinra within 1 week of baseline. 
- 
Tumor necrosis factor (TNF) inhibitors within 2 to 8 weeks (etanercept within 
2 weeks; infliximab, certolizumab, golimumab, or adalimumab within 8 weeks), or 
less than at least 5 half-lives have elapsed prior to baseline, whichever is longer. 
E 04. Therapeutic failure, including inadequate response or intolerance, or contraindication, to 
biological IL-6/(R) antagonist (prior experience with IL-6/(R) antagonist that was 
terminated for reasons unrelated to therapeutic failure at least 3 months before baseline is 
not exclusionary).  


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E 05. Use of any alkylating agents including cyclophosphamide (CYC) within 6 months of 
baseline. 
E 06. Use of immunosuppressants, such as hydroxychloroquine (HCQ), cyclosporine (CsA), 
azathioprine (AZA) or mycophenolate mofetil (MMF) or leflunomide (LEF) within 
4 weeks of baseline.(Use of MTX not exceeding 25 mg per week and have been stable for 
at least 3 months prior to baseline is not exclusionary [see Section 8.8]). 
E 07. Concurrent use of systemic CS for conditions other than GCA. 
E 08. Use of IV CS at a dose equivalent to 100 mg of methylprednisolone or higher within 
8 weeks of baseline for GCA therapy. 
E 09. Participation in any clinical research study that evaluated an investigational drug or 
therapy within 5 half-lives or 60 days of the screening visit, whichever is longer. 
E 10. History of alcohol or drug abuse within 5 years prior to the screening visit. 
E 11. Patient who withdraws consent during the screening period (following signing of the 
informed consent form). 
E 12. Based on Investigator judgment, conditions/situations such as: 
- 
Patients with short life expectancy 
- 
Patient is the INVESTIGATOR or any subinvestigator, Research Assistant, 
Pharmacist, Study Coordinator, other staff or relative thereof, directly involved in the 
conduct of the study, or, as applicable to employee of site/Investigator or Sponsor. 
- 
Uncooperative, or any condition, that could make the patient potentially noncompliant 
to the study procedures, etc, 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 13. Pregnant or breastfeeding woman. 
E 14. Woman of childbearing potential (WOCBP) not protected by highly-effective 
contraceptive method(s) of birth control (as defined in Appendix A), and/or who are 
unwilling or unable to be tested for pregnancy.  
E 15.  Exclusion related to tuberculosis (TB): 
- 
Active TB or a history of incompletely treated TB. 
- 
Quantiferon positive patients (no active disease) are excluded from the study unless 
the following conditions are met: 
 Patients with a history of prior documented completed chemoprophylaxis for latent 
tuberculosis infection (TBI) (eg, acceptable treatments would be 9 months of 
isoniazid 300 mg PO daily or equivalent proven regimen per local guidelines) or 


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treatment of active TBI, has obtained consultation with a specialist to rule out or 
treat active TBI. 
 Patients with no prior history of chemoprophylaxis for latent TBI or treatment for 
active TBI, have obtained consultation with a specialist to initiate an appropriate 
regimen of chemoprophylaxis, based on local epidemiology and applicable 
guidelines and the patient has demonstrated compliance and has tolerated treatment 
for ≥1 month. 
 Consultation with and prior approval from sponsor are required in either of the 
aforementioned scenarios. 
- 
Clinically significant abnormality consistent with prior/active TB infection based upon 
chest radiograph with at least posterior-anterior (PA) view (radiograph must be taken 
within 12 weeks prior to screening visit or during the screening period). Additional 
lateral view is recommended but not required. 
- 
Suspected extrapulmonary TB infection. 
- 
Patients at high risk of contracting TB, such as close contact with individuals with 
active or latent TB. 
- 
Patient who received Bacille Calmette Guerin (BCG)-vaccination within 12 months 
prior to screening. 
E 16. Patients with a 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 [PML]). 
E 17. Patients with fever associated with infection (>38oC), 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 Investigator judgment. 
E 18. Patients with uncontrolled diabetes mellitus, defined as Hemoglobin A1c (HbA1c) ≥9% at 
the screening visit. 
E 19. Patients with nonhealed/healing skin ulcers. 
E 20.  Patients who received any live, attenuated vaccine within 3 months prior to the baseline 
visit, such as varicella-zoster virus, oral polio or measles-mumps-rubella vaccines. 
E 21. Patients who had a positive test at screening for hepatitis B surface antigen (HBs-Ag) or 
total hepatitis B core antibody positive with negative hepatitis B surface antibody (HBs-
Ab), or total hepatitis B core antibody positive with positive HBs-Ab and presence of 
hepatitis B virus (HBV) deoxyribonucleic acid (DNA). 
E 22. Patients who are positive for hepatitis C antibodies at the screening visit. 


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E 23. Patients, who have a positive test at the screening visit or who previously had a positive 
test, or who are suspected to be positive for human immunodeficiency virus (HIV). 
E 24. Patients with a history of recurrent herpes zoster or active herpes zoster. 
E 25. Patients with a history of prior articular or prosthetic joint infection. 
E 26. 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 27. Prior or current history of other significant concomitant illness(es) that, according to 
Investigator's judgment, would adversely affect the patient's participation in the study. 
These include, but are not limited to, cardiovascular (including stage III or IV cardiac 
failure according to the New York Heart Association classification), renal, neurological 
(including demyelinating disease), active infectious diseases, endocrinological, 
gastrointestinal, hepato-biliary, metabolic, pulmonary, non-malignant lymphoproliferative 
disease or other lymphatic disease(s).  
E 28. Any patient who has had surgery within 4 weeks prior to the screening visit or with 
planned surgery during the course of the study. 
E 29. Patients with a history of a systemic hypersensitivity reaction, other than localized 
injection site reaction, to any biologic drug and known hypersensitivity to any constituent 
of the sarilumab product. 
E 30. Patients with any of the following laboratory abnormalities at the screening visit: 
- 
Hemoglobin <8.5 g/dL. 
- 
White blood cells <3000/mm3. 
- 
Neutrophils <2000/mm3. 
- 
Platelet count <150 000 cells/mm3. 
- 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 x upper 
limits of normal (ULN), unless this is a manifestation of active GCA in the opinion of 
the Investigator. 
- 
Bilirubin (total) >ULN, unless documented Gilbert's disease diagnosed by genetic 
testing. 
- 
Presence of severe uncontrolled hypercholesterolemia (>350 mg/dL, 9.1 mmol/L) or 
hypertriglyceridemia (>500 mg/dL, 5.6 mmol/L). 
- 
Patients with a calculated creatinine clearance <30 mL/minute (using Cockroft-Gault 
formula). 
Note: Laboratory parameters may be repeated during the screening period if judged to be 
spurious or due to technical error in order to determine eligibility. 


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E 31. Patients with a history of inflammatory bowel disease or severe diverticulitis or previous 
gastrointestinal perforation.  


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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
Details of IMPs are provided in Table 1.  
There are 2 IMPs to be administered in this study:  
 Sarilumab or sarilumab matching placebo 
 Prednisone or prednisone matching placebo  
In order to differentiate these 2 IMPs, sarilumab and sarilumab matching placebo are named as SC 
IMP, prednisone and prednisone matching placebo are named as oral IMP. 
Table 1 - Summary of investigational medicinal products 
 
Name of 
IMP  
Pharmaceutical 
forms 
Dose of drug per 
administration 
Route and 
method of 
administration 
Treatment 
duration 
Double blind 
phase of 
sarilumab 
Sarilumab 
Single-use 1.14 mL 
prefilled glass syringes 
containing 175 mg/mL  
(200 mg)  
 & 
Single-use 1.14 mL 
prefilled glass syringes 
containing 131.6 mg/ml 
(150 mg) 
Sarilumab 200 mg 
& 
Sarilumab 150 mg   
Subcutaneous  
 
Entire 52 week 
treatment period 
 
Double blind 
phase of 
sarilumab 
Sarilumab 
matching 
placebo 
Placebo solution for 
injection 
Matching placebo   
Subcutaneous  
 
Entire 52 week 
treatment period  
Open label 
CS taper 
phase 
Prednisone  
5 mg & 20 mg Tablets 
Refer to standard CS 
taper regimen 
Appendix B 
Oral administration 
1 to 7 weeks 
OL CS taper 
phase, 
depending on 
starting dose 
(refer to 
Appendix B) 
Double blind 
CS taper 
phase 
Prednisone  
1 mg & 5 mg Capsules 
Refer to standard CS 
taper regimen 
Appendix B  
Oral administration 
 
45 weeks 
DB CS taper 
phase (refer to 
Appendix B) 


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Name of 
IMP  
Pharmaceutical 
forms 
Dose of drug per 
administration 
Route and 
method of 
administration 
Treatment 
duration 
Double blind 
CS taper 
phase 
Prednisone 
matching 
placebo 
Capsules 
Refer to standard CS 
taper regimen 
Appendix B 
Oral administration 
45 weeks 
DB CS taper 
phase (refer to 
Appendix B) 
CS = corticosteroid; DB = double blind; IMP = investigational medicinal product; OL = open label. 
8.1.1 Sarilumab or matching placebo: 
Additional detail regarding the method of administration 
Formulation: 
Sarilumab drug product will be provided as single-use 1.14 mL prefilled syringe (PFS) containing 
131.6 mg/mL (150 mg), 175 mg/mL (200 mg) of sarilumab or placebo solution for SC injection. 
No preparation at the clinical site is required.  
Route of Administration:  
Sarilumab will be administered in non-affected skin subcutaneously in the abdomen or thigh when 
self-injected or in upper arm (lateral side) when injected 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). Each drug administration 
requires a single injection.  
Patients and/or their non-professional caregivers will be trained to prepare and administer study 
drug at the baseline visit. This training must be documented in the subject’s study file. The study 
staff should review the patient’s self-administration technique at Visit 2 (Week 0). For doses not 
given at the study site, diaries will be provided to record information pertaining to those 
injections.  If the patient is unable or unwilling to administer study drug, arrangements must be 
made for a qualified site personnel or a caregiver to administer study drug doses that are not 
scheduled to be given at the study site. 
Dose regimen: 
The IMP (sarilumab or matching placebo) should be administered every 14 days as per protocol 
IMP administration schedule, however an IMP administration time window of ±3 days is 
permitted in exceptional circumstances (eg. Laboratory test result pending, or an ongoing adverse 
event (AE) or patient schedule difficulty). For subsequent IMP administrations the initial IMP 
administration schedule should be followed again (see Table 1). 
Note: An interval of ≥11 days between 2 IMP doses must be maintained. 


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If the study visit is not performed at the site as scheduled, the dose will be administered as 
described above, either by the patient, qualified site personnel, and/or their caregiver(s).  
On days when the patient has a study visit, the IMP will be administered after clinic procedures 
and blood collection. 
Patients will be monitored for at least 30 minutes after each dose of sarilumab, or as per country 
specific requirements (eg, up to 2 hours) for any signs or symptoms of any medical events. In the 
case that the injection is administered by caregiver or self injection, patients should be instructed 
to monitor themselves for any signs or symptoms of any medical events.    
The total duration of treatment is 52 weeks. 
Dose modification/reduction: 
Sarilumab dose 200 mg may be reduced in response to elevated liver transaminases, neutropenia, 
and/or thrombocytopenia. The request for dose reduction will be managed via interactive response 
technology (IRT) and the sarilumab dose prior to and following the dose reduction will remain 
blinded to site and Sponsor (for patients in the sarilumab 150 mg or sarilumab matching placebo 
groups, the other treatment groups there will be only a sham dose reduction to maintain the blind). 
Please see Section 10.7.2, Section 10.7.3 and Section 10.7.4 for further details. Once the dose is 
reduced, no further dose increase is permitted for the remainder of the study treatment period. 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, sarilumab or matching placebo may be supplied from the site to 
the patient via a Sponsor-approved courier company where allowed by local regulations and 
approved by the subject. 
Post-trial access to sarilumab will be in compliance with all applicable national and local laws and 
regulations, including safety reporting obligations. 
8.1.2 Prednisone or matching placebo: 
Additional detail regarding the method of administration 
Patients will be trained in the use of the weekly prednisone blister packs at the baseline visit. This 
training will include instruction on use of the blister packs in the appropriate order and use of the 
“spare” row of tablets/capsules in the case of loss of a tablet/capsule during dosing. The training 
must be documented in the patient’s study file. 
All patients will receive prednisone (at doses of 60 mg/day or less) and/or matching placebo 
(double-blind prednisone tapering phase only) following different standardized prednisone-taper 
regimen for treatment of GCA depending on the assigned treatment group. In the open-label phase 
all patients will receive prednisone tablets while in the double-blind prednisone tapering phase 
patients will receive encapsulated prednisone tablets in blinded packaging. 
There will be 2 standardized CS-taper regimens defined: 
 Up to 26 week taper (Group A, Group B and Group C). 


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 Up to 52 week taper (Group D). 
There will be 2 phases for each prednisone taper regimen: 
 Open-label phase (from 1 to 7 weeks): all patients will go through this phase in order to 
have the prednisone dose tapered down to 20 mg/day. Patients may start at 60 mg/day or 
any of the incremental dosages: 50 mg/day, 40 mg/day, 35 mg/day, 30 mg/day, 25 mg/day, 
or 20 mg/day. Patients will follow the tapering schedule as per Appendix B, completing 
the open-label phase and transitioning to the blinded phase of tapering after 1 to 7 weeks, 
depending on the prednisone dose at baseline (ie, patients starting on 35 mg/day will 
transition to the double-blind phase of tapering quicker than patients starting on 
50 mg/day). 
 Blinded phase (45 weeks): Over encapsulated prednisone and/or matching placebo will be 
used to maintain blinding of the taper regimen regardless of regimens that the patient is 
assigned to. 
During the prednisone taper blinded phase, patients will be supplied with weekly blister packs 
which will be numbered and will clearly indicate the number of tablets to be taken per day. It is 
important that the blister packs be used in the correct order and that 7 days of dosing from each 
blister be taken by the patient before starting the next blister pack. If a patient visit is scheduled 
before the patient has used 7 days of a particular weekly blister pack, then this blister pack should 
be returned to the patient so that the patient can complete the remaining days of dosing with that 
blister pack before starting the next sequentially numbered blister pack. If doses have been 
missed, it is not necessary for patients to use the missed capsules before progressing to their next 
blister packs. 
During the blinded taper, the daily encapsulated dose may contain prednisone, placebo, or a 
combination of the two. The number of capsules to be taken each day will vary but will not be 
indicative of the dosage of prednisone. The number of capsules to be taken daily may increase or 
decrease during the tapering schedule but will not exceed 5 capsules per day. 
Refer to Appendix B for detailed standardized CS-taper regimen during the double-blind study 
treatment period. 
Where the visit interval exceeds 4 weeks (eg. 8-week or 12-week visit interval), the patient may 
be provided with only the first 4 weeks of treatment during the visit, and interim visits may be 
required for IMP dispensing to the patient between the protocol-scheduled on-site visits. This is to 
ensure that the patient only receives a 4-week supply of prednisone weekly blisters at any time, to 
minimize potential compliance errors. Alternatively, the prednisone may be sent directly to the 
patient by the site via a Sponsor-approved courier company where allowed by local regulations 
and approved by the subject.  


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8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Rescue therapy 
At each study visit, an assessment of the patient’s GCA disease status should be made. If the 
patient has no evidence for disease flare and is able to follow the per protocol prednisone taper 
schedule, the patient will continue with the per protocol prednisone taper of the study as per 
Appendix B for up to 52 weeks. If the patient experiences a disease flare or cannot adhere to the 
prednisone tapering schedule, then the patient must stop the per protocol prednisone taper and 
instead may receive rescue therapy, such as CSs, as per Investigator's clinical judgment. The 
patient should continue in the double-blind period of the study for the full 52 weeks and should 
continue to receive blinded SC injections unless contraindicated by safety concerns and complete 
the remainder of the study assessments. 
Once the patients are on rescue therapy at the discretion of Investigators, it is not allowed for them 
to return to per protocol prednisone taper regimen. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
8.3.1.1 Blinding of IMP 
A patient randomization list will be generated by the IRT. The lists of treatment kit numbers will 
be generated by the Sanofi Clinical Supplies Department. Both the randomization and treatment 
kit lists will be loaded into the IRT. The treatment kit numbers will be obtained by the 
Investigator at the time of patient randomization and at subsequent patient scheduled visits via 
IRT that will be available 24 hours a day. 
Blinding of Sarilumab 
Based on the double blind study design, the Investigators and patients will be blinded to the 
allocation of the sarilumab 200 mg group, sarilumab 150 mg group and sarilumab matching 
placebo groups. 
Sarilumab and matching placebo will be provided in matching glass PFS in kits suitable for 
double blinding. For example, every 4 weeks, the patient will receive 1 sarilumab PFS kit. 
In accordance with the double-blind design of the randomized treatment period, Investigators will 
remain blinded to study treatment and will not have access to the randomization (treatment codes) 
except under exceptional medical circumstances.  


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Blinding of prednisone 
Based on the double blind study design, the Investigators and patients will be blinded to the 
allocation of the different standardized protocol defined CS-taper 26-week or 52-week regimens 
as assigned group.  
Prednisone will be provided in weekly blister packs suitable for double blinding as per assigned 
protocol defined CS-taper regimen.  
In accordance with the double-blind design of the randomized treatment period, Investigators will 
remain blinded to study treatment and will not have access to the randomization (treatment codes) 
except under exceptional medical circumstances. However, in the case where the Investigator 
choses to switch the patient to rescue treatment, such as in the case of a flare, the double blind 
prednisone doses that the patient had been taking prior to rescue will remain blinded. 
8.3.1.2 Blinding of non investigational medicinal product 
Not applicable.  
8.3.2 Randomization code breaking during the study 
In case of an AE, the code must only be broken in circumstances when knowledge of the IMP is 
required for treating the patient.  
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. If the blind is broken, 
the Investigator must document the date, time of day, and reason for code breaking.  
If the blind is broken by the Investigator, for the above stated purpose, the patient must be 
withdrawn from treatment and will be asked to follow the instructions on Section 10.4.1 for the 
visits/assessments to be completed.  
Knowledge of certain laboratory data may result in inadvertent unblinding of a patient’s 
treatment. In order to maintain the blind, refer to the dual assessor manual.  
At the facilities where the PK measurements, anti-drug antibody (ADA) and selected biomarkers 
are determined, the samples will be analyzed prior to database lock leading to unblinding of 
responsible bioanalysts. Bioanalysts are excluded from the clinical trial team. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The treatment kit number lists are generated centrally by Sanofi. The IMPs are packaged in 
accordance with these lists. Patients will be randomized to one of the treatment groups via an IRT. 
Both the randomization and treatment kit lists will be loaded into the IRT. A patient will be 
considered randomized when the first treatment number has been provided by the IRT.  


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Patients who meet the entry criteria will be randomized to 1 of the 4 treatment groups at the ratio 
of 2:1:1:2. Randomization will be stratified by baseline dose (which is the starting dose 
determined by Investigator on the day of randomization) of prednisone (<30 mg/day or 
≥30 mg/day). 
A blocked randomization schedule with records pre-allocated to each of the strata (baseline 
prednisone use <30 mg/day or ≥30 mg/day) will be used for this study. The first patient 
randomized to a stratum will be assigned to the first randomization entry from the randomization 
schedule pre-allocated to that stratum. Subsequent patients randomized to the same stratum will 
be assigned to the next available randomization entry from the randomization schedule pre-
allocated to that stratum. 
At the screening Visit 1 (Day -42 to Day -1), the site coordinator will contact the IRT 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 eligibility of the patient for entry into 
the treatment period, the site coordinator will contact the IRT in order to receive the first 
treatment allocation kit numbers. At subsequent visits during the treatment period, the site 
coordinator will call IRT to obtain the next treatment kit numbers. A confirmation fax/e-mail will 
be sent to the site after each assignment.  
Patients who fail to meet eligibility criteria may be rescreened once. A different patient 
identification will be issued. There is no requirement for a waiting period between the 
screen-failure and the rescreening. The IRT report will flag rescreened patients. Patients that are 
rescreened must sign a new consent form and the Visit 1 procedures must be repeated (chest 
X-ray taken within 12 weeks of the screening visit need not be repeated). Any previously 
randomized patient cannot be rescreened. 
A randomized patient is defined as a patient who is registered and assigned a randomization 
number from the IRT. 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
The investigational products will be supplied in treatment kit boxes that are labeled in accordance 
with the local regulatory specifications and requirements and content information, dosing 
instructions and precautionary statement (“for clinical use only”). 
The number of treatment kits allocated to the patient will provide sufficient medication until the 
next clinic visit. An additional treatment kit, to provide medication to randomized patients in 
special circumstances, eg, a damaged kit, will be allocated by IRT if a “replacement call” is made 
to the IRT system. 


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8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the 
IMP/noninvestigational medicinal product (NIMP) in a secure and safe place in accordance with 
local regulations, labeling specifications, policies, and procedures.  
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound must be 
managed according to the rules provided by the Sponsor. 
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. 
All 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) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 10.5.7). 
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 the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for direct to 
patient [DTP] shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
8.7.1 Treatment accountability and compliance 
Measures taken to ensure and document treatment compliance and IMP accountability include: 
 Proper recording of treatment kit number or packaging number as required on appropriate 
electronic case report form (eCRF) page for accounting purposes. 
 All medication treatment kits (whether empty or unused) are returned by the patient at 
each visit when a treatment dispensing is planned. 
- 
As the used PFS cannot be safely returned to the study site after administration of 
IMP, the completed patient injection diary (returned to the site at each visit), returned 
treatment kit boxes and any unused PFS will be used for drug accountability purposes.  
- 
All blister packs of prednisone treatment (whether empty or unused) are returned by 
the patient at each visit when a treatment dispensing is planned. 


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 The study coordinator tracks treatment accountability/compliance, either by diary, or by 
counting the number of used treatment kits/tablets/capsules and fills in the appropriate 
page of the patient treatment log. 
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 
A detailed treatment log of the destroyed IMP and NIMP (if applicable) will be established with 
the Investigator (or the pharmacist) and countersigned by the Investigator and the monitoring 
team. The Investigator will not destroy the used and unused IMP unless the Sponsor provides 
written authorization. 
8.8 
LIST OF FORBIDDEN AND PERMITTED CONCOMITANT MEDICATIONS 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
The use of any biologics for treatment of GCA during the study is not permitted throughout the 
study treatment and until 6 weeks following the last SC IMP (sarilumab or matching placebo) 
administration unless otherwise indicated. If any of these treatments is used, the patient should be 
discontinued from IMP treatment but the patient will continue to be monitored for safety. 
Administration of any live (attenuated) vaccine is contraindicated until 3 months following the 
last IMP (sarilumab or matching placebo) administration. Treatment with non-biological 
immunosuppressive drugs (such as alkylating agents, hydroxychloroquine, CsA, MMF, AZA, etc) 
is not permitted during the course of the study, unless used for the purpose of rescue therapy. 
During the course of study, for patients in need of rescue therapy as per Investigator judgment, CS 
should be the agent of first choice. Patients may continue SC administration of sarilumab or 
matching placebo only if CS is used as rescue therapy. If the patients remain symptomatic despite 
CS rescue therapy, then other treatment options including nonbiological immunosuppressive 
drugs may be used and the patient must be discontinued from the study treatment and considered a 
nonresponder. 
Methotrexate not exceeding 25 mg per week is permitted if the dose has been stable for at least 
3 months prior to baseline. The dose should also remain stable (may be reduced or discontinued if 
for safety reasons, if necessary), but should not be initiated or increased throughout the study 
treatment duration and until 6 weeks following the last SC IMP (sarilumab or matching placebo) 
administration. 
Treatment with any IMP other than sarilumab and prednisone defined by protocol is not 
permitted. 


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8.8.1 Steroids 
There will be 2 standardized prednisone-taper regimens: one that extends for up to 26 weeks 
(Group A, B and C), the other for up to 52 weeks (Group D) (Appendix B). The total duration of 
prednisone taper in each particular case will depend on the initial dose required by patient as 
judged by the Investigator at enrollment.  
If the patient develops an AE for a condition not related to GCA that requires a CS dose 
modification (eg, increase, or decrease of current concomitant oral prednisone or equivalent), or 
the introduction of a new oral or systemic steroid medication, the Sponsor must be notified at the 
time of the steroid dose modification to verify that the patient can continue to participate in the 
study. Furthermore, the dosage modification and AE must be recorded on the patient eCRF. 
Intranasal, inhaled, ophthalmic or topical CS as per label are permitted, as needed throughout the 
course of the study. 
8.8.2 Nonsteroidal anti-inflammatory drugs and analgesics  
As there are limited treatment options for inter current pain, all analgesics, including nonsteroidal 
anti-inflammatory drugs (NSAIDs), are allowed. These analgesics must be interrupted 24 hours 
prior to efficacy assessment, including physical function and quality of life assessments. 
Acetaminophen use should be limited to ≤4 g every 24 hours. Specific attention should be paid to 
coadministration of hepatotoxic drugs.  
8.8.3 Treatment of dyslipidemia  
Treatments for dyslipidemia, such as statins, are permitted. Any change and reason for change 
should be recorded on the patients’ eCRF. Doses of medications for dyslipidemia should be stable 
for at least 6 weeks prior to screening visit. Anti-IL-6 drugs, including sarilumab are known to 
increase serum total cholesterol and this effect will be closely monitored during the study. If, 
during the treatment period of this study, patients are found to have significant increase in 
cholesterol levels, or other lipid abnormalities, then cholesterol lowering therapy with statins, or 
other treatment(s) for dyslipidemia, per American College of Cardiology (ACC)/American Heart 
Association (AHA) guideline or European Society of Cardiology (ESC)/the European 
Atherosclerosis Society (EAS) guidelines or local guidelines, should be initiated or the dose 
adjusted. A referral to a specialist should be considered when dyslipidemia is difficult to manage, 
such as patients who have elevated low-density lipoprotein (LDL) in spite of being treated with 
maximum dose of statins. 
8.8.4 Glucocorticoid-induced osteopenia/osteoporosis prevention and treatment 
Oral calcium, 25-hydroxy vitamin D supplementation, and/or bisphosphonate therapy (eg, 
alendronate 70 mg weekly or zolendronate 4 mg annually) for the prevention or treatment of 
glucocorticoid-induced osteopenia/osteoporosis are permitted, the doses and treatment duration 
should be according to local practice or clinical guidelines at the discretion of the Investigator. 


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8.8.5 CYP substrates 
Interleukin-6 has been shown to reduce cytochrome (CY)P1A2, CYP2C9, CYP2C19, and 
CYP3A4 enzyme expression in in vitro studies. Therefore, it is expected that for a molecule that 
antagonizes cytokine activity, such as sarilumab, the formation of cytochrome P450 (CYP450) 
enzymes could be normalized, and as a result drugs that are metabolized by these CYP450 
isoforms may have decreased levels when patients start receiving sarilumab. As a precautionary 
measure, drugs which are metabolized via these cytochromes and with a narrow therapeutic index 
should be adjusted if needed: doses should be increased to maintain efficacy after initiation of 
sarilumab and decreased after sarilumab is stopped. Some examples of CYP450 substrates with a 
narrow therapeutic index, requiring monitoring of effect are warfarin or monitoring of drug 
concentration include, but are not limited to, the following: warfarin, CsA, theophylline, digoxin, 
antiepileptics, such as carbamazepine (Carbatrol®, Tegretol®), divalproex (Depakote®), 
phenytoin (Dilantin®), or valproic acid (Depakene®); or antiarrhythmics, such as disopyramide 
(Norpace®), procainamide (Procan®, Pronestyl®), or quinidine (Quinidex®, Quin Release Quin-
G®). 
8.8.6 Anti-platelet therapy 
Treatments with anti-platelet therapy (eg, aspirin or clopidogrel) are permitted, the doses and 
treatment duration should be according to the local practice at the discretion of the Investigator. 


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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
9.1.1 Primary efficacy endpoint 
Proportion of patients achieving sustained remission at Week 52. Sustained remission at Week 52 
is defined by having met all of the following parameters: 
 Achievement of disease remission not later than Week 12. 
AND 
 Absence of disease flare from Week 12 through Week 52. 
AND 
 Normalization of CRP (to <10 mg/L, with an absence of successive elevations to 
≥10 mg/L) from Week 12 through Week 52, and  
AND 
 Successful adherence to the prednisone taper from Week 12 through Week 52. 
Disease remission is defined as resolution of signs and symptoms of GCA, and normalization of 
CRP (<10 mg/L). 
Note: A single CRP elevation (≥10 mg/L) is not considered absence of remission unless CRP 
remained elevated (≥10 mg/L) at the next study visit. 
Signs and symptoms of disease 
Evaluation of clinical signs and symptoms by the Efficacy Assessor at every study visit according 
to the schedule of assessment will include the following: 
 Symptoms of PMR as indicated by the Efficacy Assessor (morning stiffness and/or pain, 
in the shoulder and/or hip girdles)  
 Cranial symptoms. 
- 
Localized headache. 
- 
Temporal artery or scalp tenderness. 
- 
Visual signs or symptoms such as acute or subacute vision loss due to arteritic anterior 
ischemic optic neuropathy (A-AION), transient blurry vision (generally monocular or 
at least affecting 1 eye at a time, but potentially affecting both eyes), diplopia. 
- 
Jaw or mouth pain, tongue claudication. 


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 Constitutional syndrome, including but not limited to fever, malaise, unintentional weight 
loss, night sweat, asthenia, fatigue, loss of appetite. 
 New or worsened extremity claudication, bruits and asymmetrical pulses. 
 Other features judged by the Investigator to be consistent with a GCA or PMR flare. 
Flare is defined as either 1) recurrence of signs and symptoms attributable to active GCA plus an 
increase in CS dose due to GCA, or 2) elevation of ESR attributable to active GCA plus an 
increase in CS dose due to GCA. Increase in CS dose is defined as: 
 Any dose increase during the protocol defined steroid taper. 
 Reinitiation of prednisone therapy after the protocol defined taper has been completed.  
Blinding of CRP and ESR assessment results 
Investigators, including Efficacy Assessors, and patients will remain blinded to CRP and ESR 
results (except screening and baseline). Safety Assessors will also be blinded on post baseline 
CRP but will have access to ESR results.  
ESR kits will be provided by the central laboratory while the test will be performed locally at site, 
results (the distance in millimeters (mm) that red blood cells has descended in 1 hour) will be 
blinded to Investigators including Efficacy Assessors and staff directly involved in efficacy 
assessment of study patients. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Secondary efficacy endpoints 
9.2.1.1 Components of the sustained remission composite measure at Week 52 
 Proportion of patients who achieved disease remission by Week 12.  
 Proportion of patients who have no disease flare from Week 12 through Week 52.  
 Proportion of patients who have normalization of CRP (to <10 mg/L, with an absence of 
successive elevations to ≥10 mg/L) from Week 12 through Week 52.  
  Proportion of patients who successfully adhere to the prednisone taper from Week 12 
through Week 52. 
9.2.1.2 Total cumulative corticosteroid (including prednisone) dose over 52 weeks 
The total cumulative CS dose (including prednisone) over the 52-week period for each group will 
be analyzed. 


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9.2.1.3 Time to first GCA flare 
The duration to first GCA flare from clinical remission up to 52 weeks for each group will be 
analyzed. 
9.2.1.4 Glucocorticoid toxicity index and components 
Glucocorticoid toxicity index (GTI) is a composite scale designed to assess glucocorticoid related 
morbidity and potential steroid-sparing effect of treatment alternatives. The Composite GTI and 
Specific List constitute the overall GTI. The composite GTI consists of nine domains and 31 items 
that assess the potential side effects of glucocorticoid, and include evaluation of body mass index 
(BMI), glucose tolerance, blood pressure, lipids, bone density, steroid myopathy, skin toxicity, 
neuropsychiatric toxicity and infection. These are the potential CS toxicities that are likely to 
occur during the course of a CS treatment and may vary depending on the extent of CS exposure, 
and that are weighted and scored (see Appendix C).  
The domains of the Composite GTI will be assessed at V2 (baseline), V6 (Week 12), 
V9 (Week 24), V11 (Week 40) and V12 (Week 52) (except bone density which will be assessed at 
baseline and Week 52 only).  
 Bone mineral density assessment will be performed at V2 (baseline) and V12 (Week 52) 
using Dual-Energy X-ray Absorptiometry (DXA) scan, The scan can be performed within 
±2 weeks of baseline visit and -2 weeks of EOT visit, needs to include the lumbosacral 
and femoral neck regions. However, the baseline visit DXA scan is not required if there is 
one available within 12 weeks of baseline that includes the assessment of the lumbosacral 
and femoral neck regions. In order to minimize variability, the same machine should be 
used each time to obtain the scan and the machine should be well calibrated according to 
the recommendations of the machine’s manual.  
GC toxicity or the changes in GC toxicity (comparison with baseline data) for domains will be 
scored (score range from -36 to 439) based on the information from clinical laboratory 
assessments, vital sign assessments, concomitant medications and clinical assessments. The 
composite GTI can be reported as both a total score and domain-specific scores, in order to 
account for scenarios when improvements in certain domains compensate for worsening in others. 
The Specific List consists of 11 domains and 23 items that are not weighted, and captures other 
CS related toxicities not found in the composite GTI (see Appendix C). Information related to the 
domains/items of the Specific List will be collected when available, but no prespecified 
assessments related to the domains in the Specific List (see Appendix D), unless for cause (19) are 
required within the conduct of this study protocol. 
9.2.2 Safety endpoints 
9.2.2.1 Adverse events 
Refer to Section 10.5 to Section 10.7 for details. 


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9.2.2.2 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. 
The following laboratory tests are performed, at designated visits specified the study flow charts 
(Section 1.2): 
 Hematology: hemoglobin, hematocrit, red blood cell count and morphology (if red blood 
cell count is abnormal), white blood cell count, white blood cell differential, absolute 
neutrophil count and platelet count. 
 Full chemistry profiles: blood urea nitrogen, calcium, chloride, bicarbonate, phosphate, 
creatinine and creatinine clearance, lactate dehydrogenase, sodium, potassium, total 
protein, uric acid, and albumin, alkaline phosphatase, ALT, AST, total bilirubin, 
conjugated bilirubin, and unconjugated bilirubin.  
 ANA will be checked at baseline and End of Treatment (EOT) visits. 
 Fasting lipids: total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. 
 Fasting glucose, fasting insulin and HbA1c. 
 For women of child-bearing potential: serum pregnancy test beta-human chorionic 
gonadotropin (β-hCG) at screening (V1) only and urine pregnancy tests for the remainder 
of the study. 
 QuantiFERON® -TB Gold evaluation (screening visit only). 
 Human immunodeficiency virus-1/HIV-2 antibody testing (screening visit only). 
 Hepatitis B and C serology (screening visit, or in case of liver injury): Hepatitis B: 
Hepatitis B surface antigen (HBsAg), total HB core Antibody, Hepatitis B surface 
Antibody, and Hepatitis B viral DNA (if necessary); Hepatitis C: HCV-antibodies. 
 Urine analysis including specific gravity, pH, glucose, ketones, blood, protein, nitrite, 
leukocytes, urobilinogen, and bilirubin (by dipstick) at screening visit only. 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. 
Anti-drug antibody (see Section 9.4.2). 
Specimens are submitted for analysis as per the instructions of the central laboratory. 
9.2.2.3 Chest X-ray 
A standard PA chest X-ray (lateral view is also recommended but not required) is required during 
the screening period if no chest imaging (X-ray, CT, MRI) is available within the previous 12 
weeks of V1 that clearly documents the exclusion of TB (or >12 weeks, if appropriate according 
to local guidelines and requirements for screening of active TB). In countries for which a specific 


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approval procedure for the X-ray is required by a different committee than the local EC/IRB, a 
chest MRI between V1 and V2 can be performed. A radiologist or pulmonologist interpretation 
(signed and dated) should note the absence of calcified granulomas and/or pleural scaring and/or 
any findings consistent with TB. The information must be documented in the patient's chart and in 
the eCRF at the screening visit. In case of any symptom suggestive of TB at any time during the 
course of the study, a chest X-ray should be performed and conclusion recorded (see 
Section 10.7). 
9.2.2.4 Vital signs 
Vital signs include temperature, BP, and heart rate (HR). They will be collected at every site visit 
prior to IMP administration. Weight will be collected at the screening Visit 1 (Day -42 to Day -1), 
Visit 2 (Week 0), Visit 6 (Week 12), Visit 9 (Week 24), Visit 11 (Week 40) and Visit 12 
(Week 52). Weight should be taken with the patient wearing undergarments or very light clothing 
and no shoes and with an empty bladder. The same scale is recommended to be used throughout 
the study. Height will be collected at Visit 1 during screening only. 
Body temperature 
Body temperature must be collected using the same method for a given patient. Any fever (body 
temperature ≥38°C) associated with infection should be recorded as an AE and the Investigator 
should perform all investigations necessary to rule out infection. 
Blood pressure 
Blood pressure must be measured, using the same method consistently. Blood pressure is 
determined at each study visit using the same well-calibrated apparatus. The same arm should be 
used to measure BP throughout the study. The blood pressure should also be obtained with the 
patient in the same position (recumbent preferred) each time. 
9.2.2.5 Physical examination 
A complete physical examination will be performed at the screening Visit 1 (Day -42 to Day -1) 
and Visit 12 (Week 52) or early termination visit, and a targeted physical examination will be 
performed at baseline visit (Visit 2), Visit 6 (Week 12), Visit 9 (Week 24) and Visit 11(Week 40). 
Any clinically significant abnormalities should be reported in the patient eCRF as medical history 
if observed at Visit 1 or reported as an AE if observed during subsequent visits.  
9.2.2.6 Electrocardiogram variables 
A standard 12-lead electrocardiogram (ECG) will be performed at the screening Visit 1 only 
(Day -42 to Day -1). It will be used to determine if there is any clinically significant finding that 
would preclude the patient from participating in the study safely per protocol. 


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9.3 
OTHER EFFICACY ENDPOINTS 
9.3.1 Clinical outcome assessments 
9.3.1.1 Patient-reported outcomes 
Patients will be asked to complete the PRO questionnaires described below at baseline, Week 12, 
Week 24 and Week 52. Translations of the PRO questionnaires, where not already available, will 
follow industry best practices (20).  
9.3.1.1.1 The functional assessment of chronic illness therapy fatigue scale (FACIT-fatigue) 
The functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue) is a generic 
PRO instrument which includes 13 items to measure fatigue. Each item is rated by patients on a 0 
to 4 scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much). Scores are 
summarized to give a total score between 0 and 52. The recall period is the last 7 days (21) (see 
Appendix E). 
9.3.1.1.2 EQ-5D-3L 
The EQ-5D-3L is a generic PRO instrument which measures health status. There are two 
components to the EQ-5D; a health utility index score derived from 5 items addressing mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression “today”, and a current (“right 
now”) general health status score derived from a single 0-100 Visual Analog Scale (VAS) (see 
Appendix F). The items contributing to the EQ-5D-3L health utility index score each have the 
same 3-point response scale (1 = no problem, 2 = moderate problems, 3 = severe problems). The 
VAS is anchored with ‘Best imaginable health state’ and ‘Worst imaginable health state’ (22). 
9.3.1.1.3 SF-36v2 
The SF-36v2 is a short-form generic, 36-item PRO instrument that evaluates 8 multi-item 
dimensions of health: physical functioning (PF; 10 items), social functioning (SF; 2 items), role 
limitations due to physical problems (RP; 4 items), role limitations due to emotional problems 
(RE; 3 items), mental health (MH; 5 items), energy/vitality (VT; 4 items), bodily pain (BP; 2 
items), and general health perception (GH; 5 items). For each dimension, item scores are coded, 
summed, and transformed on to a scale from 0 (worst possible health state measured by the 
questionnaire) to 100 (best possible health state). Two standardized summary scores can also be 
calculated from the SF-36v2; the physical component summary (PCS) and the mental health 
component summary (MCS) on a scale from 0-100 (23, 24) (see Appendix G). 
9.3.1.1.4 HAQ-DI 
The HAQ-DI was developed to assess physical functional status in adults with arthritis, but is now 
commonly used among many rheumatologic conditions. It contains 25 items: 20 4-point Likert-
scale questions assessing 8 physical dimensions of activities of daily living (dressing and 
grooming, arising, eating, walking, hygiene, reaching, gripping, and errands and chores), 


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13 additional questions assessing use of assistive devices, and 8 additional questions assessing 
help received from another. The recall period is the last week. To calculate the HAQ-DI Score, 
there are 3 steps:  
 Sum the 8 category scores by using the highest sub-category score from each category. 
 Adjust for use of aids/devices and/or help from another person when indicated. 
 Divide the summed category scores by the number of categories answered (must be a 
minimum of 6) to obtain a HAQ-DI score of 0-3 (3=worst functioning). 
In addition to the above, the HAQ-DI has 2 additional questions, measured on 0 - 100 scales: 
 How much pain have you had IN THE PAST WEEK? 
 Please rate how well you are doing on a scale of 0 to 100 (0 represents “very well” and 
100 represents “very poor” health). 
These questions, measuring pain and global assessment respectively, are independently scored 
(see Appendix H). 
9.3.1.2 Clinician-reported outcomes 
9.3.1.2.1 Physician global assessment of disease activity- Visual Analog Scale [MD-VAS] 
The efficacy assessor will be requested to rate the patient’s disease activity on an anchored 
100 mm horizontal VAS where 0 is considered the best disease activity and 100 the worst (see 
Appendix I).  
9.4 
PHARMACODYNAMICS 
9.4.1 Pharmacodynamic variables 
 Changes in ESR and CRP over time from baseline through Week 52. 
 Changes of IL-6 level and soluble IL-6 receptor (sIL-6R) over time from baseline through 
Week 52.  
 Changes in markers of inflammation and disease activity over time as assessed in 
circulating immune cell types, circulating proteins, and gene expression changes as 
follows (refer to Appendix J). 
- 
Markers of inflammation will be assessed in a subset of patient population during the 
study at V2 (baseline), V4 (Week 4), V9 (Week 24) as measured by immune cells 
phenotyping. In total 120 patients will be selected via IRT for this analysis, please 
refer to Lab Manual for detail. 
 40 patients each in Group A and Group D 
 20 patients each in Group B and Group C 


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 Disease activity assessment of GCA patients will be assessed via evaluation of 
circulating proteins and gene expression. 
Serum and plasma samples will be collected at V2 (baseline), V3 (Week 2), V6 (Week12), V9 
(Week 24), V12 (Week 52 EOT) for circulating protein measurements (a separate “Future Use of 
Samples” informed consent needs to be obtained) (refer to Section 9.5). 
Deoxyribonucleic acid (DNA) samples will be collected at V2 (baseline), ribonucleic acid (RNA) 
samples will be collected at V2 (baseline) and/or V3 (Week 2) (refer to Section 1.2) for gene 
expression measurement (a separate “pharmacogenetics informed consent needs to be obtained”, 
refer to Section 9.4.3). 
9.4.2 Pharmacokinetics and antidrug antibodies 
9.4.2.1 Sampling time 
Predose blood samples at each study visit will be collected for determination of serum functional 
sarilumab, and serum ADA as designated on the randomized treatment period study flow chart 
Section 1.2). The date of collection should be recorded in the patient eCRF. 
Note: Sarilumab concentrations (functional) in serum, and antidrug antibodies results are blinded 
to both Investigator and Sponsor.  
If a serious adverse event (SAE) occurs in a patient, blood samples should be collected for 
determination of sarilumab concentration (functional), and ADA assessment at or near the onset 
and completion of the occurrence of the event, if possible. The exact date and time of sample 
collection and last dose must be recorded on the label and the unscheduled PK page in the eCRF 
should be filled in. 
9.4.2.2 Sample handling procedure 
Special procedures for collection, storage and shipping of serum are described in separate 
operational manuals. 
9.4.2.3 Bioanalytical method 
Serum samples will be assayed using validated methods as described in Table 2. 
Table 2 - Summary of bioanalytical methods for functional sarilumab and antidrug antibody 
Bioanalysis 
Functional sarilumab 
Antidrug antibody 
Matrix 
Serum 
Serum 
Analytical Technique 
ELISA 
Electrochemiluminescence 
Site of Bioanalysis 
Regeneron 
Regeneron 
ELISA = . Enzyme-linked immunosorbent assay 


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9.4.2.4 Pharmacokinetics parameters 
Predose serum sarilumab concentrations at Week 0, sarilumab trough levels at Weeks 2, 4, 12, 16, 
24, 52 and Week 58. 
In addition, postdose sample will be taken 4 to 7 days after the Week 24/V9. 
9.4.3 Pharmacogenetic assessment 
9.4.3.1 Optional stored DNA and RNA samples 
Pharmacogenetic testing is optional and voluntary. Written informed consent must be obtained 
before sampling.  
For those patients who provided written consent to the collection of the optional pharmacogenetic 
samples, blood samples for exploratory genetic analysis of DNA and RNA will be collected at the 
study visit as specified in the study flow chart (Section 1.2), and these samples will be stored for 
future analysis. Specific procedures for collection, storage, and shipping of pharmacogenetic 
samples will be provided in a lab manual (refer Appendix K for the detailed information).  
The blood DNA sample, and the DNA that is extracted, will be assigned a second number, a 
Genetic ID (de-identification code) that is different from the patient ID. This “double coding” is 
performed to separate a patient’s medical information and DNA data. 
The clinical study data (coded by patient ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by Genetic ID). The key linking patient ID and 
Genetic ID will be maintained by a third party, under appropriate access control. The matching of 
clinical data and pharmacogenetic data, for the purpose of data analysis, will be possible only by 
using this key, which will be under strict access control. All data will be reported only in coded 
form in order to maintain confidentiality. 
The aliquots of DNA and RNA sent to the bioanalytical laboratories for specific genetic testing 
will be destroyed after completion of that specific analysis and issuance of the related analytical 
data (see Appendix K). 
9.5 
FUTURE USE OF SAMPLES 
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patient(s) who have consented to it, the samples that are archived, unused or left 
over after planned testing may be used for other research purposes (any genetic analysis subject to 
additional consent per Section 9.4.3.1). For subjects who have consented to it, archival blood 
sample(s) will be collected at the visits specified in the study flow chart (see Section 1.2). 
Additional details will be provided in the laboratory manual (refer Appendix J for the detailed 
information). 


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9.5.1 Serum and plasma for future biomarker analysis (circulating proteins) 
Prior to sampling, informed consent agreeing to participate in this additional research program 
needs to be obtained as this is optional and voluntary. Once obtained, both serum and plasma will 
be collected at Visit 2 (baseline), Visit 3 (Week 2), Visit 6 (Week 12), Visit 9 (Week 24) and 
Visit 12 (Week 52). 
These samples will remain labelled with the same identifiers used during the study (ie, 
patient ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be located 
outside of the country where the study is conducted. The Sponsor has included safeguards for 
protecting subject confidentiality and personal data (see Section 14.3 and Section 14.5). 
9.6 
APPROPRIATENESS OF MEASUREMENTS  
The goals of a new therapy for GCA are to reduce the cumulative dose of prednisone and thereby 
reduce the toxicity associated with prednisone while maintaining disease remission. To this end, 
the primary endpoint is a composite that includes, firstly, a requirement to achieve disease 
remission by Week 12 of study treatment to ensure that patients are having rapid, adequate control 
of disease activity. It also includes the ability to adhere to the predefined prednisone taper that 
represents a substantial reduction in prednisone exposure compared to usual care. Lastly it 
assesses the durability of treatment response (maintenance of remission) over an extended period 
of time compared to current usual prednisone treatment, which is important for a chronic disease, 
such as GCA. The secondary endpoints evaluate specific components of the primary endpoint and 
thereby provide additional evaluation of total CS use and disease activity to further assess the 
efficacy of sarilumab as a steroid-sparing treatment option in the target patient population.  
The safety assessments are performed in accordance to the known profile of sarilumab and will 
further inform the safety profile of sarilumab when administered to GCA patients. The patient and 
clinician reported outcomes will further evaluate the potential clinical benefits of sarilumab in the 
treatment of GCA. The PK and PD assessments will provide additional information related to the 
exposure of sarilumab and biological effect of sarilumab in GCA patients. 


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10 
STUDY PROCEDURES 
10.1 
INDEPENDENT EFFICACY AND SAFETY ASSESSORS 
A dual assessor approach will be required during this study in order to maintain the blind during 
the double-blind treatment period with sarilumab, placebo, and prednisone. The precise 
definitions of the efficacy and safety assessors’ roles and responsibilities are specified in the Dual 
Assessor Guidance Document supplied to sites. An overview of those definitions is provided 
below. 
Efficacy Assessor 
The Efficacy Assessor will be responsible for completing the overall evaluation and management 
of GCA disease activity including the following: 
 Assessment of clinical signs and symptoms of GCA (without access to ESR and any 
central laboratory data including CRP). 
 Assessment of adherence to the protocol defined prednisone taper regimen.  
 Management of rescue medication which is led by Investigator per protocol.  
The Efficacy Assessor should not have access to central laboratory results obtained per protocol. 
If knowledge of the ESR is absolutely required in making a medical decision related to disease 
activity, the Efficacy Assessor may request the last available value obtained per protocol from the 
Safety Assessor or obtain a local laboratory value for ESR. Otherwise it is strongly recommended 
for the Efficacy Assessor not to have access to any laboratory data. Additionally, if necessary for 
the management of any safety concern for a particular patient that cannot wait to be addressed by 
the Safety Assessor, the Efficacy Assessor may arrange for local laboratory assessments to be 
performed and will have access to the results of these assessments.  
To ensure consistency of assessments, it is encouraged that efficacy evaluations throughout the 
study be conducted by the same Efficacy Assessor for all study visits for a given patient, 
whenever possible. 
It is mandatory that assessments by the Efficacy Assessor be completed before assessments by the 
Safety Assessor. 
The Efficacy Assessor may permanently discontinue oral IMP (prednisone as per taper regimen) 
and initiate rescue therapy in order to properly manage disease activity, if necessary. In such a 
scenario, the SC IMP (sarilumab or matching placebo) may continue per protocol unless 
nonbiological immunosuppressive drugs are used and a safety concern is raised by the Safety 
Assessor.  


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Safety Assessor 
The Safety Assessor will be responsible for assessing and managing any safety concerns of the 
patient during the course of the study. The specific responsibilities include: 
 Eliciting and recording of any clinical and/or laboratory AEs.  
 Management of any clinical and/or laboratory AEs. 
 Review of all laboratory data (except CRP after baseline). 
 Perform the assessments related to GTI. 
The Safety Assessor may temporarily (or permanently) discontinue IMP (SC and/or oral) during 
the management of an AE and only the Safety Assessor may reinitiate the IMP upon his/her 
discretion. If the IMP is permanently discontinued, both Efficacy and Safety Assessors should be 
informed in order to make subsequent medical management decisions. 
10.2 
VISIT SCHEDULE 
It is preferred that all study visits that require fasting blood samples to take place in the morning. 
The study visits occur on the planned dates (relative to randomization date), as scheduled. The 
visit schedule should be adhered to within the ±3 day visit window. In general, PRO assessments 
should be completed at the study site as part of the visit (per study flow chart Section 1.2) but 
prior to any meaningful communication with a health care professional or any other study 
procedures, unless noted otherwise in the suggested order of the study procedures for each 
individual visit described below: 
 Consent  
 Eligibility  
 Randomization 
 PRO questionnaires 
 GCA assessments 
 Other clinical assessments and AE reporting 
 Blood sampling 
 IRT call to obtain resupply treatment 
 Dose administration 
10.2.1 Visit 1: Screening from Day -42 to Day -1 
The following activities will be performed: 
 An explanation of the purpose, procedures, potential risks, and benefits of this study will 
be provided to the patient. 


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 Informed consent signature and date will be collected. 
 If required locally, the locally provided consent for the required HIV screening test will be 
collected. 
 Call IRT to assign patient number and register screening visit. 
 Patient demography will be recorded. 
 Medical/surgical/smoking/alcohol history. 
 Review of prior and concomitant medication history. 
 Family cardiovascular history. 
 Full physical examination. 
 GCA clinical assessments (including disease flare). 
 Measure vital signs (including systolic and diastolic BP [mmHg], HR [beats per minute], 
body temperature [°C], and height [cm]). 
 Body weight [kg]. 
 Perform blood sampling (fasting) for the following tests:  
- 
Hematology, chemistry. 
- 
Fasting lipids, fasting glucose and fating insulin. 
- 
HbA1c. 
- 
CRP and ESR. 
- 
Virology. 
- 
Serum β-hCG pregnancy test (for WOCBP). 
 Tuberculosis assessment including Quantiferon gold testing. 
 Urinalysis (dipstick) 
 12-lead ECG. 
 Perform chest X-ray if not performed at least 12 weeks prior to screening visit date. 
 Confirmation of eligibility by the Investigator.  
 Schedule a Visit 2 (D1, Week 0) within a maximum of 42 days from Visit 1. 
Note: if the ultrasound is being used as a diagnostic tool for GCA to satisfy the Inclusion Criteria 
I01, the image needs to be submitted to the central reader for confirmation of eligibility. 


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10.2.2 Double blind period (52 weeks) 
10.2.2.1 Visit 2/Baseline visit (Day 1, Week 0) 
 Review of concomitant medication. 
 Confirm eligibility by review of Inclusion/Exclusion Criteria. 
If the patient meets all the inclusion criteria and does not meet any exclusion criteria, 
please conduct the following procedures in the recommended order, if possible: 
 Call IRT to randomize the patient and obtain the initial treatment kit assignments.  
 If the patient has been selected to complete the immunophenotyping blood sampling, the 
system will provide this information during the call. 
 Administer PRO questionnaires (EQ-5D, FACIT-Fatigue, SF-36v2, HAQ-DI) and VAS. 
Note: PRO questionnaires should be completed prior to any significant interaction with the 
study team and prior to any physical examination or sampling. 
 Measure vital signs (including systolic and diastolic BP [mmHg], and HR [beats per 
minute], body temperature [°C]).  
 Body weight (kg). 
 GCA clinical assessments (including disease flare). 
 Complete physician global assessment (MD-VAS). 
 Inquire about AEs/SAEs.  
 Tuberculosis assessment. 
 Targeted physical examination (including head, eyes, ears, neck and throat, skin, 
respiratory, cardiovascular, neurologic, lymphatic examinations and abdominal 
examination). 
 GTI Assessment. 
 Bone density assessment by DXA (dual-energy x-ray absorptiometry) (±2 week time 
window is allowed at baseline visit).  
Note: Bone density assessment is not required if already available within 12 weeks prior to 
screening visit. 
 Perform blood sampling (prior to administration of IMP) for the following tests:  
- 
Hematology and chemistry. 
- 
ANA. 
- 
CRP and ESR. 
- 
Serum sarilumab and ADA. 
- 
Biomarkers IL-6, sIL-6R. 


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- 
Serum and plasma sampling for circulating protein (for consented patients only). 
- 
Sample for DNA and RNA for those patients who have consented to 
pharmacogenetics. 
- 
Sample for circulating immune cell phenotyping for patients identified to perform this 
test. 
 Perform urine pregnancy test (for WOCBP). 
 Dispense patient diary to record injections performed at home (date, time, injection 
location, and local reaction or any medical events pertaining to the injection). 
 IMP training. Provide instructions on preparation and self-injection of the prefilled 
syringes and the use of the weekly blister packs of prednisone. Document this training in 
the patients study file. Note: If the patient is unable or unwilling to perform the SC 
injections themselves, arrangements must be made for qualified site personnel and/or 
caregiver to administer SC study drug every 2 weeks for doses that are not scheduled to be 
given at the study site. 
 Dispense and administer IMP. Patients will be monitored for at least 30 minutes or up to 
2 hours as per country specific requirements after first dose of IMP for any signs or 
symptoms of a hypersensitivity reaction. 
 Schedule an appointment for the next visit. 
10.2.2.2 Visit 3 (Day 15 ±3, Week 2) 
 Review of concomitant medication. 
 Dispense new patient diary and review last visit patient diary. 
 Measure vital signs (including systolic and diastolic BP [mmHg], HR [beats per minute], 
and body temperature [°C]). 
 GCA clinical assessments (including disease flare). 
 Inquire about AEs/SAEs.  
 Tuberculosis assessment. 
 Perform blood sampling (prior to administration of IMP) for the following tests:  
- 
CRP and ESR. 
- 
Serum sarilumab. 
- 
Biomarkers IL-6, sIL-6R. 
- 
Serum and plasma sampling for circulating protein (for consented patients only). 
- 
Sample for RNA for those patients who have consented to pharmacogenetics. 
 Administration of IMP. Patients will be monitored for at least 30 minutes or up to 2 hours 
as per country specific requirements after first dose of IMP for any signs or symptoms of a 
hypersensitivity reaction. 


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 Call IRT to register visit and obtain next treatment kit assignments. 
 Schedule an appointment for the next visit. 
10.2.2.3 Visit 4-11 (Day 29 ±3, Week 4 to Day 281±3, Week 40) 
 Administer PRO questionnaires (EQ-5D, FACIT-Fatigue, SF-36v2, HAQ-DI) (Applicable 
only at Visits 6 and 9; at these visits PRO questionnaires should be completed prior to 
any significant interaction with the study team and prior to any physical examination or 
sampling). 
 Review of concomitant medication. 
 Dispense new patient diary and review last visit patient diary. 
 Measure vital signs (including systolic and diastolic BP [mmHg], HR [beats per minute], 
and body temperature [°C]). (Applicable only at Visits 6, 9 and 11). 
 Measure body weight (Kg) (Applicable only at Visits 6, 9 and 11). 
 GCA clinical assessments (including disease flare). 
 Complete physician global assessment (MD-VAS) at Visits 6 and 9. 
 Inquire about AEs/SAEs.  
 Tuberculosis assessment. 
 Targeted physical examination (including head, eyes, ears, neck and throat, skin, 
respiratory, cardiovascular, neurologic, lymphatic examinations and abdominal 
examination) (Applicable only at Visits 6, 9, and 11). 
 GTI Assessment (Applicable only at Visits 6, 9 and 11). 
 Perform blood sampling (prior to administration of IMP) for the following tests:  
- 
CRP and ESR. 
 Perform blood sampling (fasting, prior to administration of IMP) for the following tests: 
(Applicable only at Visits 4, 6, 9 and 11) 
- 
Hematology and chemistry. 
- 
Fasting lipids, fasting glucose and fasting insulin. 
- 
HbA1c. 
 Perform blood sampling (prior to administration of IMP) for the following tests: 
(Applicable only at Visits 4, 6, 7 and 9) 
- 
Serum sarilumab. 
- 
Note: Additional sample is to be drawn 4-7 days after Visit 9 dosing. May be 
performed at the patient's home, if compatible with local organization. 
- 
Sample for circulating immune cell phenotyping for patients identified to perform this 
test. (Applicable only at Visits 4 and 9). 


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 Perform blood sampling (prior to administration of IMP) for the following tests: 
(Applicable only at Visits 6 and 9) 
- 
Antidrug antibody. 
- 
Biomarkers IL-6, sIL-6R. 
- 
Serum and plasma sampling for circulating protein (for consented patients only). 
 Perform urine pregnancy test (for WOCBP). 
 Call IRT to register visit and obtain next treatment kit assignments. 
 Administration of IMP. Patients will be monitored for at least 30 minutes or up to 2 hours 
as per country specific requirements after first dose of IMP for any signs or symptoms of a 
hypersensitivity reaction. 
- 
Where the visit interval will exceed 4 weeks (Applicable only at Visits 9, 10 and 11), 
interim shipments of IMP to patients home may be performed using DTP shipping 
(according to local regulations and logistics), in order to provide the patient with only 
4 weeks IMP at a time in order to minimize compliance errors. 
 Schedule an appointment for the next planned visit. 
10.2.2.4 Visit 12/End of Treatment (Day 365 ±3, Week 52) 
 Call IRT to register visit. 
 Administer PRO questionnaires (EQ-5D, FACIT-Fatigue, SF-36v2, HAQ-DI). 
Note: PRO questionnaires should be completed prior to any significant interaction with the 
study team and prior to any physical examination or sampling. 
 Review of concomitant medication.  
 Review last visit patient diary. 
 Measure vital signs (including systolic and diastolic BP [mmHg], and HR [beats per 
minute], body temperature [°C]).  
 Body weight (kg). 
 GCA clinical assessments (including disease flare). 
 Complete physician global assessment (MD-VAS). 
 Inquire about AEs/SAEs.  
 Tuberculosis assessment. 
 Full physical examination. 
 GTI Assessment. 
 Bone density assessment by DXA (-2 week time window is allowed). 


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 Perform blood sampling (fasting) for the following tests:  
- 
Hematology and chemistry. 
- 
ANA. 
- 
Fasting lipids, fasting glucose and fasting insulin. 
- 
HbA1c. 
- 
CRP and ESR. 
- 
Serum sarilumab and ADA. 
- 
Biomarkers IL-6, sIL-6R. 
- 
Serum and plasma sampling for circulating protein (for consented patients only). 
 Perform urine pregnancy test (for WOCBP). 
 Schedule an appointment for Visit 13. 
10.2.3 Post-treatment follow up period (24 weeks) 
10.2.3.1 Visit 13 (Day 407 ±3, Week 58) 
 Review of concomitant medication. 
 Measure vital signs (including systolic and diastolic BP [mmHg], HR [beats per minute], 
and body temperature [°C]). 
 GCA clinical assessments (including disease flare). 
 Inquire about AEs/SAEs.  
 Tuberculosis assessment. 
 Perform blood sampling for the following tests:  
 Serum sarilumab and ADA. 
10.2.3.2 Visit 14/End of study (Day 532 ±3, Week 76) 
 Call IRT to register visit. 
 Review of concomitant medication. 
 Measure vital signs (including systolic and diastolic BP [mmHg], HR [beats per minute], 
and body temperature [°C]). 
 GCA clinical assessments (including disease flare). 
 Inquire about AEs/SAEs. 


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10.3 
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. 
The following data collected in the case report forms (CRFs) will be source data: 
 SF-36v2 
 FACIT-F 
 EQ-5D-3L and associated VAS 
 HAQ-DI and associated VAS 
Additional data that are considered to be source data are: 
 Chest X-ray or signed documented X-ray and reports. 
 Patient home dosing diaries. 
 ECG tracings and reports. 
 Diagnostic imaging or biopsy reports for inclusion. 
 Central lab reports. 
 Local lab reports and ESR results. 
 Bone density assessment results by DXA.  
 Diagnostic results from other healthcare professionals, if appropriate, for GCA and GTI 
assessments. 
10.4 
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 must be fully documented in the eCRF. In any case, the 
patient should remain in the study as long as possible. 
In case of permanent sarilumab discontinuation, the patient will also withdraw from prednisone 
tapering.  
10.4.1 Temporary treatment discontinuation with investigational medicinal product 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and 


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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). 
For all temporary treatment discontinuations, duration must be recorded by the Investigator in the 
appropriate pages of the eCRF.  
Temporary IMP (sarilumab or matching placebo) treatment discontinuation decided by the 
Investigator corresponds to ≥1 dose not administered to the patient. 
A temporary discontinuation of IMP (sarilumab or matching placebo) that is >31 consecutive days 
will be considered permanent.  
For all confirmed temporary treatment discontinuations, duration should be recorded by the 
Investigator in the appropriate pages of the eCRF. 
The following is a list of criteria for temporary discontinuation (refer to Section 10.7 for details): 
 Increase in ALT level to ≥3 x ULN to ≤5 x ULN and bilirubin ≤2 x ULN. The IMP 
(sarilumab or matching placebo) can be resumed only after the ALT has returned to a 
value <3 x ULN and all requirements for resumption of study drug administration are met 
based on Investigator judgment. The IMP (sarilumab or matching placebo) may be 
resumed at the same dose or at the lower dose of 150 mg q2w in such cases, if the patient 
is randomized to the sarilumab 200 mg q2w dose group (see Section 10.7.2 and Appendix 
L) 
 Decrease in neutrophil count to a level ≥500/mm3 to <1000/mm3 without signs of 
infection. The IMP (sarilumab or matching placebo) can be resumed only after the 
neutrophils have returned to a value ≥1000/ mm3 and all requirements for resumption of 
study drug administration are met based on Investigator judgment. The IMP (sarilumab or 
matching placebo) may be resumed at the same dose or at the lower dose of 150 mg q2w 
in such cases, if the patient is randomized to the sarilumab 200 mg q2w dose group (see 
Section 10.7.3 and Appendix L). 
 Decrease in platelet count to a level of ≥50 000 cells/mm3 to <100 000 cells/mm3 without 
spontaneous bleeding. The IMP can be resumed only after the platelet count is 
≥100 000/mm3 and all requirements for resumption of study drug administration are met 
based on Investigator judgment. The IMP may be resumed at the same dose or at the lower 
dose of 150 mg q2w in such cases if the patient is randomized to the sarilumab 200 mg 
q2w dose group (See Section 10.7.4 and Appendix L). 
 Intercurrent infections requiring oral or parenteral treatment with antibacterial, antiviral 
and/or antifungal agents. 


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10.4.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to reexpose the patient to the IMP at any time during 
the study, or from the patient not to be reexposed to the IMP whatever the reason. 
10.4.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the eCRF. 
Investigational medicinal products will be permanently discontinued in case of the following 
events (refer to Section 10.7 for details): 
 Opportunistic infections (as assessed by the Investigator) including, but not limited to, 
active TB. 
- 
The initial diagnosis of TB may be made either on symptoms or on a chest radiograph 
suggestive of active TB. Patients should be referred to appropriate medical specialists 
and whenever possible, culture confirmation of disease should be obtained and 
recorded in the eCRF. 
- 
Culture positive for nonTB mycobacteria. 
 The patient is at risk through close contact with a person with active TB and the patient 
refuses to undergo TB evaluation. 
 Symptoms of systemic hypersensitivity or anaphylactic reactions. 
 Severe neurologic disease such as demyelinating disease or PML. 
 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 <500/mm3, or neutrophil count <1000/mm3 with evidence of 
infection. 
- 
platelet count <50 000/mm3, or platelet count <100 000/mm3 with evidence of 
bleeding. 
 Acute renal failure (refer Section 10.7.8). 
 Pregnancy in female participant. 
 Use of any biologic DMARDs other than IMP. 
 Any AEs, per Investigator’s judgment, that may jeopardize the patient’s safety. 
Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision of permanent discontinuation of the IMP for the concerned patient. 


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10.4.4 Handling of patients after permanent treatment discontinuation 
Every effort should be made to maintain patients in the study after permanent study treatment 
discontinuation. Patients should be followed up according to the study procedures as specified in 
this protocol up to the scheduled date of study completion, or up to recovery or stabilization of 
any AE to be followed up as specified in this protocol, whichever comes last. The scientific value 
of the complete collection of data will be explained to patients, and site personnel will receive 
training regarding strategies for patient retention, and access to tools to assist with this during the 
study. 
If a patient prematurely and permanently discontinues study treatment, a premature EOT visit (see 
Section 10.4.2) should be scheduled at the time of treatment discontinuation, if possible. If not 
possible, the EOT should be scheduled as soon as possible after treatment discontinuation. The 
IRT should be notified of EOT. Of note, during this premature EOT visit, the bone density test 
does not need to be performed if it has been less than 6 months since the bone density test from 
the baseline visit. 
Following the premature EOT visit, the remaining visits will be performed as scheduled. All 
efforts should be made to follow the patients for safety at least 6 weeks after the last dose of SC 
IMP and for primary endpoint, key secondary endpoints a through the remainder of the study 
visits up to Week 52 after premature EOT. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. Details recording the specific 
reasons for discontinuation should be collected. 
10.4.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Discontinuation of study treatment should be distinguished 
from withdrawal of consent for follow up visits and from withdrawal of consent for nonpatient 
contact follow up, eg, medical records check. Patients will be told that they are free to withdraw 
from the study at any time without any adverse effect on their care. However, if they no longer 
wish to take the IMP, they will be encouraged to remain in the study and attend the remaining 
visits. The value of critical study data collected during their continued involvement will be 
emphasized as important to the public health value of the study. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Should the 
patient or the patient’s representatives withdraw from the study without a preferred written 
withdrawal of consent, the site should clearly document and sign the reason for the patient’s 
reason for withdrawal of consent, if known. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
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. 


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For patients who withdraw from the study, unless the patient withdraws consent for follow up, the 
Investigator should make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review 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). 
Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused. 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.5.1 Definitions of adverse events 
10.5.1.1 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. 
10.5.1.2 Serious adverse event 
A SAE is any untoward medical occurrence that at any dose: 
 Results in death, or 
 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. 
 Requires inpatient hospitalization or prolongation of existing hospitalization, or 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect 
 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. 
Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered a medically important event. The list 
is not intended to be exhaustive: 


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 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). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study  
 Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
10.5.1.3 Adverse event of special interest 
An AE of special interest (AESI) is an AE (serious or nonserious) 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 is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
The following listed events are considered as AESI: 
 Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP; Pregnancy occurring in a 
female patient entered in the clinical trial or in a female partner of a male patient entered 
in the clinical trial. It will be qualified as an SAE only if it fulfills one of the seriousness 
criteria (see Section 10.5.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
An attempt to follow up of the pregnancy in a female participant or in a female partner 
of a male participant is made until the outcome has been determined (see Appendix A). 
 Symptomatic overdose (serious or nonserious) with SC IMP. 
 An overdose (accidental or intentional) with the SC IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
intended dose during an interval of <11 days (for sarilumab or matching placebo). 
Of note, both symptomatic and asymptomatic overdoses have to be reported on a specific 
AE page. The circumstances (ie, accidental or intentional) should be clearly specified in 
the verbatim and symptoms, if any, entered on separate AE forms. 


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 Increase in alanine transaminase (ALT) ≥3 x ULN (see the “Increase in ALT” flow 
diagram in Appendix L).Clinically significant infections including: 
- 
Confirmed diagnosis of opportunistic infections based on the Investigator’s assessment 
with appropriate diagnostic workups and consultations. For any infection from the list 
of potential opportunistic infections provided in Appendix M, for reporting purpose, 
even if it is not confirmed to be an opportunistic infection based on the Investigator’s 
assessment, it should still be reported as AESI. 
- 
Active/latent TB or initiation of medications for suspected TB. 
- 
Note: Parasitic infections are not considered opportunistic infections. Fungal infections 
are not considered opportunistic infections, unless they are systemic and/or extensive 
muco-cutaneous cases. 
- 
Infection requiring prolonged medication (>14 days). These are infections which 
require treatment (continuous or intermittent) for >14 days, with antibiotics, 
antifungals, or antivirals (exclude when medications are only administered topically).  
- 
Infections requiring any parenteral antibiotics, parenteral antifungals, or parenteral 
antiviral agents.  
 The following laboratory abnormalities:  
- 
ALT increase leading to permanent discontinuation. 
- 
ANC decrease leading to permanent discontinuation. 
- 
Thrombocytopenia leading to permanent discontinuation. 
10.5.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities 
Not applicable. 
10.5.3 General guidelines for reporting adverse events  
 All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the eCRF. 
 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 or by the study procedure(s).  
 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 


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investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
At the prespecified study end-date, patients who experience an ongoing SAE or an AESI 
should be followed until resolution, stabilization, or death and related data will be 
collected. 
 When treatment is prematurely discontinued, the patient’s observations will continue until 
the End of Study as defined by the protocol for that patient. 
 Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic 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 
10.5.4 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
 ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
 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 email 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. 
 All further data updates should be recorded in the eCRF 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. 
 A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study 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. 


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10.5.5 Guidelines for reporting adverse events of special interest  
For AESIs and SAEs, the Sponsor must be informed immediately (ie, within 24 hours), as per 
SAE notification guidelines described in Section 10.5.4, even if not fulfilling a seriousness 
criterion, using the screens in the eCRF. Instructions for AE reporting are summarized in 
Section 10.5.3. 
10.5.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix L. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
 Neutropenia (also refer to Section 10.7.3) 
 Thrombocytopenia (also refer to Section 10.7.4) 
 Increase in ALT (also refer to Section 10.7.2) 
 Increase in serum creatinine 
10.5.7 Guidelines for reporting product complaints (IMP) 
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
10.6 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
 All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, independent ethics committee (IECs)/institutional review boards 
(IRBs) as appropriate and to the Investigators. 
 All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition (eg, progression of 
disease) and thus will not be considered unexpected. 
For the IMP, any other AE not listed as an expected event in the IB for sarilumab or defined in 
this protocol or local label summary of product characteristics(SmPC)/package insert for 
prednisone will be considered unexpected. 


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For safety, the Sponsor will report to the Health Authorities of any SUSAR and reasonably 
associated with the use of the SC IMP (sarilumab or matching placebo) 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 clinical 
study report. 
10.7 
SAFETY INSTRUCTIONS 
10.7.1 Infections 
Biologics including TNF antagonists and tocilizumab (another IL-6 receptor 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 sarilumab studies, the most commonly 
reported Treatment-emergent AEs (TEAEs) were infections (mostly nonserious upper respiratory 
and urinary tract infections), 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 eCRF 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 eCRF from. Treatment with antibiotics if any should be 
recorded including the route of administration.   
Clinically significant infections including opportunistic infections are AESI and should be 
reported accordingly (see Section 10.5.1.3). Infections requiring prolonged treatment (>14 days) 
or anti-TB medication are considered AESI with immediate notification. Systemic opportunistic 
infections should be reported as SAE. The IMP must be withheld in case of suspicion of a 
clinically significant infection and a complete diagnosis work-up should be performed including 
but not limited to cultures for bacterial infections, fungi and/or mycobacteria, histopathological or 
cytological evaluation, antigen detection and serum antibody titers. 
 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. 
- 
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.  


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- 
A QuantiFERON TB Gold test will be performed at screening and can be repeated at 
any time during the course of the studies in case of suspicion of TB. A repeat chest 
X-ray should be performed in all patients with suspected TB. 
- 
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 PA chest X-ray (lateral view is also recommended but not 
required) is required during the screening period if no chest imaging (X-Ray, CT, MRI) is 
available within the previous 12 weeks of V1 that clearly documents the exclusion of TB 
(or >12 weeks, if appropriate according to local guidelines and requirements for screening 
of active TB). In countries for which a specific approval procedure for the x-ray is 
required by a different committee than the local EC/IRB, a chest MRI between V1 and V2 
can be performed. A radiologist or pulmonologist interpretation (signed and dated) should 
note the absence of calcified granulomas and/or pleural scaring and/or any findings 
consistent with TB. The information must be documented in the patient’s chart and in the 
eCRF at the screening visit. In case of any symptom suggestive of TB at any time during 
the course of the study, a chest X-ray should be performed and conclusion recorded. 
 Repeat chest radiographs should be performed as indicated by local treatment guidelines 
or practice for monitoring while on immunosuppressive/immunomodulatory therapy. If 
such guidelines are not available/applicable, routine chest X-rays should be performed 
when clinically necessary. 
 QuantiFERON TB Gold test will be performed at screening. This is an in vitro TB test that 
measures a memory T-cell mediated response (production of interferon γ) in TB-infected 
patients. This test is unaffected by Bacillus Calmette-Guerin vaccination or 
nontuberculous mycobacteria. The test received regulatory and policy approvals in the US, 
Japan, EU, Canada. Blood samples will be incubated within 16 hours of blood collection 
and sent to the central laboratory for analysis the day after collection or as soon as 
possible. In case of suspicion of TB, those patients will be referred to a specialist for 
follow up. 
10.7.2  Liver function tests 
Please refer to Section 10.5.1.3 for liver function test (LFT) abnormalities to be reported as AESI 
with immediate notification.  
The Sponsor relies on the Investigator’s, particularly Safety Assessor’s judgment and safety 
Assessor for adapting concomitant medication in case of LFT abnormalities. 
In the present protocol, in order to closely follow LFT, assessment of ALT, AST, alkaline 
phosphatase, and bilirubin (total, conjugated) are performed per specifications on the study flow 
charts (see Section 1.2). 
 The IMP (sarilumab or matching placebo) should be permanently discontinued in case of 
confirmed ALT >5 x ULN or in case of confirmed ALT >3 x ULN and concomitant total 
bilirubin >2 x ULN (unless the patient has documented Gilbert’s disease). A complete 


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serological and ultrasonography work-up should be conducted in case of ALT >5 x ULN 
or ALT >3 x ULN and concomitant total bilirubin >2 x ULN (see Appendix K). 
 If ALT is ≥3 x ULN and ≤5 x ULN and bilirubin is ≤2 x ULN, administration of IMP must 
be temporarily interrupted, and LFT must be repeated within 48 hours from the study 
Investigator’s awareness for confirmation of transaminase levels. If the elevated ALT level 
is confirmed but stays below the 5 x ULN thresholds, then LFTs must be repeated 
according to the provided guideline and at a minimum of every 7 days until conditions for 
resumption of IMP administration are met (see Appendix K).  
 The IMP may then be restarted at the Investigator’s discretion after conditions for 
resumption of IMP administration are met (ALT <3 x ULN). Safety assessor will either 
resume the patient at the initial dose or perform blinded dose reduction request through 
IRT (dose of sarilumab may be reduced to 150 mg if patient was randomized to the 
200 mg group).  
10.7.3  Neutrophils 
Refer to Section 10.5.1.3 criteria for reporting neutropenia as AESI with immediate notification. 
 Absolute neutrophil count (ANC) >1000/mm3 current dosage of sarilumab can be 
maintained. 
In case of a decrease in neutrophil count to a level ≥500/mm3 and <1000/mm3: 
 The IMP (sarilumab or matching placebo) must be temporarily discontinued, the patient 
must be assessed for evidence of infection and CBC blood test repeated within 48 hours 
from the study Investigator’s awareness of neutrophil count ≥500/mm3 and <1000/mm3. 
 Discontinuation of IMP is maintained until the neutrophil count returns to ≥1000/mm3.  
 After the patient meets all requirements for resumption of IMP administration, including 
neutrophil count ≥1000/mm3, then IMP administration may resume based on 
Investigator’s clinical judgment. Safety assessor will either resume the patient at the initial 
dose or perform blinded dose reduction request through IRT (dose of sarilumab may be 
reduced to 150 mg if patient was randomized to the 200 mg group).  
IMP must be permanently discontinued in case of a decrease in neutrophil count <1000/mm3 and 
signs of infection or neutrophil count <500/mm3. 
 The patient must be assessed for evidence of infection and CBC blood test repeated within 
48 hours from the study Investigator’s awareness of neutrophil count <1000/mm3 with 
signs of infection or neutrophil count <500/mm3. 
 It is recommended to admit the patient to the hospital in case of neutrophil count 
<1000/mm3 with suspicion of infection or neutrophil count <500/mm3. 
 The neutrophil count <500/mm3 persisting for more than 5 days are reported as an SAE. 


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10.7.4  Platelets 
Refer to Section 10.5.1.3 for criteria for reporting thrombocytopenia as AESI. 
A level ≥50 000/mm3 and <100 000/mm3: 
 The IMP must be temporarily discontinued, the patient must be assessed for evidence of 
spontaneous bleeding, and CBC blood test repeated within 48 hours from the study 
Investigator’s awareness of platelet count ≥50 000/mm3 and <100 000/mm3. 
 Discontinuation of IMP is maintained until the platelet count returns to ≥100 000/mm3.  
 After the patient meets all requirements for resumption of IMP administration, including 
platelet count ≥100 000/mm3, then IMP administration may resume based on 
Investigator’s clinical judgment. Safety assessor will either resume the patient at the initial 
dose or perform blinded dose reduction request through IRT (dose may be reduced to 
150 mg if patient was randomized to the 200 mg group).  
The IMP must be permanently discontinued if platelet count is <50 000/mm3 or if <100 000/mm3 
with spontaneous bleeding (see Section 10.4.2). 
10.7.5 Systemic hypersensitivity reactions/anaphylaxis 
Severe systemic hypersensitivity reactions (in rare cases, fatal anaphylaxis) have been reported 
with biologics, including tocilizumab. Rare, severe, nonfatal, 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 Dosing 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, etc; see Section 10.5.1.2) should be reported as SAEs. 
Appendix N 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. 
10.7.6 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. 


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Gastro-intestinal perforation must be reported as SAE (see Section 10.5.4). Confirmed 
diverticulitis or gastrointestinal ulceration should be reported as AEs. 
10.7.7 Management of dyslipidemia 
Patients treated with tocilizumab have been observed to have increased elevations of all lipid 
parameters, including LDL cholesterol. A similar finding has been observed for sarilumab. The 
potential cardiovascular effect of the lipid elevations, including LDL levels with antiIL-6R 
antagonists is unknown. 
Patients who are found to have dyslipidemia during the course of the study should be treated 
according to the American College of Cardiology (ACC)/American Heart Association (AHA) 
guideline or European Society of Cardiology (ESC)/the European Atherosclerosis Society (EAS) 
guidelines or applicable local guideline. 
10.7.8 Acute renal failure 
Sarilumab is not known to be associated with a clinically significant effect on renal function. 
10.8 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 


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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations are based on the primary efficacy variable of sustained remission at 
Week 52. Assuming the treatment effect of sarilumab compared to placebo will be similar to what 
was observed from GiACTA, a trial that evaluated the safety and efficacy of tocilizumab (another 
IL-6 receptor antagonist similar to sarilumab) in patients with GCA (9), it is expected that the 
sustained remission rate at Week 52 will be approximately 14% for Group C (placebo + 26 week 
taper), approximately 18% for Group D (placebo + 52 week taper), and approximately 54% for 
Group A (sarilumab 200 mg q2w +26 week taper). A slightly lower sustained remission rate of 
approximately 50% is assumed for Group B (sarilumab 150 mg q2w + 26 week taper). The details 
of the power calculations are summarized in the table below, where the proposed sample sizes 
will provide at least 90% overall power for all the 4 between-group comparisons at 0.01 level.  
Table 3 - Sample size determination 
Treatment 
Estimate of the 
sustained 
remission rate 
Sample 
size 
 
Comparison 
Power 
Group A 
54% 
120 
Group A vs. Group C 
99% 
Group B 
50% 
60 
Group A vs. Group D 
99% 
Group C 
14% 
60 
Group B vs. Group C 
96% 
Group D 
18% 
120 
Group B vs. Group D 
96% 
 
 
 
Overall  
>90% 
Treatment Group A: sarilumab 200 mg q2w with a 26 week taper of CS.  
Treatment Group B: sarilumab 150 mg q2w with a 26 week taper of CS.  
Treatment Group C: sarilumab matching placebo q2w with a 26 week taper of CS.  
Treatment Group D: sarilumab matching placebo q2w with a 52 week taper of CS.  
Power was calculated based on a 2-sided alpha level of 0.01 using the Chi-square test for each comparison. 
The sample size has also been selected to ensure adequate power for sensitivity analyses 
excluding acute phase reactants from the primary endpoint definition (9). 
Calculations were made using nQuery Advisor 7.0. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who signed informed consent.  


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Randomized patients consist of all patients, with signed informed consent, with a treatment kit 
number allocated and recorded in the IRT database, regardless of whether the treatment kit was 
used or not. These patients form the randomized population.  
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population.  
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
11.3.1.1 Intent–to-treat population 
Intent-to-treat (ITT) population: all randomized patients analyzed according to the treatment 
group allocated by randomization. All efficacy analyses will use this population. 
11.3.2 Safety population 
Safety population: all randomized patients who have received at least one dose or part of a dose of 
the study medication (IMP) analyzed according to the treatment they have actually received. 
In addition:  
 Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
 Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
 For patients receiving more than 1 study treatment during the trial, the treatment group 
allocation for as-treated analysis will the treatment for which the patient received the 
majority of doses.  
11.3.3 Pharmacokinetic analysis population 
The PK population will consist of all patients in the safety population with at least 1 postdose, 
nonmissing serum sarilumab concentration. 


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11.3.4 Antidrug antibody (ADA) population 
The ADA population will consist of all patients in the safety population with at least one 
nonmissing ADA result in the ADA assay following the first dose of the study medication. 
11.4 
STATISTICAL METHODS 
Analysis of the randomization DB phase is described below. The posttreatment follow up phase 
will be presented separately without formal statistical testing, and details of the follow up phase 
will be provided in the SAP. 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population.  
11.4.1.1 Extent of investigational medicinal product exposure 
Duration of IMP (sarilumab) exposure is defined as: last double-blind dose date - first double-
blind dose date +14 days, regardless of unplanned intermittent discontinuations. 
Duration of exposure to the double-blind IMP will be summarized for each treatment group 
descriptively as a quantitative variable (N, Mean, standard deviation [SD], Median, minimum 
[Min], and maximum [Max]). 
In addition, the number and percentage of patients randomized and exposed to the double-blind 
IMP will be presented by specific time periods for each treatment group. 
11.4.1.2 Compliance  
Treatment compliance to the double-blind IMP is defined as the actual amount of injections 
received compared to the scheduled amount of injections during the double-blind treatment 
period. It is calculated according to the following formula: 
100 x total number of injections administered/(nominal number of injections for the duration of 
double-blind exposure). 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of injection as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, Mean, SD, Median, Min, and Max). The percentage of patients with compliance 
is <80% will be summarized. In addition, number and percentage of patients with at least 
1 above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, (0, 20%), and >20% under-planned dosing administrations. 


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11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
The primary endpoint is the proportion of patients achieving sustained remission at Week 52 
compared between the sarilumab 200 mg q2w arm and the placebo arm with 26-week taper and 
analyzed in the ITT population. The primary endpoint will be summarized as counts and 
proportions in each treatment group and analyzed using a Cochran-Mantel-Haenszel (CMH) test, 
stratified by baseline prednisone dose. Patients who do not achieve remission, receive rescue 
treatment with open label prednisone (or equivalent), withdraw from the study before Week 52, or 
have missing data that prevents assessment of the primary endpoint will be considered as 
nonresponders. Successful adherence to the prednisone taper may include the use of any excess 
prednisone (beyond the per protocol CS tapering regimen) with a cumulative dose of ≤100 mg (or 
equivalent), such as those employed to manage AE not related to GCA. The significance level for 
all tests will be 0.01 (2-sided). 
Secondary comparisons will be made between the sarilumab 200 mg q2w arm and the placebo 
arm with 52 week taper using the CMH test as described previously. 
Sensitivity analyses will be performed based on a revised remission definition excluding acute 
phase reactants. 
11.4.2.2 Analyses of secondary efficacy endpoints 
Other binary endpoints will be analyzed as described for the primary endpoint.   
The cumulative prednisone dose will be analyzed using a nonparametric van Elteren test stratified 
by baseline prednisone dose and the mean and median dose will be summarized. 
Time events will be analyzed by Kaplan-Meier method. Treatment groups will be compared with 
the use of Cox proportional hazards models, with adjustment for the baseline prednisone dose. 
Data censoring will be used for patients who withdraw from the study. 
The GTI assessment (total score and domain-specific scores) will be analyzed with a mixed model 
repeated measures (MMRM) approach. The model, including treatment, visit, treatment-by-visit 
interaction, baseline prednisone dose (<30 mg/day or ≥30 mg/day) as fixed effects and baseline 
score as a covariate, will be used to test the difference of least-square means (LS means) between 
treatment groups. Descriptive statistics including number of subjects, mean, standard error and 
LS means will be provided. In addition, difference in LS means, the corresponding 99% CI and 
the p-value will be provided. 
11.4.2.3 Multiplicity considerations 
In order to maintain an overall type I error of 0.01 a hierarchical testing approach will be used.  


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The testing sequence for the primary endpoint will be: 
 Comparison of 200 mg versus placebo with 26 week taper for primary endpoint. 
 Comparison of 200 mg versus placebo with 52 week taper for primary endpoint. 
 Comparison of 150 mg versus placebo with 26 week taper for primary endpoint. 
 Comparison of 150 mg versus placebo with 52 week taper for primary endpoint. 
Since sarilumab 200 mg q2w is the primary dose for the study while sarilumab 150 mg q2w is 
added to provide additional information on efficacy and safety in GCA patients, the comparisons 
on the secondary endpoints will be focusing on the 200 mg q2w only.  
After significance is established at a 0.01 level for all 4 comparisons on the primary endpoint as 
listed above, the following secondary endpoints will be tested sequentially as below: 
 Total cumulative corticosteroid dose 
 Time to first flare after remission 
For each secondary endpoint, the comparison between 200 mg versus placebo + 26 week taper 
will be performed first; if significance is achieved at a 0.01 level, then the comparison between 
200 mg versus placebo + 52 week taper will be performed. 
Nominal p-values will be provided for the comparisons of all other secondary endpoints. 
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group. Incidence rates and exposure 
adjusted event summaries will be provided for categorical safety summaries.  
All safety analyses will be performed on the safety population using the following common rules: 
The baseline value is defined generally as the last available value before randomization. 
 The observation period to be used for the safety population is the TEAE period. The 
TEAE period is defined as the time from first dose of randomized study treatment to the 
last dose date of IMP + 60 days. 
 For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group. 
 The analysis of the safety variables will be essentially descriptive and no hypothesis 
testing is planned. 
The following definitions will be applied to laboratory parameters, vital signs and ECG. 
 The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 


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criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG.  
 PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.   
11.4.3.1 Analysis of adverse event data 
Treatment-emergent AEs, treatment-emergent SAEs, TEAEs leading to treatment discontinuation 
and treatment-emergent AESIs will be summarized for each treatment group based on MedDRA 
coding of verbatim terms reported by Investigators. 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment period. The denominator for 
computation of percentages is the safety population within each treatment group. 
Treatment-emergent AESI, by AESI category and PT, will show number (%) of patients overall, 
sorted by decreasing incidence of PT within each AESI category. The AESIs include, but are not 
limited to, the following categories and details of the MedDRA coding will be provided in the 
statistical analysis plan: Neutropenia, thrombocytopenia, infections, hepatic disorders, 
diverticulitis/GI ulcerations/GI perforations, elevation in lipids, systemic allergic reactions, 
malignancy, autoimmune or drug-induced lupus like syndrome and demyelinating disorders. 
Death: The following deaths summaries will be generated: 
 Number (%) of patients who died by study period (TEAE, on-study) summarized on the 
safety population by treatment received 
 Death in nonrandomized patients or randomized and not treated patients   
 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 showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT.  
11.4.3.2 Analysis of laboratory data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
laboratory variables will be calculated for each visit or study assessment (baseline, each 
post-baseline time point, endpoint) by treatment group. Listings will be provided with flags 
indicating the out of range values as well as the PCSA values. 
The incidence of PCSA at any time will be summarized by treatment group for each laboratory 
parameter. Shift tables showing changes with respect to the baseline status will be provided. 


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11.4.3.2.1 Neutropenia 
The incidence of neutropenia by maximal grade (lowest neutrophils value reported) during the 
TEAE period will be summarized. The 4 grades are defined as below:  
 Grade 1: ≥1.5 Giga/L - LLN  
 Grade 2: ≥1.0 - 1.5 Giga/L 
 Grade 3: ≥0.5 - 1.0 Giga/L 
 Grade 4: <0.5 Gigal/L 
For patients with Grade 3 or 4 neutropenia, a listing with the individual neutropenia counts, and 
selected laboratory tests at each visit (including unscheduled visits for retest) will be provided. In 
addition, the neutrophil counts at each scheduled visit during the study will be plotted by 
treatment groups. 
11.4.3.2.2 Assessment of potential drug-induced liver injury 
The LFT, namely ALT, AST, alkaline phosphatase 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 treatment group for each parameter. The proportion of 
patients with PCSA values at any post-baseline visit will also be displayed by duration of 
exposure for each treatment group. 
Time to onset of the initial ALT elevation (>3x ULN), time to onset of the initial AST elevation 
(>3x ULN), time to onset of the initial total bilirubin elevation (>2x ULN), and time to first 
observation of ALT >3ULN or Total Bilirubin >2 ULN (whichever comes first) will be analyzed 
using Kaplan-Meier estimates, using the midpoint of the time interval between the first 
assessment showing the elevation and the previous assessment, presented by treatment group. A 
graph of 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 3xULN for ALT and a 
horizontal line corresponding to 2x ULN for total bilirubin. 
Summarize the normalization by parameter (to ≤1 ULN or return to baseline) of elevated LFT by 
categories of elevation (1-<3x, 3x, 5x, 10x, 20x ULN for ALT and AST, 1.5 x ULN for Alkaline 
phosphatase, and 1.5x and 2x ULN for total bilirubin), with following categories of normalization: 
never normalized, normalized after IMP discontinuation. Note that a patient will be counted only 
under the maximum elevation category. 1 - 3, 3 - 5, 5 - 10, 10 - 20, >20.  
The incidence of liver-related AEs will be summarized by treatment group. The selection of 
preferred terms will be based on standardized MedDRA query (SMQ) Hepatic disorder. Time to 
liver-related treatment discontinuation and time to liver death may also be provided based on 
hepatic disorder SMQ. 


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11.4.3.3 Analysis of the vital signs data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
vital signs variables will be calculated for each visit or study assessment (baseline, each 
post-baseline time point, endpoint) by treatment group. 
The incidence of PCSA at any time will be summarized by treatment group for each vital signs 
variable. Shift tables showing changes with respect to the baseline status will be provided. 
Listings will be provided with flags indicating the out of range values as well as the PCSA values. 
11.4.3.4 Analysis of antidrug antibody data 
Antidrug (sarilumab) antibody (ADA) variables include status (positive or negative) and titer as 
follows: 
 Total number of patients negative in ADA assay at all time 
 Total number of patients with preexisting immunoreactivity - defined as either an ADA 
positive response in the assay at baseline with all post-baseline ADA results negative, or a 
positive response at baseline with all post-baseline ADA titer <4-fold over baseline titer 
level 
 Total number of patients with treatment-emergent ADA response in ADA assay - defined 
as a positive response in the ADA assay post-first dose, when baseline results are negative, 
or missing: 
 Total number of patients with treatment-boosted ADA response in ADA assay - defined as 
a positive ADA assay response at baseline with any post-baseline ADA titer ≥4-fold over 
baseline titer level. 
 Titer value category 
- 
Low (titer <1,000) 
- 
Moderate (1,000≤ titer ≤10,000) 
- 
High (titer >10,000) 
Antidrug antibody positive samples will be further characterized for the presence of neutralizing 
antibody (NAb) response: 
 Total number of patients positive in the NAb assay at the time points analyzed. 
These ADA variables will be summarized using descriptive statistics by treatment group. Drug 
concentration data will be examined and the influence of ADAs on individual concentration-time 
profiles will be evaluated. Assessment of the potential impact of ADA on safety and efficacy may 
be provided. 


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11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables 
Serum concentrations of functional sarilumab will be summarized using arithmetic and geometric 
means, SD, standard error of the mean (SEM), coefficient of variation (CV%), minimum, median, 
and maximum by visit. 
IL-6 and sIL-6R will be summarized using arithmetic and geometric means, SD, SEM, CV%, 
minimum, median, and maximum by visit. 
11.4.5 Analyses of patient reported outcomes  
Change from baseline in patient reported endpoints at Weeks 12, 24, and 52 will be analyzed with 
a mixed model repeated measures approach as appropriate (all data is continuous):  
 SF-36v2 physical component summary score  
 SF-36v2 mental component summary score 
 Each SF-36v2 domain (n= 8) 
 The EQ-5D-3L single index utility score  
 The EQ-5D-3L VAS score 
 The FACIT-Fatigue total score 
 The HAQ-DI standardized score 
 The HAQ-DI pain score 
 The HAQ-DI global assessment score 
The model, including treatment, visit, treatment-by-visit interaction, baseline prednisone dose 
(<30 mg/day or ≥ 30mg/day) as fixed effects and baseline score as a covariate, will be used to test 
the difference of least-square means (LS means) between treatment groups in each variable. 
Descriptive statistics including number of subjects, mean, standard error and LS means will be 
provided. In addition, difference in LS means, the corresponding 99% CI and the p-value will be 
provided. 
11.5 
INTERIM ANALYSIS 
No interim analysis is planned, 
Primary analysis at Week 52 will be conducted after the final patient has completed the double 
blind treatment period and all data have been cleaned. 
Patients will continue into the 24-week posttreatment follow up period with the database lock 
occurring after the last patient has completed the EOS Visit. 


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Planned database lock date 
The first data snapshot will occur approximately 4 weeks after last patient last visit for Week 52 
(primary analysis). The database lock will occur approximately 4 weeks after the last patient has 
completed the EOS Visit (Week 76). 


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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, and delegated Investigator 
staff and Subinvestigator, 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 International Conference on Harmonisation (ICH) 
guidelines for good clinical practice (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 of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative (as specified for Germany: only in cases where the patient can be consented but 
cannot sign his or her name), and by the person who conducted the informed consent discussion. 
A copy of the signed and dated written informed consent form will be provided to the patient.  
If informed consent is obtained under special circumstances (emergency, etc), the method should 
be specified following the ICH requirements.  
Prior to collection of blood for pharmacogenetics and blood for biomarker of circulating protein 
analysis, the ICF of optional participating in the additional research program (written) should be 
completed by the patient or by the subject’s legally acceptable representative, and by the person 
who conducted the informed consent discussion. 
The ICF, including the optional for participating in the additional research program, used by the 
Investigator for obtaining the patient's informed consent must be reviewed and approved by the 
Sponsor prior to submission to the appropriate ethics committee (IRB/IEC) for approval/favorable 
opinion. 


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12.3 
HEALTH AUTHORITIES AND 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 health authorities (competent regulatory authority) and 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. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, IB with any addenda or labeling documents [summary of 
product characteristics, package insert] Investigator’s curriculum vitae [CV], etc) and the date of 
the review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. 
The 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 health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They 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 IB or labeling information will 
be sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
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 eCRF, 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 subinvestigators shall be appointed and listed in a timely manner. The 
subinvestigators 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 eCRFs. 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 eCRF entries against the source 
documents, except for the preidentified source data directly recorded in the eCRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 


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personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the eCRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). 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 eCRFs (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 eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor 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 eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file. 


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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the CV describing the experience, qualification and training of each 
Investigator and subinvestigator 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 (or longer if required by local 
regulation) 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 IB 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 subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the subinvestigators 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. 


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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 /subinvestigator 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 subinvestigators 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 
 The patient's personal data, which are included in the Sponsor database, shall be treated in 
compliance with all applicable laws and regulations. 
 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. 
 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. 
Analyses of subject genetic data will be conducted as described in the protocol as this is needed 
for pharmacogenetics analyses required for the purposes of the study or by regulatory authorities. 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
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. 


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The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
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, good clinical practice, 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:  
 The information on the product leads to doubt as to the benefit/risk ratio. 
 Patient enrollment is unsatisfactory. 
 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. 
 Noncompliance of the Investigator or subinvestigator, 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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 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 (30) 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 clinical study report 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 12 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 to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, 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 case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be recollected if 
necessary. 


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Rehabilitation. 2002 Dec:83(12 Suppl 2):S10-7. 
22. EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199-208. 
23. Maruish ME (2011) User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated. 
24. Ware JE Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36): I. 
Conceptual Framework and Item Selection. Medical Care 1992 Jun;30(6):473-83.  
 
 


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17 
APPENDICES 


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Appendix A 
Contraceptive guidance and collection of pregnancy information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
NOTE: Documentation can come from the review of subject’s medical records, medical 
examination, or medical history interview. 
- 
Documented hysterectomy. 
- 
Documented bilateral salpingectomy. 
- 
Documented bilateral oophorectomy. 
2. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH)/estradiol level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH/estradiol measurement is 
insufficient.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Women of Child bearing potential should avoid pregnancy and should use the highly effective 
contraceptive methods detailed below through the course of the entire study (until the End of the 
Study Visit) or until 12 weeks after the last dose of sarilumab or matching placebo if the patient 
early withdraw from the study. 


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Female subjects: 
Highly Effective Contraceptive Methods That Are User Dependent 
 Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 
- 
oral 
- 
intravaginal 
- 
transdermal 
 Progestogen-only hormone contraception associated with inhibition of ovulation 
- 
oral 
- 
injectable 
- 
implantable 
Highly Effective Methods That Are User Independent 
 Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
 Intrauterine device  
 Intrauterine hormone-releasing system  
 Bilateral tubal occlusion 
 Vasectomized partner 
 Sexual abstinence if this is the preferred and usual lifestyle of the subject 
Male subjects with partners of reproductive potential who become pregnant  
 The Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. This applies 
only to subjects who receive study treatment. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy.  
 Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor.  
 Generally, follow up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.  


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Female subjects who become pregnant  
 The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  
 Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy.  
 Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date.  
 Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  
 A spontaneous abortion is always considered to be an SAE and will be reported as such. 
For UK and Germany Only:  
Acceptable forms of effective contraception include: 
 Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation; 
 Established use of oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation; 
 Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS); 
 Bilateral tubal occlusion; 
 Male sterilization (provided that the partner is the sole sexual partner of the woman of 
childbearing potential study participant and that the sterilized partner has received medical 
assessment of the surgical success.); 
 True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception). 
For Denmark Only: 
Acceptable methods of contraception include: 
 Intra-uterine devices (IUD); 
Hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal 
devices or injections with prolonged release). 


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Appendix B 
Standardized corticosteroid-taper regimen during study treatment 
period 
Week 
Daily prednisone dose 26 week taper regimen 
(mg/Day) 
0 
(Day 1) 
60a,b 
50a,b 
40ab 
35a,b 
30a,b 
25a,b 
20a,b 
 1 
50a 
40a 
35a 
30a 
25a 
20a 
15 
 2 
40a 
35a 
30a 
25a 
20a 
15 
13 
 3 
35a 
30a 
25a 
20a 
15 
13 
12 
 4 
30a 
25a 
20a 
15 
13 
12 
10 
 5 
25a 
20a 
15 
13 
12 
10 
9 
 6 
20a 
15 
13 
12 
10 
9 
8 
 7 
15 
13 
12 
10 
9 
8 
7 
 8 
13 
12 
10 
9 
8 
7 
6 
 9 
12 
10 
9 
8 
7 
6 
6 
 10 
10 
9 
8 
7 
6 
6 
5 
 11 
9 
8 
7 
6 
6 
5 
5 
 12 
8 
7 
6 
6 
5 
5 
4 
 13 
7 
6 
6 
5 
5 
4 
4 
 14 
6 
6 
5 
5 
4 
4 
3 
 15 
6 
5 
5 
4 
4 
3 
3 
 16 
5 
5 
4 
4 
3 
3 
2 
 17 
5 
4 
4 
3 
3 
2 
2 
 18 
4 
4 
3 
3 
2 
2 
1 
 19 
4 
3 
3 
2 
2 
1 
1 
 20 
3 
3 
2 
2 
1 
1 
PS placebo 


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 21 
3 
2 
2 
1 
1 
PS placebo 
PS placebo 
 22 
2 
2 
1 
1 
PS placebo 
PS placebo 
PS placebo 
 23 
2 
1 
1 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
 24 
1 
1 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
 25 
1 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
 26 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
 27 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
 28 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  29 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  30 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  31 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  32 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  33 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  34 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  35 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  36 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  37 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  38 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  39 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  40 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  41 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  42 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  43 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  44 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 


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  45 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
  46 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
No PS 
dosing 
  47 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
PS placebo 
No PS 
dosing 
No PS 
dosing 
  48  
PS placebo 
PS placebo 
PS placebo 
PS placebo 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
  49 
PS placebo 
PS placebo 
PS placebo 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
 50 
PS placebo 
PS placebo 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
 51 
PS placebo 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
a prednisone will be provided as open label.  
b Prednisone Starting dose 


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Week 
Daily prednisone dose 52 week taper regimen 
(mg/Day) 
0 
(Day 1) 
60a,b 
50a,b 
40a,b 
35a,b 
30ab 
25ab 
20ab 
1 
50a 
40a 
35a 
30a 
25a 
20a 
17 
2 
40a 
35a 
30a 
25a 
20a 
17 
17 
3 
35a 
30a 
25a 
20a 
17 
17 
15 
4 
30a 
25a 
20a 
17 
17 
15 
15 
5 
25a 
20a 
17 
17 
15 
15 
12 
6 
20a 
17 
17 
15 
15 
12 
10 
7 
17 
17 
15 
15 
12 
10 
10 
8 
17 
15 
15 
12 
10 
10 
10 
9 
15 
15 
12 
10 
10 
10 
10 
10 
15 
12 
10 
10 
10 
10 
9 
11 
12 
10 
10 
10 
10 
9 
9 
12 
10 
10 
10 
10 
9 
9 
9 
13 
10 
10 
10 
9 
9 
9 
9 
14 
10 
10 
9 
9 
9 
9 
8 
15 
10 
9 
9 
9 
9 
8 
8 
16 
9 
9 
9 
9 
8 
8 
8 
17 
9 
9 
9 
8 
8 
8 
8 
18 
9 
9 
8 
8 
8 
8 
7 
19 
9 
8 
8 
8 
8 
7 
7 
20 
8 
8 
8 
8 
7 
7 
7 
21 
8 
8 
8 
7 
7 
7 
7 


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22 
8 
8 
7 
7 
7 
7 
6 
23 
8 
7 
7 
7 
7 
6 
6 
24 
7 
7 
7 
7 
6 
6 
6 
25 
7 
7 
7 
6 
6 
6 
6 
26 
7 
7 
6 
6 
6 
6 
5 
27 
7 
6 
6 
6 
6 
5 
5 
28 
6 
6 
6 
6 
5 
5 
5 
29 
6 
6 
6 
5 
5 
5 
5 
30 
6 
6 
5 
5 
5 
5 
4 
31 
6 
5 
5 
5 
5 
4 
4 
32 
5 
5 
5 
5 
4 
4 
4 
33 
5 
5 
5 
4 
4 
4 
4 
34 
5 
5 
4 
4 
4 
4 
3 
35 
5 
4 
4 
4 
4 
3 
3 
36 
4 
4 
4 
4 
3 
3 
3 
37 
4 
4 
4 
3 
3 
3 
3 
38 
4 
4 
3 
3 
3 
3 
2 
39 
4 
3 
3 
3 
3 
2 
2 
40 
3 
3 
3 
3 
2 
2 
2 
41 
3 
3 
3 
2 
2 
2 
2 
42 
3 
3 
2 
2 
2 
2 
1 
43 
3 
2 
2 
2 
2 
1 
1 
44 
2 
2 
2 
2 
1 
1 
1 
45 
2 
2 
2 
1 
1 
1 
1 


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46 
2 
2 
1 
1 
1 
1 
No PS 
dosing 
47 
2 
1 
1 
1 
1 
No PS 
dosing 
No PS 
dosing 
48 
1 
1 
1 
1 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
49 
1 
1 
1 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
50 
1 
1 
No PS dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
51 
1 
No PS 
dosing 
No PS dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
No PS 
dosing 
a prednisone will be provided as open label medication.  
b Prednisone Starting dose. 


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Appendix C 
Composite Glucocorticoid Toxicity Index  
 


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Appendix D 
Specific list for Glucocorticoid Toxicity Index 
 


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Appendix E 
FACIT Fatigue Scale (Version 4) (Paper Version)* 
 
*This version will be adapted for use in the electronic format.  
 


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Appendix F 
EuroQol Questionnaire (EQ-5D-3L) (Paper Version)* 
 


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 *This version will be adapted for use in the electronic format.  


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Appendix G 
SF-36 (Version 2) (Paper Version)* 
 


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*This version will be adapted for use in the electronic format.  
 


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Appendix H 
Health Assessment Questionnaire (HAQ-DI) (Paper Version)* 
 


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Your PAIN: How much pain have you had IN THE PAST WEEK: 
Place a vertical (I) mark on the line to indicate the pain 
 
 
 
 
 
No pain 
 
 
 
 
Severe pain 
0 mm 
 
100 mm 
 
Your HEALTH: Please rate how well you are doing on a scale of 0 to 100 (0 represents 
“very well” and 100 represents “very poor” health) 
Please place a vertical mark (I) on the line below to indicate how well you are doing. 
 
 
 
 
 
Very well 
 
 
 
 
Very poor 
0 mm 
 
100 mm 
 
*This version will be adapted for use in the electronic format. 
 


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Appendix I 
Physician’s Global Assessment of Disease Activity (Paper Version)* 
 
PHYSICIAN’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
Place a vertical mark on the line for how you would assess your patient’s current disease activity 
 
 
 
 
Not active 
 
 
 
 
Very active  
0 mm 
 
100 mm 
*This version will be adapted for use in the electronic format. 
 


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Appendix J 
GCA Biomarker Objectives 
The objectives of the Precision Medicine Plan are to characterize the disease activity of GCA 
patients while on steroid taper or sarilumab treatment. Both treatment arms will be exposed to 
anti-inflammatory agents so evaluation of baseline inflammation and changes over time will be 
evaluated using comprehensive approaches to evaluating circulating immune cell types, 
circulating proteins and evaluation of gene expression changes. 
Whole blood for immunophenotyping of circulating immune cells 
The contribution of the innate and adaptive immune systems to GCA disease activity and 
treatment response are not well understood. In order to better characterize alterations of the innate 
and adaptive immune system predose and after steroid taper or sarilumab treatment, whole blood 
collections at predose at V2, V4 and V9 are proposed to characterize T cell subsets that are 
purported to be dysregulated in patients and that may not be controlled by steroids CD4 (Treg, 
Th1, Th17), CD8 (cytotoxic lymphocytes) 1-5 or cells that produce or are activated by IL6 
signaling (monocytes 6, B cells 8 respectively). In total 120 patients will be selected via IRT for 
this analysis, please refer to Lab Manual in detail 
- 
40 patients each in Group A and Group D 
- 
20 patients each in Group B and Group C 
Optional Future Biomarker Serum and Plasma for circulating protein analysis  
The purpose of banking serum and plasma is to analyze proteins at baseline and after treatment 
that may be associated with disease progression, severity and treatment response to anti IL-6R 
therapy. Although acute phase reactants have been well described in GCA patients, proteins that 
associate with overlapping PMR symptoms of morning stiffness and shoulder and hip pain have 
not been explored in the other studies. Proteins that may be explored but not limited to the 
following: proteins involved in the IL6 signaling pathway (IL-6, soluble IL-6R, fibrinogen, serum 
amyloid A etc), synovitis and bursitis (adhesion and proteases 9,10 ), cytokines involved in 
TH1/Th17 pathway and the HPA axis (cortisol) . 
Optional Pharmacogenetics analysis for DNA and RNA 
DNA will be collected at a single visit to analyze the sequence to determine if there are genetic 
variants that predict disease flare, remission or response to anti-IL-6R therapy.  RNA will be 
collected predose at V2 and then predose at V3 2 weeks after the first study drug administration to 
determine if anti-IL6R therapy changes gene expression patterns in circulating blood cells 
compared to steroid taper + placebo. DNA and RNA samples for the genomics sub-study will be 
double-coded as defined by the International Council for Harmonisation (ICH) guideline E15. 
Sub-study samples will be stored for up to 15 years after the final date of the database lock and 
may be used for research purposes.  The purpose of the genomic analyses is to identify genomic 
associations with clinical or biomarker response, other clinical outcome measures and possible 
AEs.  In addition, associations between genomic variants and prognosis or progression of  as well 


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Page 141 
as related diseases may also be studied. These data may be used or combined with data collected 
from other studies to identify and validate genomic markers related to the study drug or  and 
related diseases. Analyses may include sequence determination or single nucleotide 
polymorphism studies of candidate genes and surrounding genomic regions.  Other methods, 
including whole-exome sequencing, whole-genome sequencing, DNA copy number variation, and 
transcriptome sequencing may also be performed.  The list of methods may be expanded to 
include novel methodology that may be developed during the course of this study or sample 
storage period. 
References: 
1. Deng et al 2010 
2. Visvanathan et al, 2011 
3. Corbera-Bellata 2015 
3. Samson et al., journal of autoimmunity 2016 
4. Samson et al. 2012;  
5. Miyabe et al. Annu Review Rheum. 2017 
6. Van Sleen et al, Nature Scie Rep 2017 7:6553 
7. Nadkarni et al Circ Cell. 2014 
8. Alegria et al, Rheumatology 2016 
9. Ribbens 2002 ARD 61:161 
10. Kim 2013 J Bone Joint Surg Am. 20;95(4):e181-8 
 


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Appendix K 
Procedure for collection, handling, storage, and shipment of 
SAR153191 specimens for pharmacogenetic samples 
Detailed information regarding collection, handling, storage, shipments of pharmacogenetics 
samples will be provided as separate lab manual. 


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Appendix L 
General guidance for the follow up of laboratory abnormalities by 
Sanofi 
Neutropenia 
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.5.3 is met. 


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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.5.3 is met. 


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Increase in ALT 
 
 


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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
INCREASE IN SERUM CREATININE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
investigational medicinal product by 
renal route
1.
Investigational medicinal 
product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
investigational medicinal product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
 
Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs in Section 10.5.3 is met. 
 


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Appendix M 
List of opportunistic infections 
 Aspergillosis 
 Blastomyces dermatitidis (endemic in the south-eastern and south-central Unites States, 
along Mississippi and Ohio rivers) 
 Systemic candidiasis and extensive cutaneous cases 
 Coccidioides immitis (endemic Southwestern US and Central and South America) 
 Cryptococcus infection 
 Cytomegalovirus infection 
 Herpes simplex (severe/disseminated) 
 Herpes zoster infection 
 Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-
Ohio-Mississippi river basins) 
 Listeriosis 
 Malaria (developing world) 
 Infection with mycobacterium avium and other non-TB mycobacteria 
 Pneumocystis Carinii pneumonia (PCP) 
This list is indicative and not exhaustive 


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Appendix N 
Definition of Anaphylaxis 
“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 O 
Country-specific Requirements 
Not applicable. 


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Appendix P 
Protocol Amendment History 
Not applicable. 
 

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
A randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of sarilumab in patients with giant cell arteritis 
SAR153191-EFC15068 
STATISTICIAN:
DATE OF ISSUE: 08-Jan-2021 
Total number of pages: 
87 
NCT03600805


Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 8 
1.2.1 
Primary objectives ............................................................................................................................ 8 
1.2.2 
Secondary objectives ....................................................................................................................... 8 
1.2.3 
Other objectives ............................................................................................................................... 8 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 9 
1.4 
STUDY PLAN ................................................................................................................................. 10 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 12 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 12 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 14 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 14 
2.1.1 
Demographic and baseline characteristics .................................................................................... 14 
2.1.2 
Prior or concomitant medications ................................................................................................... 16 
2.1.3 
Efficacy endpoints .......................................................................................................................... 16 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 16 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 19 
2.1.4 
Safety endpoints ............................................................................................................................ 24 
2.1.4.1 
Adverse events variables ............................................................................................................... 25 
2.1.4.2 
Deaths ............................................................................................................................................ 26 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 26 
2.1.4.4 
Vital signs variables ....................................................................................................................... 27 
2.1.4.5 
Antinuclear antibodies .................................................................................................................... 27 
2.1.5 
Immunogenicity endpoints ............................................................................................................. 27 
2.1.6 
Pharmacokinetic variables ............................................................................................................. 28 
2.1.7 
Pharmacodynamic/genomics endpoints ........................................................................................ 28 
2.1.8 
Other efficacy endpoints ................................................................................................................ 28 


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2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 32 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 34 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 34 
2.3.1 
Efficacy populations ....................................................................................................................... 35 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 35 
2.3.2 
Safety population ........................................................................................................................... 35 
2.3.3 
Pharmacokinetics and ADA populations ........................................................................................ 36 
2.4 
STATISTICAL METHODS ............................................................................................................. 36 
2.4.1 
Demographics and baseline characteristics .................................................................................. 36 
2.4.2 
Prior or concomitant medications ................................................................................................... 36 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 37 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 37 
2.4.3.2 
Compliance .................................................................................................................................... 38 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 38 
2.4.4.1 
Analysis of primary and additional efficacy endpoint(s) ................................................................. 38 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 39 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 41 
2.4.5 
Analyses of safety data .................................................................................................................. 41 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 42 
2.4.5.2 
Deaths ............................................................................................................................................ 44 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 44 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 46 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 46 
2.4.7 
Analyses of quality of life variables ................................................................................................ 46 
2.4.8 
Analysis of immunogenicity endpoints ........................................................................................... 47 
2.4.9 
DNA/RNA ....................................................................................................................................... 48 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 48 
2.5.1 
General conventions ...................................................................................................................... 48 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 48 
2.5.3 
Missing data ................................................................................................................................... 49 
2.5.4 
Windows for time points ................................................................................................................. 50 
2.5.5 
Unscheduled visits ......................................................................................................................... 50 
2.5.6 
Remote Assessment ...................................................................................................................... 50 
2.5.7 
Pooling of centers for statistical analyses ...................................................................................... 51 
2.5.8 
Statistical technical issues ............................................................................................................. 51 
3 
INTERIM ANALYSIS ..................................................................................................................... 52 
4 
DATABASE LOCK ........................................................................................................................ 53 


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5 
SOFTWARE DOCUMENTATION ................................................................................................. 54 
6 
REFERENCES ............................................................................................................................... 55 
7 
LIST OF APPENDICES ................................................................................................................. 56 
APPENDIX A 
STUDY FLOW CHART ........................................................................................................ 57 
APPENDIX B 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA ......... 62 
APPENDIX C 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 68 
APPENDIX D 
SF-36 V2 SCORING ............................................................................................................ 71 
APPENDIX E 
FACIT-FATIGUE SCORING GUIDELINES (VERSION 4) .................................................. 73 
APPENDIX F 
SAS CODE FOR EQ-5D-3L INDEX UTILITY SCORING .................................................... 74 
APPENDIX G 
SAS CODE FOR SF-36 SCORING .................................................................................... 75 
APPENDIX H 
VISIT WINDOWS BASED ON DAY RANGES .................................................................... 83 
APPENDIX I 
BASELINE GLUCOCORTICOID TOXICITY ......................................................................... 86 
 


Statistical Analysis Plan  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA: 
antidrug antibody 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANA: 
antinuclear antibodies 
AST: 
asparate aminotransferase 
BMI: 
body mass index 
CRF: 
case report form 
CSR: 
clinical study report 
ds-DNA: 
double-stranded DNA 
EOS: 
end of study 
EQ-5D-3L: 
EuroQol five-dimensional three-level questionnaire 
FACIT-Fatigue: functional assessment of chronic illness therapy fatigue scale 
GTI: 
glucocorticoid toxicity index 
HAQ-DI: 
health assessment questionnaire disability index 
HbA1c: 
hemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol 
HLGT: 
high level group term 
HLT: 
high level term 
ID: 
identification 
IMP: 
investigational medicinal product 
LDH: 
lactate dehydrogenase 
LDL-C: 
low density lipoprotein cholesterol 
LLN: 
lower limit of normal 
LLOQ: 
lower limit of quantification 
LLT: 
lower level term 
MD-VAS:
physician global assessment of disease activity- visual analog scale 
MedDRA:
Medical Dictionary for Regulatory Activities 
NCEP ATPIII: 
National Cholesterol Education Program Adult Treatment Panel III 
PRO: 
patient reported outcome 
PT: 
preferred term 
RBC: 
red blood cell 
SAEs: 
serious adverse events 
SF-36v2: 
short form 36 version 2 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
WBC: 
white blood cell 
WHO-DD: 
World Health Organization - Drug Dictionary 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
This statistical analysis plan (SAP) provides a comprehensive and detailed description of 
statistical strategy and methodology to be used to analyze the data from sarilumab EFC15068 
study in patients with giant cell arteritis (GCA). 
Due to the ongoing pandemic of COVID-19 (the disease caused by the novel coronavirus), the 
operations of sarilumab (Kevzara®) clinical trial EFC15068 have been significantly disrupted in 
various countries and sites. Consequently, the screening/recruitment activities for this study have 
been suspended since 19th of March 2020. Due to the protracted recruitment timeline and internal 
portfolio reprioritization, in July 2020, Sanofi has decided not to re-open the 
screening/recruitment activities and to discontinue the study. This decision is not related to any 
safety issues arising from the administration of sarilumab. 
A total of 83 patients (out of 360 planned patients) have been randomized in the study. While the 
number of randomized patients may not be adequate to demonstrate a statistically significant 
benefit, the data generated from the treated patients may contribute to the further understanding of 
IL-6 signaling blockade in this disease state. 
1.1 
STUDY DESIGN AND RANDOMIZATION  
Original study design 
This is a multicenter, randomized, double-blind, placebo controlled 52-week Phase 3 study with a 
24-week post-treatment follow up phase, evaluating the efficacy and safety of sarilumab in 
patients with giant cell arteritis (GCA). 
Approximately 360 patients with GCA (new onset or refractory [eg, disease relapse] GCA) who 
meet the entry criteria will be randomized to 4 parallel treatment groups with sarilumab 200 mg 
q2w, 150 mg q2w, or placebo q2w plus 26-week prednisone taper, or placebo q2w with 52-week 
standardized prednisone taper at a ratio of 2:1:1:2 as described below. Randomization will be 
stratified by the starting dose of prednisone at baseline (<30 mg/day or ≥30 mg/day) using a block 
randomization schedule, and aim to enroll at least 30% of new onset patients by capping 
enrolment of refractory patients to ≤70% of total patients randomized. 
• Treatment Group A: sarilumab 200 mg q2w with a 26-week taper of CS. 
• Treatment Group B: sarilumab 150 mg q2w with a 26-week taper of CS. 
• Treatment Group C: sarilumab matching placebo q2w with a 26-week taper of CS. 
• Treatment Group D: sarilumab matching placebo q2w with a 52-week taper of CS. 
It is important to optimize CS treatment prior to randomization to minimize the risk of adverse 
sequelae from GCA. Patients will be dosed with prednisone between 20 to 60 mg/day at the time 
of randomization (baseline) and initiate a taper according to the protocol defined schedule. 
Patients will be initiated on a standardized taper of prednisone from the time of randomization. 


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The taper will initially be open label; patients will have between 1 to 7 weeks to taper prednisone 
dose to 20 mg/day following randomization. 
The further tapering of prednisone once a dose of 20 mg/day is achieved will be done in a blinded 
manner. To achieve the appropriate daily dose during this phase, patients will receive a 
combination of prednisone and/or placebo to prednisone depending on the assigned treatment 
group and associated taper regimen. 
The total tapering period (open label plus double blind prednisone periods) will be between 
46 weeks to 52 weeks depending on the initial prednisone dose at randomization. 
At each site visit, the patient’s disease will be assessed to determine whether the patient can 
adhere to the protocol defined prednisone taper schedule. 
During the course of study, for patients in need of rescue therapy as per Investigator judgment, CS 
should be the agent of first choice. Patients may continue SC administration of sarilumab or 
matching placebo only if CS is used as the rescue therapy. If the patients remain symptomatic 
despite CS rescue therapy, then other treatment options including nonbiological 
immunosuppressive drugs may be used and the patient must be discontinued from the study 
treatment and considered a non-responder. 
If the patient or Investigator decides to discontinue the administration of blinded sarilumab 
injections, then the patient will be asked to return to the site for study assessments as per protocol 
until end of study (EOS) evaluation, unless the patient cannot or does not wish to continue the 
assessments, in which case an early withdrawal visit and safety follow up should be performed. It 
is recommended that patients complete Visit 13, if possible. 
Total duration of study participation for each patient is up to 82 weeks: 
• Up to 6 weeks screening period. 
• 52-week treatment period (sarilumab or placebo, double-blind phase). 
• 24-week post treatment follow-up period. 
The last patient last visit will occur when the last patient has completed the 24-week follow up 
period (EOS). The end of the clinical trial is defined as the last patient’s last visit. 
Study discontinuation plan 
As mentioned in Section 1 , due to the protracted recruitment timeline and internal portfolio 
reprioritization, Sanofi has decided to terminate the EFC15068 study in July 2020. For patients 
who were already enrolled with ongoing treatment in the study, investigators were instructed to 
discontinue the study drugs and transition these patients into post-treatment follow-up period for 
safety assessments. The study discontinuation plan is as follows: 
• All randomized patients should stop by 12 weeks from the date of announcement to the 
sites and should be scheduled for the end of study treatment visit at their earliest 


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convenience and no later than October 13, 2020, which would ensure sufficient time for 
patients to identify alternative therapy as needed. 
• All patients will have a follow-up (EOS) visit that is 6 weeks after treatment cessation and 
no later than November 24, 2020. 
Thus, the last patient last visit will occur when the last patient has completed the 6-week follow-
up period (EOS). The end of the clinical trial is defined as the last patient’s last visit. 
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
To evaluate the efficacy of sarilumab in patients with GCA as assessed by the proportion of 
patients with sustained remission at Week 52 for sarilumab compared to placebo, in combination 
with a 26-week CS tapering course. 
1.2.2 Secondary objectives  
• To demonstrate the efficacy of sarilumab in patients with GCA compared to placebo, in 
combination with (either 26 or 52 weeks) CS tapering course with regard to: 
- 
Clinical responses (such as responses based on disease remission rates, time to first 
disease flare) over time.  
- 
Cumulative CS (including prednisone) exposure. 
• To assess the safety (including immunogenicity) and tolerability of sarilumab in patients 
with GCA. 
• To measure sarilumab serum concentrations in patients with GCA. 
• To assess the effect of sarilumab on sparing glucocorticoid toxicity as measured by 
glucocorticoid toxicity index (GTI). 
1.2.3 Other objectives  
• To assess the effect of sarilumab on physician assessment of disease activity as measured 
by a visual analogue scale (MD-VAS). 
• To assess the effect of sarilumab compared with placebo, in combination with a 26-week 
CS taper as on a variety of patient reported outcome (PRO) concepts including fatigue 
(FACIT-Fatigue), health status (EuroQol five-dimensional three-level questionnaire 
[EQ-5D-3L], Short form 36 version 2 [SF-36v2]), physical functioning (health assessment 
questionnaire disability index [HAQ-DI]), including pain (visual analogue scale) and 
patient assessment of disease activity (visual analogue scale). 
• To assess the impact of ESR/CRP levels on remission status. 


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•
To characterize the disease activity of GCA patients while on steroid taper or sarilumab
treatment in a subset of patients using comprehensive approaches to evaluate circulating
immune cell types.
•
To characterize the disease activity of GCA patients while on steroid taper or sarilumab
treatment by evaluating circulating proteins, genetics and gene expression in consenting
patients.
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations are based on the primary efficacy variable of sustained remission at 
Week 52. Data from another trial that evaluated the safety and efficacy of tocilizumab in a similar 
population show that the expected event rate in Group C (placebo with 26-week taper, n = 60) is 
14% and in Group D (placebo with 52-week taper, n = 120) is 18% (1). Assuming a treatment 
difference of 40% and a significance level of 0.01 (2-sided) this will ensure that all comparisons 
of the primary endpoint in Group A (sarilumab 200 mg, n = 120) and Group B (sarilumab 150 mg, 
n = 60) compared to the 2 control groups will have at least 90% power. The sample size has also 
been selected to ensure adequate power for sensitivity analyses excluding acute phase reactants 
from the primary endpoint definition. 
The above calculations were for the full enrollment. However, the number of randomized patients 
is 83 in 4 arms at the time of the premature termination of the study. In addition, based on 
patients’ enrollment dates and the study discontinuation plan, only about 36 patients (out of 83) 
had an opportunity to complete the 52-week treatment period. For the cohort of patients who did 
not have an opportunity to complete the 52-week treatment period, it is not meaningful to define 
the endpoint of sustained remission at Week 52. Therefore, the analysis of primary endpoint will 
be limited to the cohort of patients who had an opportunity to complete the 52-week treatment 
period. Due to the small number of patients (n=36) in this cohort (see Section 2.3.1 for definition 
of the cohort), the powers on the primary endpoint are minimal. As a result, all the efficacy 
analyses will be descriptive in nature and all reported p-values will be nominal for the study. 
Based on patients’ enrollment dates, all enrolled patients (n=83) had an opportunity to complete at 
least 24 weeks of treatment, therefore, an additional endpoint, sustained remission at Week 24 is 
added in the SAP (see Section 2.1.3.1 for the detail definition). Table 1 provides the power 
calculations on the additional endpoint of sustained remission at Week 24. Due to the small 
number of patients in each individual treatment group, the power calculations were also provided 
for the comparison between the combined sarilumab groups (i.e., Group A+B) and the combined 
placebo groups (i.e., Group C+D) assuming the same effect sizes as mentioned above. 
Table 1: Updated power calculations 
Treatment 
Estimate of 
the sustained 
remission 
rate 
Estimated 
Sample 
size 
Comparison 
Power [1] 
(%) 
Power [2] 
(%) 
Group A 
54% 
28 
Group A versus Group C 
45.7 
74.0 
Group B 
50% 
14 
Group A versus Group D 
58.6 
81.1 


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Group C  
14%  
14  
Group B versus Group C  
28.1  
53.5 
Group D  
18%  
27  
Group B versus Group D  
33.6  
57.1 
Group A + B 
(combined sarilumab) 
53% 
42 
Group A+B versus Group 
C+D  
82.3 
94.5 
Group C + D 
(combined placebo) 
17% 
41 
Power [1] was based on an alpha level of 0.01. 
Power [2] was based on an alpha level of 0.05.  
Treatment Group A: sarilumab 200 mg q2w with a 26 week taper of CS.  
Treatment Group B: sarilumab 150 mg q2w with a 26 week taper of CS.  
Treatment Group C: sarilumab matching placebo q2w with a 26 week taper of CS.  
Treatment Group D: sarilumab matching placebo q2w with a 52 week taper of CS.  
Powers were calculated using the Chi-square test for each comparison; Calculations were made using nQuery Advisor 7.0. 
1.4 
STUDY PLAN  
The schedule of the safety, efficacy, pharmacokinetic (PK), and immunogenicity assessments 
from Section 1.2 of the study protocol is provided in Appendix A. The graphical study design is 
provided in Figure 1. 
 


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Figure 1 – Graphic study design 
 
 
 
 
 
 
 
 
Patients will be randomized to 4 groups with the ratio of 2:1:1:2               *Patients experiencing a disease flare may be rescued with open-label 
                                                                                                                                               treatment as per Investigator judgment during the study treatment period. 
6 weeks 
screening 
V1 
W4 
V4 
W2 
 V3 
D1
V2 
W8 
V5 
W24
V9 
W52
V12 
EOT 
W12 
V6 
W16
V7 
52 weeks 
Double blind period*  
R 
6 weeks  
follow up 
W58 
V13 
W40
V11 
W32
V10 
Treatment Group A: Sarilumab 200 mg q2w with 26 wk corticosteroid taper   N=120 
Treatment Group B: Sarilumab 150 mg q2w with 26 wk corticosteroid taper  N=60 
Treatment Group C: Sarilumab matching placebo with 26 wk corticosteroid taper 
N=60 
Treatment Group D: Sarilumab matching placebo with 52 wk corticosteroid taper 
N=120 
W20
V8 
W76 
V14 
EOS 
Post medication follow up 


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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
There was one protocol amendment for EFC15068 study (see Table 2). The overall rationale for 
the changes implemented in the protocol amendment 01 was to address several comments raised 
by the European Regulatory Authorities during the initial protocol review. The changes made in 
the statistical section in the protocol amendment 01 are summarized in Table 3. 
Table 2: Protocol amendment history 
Document 
Country/Countries 
impacted by 
amendement 
Date, version 
Amended Clinical Trial Protocol 01 
All 
12-Sep-2018, version 1 (electronic 2.0) 
Original Protocol 
All 
09-Feb-2018, version 1 (electronic 4.0) 
Table 3: Summary of changes of the statistical section - Protocol amendment 01 
Section # and 
Name 
Description of Change 
Brief Rationale 
Clinical Trial 
Summary –Statistical 
Consideration AND 
Section 11.1 
Determination of 
sample size 
More details on the power calculations were 
added. 
The assumed treatment effects used for the power 
calculations were added for clarity. 
Section 11.4.2.1 
Analysis of primary 
efficacy endpoint(s) 
The non-inferiority test between Sarilumab 
200 mg q2w arm and the placebo with 
52 weeks taper arm was removed. 
Based on the results from the GiACTA study, the non-
inferiority test is deemed as unnecessary and thus 
removed from the protocol 
Section 11.4.2.3 
Multiplicity 
considerations 
The hierarchical testing approach including 
the testing sequence for the secondary 
endpoints were clarified. 
Details on the hierarchical testing sequence for the 
secondary endpoints were added for clarification to 
address a specific request from the European 
Regulatory Authorities. 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
Due to the early termination of the study and study discontinuation plan, a large amount of data 
will not be able to be collected since many enrolled patients will not complete all planned study 
visits and study procedures for the assessments of efficacy, ADA, and biomarker endpoints. In 
addition, the number of randomized patients is 83 in 4 arms (out of 360 planned) at the time of the 
premature termination of the study. The changes from the statistical analysis plan outlined in the 
protocol are summarized below. 
• The primary endpoint for the study is sustained remission at Week 52. Based on patients’ 
enrollment dates and the study discontinuation plan, only about 36 patients (out of 83) had 
an opportunity to complete the 52-week treatment period. For the cohort of patients who 


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did not have an opportunity to complete the 52-week treatment period, it is not meaningful 
to define the endpoint of sustained remission at Week 52. Therefore, the analysis of 
primary endpoint will be limited to the cohort of patients who had an opportunity to 
complete the 52-week treatment period. Details can be found in Section 2.1.3.1 and 
Section 2.4.4.1. 
•
Based on patients’ enrollment dates and the study discontinuation plan, all patients should 
have had the opportunity to be treated for at least 24 weeks, so an additional endpoint, 
sustained remission at Week 24, is added in the SAP. Details can be found in
Section 2.1.3.1.
•
Due to the same reason as mentioned above, the secondary endpoints of cumulative GTI 
scores at Week 52 will be limited to the cohort of patients who had an opportunity to 
complete the 52-week treatment period. In addition, the cumulative GTI scores will also be 
assessed at Week 24. Details are provided in Section 2.1.3.2.
•
The missing data imputation strategy for defining the endpoints of sustained remission at 
W24 and W52, and cumulative GTI scores at W24 and W52 can be found in
Section 2.1.3.1 and Section 2.1.3.2, respectively; the rest of efficacy analyses will be based 
on data as observed, no missing data will be imputed.
•
A statistically significance level of 0.01 (2-sided) was prespecified in the protocol for all 
the between group comparisons. Due to reason mentioned in the first bullet, the analysis of 
the primary endpoint of sustained remission at Week 52 will be limited to the cohort of 
patients who had an opportunity to complete the 52-week treatment period (n=36). With a 
total of 36 patients, the powers on the primary endpoint are minimal. Therefore, all the 
analyses will be descriptive in nature.
a)
For majority of the efficacy endpoints, only descriptive summary statistics will be 
provided by 4 treatment groups.
b)
For the primary and some selected important secondary endpoints, summary statistics 
and formal statistical tests on between group comparisons (with 95% CI and p-value) 
will be provided for the 2 combined treatment groups (ie, 2 sarilumab groups combined 
versus 2 placebo groups combined). Details are provided in Section 2.4.4.
•
No multiplicity/hierarchy testing will be applied; all p-values will be nominal.
•
No subgroup analyses will be planned due to the small sample sizes.


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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
Data analyses will be performed in the double-blind (DB) 52-week treatment period. The analysis 
results will be presented by 4 treatment groups (Groups A, B, C and D) in the DB assessment 
period.  The posttreatment follow-up phase will be presented separately without formal statistical 
testing as needed. 
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value prior to the first dose of study medication, 
SC IMP. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the efficacy and safety sections (Section 2.4.4 and 
Section 2.4.5). 
Demographic characteristics 
The following demographic characteristics will be summarized separately by treatment and 
overall: 
•
Sex (Male, Female)
•
Race (Caucasian/White, Black, Asian/Oriental, Other)
•
Ethnicity (Hispanic, Not Hispanic)
•
Region (Region 1 [Western countries], Region 2 [South America], and Region 3 [Rest of
the World]); definitions of the regions are provided in Section 2.5.7
•
Age (years)
•
Age group (≥50 and <65, ≥65 and <75, ≥75 and <85, ≥85 years)
•
Weight (kg)
•
Weight group (<60, ≥60 and <100, ≥100 kg)
•
Body mass index (BMI, kg/m2)
•
BMI group (<25, ≥25 and < 30, ≥30 kg/m2)
•
Smoking status (never, former, current)
•
Alcohol habits (never, occasional, monthly, weekly, daily)
Medical or surgical history 
Medical or surgical history includes all the relevant findings within the lifetime of the patient. 


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This information will be coded to a “Lower Level Term (LLT)”, “Preferred Term (PT)”, “High 
Level Term (HLT)”, “High Level Group Term (HLGT)”, and associated primary “System Organ 
Class (SOC)” using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Sanofi at the time of database lock. 
Disease characteristics at baseline 
The following baseline disease characteristics as well as the other baseline characteristics will be 
summarized separately by treatment group: 
•
Unequivocal cranial symptoms of GCA (Yes, No)
•
Unequivocal symptoms of PMR (Yes, No)
•
Other features judged by the investigator to be consistent with GCA or PMR flares (Yes,
No)
•
Diagnostic temporal artery biopsy (Yes, No)
•
Diagnostic imaging performed (Yes, No) and imaging methodology (Angiography, CTA,
MRA, PET-CT, Ultrasound)
•
Duration of GCA (from diagnosis date to baseline)
•
GCA Disease onset (new onset, refractory)
•
Prior GCA flares (≤6 months, 6 to 12 months or >12 months prior to screening)
•
Prednisone dose at baseline
•
Prednisone dose group at baseline (≤30 mg/day, >30 mg/day)
•
Highest dose and duration of corticosteroid taper taken for GCA within 24 weeks prior to
screening
•
Physician global assessment of disease activity (MD-VAS)
•
C-reactive protein (CRP) at baseline
•
CRP group (≤median, >median)
•
ESR at baseline
•
ESR group (≤median, >median)
•
ESR ≥ 30 mm/h and/or CRP ≥ 10mg within 6 weeks prior to screening (Yes, No)
•
Glucocorticoid toxicity at baseline*
*The baseline glucocorticoid toxicity is established by a composite index calculated from
weighted scores assigned by toxicities. The scores are described in Appendix I.
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 2.5. 


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2.1.2 Prior or concomitant medications  
All medications taken within a certain period of time before randomization and until the end of 
the study, including vaccines taken before screening, biological/non-biological disease modifying 
anti-rheumatic drugs [DMARDs] and immunosuppressive agents taken for patients with 
symptomatic GCA disease are to be reported in the case report form (CRF) pages. The highest 
dose and duration of all corticosteroids taper taken for GCA within the 24 weeks prior to 
screening and all corticosteroids taken during the study are also reported. 
All medications will be coded using the World Health Organization – Drug Dictionary 
(WHO-DD) version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the patient used prior to first investigational medicinal product 
(IMP) intake. Prior medications can be discontinued before first dosing or can be ongoing 
during treatment phase. 
• Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, during the treatment-emergent period (Section 2.1.3). 
A given medication can be classified as a prior medication, as a concomitant medication, and/or 
as a post-treatment medication. 
For patients who experience a disease flare and are in need of rescue therapy, study patients 
prescribed with rescue corticosteroids (non-investigational medicinal product) per investigator 
judgement during the course of the study will continue administration of subcutaneous (SC) IMP 
(sarilumab or its matching placebo) for the full duration of the 52-week treatment period. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints  
2.1.3.1 Primary efficacy endpoint(s)  
The primary endpoint is the proportion of patients achieving sustained remission at Week 52, 
where the sustained remission at Week 52 is defined as having met all following parameters: 
1. Achievement of disease remission not later than Week 12, 
2. Absence of disease flare from Week 12 through Week 52, 
3. Normalization of CRP (to <10 mg/L, with an absence of successive elevations to 
≥10 mg/L) from Week 12 through Week 52, and  
4. Successful adherence to the prednisone taper from Week 12 through Week 52. 
Based on patients’ enrollment dates and the study discontinuation plan, not all the patients had an 
opportunity to complete the 52-week treatment period. For the cohort of patients who did not have 
an opportunity to complete the 52-week treatment period, it is not meaningful to define the 
endpoint of sustained remission at Week 52. Therefore, the analysis of primary endpoint will be 


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limited to the cohort of patients who had an opportunity to complete the 52-week treatment 
period. The detail definition of this cohort can be found in Section 2.3.1. 
Components of primary endpoint are described as below: 
1.  Achievement of disease remission not later than Week 12 
Disease remission is defined as resolution of signs and symptoms of GCA, and normalization of 
CRP (<10 mg/L). Note that a single CRP elevation (≥10 mg/L) is not considered absence of 
remission unless CRP remained elevated (≥10 mg/L) at the next study visit. 
The status of normalization of CRP (<10 mg/L) will be determined based on the last two non-
missing post-baseline CRP values measured up to Week 12. If at least one of them is <10 mg/L, 
then it is considered as normalization of CRP. 
Signs and symptoms of disease 
Evaluation of clinical signs and symptoms by the Efficacy Assessor at every study visit according 
to the schedule of assessment will include the following: 
• 
Symptoms of PMR as indicated by the Efficacy Assessor (morning stiffness and/or pain, in 
the shoulder and/or hip girdles) 
• 
Cranial symptoms. 
- 
Localized headache. 
- 
Temporal artery or scalp tenderness. 
- 
Visual signs or symptoms such as acute or subacute vision loss due to arteritic anterior 
ischemic optic neuropathy (A-AION), transient blurry vision (generally monocular or at 
least affecting 1 eye at a time, but potentially affecting both eyes), diplopia. 
- 
Jaw or mouth pain, tongue claudication. 
• 
Constitutional syndrome, including but not limited to fever, malaise, unintentional weight 
loss, night sweat, asthenia, fatigue, loss of appetite. 
• 
New or worsened extremity claudication, bruits and asymmetrical pulses. 
• 
Other features judged by the Investigator to be consistent with a GCA or PMR flare. 
The resolution of signs and symptoms of GCA is identified in eCRF “GCA Assessment” page 
with the question “Based upon the patient’s relevant medical history and the clinical assessment 
and responses provided above, does the patient have active GCA?” ticked as “No”. The resolution 
of signs and symptoms of GCA by Week 12 will be determined based on the last non-missing 
post-baseline GCA assessment measured up to Week 12. 
Patients who took rescue CS due to active GCA prior to Week 12 or who permanently withdraw 
from the study treatment prior to Week 12 will be considered as not achieved disease remission by 
Week 12. 


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2. Absence of disease flare from Week 12 through Week 52. 
Flare is defined as either 1) recurrence of signs and symptoms attributable to active GCA plus an 
increase in CS dose due to GCA, or 2) elevation of ESR attributable to active GCA plus an 
increase in CS dose due to GCA. Increase in CS dose is defined as: 
• Any dose increase during the protocol defined steroid taper, or 
• Reinitiation of prednisone therapy after the protocol defined taper has been completed. 
Patients with disease flare are identified as those with the reason for treatment ticked “rescue 
therapy” in eCRF “Steroid Medication” page and to the question “If Rescue Therapy, please 
specify” ticked either “Active GCA” or “Elevated ESR Attributable to Active GCA”. 
3. Normalization of CRP (to <10 mg/L, with an absence of successive elevations to 
≥10 mg/L) from Week 12 through Week 52 
The status of normalization of CRP from Week 12 through Week 52 will be determined based on 
the CRP values measured at Week 16, Week 20, Week 24, Week 32, Week 40 and Week 52. If 
there are two or more consecutive visits with CRP≥10 mg/L, then it is categorized as no 
normalization of CRP. Intermittent missing CRP at Week 16, Week 20, Week 24, Week 32, Week 
40 or Week 52 will be imputed using last value carried forward (LOCF) approach. 
4. Successful adherence to the prednisone taper from Week 12 through Week 52 
Successful adherence to the prednisone taper from Week 12 through Week 52 is defined as 
patients did not take rescue therapy from Week 12 through Week 52 and may include the use of 
any excess prednisone (beyond the per protocol CS tapering regimen) with a cumulative dose of 
≤100 mg (or equivalent), such as those employed to manage AE not related to GCA. The 
cumulative dose of excess prednisone use will be counted from baseline to Week 52. 
In addition, patients who permanently withdraw from the study treatment prior to Week 52 will be 
considered as not achieved component 2, 3, or 4 for the primary endpoint. 
Additional Endpoint: Sustained remission at Week 24 
Based on patients’ enrollment dates and the study discontinuation plan, all patients would have 
had the opportunity to be treated for at least 24 weeks. As a result, an additional endpoint, 
sustained remission at Week 24, which is defined similarly as the primary endpoint but with 
shorter sustained period, is added in the SAP. 
The sustained remission at Week 24 is defined by having met all of the following parameters: 
• Achievement of disease remission not later than Week 12, 
• Absence of disease flare from Week 12 through Week 24, 
• Normalization of CRP (to <10 mg/L, with an absence of successive elevations to 
≥10 mg/L) from Week 12 through Week 24, and  
• Successful adherence to the prednisone taper from Week 12 through Week 24. 


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Components of the sustained remission at Week 24 are described as below: 
1. Achievement of disease remission not later than Week 12, which is defined in the same 
way as described for the primary endpoint. 
2. Absence of disease flare from Week 12 through Week 24, where disease flare is defined 
in the same way as described for the primary endpoint. 
3. Normalization of CRP (to <10 mg/L, with an absence of successive elevations to 
≥10 mg/L) from Week 12 through Week 24 
The status of normalization of CRP from Week 12 through Week 24 will be determined based on 
the CRP values measured at Week 16, Week 20, Week 24. If there are two or more consecutive 
visits with CRP≥10 mg/L, then it’s categorized as no normalization of CRP. Intermittent missing 
CRP at Week 16, Week 20 or Week 24 will be imputed using last value carried forward (LOCF) 
approach. 
4. Successful adherence to the prednisone taper from Week 12 through Week 24 
Successful adherence to the prednisone taper from Week 12 through Week 24 is defined as 
patients did not take rescue therapy from Week 12 through Week 24 and may include the use of 
any excess prednisone (beyond the per protocol CS tapering regimen) with a cumulative dose of 
≤100 mg (or equivalent), such as those employed to manage AE not related to GCA. The 
cumulative dose of excess prednisone use will be counted from baseline to Week 24. 
In addition, patients who permanently withdraw from the study treatment prior to Week 24 will be 
considered as not achieved component 2, 3, or 4 for the primary endpoint. 
Blinding of CRP and ESR assessment results 
Investigators, including Efficacy Assessors, and patients will remain blinded to CRP and ESR 
results (except screening and baseline). Safety Assessors will also be blinded on post baseline 
CRP but will have access to ESR results. 
ESR kits will be provided by the central laboratory while the test will be performed locally at site, 
results (the distance in millimeters (mm) that red blood cells has descended in 1 hour) will be 
blinded to Investigators including Efficacy Assessors and staff directly involved in efficacy 
assessment of study patients. 
2.1.3.2 Secondary efficacy endpoint(s)  
The following efficacy variables will be assessed: 
• Components of sustained remission composite measure at Week 52 and Week 24 
• Total cumulative corticosteroid (including prednisone) dose over during the treatment 
period 
• Time to first GCA flare during the treatment period 


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• GTI Cumulative worsening score (CWS) and Aggregate improvement score (AIS) at 
Week 52 and Week 24.  
Below are descriptions of these variables. Details related to imputation of GTI scores are 
described in Section 2.5.2. 
Components of sustained remission composite measure at Week 52 
1. Proportion of patients who achieved disease remission by Week 12. 
2. Proportion of patients who have no disease flare from Week 12 through Week 52. 
3. Proportion of patients who have normalization of CRP (to <10 mg/L, with an absence of 
successive elevations to ≥10 mg/L) from Week 12 through Week 52. 
4.  Proportion of patients who successfully adhere to the prednisone taper from Week 12 
through Week 52. 
Components of sustained remission composite measure at Week 24 
1. Proportion of patients who achieved disease remission by Week 12. 
2. Proportion of patients who have no disease flare from Week 12 through Week 24. 
3. Proportion of patients who have normalization of CRP (to <10 mg/L, with an absence of 
successive elevations to ≥10 mg/L) from Week 12 through Week 24. 
4. Proportion of patients who successfully adhere to the prednisone taper from Week 12 
through Week 24. 
Total cumulative corticosteroid (including prednisone) dose during the treatment period 
The total cumulative corticosteroid includes prednisone taper regimen per protocol, use of 
prednisone (an excess of ≤100 mg of prednisone during the study treatment period such as those 
employed to manage AE not related to GCA is permissible for meeting the definition of 
maintenance of sustained remission) and rescue corticosteroids dose prescribed for rescue therapy 
over the treatment period for GCA disease only. 
Time to first GCA flare during the treatment period 
The duration (in days) from randomization to first GCA flare after clinical remission and up to 
52 weeks. Patients who never achieve remission will be censored at randomization day; and those 
who achieved clinical remission and never flared will be censored at the end of treatment 
assessment date up to Week 52. 
The definition of GCA flare is provide in Section 2.1.3.1 primary efficacy endpoint. 
Clinical remission is defined as resolution of signs and symptoms and normalization of CRP 
(<10 mg/L). Intermittent missing CRP at visit will be imputed using last value carried forward 
(LOCF) approach. If missing signs and symptoms, then clinical remission is not achieved. 


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Glucocorticoid toxicity index (GTI) scores and components 
The GTI is intended to capture glucocorticoid (GC)-related morbidity and GC-sparing ability of 
other therapies (2).  
The GTI is composed of two components, the Composite GTI and the Specific List (Table 4). The 
Composite GTI consists of nine domains (body mass index (BMI), glucose tolerance, blood 
pressure,  Hyperlipidemia,  Bone Health (BMD), steroid myopathy,  Skin steroid-related Toxicity,  
Neuropsychiatric - steroid related symptoms and infection) on common steroid-related adverse 
events anticipated to occur in ≥5% of patients treated in a clinical trial involving glucocorticoids. 
The Specific List consists of 23 items (11 domains) that are mainly less common but serious 
adverse effects, serving as a complementary tool to the Composite GTI to ensure that all 
important elements of glucocorticoid toxicity were captured. 
The domains of the Composite GTI and the specific list of the GTI will be assessed at baseline, 
Week 12, Week 24, Week 40 and Week 52, except for bone density (BMD) which will be 
assessed at Baseline and Week 52 only. 
Please note, due to early termination of the study, most patients will not have BMD assessed at 
Week 52. In addition, for patients who withdraw from the study prior to Week 24, the BMD will 
not be measured at the EOT visit as no substantial changes are expected within 6 months of 
treatment. As a result, missing BMD score will be imputed as ‘no change’. The BMD measured at 
the end of treatment (EOT) visit will be included in the definition of cumulative GTI scores 
(i.e., CWS and AIS as defined below) at Week 52 regardless when the EOT visit is occurred. The 
BMD domain score will be set to ‘no change’ in the calculation of the cumulative GTI scores at 
Week 24. 
Scoring of the Glucocorticoid Toxicity Index (GTI) 
Domain-specific score for each patient at a visit is defined as the weight assigned based on the 
change in severity level as described for each domain in Table 4. 
Composite GTI score for each patient at a visit is the sum of 9 domain-specific scores at each 
visit. 
Cumulative GTI score is the sum of composite GTI score across visits. Two cumulative GTI 
scores, CWS and AIS, will be defined. 
• Cumulative worsening score (CWS) 
CWS is designed to assess cumulative GC toxicity, regardless of whether the toxicity has 
lasting effects or is transient. New toxicities that occur are added, but toxicities that appear to 
resolve on follow-up are not removed. Thus, the CWS serves as a lasting record of GC 
toxicity observed and can only increase or remain the same over time. 
CWS will be lower in the treatment arm compared to the placebo arm at the end of trial, if the 
treatment is effective at decreasing GC toxicity over time. 


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• Aggregate improvement score (AIS) 
Patients are anticipated to have some GC toxicity at baseline, the AIS would be important in 
establishing that the new therapy is effective at diminishing any baseline GC toxicity over 
time. With the AIS, toxicities can be removed if improvement occurs, and added if worsening 
occurs. 
AIS decrease over time means that the treatment is effective in decreasing GC toxicity level, 
compared to placebo which may show fluctuation of CIS over time. Negative score reflects 
that toxicities present at baseline (or occurring during the trial) resolved over the treatment 
period. 
The steps to calculate the CWS and AIS at Week 24 and Week 52 are described below. 
Step 1: Calculate domain-specific worsening score (for computing CWS in Step 2) and 
improvement score (for computing AIS in Step 2) at each visit. 
For Domains without sub-items (Body Weight, Glucose Metabolism, Blood Pressure, Lipid 
Metabolism, Bone Health and Steroid Myopathy), 
a) For worsening score, only consider positive domain-specific score at each visit. For 
domain with a negative domain-specific score, the worsening score will be 0. 
b) For improvement score, all domain-specific scores (could be positive or negative) at 
each visit will be considered. 
The Skin and Neuropsychiatric domains both have sub-items. For the Skin domain, these are 
Acneiform Rash, Easy Bruising, Hirsutism, Atrophy/Striae, and Erosions/tears/ulcerations. For 
the Neuropsychiatric domain, these are Insomnia, Depression, Mania, and Cognitive Impairment. 
a) For worsening score, only the item with the highest weight is scored for any GTI 
interval (typically three months) with the CWS.  As an example, if neither insomnia 
nor depression were present at the baseline visit but there is now mild Insomnia and 
moderate depression present at follow-up, then only the moderate depression is scored 
(+63 points). 
b) For improvement score, improvement as well as worsening can be recorded. Because it 
is conceivable that one item might improve while another worsens, the item of greatest 
improvement (highest absolute weight) and the item of greatest worsening (highest 
weight) are recorded for given GTI interval. 
For Infection Domain, the worsening score and improvement score handle the scoring of 
infections differently, because the CWS and AIS reflect reciprocal measures of GC toxicity. 
a) For worsening score, the most severe infection in every GTI interval is scored. 
b) For improvement score, only the most severe infection occurring over the course of the 
entire trial is scored. 
Step 2: Calculate composite worsening score and improvement score at each visit by summing 
the 9 domain-specific score. 
a) For composite worsening score, sum the 9 domain-specific worsening scores. 


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b)
For composite improvement score, sum the 9 domain-specific improvement scores.
Step 3: Calculate cumulative GTI scores by summing composite scores across visits. 
a)
For CWS at Week 24, summing composite GTI worsening score at Week 12 and
Week 24.
b)
For CWS at Week 52, summing composite GTI worsening score at Week 12, Week
24, Week 40, and Week 52.
c)
For AIS at Week 24, summing composite GTI improvement score at Week 12 and
Week 24.
d)
For AIS at Week 52, summing composite GTI improvement score at Week 12, Week
24, Week 40, and Week 52.
Table 4 – The Glucocorticoid Toxicity Index 
Composite GTI 
Item 
weight 
Specific List1 
1.BMI
Decrease by >/= 5 BMI units
-36
Major increase in BMI 
Decrease by >2 but <5 BMI units
-21
No significant change (+/- 2 BMI units)
0
Increase of >2 to <5 BMI units
21
Increase of 5 or more BMI units
36
2.Glucose tolerance
Improvement in HbA1c AND decrease in medication
-44
Diabetic retinopathy 
Improvement in HbA1c OR decrease in medication
-32
Diabetic nephropathy 
No significant change
0
Diabetic neuropathy 
Increase in HbA1c OR increase in medication
32
Increase in HbA1c AND increase in medication
44
3.Blood pressure
Improvement in BP AND decrease in medication
-44
Hypertensive emergency 
Improvement in BP OR decrease in medication
-19
Posterior reversible encephalopathy 
syndrome 
No significant change
0
Increase in BP OR increase in medication
19
Increase in BP AND increase in medication
44
4.Hyperlipidemia
Decrease in LDL AND decrease in medication
-30
Decrease in LDL OR decrease in medication
-10
No significant change
0
Increase in LDL OR increase in medication
10
Increase in LDL AND increase in medication
30
5.Bone Health (BMD)
Increase in BMD (gain of more than 3%)
-29
Major decrease in bone density 
No significant change in BMD (+/- 3%)
0
Insufficiency fracture 


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Composite GTI 
Item 
weight 
Specific List1 
  Decrease in BMD (loss of more than 3%) 
29 
  
6.Steroid myopathy 
 
  
  Moderate weakness to none 
-63 
Severe steroid myopathy 
  Moderate to Mild weakness 
-54 
  
  Mild weakness to none 
-9 
  
  No significant change 
0 
  
  None to Mild weakness (without functional limitation) 
9 
  
  Mild to Moderate weakness 
54 
  
  None to Moderate weakness (with functional limitation) 
63 
  
7.Skin steroid-related Toxicity 
 
  
  Decrease in Skin Toxicity - Moderate to None 
-26 
Severe skin toxicity 
  Decrease in Skin Toxicity - Moderate to Mild 
-18 
  
  Decrease in Skin Toxicity - Mild to None 
-8 
  
  No significant change 
0 
  
  Increase in Skin Toxicity - None to Mild 
8 
  
  Increase in Skin Toxicity - Mild to Moderate 
18 
  
  Increase in Skin Toxicity - None to Moderate 
26 
  
8.Neuropsychiatric - steroid related symptoms 
 
  
  Decrease in NP Toxicity - Moderate to None 
-74 
Psychosis 
  Decrease in NP Toxicity - Moderate to Mild 
-63 
GC-induced violence 
  Decrease in NP Toxicity - Mild to None 
-11 
Other severe neuropsychiatric 
symptoms 
  No significant change 
0 
  Increase in NP Toxicity - None to Mild 
11 
  
  Increase in NP Toxicity - Mild to Moderate 
63 
  
  Increase in NP Toxicity - None to Moderate 
74 
  
9.Infection 
 
  
  No infection 
0 
Grade IV infection 
  Oral or vaginal candidiasis or non-complicated zoster 
(<Grade3) 
19 
Grade V infection 
  Grade 3, 4, or 5 infection 
93 
  
1 Maximum weight is given for specific list events in Blood pressure, Steroid myopathy, Skin toxicity, Neuropsychiatric and Infection domains at 
each visit. For the rest of domains, specific list events will not affect the corresponding domain specific score. 
2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events (AEs), serious AEs (SAEs) and 
adverse events of special interest (AESIs) including but not limited to neutropenia, 
thrombocytopenia, elevations in hepatic enzymes leading to permanent discontinuation and 


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tuberculosis, and other opportunistic infections. Other safety information, such as clinical 
laboratory data and vital signs will also be assessed. 
Observation period  
The observation period will be divided into 4 epochs: 
• 
The screening epoch is defined as the time from the signed informed consent date up to 
the time prior to first dose of SC IMP. 
• 
The treatment epoch is defined as the time from the first dose of the IMP to the last dose 
of the SC IMP in the DB period +13 days. 
• 
The residual treatment epoch is defined as the time from the end of TREATMENT 
epoch to the last dose of the SC IMP +60 days. 
The post-treatment epoch is defined as the time after the last dose of SC IMP +60 days.  The 
rationale of having “last dose of SC IMP +60 days” as the end of follow-up epoch is to capture the 
events observed within an approximately 5 half-lives of the last sarilumab SC IMP.  
The treatment-emergent adverse event (TEAE) period includes both treatment and residual 
treatment epochs. 
2.1.4.1 Adverse events variables  
Adverse event observation period  
• 
Pre-treatment AEs are AEs that developed or worsened or became serious from the signed 
informed consent date up to first administration of SC IMP 
• 
TEAEs are AEs that developed or worsened or became serious during the TEAE period 
• 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period 
All AEs (including SAEs and AESIs) will be coded to a “LLT”, “PT”, “HLT”, “HLGT”, and 
associated primary “SOC” using the version of MedDRA currently in effect at Sanofi at the time 
of database lock. 
The occurrence of AEs (including SAEs and AESIs) will be recorded from the time of signed 
informed consent until the end of the study. 
Any SAE brought to the attention of the Investigator at any time after the end of the study 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. 
Adverse event of special interest (AESI) 
Adverse events of special interest will be flagged in the database. The AESIs and its search 
criteria are listed in Table 5 below: 


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Table 5 - Protocol defined AESIs and search criteria 
AESI flag 
Search criteria 
Clinically significant infections including: 
• 
Opportunistic infections 
• 
Tuberculosis 
• 
Infections requiring prolonged medication 
• 
Infections requiring parenteral treatment 
Reported by the investigators on the AE CRF page with AESI 
box ticked. 
Lab abnormalities including: 
• 
ALT increase leading to permanent discontinuation 
• 
ANC decrease leading to permanent discontinuation 
• 
Thrombocytopenia leading to permanent 
discontinuation 
ALT >= 3xULN 
Pregnancy 
CRF checkbox: Pregnancy 
Overdose 
CRF checkbox: Symptomatic Overdose 
 
2.1.4.2 Deaths  
The deaths per the observation period will be summarized.  
• 
Death on-treatment: deaths occurring during the treatment period (i.e., treatment Epoch)  
• 
Death during follow-up: deaths occurring during the residual treatment period 
• 
Death post-treatment: deaths occurring during the post-treatment period 
2.1.4.3 Laboratory safety variables  
Clinical laboratory data will include hematology, clinical chemistry, and urinalysis. Clinical 
laboratory values will be converted to standard international units; international units will be used 
in all listings and tables. In addition, the lipids parameters will also be summarized in US units. 
Hematology and chemistry data will be collected at screening, baseline, Weeks 4,12, 24, 40, and 
52, and/or early termination unless otherwise specified. The laboratory parameters will be 
classified as follows: 
• Hematology 
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, platelet 
count, red blood cell (RBC) count, and RBC morphology (if RBC count is abnormal). 
- 
White blood cells: white blood cell (WBC) count and WBC differential (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils). 
• Clinical chemistry  
- 
Metabolism: fasting lipids (total cholesterol, high density lipoprotein cholesterol 
(HDL-C), low density lipoprotein cholesterol (LDL-C), ratio of HDL-C versus LDL-C 
(HDL-C:LDL-C), triglycerides), total proteins, CRP, fasting glucose, and  hemoglobin 
A1c (HbA1c). 


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- 
Electrolytes: sodium, potassium, chloride, calcium, phosphate, and bicarbonate. 
- 
Renal function: creatinine, creatinine clearance, uric acid, and blood urea nitrogen 
(BUN). 
- 
Liver function: alanine aminotransferase (ALT)/SGPT, aspartate aminotransferase 
(AST)/SGOT, alkaline phosphatase (ALP), albumin, total bilirubin, conjugated and 
unconjugated bilirubin, and lactate dehydrogenase (LDH). 
- 
Pregnancy test: Serum β-hCG for all women of childbearing potential (screening 
only).  
- 
TB screen:  QuantiFERON®-TB Gold evaluation. 
- 
Hepatitis screen: Hepatitis B and C serology, human immunodeficiency virus 
serology. 
Urine samples will be collected as follows: 
• Urinalysis - dipstick: pH, specific gravity, blood, glucose, protein, nitrates, leukocyte 
esterase, and bilirubin.  If any parameter on the dipstick is abnormal, a urine sample was to 
be sent to the central laboratory for testing.  
A urine pregnancy test was done for all women of childbearing potential at baseline, all visits up 
to Week 52 or early termination.  
2.1.4.4 Vital signs variables  
Vital signs variables include heart rate, systolic blood pressure, and diastolic blood pressure, 
height, weight, and body temperature. 
2.1.4.5 Antinuclear antibodies  
Antinuclear antibodies (ANA) will be measured at baseline and EOT visits. 
2.1.5 Immunogenicity endpoints  
The immunogenicity blood samples will be collected before injection during the same visit 
according to the Study Flow Chart (Appendix A). 
Samples analyzed in the antidrug antibody (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. 


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ADA positive patient is defined as patient with at least one treatment-emergent or 
treatment-boosted ADA positive sample during the TEAE period, where 
• 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. 
• 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 patient without a treatment-emergent or treatment-boosted 
ADA positive sample during the TEAE period.  
A treatment-emergent positive response is further classified as persistent or transient. 
Persistent ADA response: treatment-emergent ADA detected at two or more consecutive 
sampling time points during the TEAE period, where the first and last ADA positive samples are 
separated by a period of at least 16 weeks. Also persistent in case last sample analyzed is positive. 
Transient ADA response: A treatment-emergent response that is not determined to be persistent. 
2.1.6 Pharmacokinetic variables  
The blood samples for the determination of functional sarilumab concentrations in serum will be 
collected before injection during the same visit according to the Study Flow Chart (refer to 
Section 1.2 in the study protocol) and at or near the onset and completion of the occurrence of a 
SAE.  
2.1.7 Pharmacodynamic/genomics endpoints  
Blood samples (DNA and genetic RNA) will be collected from each consenting patient to 
participate in the pharmacogenomics substudy. Details of any analysis will be described in a 
separate plan.  
2.1.8 Other efficacy endpoints  
Quality-of-life endpoints 
Other efficacy endpoints in the clinical outcome assessments will be summarized. Patients are 
asked to complete the following patient-reported outcome (PRO) questionnaires described below 
at Visit 2 (baseline visit), Visit 6 (Week 12), Visit 9 (Week 24), and Visit 12 (Week 52). 


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Patient-Reported Outcomes 
Short Form 36 Version 2 (SF-36 V2) 
The SF-36 V2 is a multi-purpose, short-form health survey with 36 questions. It yields scores for 
eight domains (Physical Functioning, Role-Physical, Bodily pain, General health, Vitality, Social 
Functioning, Role-Emotional, and Mental Health, each scale is scored from 0 to 100 where higher 
scores indicate better health and well-being), as well as two summary measures of physical and 
mental health: the Physical Component Summary (PCS) and Mental Component Summary 
(MCS).  
The scoring process is summarized below: 
• Enter item response data. 
• Recode item response values. 
• Determine health domain scale raw scores. 
• Transform health domain scale raw scores to 0 to 100 scores. 
• Transform health domain scale 0 to 100 to normal-based scores. 
• Score physical and mental component summary measures. 
The following table shows the construction and summary measures of the SF-36 scales: 
Table 6 - SF-36 V2 measurement model 
Summary measures 
Scales 
Items 
Physical Component  
Physical Functioning (PF) 
3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j 
Summary (PCS)* 
Role-Physical (RP) 
4a, 4b, 4c, 4d 
 
Bodily Pain (BP) 
7, 8 
 
General Health (GH) 
1, 11a, 11b, 11c, 11d 
Mental Component 
Vitality (VT) 
9a, 9e, 9g, 9i 
Summary (MCS)* 
Social Functioning (SF) 
6, 10 
 
Role-Emotional (RE) 
5a, 5b, 5c 
 
Mental Health (MH) 
9b, 9c, 9d, 9f, 9h 
*MCS and PCS derived from the eight scales 
The score of each of the 36 items is collected in CRF. Appendix G provides the SAS code to 
calculate the eight scales, the two summary measure scores and the standardized summary scores. 
The PCS and MCS summary measure scores will be computed if at least 50% of the component 
scales are available. The scale scores will be computed if at least 50% of items are available 
within the corresponding scale. The missing items will be imputed by the mean of available items. 
Change from baseline in SF-36 scores (physical component summary score and mental 
component summary score as well as the eight domains) at each visit will be analyzed. 


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Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue) 
The FACIT-Fatigue will be used to assess fatigue. The FACIT-Fatigue is a 13-item questionnaire 
rated 0 to 4 originally developed to measure fatigue in patients with cancer and is widely used in 
rheumatoid arthritis patients to demonstrate good consistency and sensitivity to change. The 
patient will be asked to answer 13 questions rated 0 to 4 (0 = not at all, 1 = a little bit, 
2 = somewhat, 3 = quite a bit, 4 = very much). The fatigue scale has 13 items, with 52 as the 
highest possible score. A higher score in the fatigue scale corresponds to a lower level of fatigue 
and indicates better Quality of Life. 
To calculate the FACIT-fatigue score, the response scores on negatively phrased questions are 
reversed and then the 13 item responses are added. Eleven items with responses have their scores 
reversed (item score = 4 – response, if the response is not missing), and two items (items 7 and 8) 
have their responses unchanged (Appendix E). All items are added so that higher scores 
correspond to less fatigue. In cases where individual questions are skipped, scores are prorated 
using the average of other answers in the scale. 
FACIT-Fatigue = 13 * [sum (reversed items) + sum (items 7 and 8)] / number of answered items 
EuroQol 5 Dimension 3 Level (EQ-5D-3L) 
The EQ-5D-3L is a standardized, generic measure of health outcome (3). EQ-5D is designed for 
selfcompletion by patients. Instructions to respondents are included in the questionnaire. The 
EQ5D is specifically included to address concerns regarding the health economic impact of RA, 
which have been considered in cost effectiveness arguments. The EQ-5D-3L comprises five 
questions on mobility, self-care, pain, usual activities, and psychological status with three possible 
answers for each item (1 = no problem, 2 = moderate problems, 3 = severe problems) and a 
vertical visual analog scale that allows the patients to indicate their health state today that can 
range from 0 (worst imaginable) to 100 (best imaginable). 
The 5 dimensional 3-level systems are converted into a single index utility score. Values for the 
243 theoretically possible health states defined by the EuroQol classification are calculated using 
a regression model and weighted according to the social preferences of the GB population. The 
minimum value for the single index utility score is -0.594, which corresponds to a level 3 (severe 
problems) for mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 
maximum value for this index is 1.0, which corresponds to a full health (level 1 [no problem] for 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression). 
The VAS records the respondent’s self-rated health on a vertical visual analogue scale. The VAS 
“thermometer” has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst 
imaginable health state) at the bottom. This information can be used as a quantitative measure of 
health outcomes as judged by the individual respondents. EQ 5D self-reported VAS data 
generates information on the self-perceived overall health-related quality of life. 
Appendix F provides the SAS code to derive the index utility score using GB based population. 


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Health Assessment Questionnaire Disease Index (HAQ-DI) 
• Patient’s Assessment of Physical function 
The HAQ-DI is a standardized questionnaire developed to assess physical functional status in 
adults with arthritis but is now commonly used among many rheumatologic conditions. The 
HAQ-DI, with the past week as the time frame, focuses on whether the respondent “is able to…” 
do the activity and covers eight categories in 20 items: dressing and grooming, arising, eating, 
walking, hygiene, reach, grip and activities, for which there are at least two questions by category. 
The four responses for the HAQ-DI questions are graded as follows: without any difficulty=0; 
with some difficulty=1; with much difficulty=2; and unable to do=3. To calculate the Standard 
HAQ-DI Score (With Aids/Devices), there are 3 steps: 
1. Sum the eight category scores by using the highest sub-category score from each category. 
• For example, in the category EATING there are three sub-category items. A patient 
responds with a 1, 2, and 0, respectively; the category score is 2. 
2. Adjust for use of aids/devices and/or help from another person when indicated. 
• When there are NO aids or devices or help indicated for a category, the category’s score is 
not modified. 
• When aids or devices or help ARE indicated by the patient: 
- 
Adjust the score for a category by increasing a 0 or a 1 to a 2. 
- 
If a patient's highest score for that sub-category is a 2 it remains a 2, and if a 3, it 
remains a 3. 
- 
The data entered at field “Other specify” will not be used for score adjustment. 
3. Divide the summed category scores by the number of categories answered (must be a 
minimum of 6) to obtain a HAQ-DI score of 0 to 3 (3=worst functioning). 
A HAQ-DI score cannot be calculated validly when there are scores for less than six of the 
eight categories. If there are less than 6 categories completed, a HAQ-DI cannot be computed, 
whether the missing categories are due to missing values or they do not apply to the respondent. 
HAQ-DI disability index scoring ranges between 0 and 3 with higher score indicating greater 
disability. A high HAQ-DI score has been found to be a strong predictor of morbidity and 
mortality in RA. A 0.22 unit difference is considered clinically meaningful. 
In addition to the above, the HAQ-DI has two additional questions to measure pain and global 
assessment described below. 
• Patient’s Assessment of Pain 
Patients will be requested to indicate their pain intensity due to PMR using a 100 mm horizontal 
VAS to the question “How much pain have you had IN THE PAST WEEK?”, where 0 is 
considered “No pain” and 100 “the worst pain you can imagine”. 


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To obtain the patient score, using a metric ruler, measure the distance in centimeters from the left 
anchor (at base zero) to their mark and multiply by 0.2. This converts the number of centimeters 
into the appropriate score and yields a score from 0 to 3. For example, the mark is at 8 centimeters 
– 8 x 0.2 = a pain score of 1.6. 
In case a 0-100 mm scale is used, pain severity coding translations follow below:  
PAIN SEVERITY CODING TRANSLATIONS  
 
Measurement (m) = Score 
Measurement (m) = Score [continue] 
0 = 0  
7.8 - 8.2 = 1.6  
0.1 - 0 .7 = 0.1  
8.3 - 8.7 = 1.7  
0.8 - 1.2 = 0.2  
8.8 - 9.2 = 1.8  
1.3 - 1.7 = 0.3  
9.3 - 9.7 = 1.9  
1.8 - 2.2 = 0.4  
9.8 - 10.2 = 2.0  
2.3 - 2.7 = 0.5  
10.3 - 10.7 = 2.1  
2.8 - 3.2 = 0.6  
10.8 - 11.2 = 2.2  
3.3 - 3.7 = 0.7  
11.3 - 11.7 = 2.3  
3.8 - 4.2 = 0 .8  
11.8 - 12.2 = 2.4  
4.3 - 4.7 = 0 .9  
12.3 - 12.7 = 2.5  
4.8 - 5.2 = 1.0  
12.8 - 13.2 = 2.6  
5.3 - 5.7 = 1.1  
13.3 - 13.7 = 2.7  
5.8 - 6.2 = 1.2  
13.8 - 14.2 = 2.8  
6.3 - 6.7 = 1.3  
14.3 - 14.7 = 2.9  
6.8 - 7.2 = 1.4  
14.8 - 15.0 = 3.0  
 
• Patient’s Global Assessments of Disease Activity 
Patient’s global assessments of their current disease activity will be rated on an anchored 100 mm 
horizontal VAS, with the given instruction to “Please rate how well you are doing on a scale of 0 
to 100 (0 represents “very well” and 100 represents “very poor” health)”. 
It is scored similarly to the VAS Pain Scale. 
Clinician-Reported Outcomes 
Physician’s Global Assessments of Disease Activity - Visual Analog Scale [MD-VAS] 
Physician’s global assessments of the patient’s current disease activity will be assessed on an 
anchored 100 mm horizontal VAS where 0 is considered the best disease activity (no disease 
activity) and 100 the worst (most disease activity). 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient status and the patient populations. 
Screened patients are defined as all patients who signed the informed consent. 


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Randomized patients consist of all patients who signed informed consent with a treatment kit 
number allocated and recorded in the Interactive Voice Response System/Interactive Web 
Response System database, regardless of whether the treatment kit was used or not. 
For patient status in the DB treatment period, the total number of patients for each one of the 
following categories will be presented in the clinical study report (CSR) using a summary table: 
• Screened patients 
• Screen failure patients and reasons for screen failure 
• Non-randomized but treated patients 
• Randomized patients 
• Randomized but not treated patients 
• Randomized and treated patients 
• Patients who completed SC IMP treatment up to Week 24 
• Patients who discontinued SC IMP treatment before Week 24 and the reasons for 
permanent treatment discontinuation 
• Patients who completed 52-week SC IMP study treatment period 
• Patients who discontinued from 52-week study treatment period and the reasons for 
permanent SC IMP treatment discontinuation 
• Patients who completed the study 
• Patients who discontinued the study and the reasons for study discontinuation 
• Patients who took CS rescue therapy 
• Subject status at end of study visit 
For all categories of patients (except for the screened and non-randomized categories) percentages 
will be calculated using the number of randomized patients as the denominator. Reasons for 
discontinuation with regards to SC IMP treatment will be presented in tables giving numbers and 
percentages by treatment group. 
A patient is considered as lost to follow-up at the end of the study if he/she is not assessed at the 
end of study visit. 
All critical or major deviations potentially impacting efficacy analyses, randomization and drug 
dispensing irregularities and other major/critical deviations will be summarized in tables giving 
numbers and percentages of deviations by treatment groups. 
Additionally, the analysis populations for safety, efficacy, PK, and immunogenicity will be 
summarized in a table by patient counts based on the randomized populations (See definitions in 
Section 2.3). 
• Efficacy population 


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• Safety population 
• PK population 
• ADA population 
2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error. 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis. 
All randomization and drug-dispensing irregularities will be documented in the CSR.  If the 
number of irregularities is large enough to make a tabular summary useful, the irregularities will 
be categorized and summarized among randomized patients (number and percentages).  
Nonrandomized, treated patients will be described separately. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to: 
Table 7 - Randomization and Drug Allocation Irregularities 
Randomization and Drug Allocation Irregularities 
Kit dispensation without IVRS transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Subject randomized twice 
Forced randomization 
Subject switched to another site 
IVRS=Interactive Voice Response System 
2.3 
ANALYSIS POPULATIONS  
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 


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Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 Efficacy populations  
Week 52 Analysis set: The primary endpoint for the study is sustained remission at Week 52. 
Based on patients’ enrollment dates and the study discontinuation plan, not all the patients had an 
opportunity to complete the 52-week treatment period. For the cohort of patients who did not have 
an opportunity to complete the 52-week treatment period, it is not meaningful to define the 
endpoint of sustained remission at Week 52. Therefore, the analysis of primary endpoint will be 
limited to the Week 52 Analysis set, which includes the cohort of patients who had an opportunity 
to complete the 52-week treatment period. This cohort of patients is defined as the patients with a 
randomization date prior to Oct 16, 2019 (i.e., Oct 13, 2019+3 days IMP administration time 
window, where Oct 13, 2019 is 1-year before the targeted last patient last EOT visit date [i.e., Oct 
13, 2020] according to the study discontinuation plan), which contains a total of 36 patients (out 
of 83 randomized patients). 
For the same reason, the analysis of secondary endpoint of cumulative GTI scores at Week 52 will 
also be limited to the cohort of patients who had an opportunity to complete the 52-week 
treatment period. 
For the rest of the efficacy endpoints, the primary analysis population will be the ITT population 
as defined in Section 2.3.1.1. 
2.3.1.1 Intent–to-treat population  
The intent-to-treat (ITT) population is the randomized population analyzed according to the 
treatment group allocated by randomization.  
2.3.2 Safety population  
The safety population is defined as randomized population who actually received at least 1 dose 
or part of a dose of the SC IMP, analyzed according to the treatment actually received 
In addition:  
• Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately 
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 


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• For patients receiving more than one SC IMP during the trial, the treatment group 
allocation for as-treated analysis will be the treatment group for which the patient received 
the majority of doses.  In such cases, individual patient listings will be provided for each 
treatment group with treatment start and end date for each treatment exposed. 
2.3.3 
Pharmacokinetics and ADA populations  
The PK population will consist of all patients in the safety population with at least one post-dose, 
non-missing serum sarilumab concentration value. 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. 
2.4 
STATISTICAL METHODS  
2.4.1 Demographics and baseline characteristics  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group. 
Parameters will be summarized based on the randomized populations. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall using 
descriptive statistics. 
Medical and surgical history will be summarized by SOC and PT sorted by internationally agreed 
order of SOC and by the decreasing frequency of PT within SOC in total group (including all the 
randomized patients). P-values on demographic and baseline characteristic data will not be 
calculated. 
No specific description of the safety parameters will be provided at baseline. If relevant, the 
baseline values will be described along with each safety analysis. 
2.4.2 Prior or concomitant medications  
The prior and concomitant medications will be summarized based on the randomized populations 
as follows:  
• Prior medications discontinued before the first dose of IMP in the DB period 
• Prior medications that continued at the time of the first dose of IMP in the DB period 
• Concomitant medications 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the 


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generic names.  All ATC codes corresponding to a medication will be summarized. Patients will 
be counted once in each ATC category (anatomic or therapeutic) linked to the medication; 
therefore, patients may be counted several times for the same medication. 
In addition, the following summaries will also be provided: 
• Vaccines (prior and concomitant vaccines will be summarized separately) 
• Other prior DMARDs/immunosuppressive agents taken since diagnosis of GCA and 
discontinued before the first dose of IMP 
The table for prior medications will be sorted by decreasing frequency of anatomic category 
followed by all other generic names based on the overall incidence across treatment groups.  In 
case of equal frequency regarding anatomic categories (respectively, generic names), alphabetical 
order will be used. 
The tables for concomitant medications will be sorted by decreasing frequency of anatomic 
category followed by all other generic names based on the incidence of the total group (including 
all the randomized patients). In case of equal frequency regarding anatomic categories 
(respectively, generic names), alphabetical order will be used. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of SC IMP exposure and compliance will be assessed and summarized by actual 
treatment group within the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure  
The extent of SC IMP exposure will be assessed by the duration of SC IMP exposure and actual 
dose information. 
The duration of SC IMP exposure is defined as last DB dose date – first DB dose date +14 days, 
regardless of unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of 
missing or incomplete data). 
Duration of SC IMP exposure will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum).  In addition, duration of treatment 
exposure will also be summarized categorically by numbers and percentages for each of the 
following categories and cumulatively according to these categories: ≤4 weeks, >4 and ≤8 weeks, 
>8 and ≤12 weeks, >12 and ≤16 weeks, >16 and ≤20 weeks, >20 and ≤24 weeks, >24 and ≤32 
weeks, >32 and ≤40 weeks, >40 and ≤52 weeks and >52 weeks. 
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. 


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2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Percentage of compliance for SC IMP will be defined as the number of administrations the patient 
was compliant divided by the total number of administrations the patient was planned to take on 
or before the last dose date during the DB treatment period. 
Percentage of compliance for oral IMP compliance rate will be defined as the total number of 
days patient with partial or complete oral IMP intake divided by total number of days between the 
first oral IMP intake date and day prior to rescue therapy start date or EOT date which is earlier. 
Treatment compliance percentages will be summarized descriptively as quantitative variables 
(number, mean, SD, median, minimum, and maximum). The percentage of patients whose 
compliance is <80% will be summarized. 
Cases of overdose (administering two or more doses of sarilumab or its matching placebo in less 
than 11 calendar days) will constitute AESI and will be listed as such.  More generally, dosing 
irregularities will be listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints  
The analyses of efficacy endpoints will be descriptive in nature. For majority of the efficacy 
endpoints, only descriptive summary statistics will be provided by 4 treatment groups. For the 
primary and some selected important secondary endpoints, summary statistics and formal 
statistical tests on between group comparisons (with 95% CI and p-value) will be provided for the 
2 combined treatment groups (ie, 2 sarilumab groups combined versus 2 placebo groups 
combined); no formal comparisons will be performed between 4 individual treatment groups due 
to the small sample size. 
2.4.4.1 Analysis of primary and additional efficacy endpoint(s)  
The analysis of primary endpoint of sustained remission at Week 52 will be limited to the cohort 
of patients who had an opportunity to complete the 52-week treatment period (i.e., Week 52 
Analysis set). 
The proportion of patients achieving sustained remission at Week 52 will be summarized using 
counts and percentages by the 4 treatment groups. In addition, the treatment effects between the 
combined sarilumab (group A+B) group and the combined placebo group (Group C+D) will be 
compared using a Cochran-Mantel-Haenszel (CMH) test stratified by prednisone dose at baseline 
(<30 mg/day or ≥30 mg/day). 
The additional endpoint of sustained remission at Week 24 will be analyzed in the same fashion in 
the ITT population. 


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Sensitivity analysis excluding acute phase reactants: 
Sensitivity analysis will be performed for the primary endpoint by removing the acute phase 
reactants (CRP and ESR) from the definition to mitigate against the possibility of biasing the 
results due to the known PD effect of sarilumab on acute phase reactants. 
Patients achieving sustained remission at Week 52 (or Week 24) excluding acute phase 
reactants is defined by having met all of the following parameters: 
• Achievement of disease remission not later than Week 12. Disease remission is defined as 
resolution of signs and symptoms of GCA. 
AND 
• Absence of disease flare from Week 12 through Week 52 (or Week 24). Flare is defined 
as recurrence of signs and symptoms attributable to active GCA plus an increase in CS 
dose due to GCA. 
AND 
• Successful adherence to the prednisone taper from Week 12 through Week 52 (or 
Week 24). 
The sensitivity analysis will be performed in the same fashion as for the primary endpoint. 
Descriptive statistics (i.e., counts and percentages) will be provided for the three individual 
components. 
Subgroup analyses: 
No subgroup analyses will be performed due to the small sample size. 
2.4.4.2 Analyses of secondary efficacy endpoints  
Components of sustained remission composite measure at Week 52 and Week 24 
Descriptive statistics (i.e., counts and percentages) will be provided for the following binary 
variables by treatment groups: 
• Patients who achieve disease remission by Week 12 
• Patients who have absence of disease flare from Week 12 through Week 52 (or Week 24) 
• Patients who have normalization of CRP (decrease to <10 mg/L) with sustained 
normalization from Week 12 through Week 52 (or Week 24) 
• Patients who successfully adhere to the prednisone taper from Week 12 through Week 52 
(or Week 24) 
Total cumulative corticosteroid (including prednisone) dose 
Descriptive statistics including the number of subjects, mean, and median of the total cumulative 
prednisone (or equivalent) dose will be presented for each treatment group. The difference 
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p-value from the non-parametric Wilcoxon rank-sum test between the two combined treatment 
groups will also be provided. 
The total cumulative CS dose will be based on the total number of days with complete or partial 
intake, no imputation will be done on missed tablets. Patients who received increased prednisone 
or equivalent in rescue therapy will be included in their original treatment groups. 
In the scenario that a patient has already taken external CS for the disease before randomization 
on the day of randomization, the CS dose taken will be considered as the first dose of oral IMP. 
The first dose of prednisone per tapering regimen will be skipped, and the patient will take the 
second dose of prednisone on the next day. 
Time to first GCA flare during the treatment period 
Time (from randomization) to the first GCA flare after clinical remission up to Week 52 will be 
analyzed by Kaplan-Meier method providing the median, 25th and 75th percentiles (where 
possible) along with the 95% CI for the median. The comparison between the two combined 
groups will be performed using Cox proportional hazards model with prednisone dose at baseline 
(<30 mg/day or ≥30 mg/day) included as a covariate. Hazard ratio and the corresponding 95% CI 
and p-value will be provided. 
Composite GTI and Specific List 
GTI analyses 
Descriptive statistics including number, mean, SD, SE, median, minimum, and maximum will be 
provided by treatment group and by visit for domain-specific GTI score, composite GTI total 
score, composite worsening score and composite improvement score. For CWS and AIS at Week 
52 and Week 24, analysis of covariance (ANCOVA) model with treatment (combined sarilumab 
groups and combined placebo groups), baseline glucocorticoid toxicity score and baseline 
prednisone dose (<30 mg/day or ≥30 mg/day) as fixed effects, will be used to test the difference 
of the least-square means (LS means) between the two combined groups. Difference in LS means 
and the corresponding 95% CI along with the p-value will be provided. 
In addition, descriptive statistics (i.e., counts and percentages) will be provided for not worsening 
(CWS > 0), worsening (CWS ≤ 0), improved (AIS < 0) and not improved (AIS ≥0) at Week 52 
and Week 24. Odds ratios and exact 95% CIs of not worsening versus worsening and improved 
versus not improved will be provided for the comparisons between the combined sarilumab 
groups and combined placebo groups as well. 
Please note, the analysis of cumulative GTI scores (i.e., CWS and AIS) at Week 52 will be limited 
to the cohort of patients who had an opportunity to complete the 52-week treatment period (i.e., 
Week 52 Analysis set). 
Analyses of items in Specific list 
Number and percentage of patients with each item in specific list will be summarized by treatment 
groups and by visit. 


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2.4.4.3 Multiplicity issues  
No adjustments for multiplicity will be applied for this study due to the small sample size and the 
fact that many patients will not have the opportunity to complete the planned 52-week treatment 
period. All reported p-values will be nominal. 
2.4.5 Analyses of safety data  
The summary of safety results will be presented by treatment groups. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately 
• The baseline value is defined as the last available value prior to the first dose of study 
medication. 
• 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, vital signs, and ECG (PCSA in BTD-009536 version 3, see Appendix B) 
• 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 
• 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 treatment-emergent 
adverse event period by treatment group on the safety population. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group.  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. 
• Analyses of the safety variables will be essentially descriptive and no systematic testing is 
planned. 


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2.4.5.1 Analyses of adverse events  
Generalities 
The primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-treatment AEs will 
be described separately. 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, or TEAE, or post-treatment 
AE.  The algorithm for imputing date/time of onset will be conservative and will classify an AE as 
treatment-emergent unless there is definitive information to determine it is pre-treatment or post-
treatment. Details on classification of AEs with missing or partial onset dates are provided in 
Section 2.5.3. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in SOC 
internationally agreed order and then alphabetical order, and present the number (n) and 
percentage (%) of patients experiencing an AE by treatment group. 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 treatment 
group. 
The tables by primary SOC and PT will be sorted by internationally agreed order of SOC and 
decreasing frequency of PT within SOC.  Sorting will be based on results for the sarilumab 
200mg arm. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 
• Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE 
- 
Serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
• All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least one TEAE sorted by SOC internationally agreed order. The other level (HLGT, 
HLT, PT) will be presented in an alphabetic order. 
• All TEAEs by primary SOC and PT, showing number (%) of patients with at least one 
TEAE, sorted by SOC internationally agreed order and decreasing incidence of PTs within 
SOC. This sorting order will be applied to all other tables, unless otherwise specified.  
• All TEAEs by primary SOC, showing number (%) of patients with at least one TEAE, 
sorted by internationally agreed order of primary SOC. 


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• All TEAEs by relationship, presented by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least one TEAE, sorted by SOC internationally agreed 
order. The other level (HLGT, HLT, PT) will be presented in an alphabetic order. 
• All TEAEs by maximal severity, presented by primary SOC and PT, showing number (%) 
of patients with at least one TEAE by severity (ie, mild, moderate, or severe), sorted by 
sorting order defined above.  
Analysis of all treatment emergent serious adverse event(s) 
• All treatment-emergent SAEs by primary SOC, HLGT, HLT, and PT, showing number 
(%) of patients with at least one serious TEAE, sorted by SOC internationally agreed 
order. The other level (HLGT, HLT, PT) will be presented in an alphabetic order. 
• All treatment-emergent SAEs by primary SOC and PT, showing number (%) of patients 
with at least one TEAE 
• All treatment-emergent SAEs by primary SOC, showing number (%) of patients with at 
least one TEAE, sorted by internationally agreed order of primary SOC 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT, 
showing number (%) of patients sorted by SOC internationally agreed order. The other 
level (HLGT, HLT, PT) will be presented in an alphabetic order. 
• All TEAEs leading to treatment discontinuation, by primary SOC and PT, showing 
number (%) of patients with at least one TEAE 
• All TEAEs leading to treatment discontinuation, by primary SOC, showing number (%) of 
patients with at least one TEAE, sorted by internationally agreed order of primary SOC 
Analysis of all treatment-emergent adverse event(s) leading to dose reduction  
• For the management of pre-defined laboratory abnormalities, sarilumab dose can be 
reduced to 150 mg q2w.  All treatment-emergent adverse events leading to dose reduction, 
by primary SOC, HLGT, HLT and PT, showing the number (%) of patients, sorted by the 
sorting order defined above 
Analysis AESI  
• Summaries of AESI defined by the search criteria: 
- 
All treatment-emergent AESIs, by AESI category and PT, showing number (%) of 
patients, sorted by decreasing incidence of PT within each AESI category. 
- 
Within each treatment-emergent AESI category, at a minimum the data display will 
include: 
- 
Overview summary 
- 
Treatment duration summary 
- 
Incidence by patient and by event 


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-
Serious TEAEs
-
TEAEs leading to treatment discontinuation
-
TEAEs leading to death
-
Possibly related TEAEs
2.4.5.2 Deaths  
The incidence of death will be generated on the safety populations. 
•
Number (%) of patients who died by study period (on-treatment, treatment residual, and
post-treatment).
•
Death in non-randomized patients or randomized but not treated patients.
•
TEAE leading to death (death as an outcome on the AE CRF page as reported by the
Investigator) by primary SOC and PT, showing number (%) of patients sorted by
internationally agreed order of SOC and and decreasing frequency of PT within a SOC in
the Sarilumab 200mg q2w treatment group.
Listings will be provided for all deaths with flags indicating during treatment or post-treatment 
status. 
2.4.5.3 Analyses of laboratory variables 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
laboratory variables (central laboratory values and changes from baseline) will be calculated for 
each visit or study assessment (baseline, each post baseline time point, endpoint) by treatment 
group.  This section will be organized by biological function as specified in Section 2.1.4.3. 
In addition, for all laboratory parameters, the mean value and mean change from baseline at each 
scheduled visit during the treatment period will be plotted by treatment group. 
The incidence of PCSAs (list provided in Appendix B) at any time during TEAE period will be 
summarized by biological function and treatment group whatever the baseline level and/or 
according to the following baseline status categories:  
•
Normal/missing
•
Abnormal according to PCSA criterion or criteria
For lipids, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) 
classification will be used for the baseline. 
The incidence of abnormal laboratory values at any time during the TEAE period will be 
summarized in shift tables by biological function and treatment group whatever the baseline level 
and/or according to the following baseline status categories: 
•
Normal/Missing


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• Abnormal high according to the normal range 
• Abnormal low according to the normal range 
Time to onset of the initial LDL-C elevation (≥4.1 mmol/L, ≥4.9 mmol/L), time to onset of the 
initial total cholesterol elevation (≥6.2 mmol/L), time to onset of the initial Grade 3 or Grade 4 
neutropenia (neutrophil count <1.0 Giga/L), time to onset of the initial platelet count <100 
Giga/L, time to onset of the initial lymphocyte count <1.0 Giga/L, time to onset of the initial ALT 
elevation (>3 x ULN, >5 x ULN), time to onset of the initial AST elevation (>3 x ULN, >5 x 
ULN), and time to onset of initial total bilirubin >2 x ULN will be analyzed using Kaplan-Meier 
estimates, using the midpoint of the time interval between the first assessment showing the 
elevation and the previous assessment, presented by treatment group. 
Listings will be provided with flags indicating the out of range values as well as the PCSA values. 
Neutrophils 
The incidence of neutropenia by maximal grade (lowest absolute neutrophil count reported during 
the TEAE period) will be summarized. The 4 grades are defined as below: 
• Grade 1: ≥1.5 Giga/L-LLN. 
• Grade 2: ≥1.0 Giga/L- <1.5 Giga/L. 
• Grade 3: ≥0.5 Giga/L- <1.0 Giga/L. 
• Grade 4: <0.5 Giga/L. 
Thrombocytopenia 
The incidence of thrombocytopenia by maximal grade (lowest platelet count reported during the 
TEAE period) as defined below will be summarized. 
• ≥75 Giga/L-100 Giga/L. 
• ≥50 Giga/L-<75 Giga/L. 
• ≥25 Giga/L-<50 Giga/L. 
• <25 Giga/L. 
Hepatic disorders 
The liver function tests, 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 treatment group for each parameter. The proportion of 
patients with PCSA values at any post baseline visit may be displayed by duration of exposure for 
each treatment group. 
A graph of 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 


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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. 
2.4.5.4 Analyses of vital sign variables  
The summary statistics (including number, mean, median, SD, 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 treatment group. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group whatever the baseline level and/or according to the following baseline status categories: 
• Normal/Missing 
• Abnormal according to PCSA criterion or criteria 
Listings will be provided with flags indicating the PCSA values. 
2.4.6 Analyses of pharmacokinetic variables  
All the PK analyses will be performed using the PK populations including only the sarilumab 
treated patients. 
Serum concentrations of functional sarilumab will be summarized using descriptive statistics 
(including number, arithmetic and geometric means, SD, standard error of the mean, coefficient of 
variation, minimum, median, and maximum) 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 every other week regimens.  Concentrations below the lower limit of quantification 
(LLOQ) will be set to zero for samples at baseline (i.e., predose at Week 0). Other post-treatment 
concentrations below LLOQ will be replaced by LLOQ/2. In addition, serum concentrations of 
functional sarilumab will be summarized using descriptive statistics mentioned above by 
immunogenicity status for each visit. 
Listings of serum concentration will be provided for each individual patient. The listings include 
subject identification (ID), gender, age, first dose date, visit number, categorized time point (0 for 
trough level and 1 for pre-dose), date/time of previous dose, PK sampling date/time, duration 
since first dose (days), duration since previous dose (dd:hh), serum concentration (ng/mL). 
2.4.7 Analyses of quality of life variables  
Descriptive statistics including number of subjects, mean, median, SD, minimum, maximum will 
be provided by treatment groups for the value and change from baseline at each visit (baseline, 
Week 12, Week 24 and Week 52) for the 2 summary measures of SF-36 (physical component 
summary score and mental component summary score) and the 8 domains, the quantitative 
variables of EQ-5D-3L (visual analog scale and single index utility), FACIT-Fatigue, HAQ-DI 
(standardized score, pain score and patient global assessment) and MD-VAS. Analyses will be 
performed based on data as observed; no missing data will be imputed. 


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2.4.8 Analysis of immunogenicity endpoints  
The following summary will be provided separately for ADA positive patients, ADA negative 
patients, patients with persistent ADA response, and patients with transient ADA responses. 
ADA prevalence and titer 
The following summary will be provided based on the ADA populations: 
• 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. 
• Number (%) of patients with an ADA negative sample at baseline. 
ADA incidence and titer 
The following summary will be provided based on the ADA populations during TEAE period: 
• Number (%) of ADA-negative patients. 
• Number (%) of ADA-positive patients: 
- 
Number (%) of patients with neutralizing antibody. 
- 
Number (%) of patients with non-neutralizing antibody. 
- 
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) 
of the peak post-baseline titer for all ADA-positive patients. 
• 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. 
- 
Number (%) of transient treatment-emergent ADA-positive patients: 
- 
Number (%) of patients with neutralizing antibody. 
- 
Number (%) of patients with non-neutralizing antibody. 
- 
Number (%) of persistent treatment-emergent ADA positive patients: 
- 
Number (%) of patients with neutralizing antibody. 
- 
Number (%) of patients with non-neutralizing antibody. 
- 
Number (%) of persistent treatment-emergent ADA positive patients because last 
sample was positive. 
• Number (%) of treatment-boosted ADA positive patients:  


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- 
Number (%) of patients with neutralizing antibody. 
- 
Number (%) of patients with non-neutralizing antibody. 
- 
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) 
of the peak post-baseline titer for all treatment-boosted ADA-positive patients. 
In addition, number (%) of patients with ADA positive or negative response at each visit will be 
summarized by treatment group.  
ADA and PK 
By visit descriptive summary of functional sarilumab concentrations in serum will be provided by 
ADA patient classifications (positive or negative) for the sarilumab treatment groups. 
2.4.9 DNA/RNA  
The DNA test is optional and patients need to sign a separate informed consent for DNA testing.  
Exploratory analysis of DNA/RNA will be addressed in a separate document by a separate 
biomarker analysis group. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computations of parameters. 
Demographic formulas: 
BMI is calculated as follows: 
BMI = Weight in kg/(height2 in meters). 
2.5.2 Data handling conventions for secondary efficacy variables  
GTI 
General Considerations 
For vital signs and laboratory data used together with the GTI CRF to derive the scoring the 
scheduled measurements at the time of the visit should generally be used, but if any of these are 
missing they can be replaced by the last available measurement in the corresponding time window 
for that parameter. 
GTI missing domains 
The missing lab measurement for any GTI domain at a visit will be imputed by last observation 
carried forward (LOCF) method, and missing medication information for Glucose, Blood Pressure 


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and Hyperlipidemia domains will be imputed as ‘no change’ in order to calculate the composite 
and cumulative GTI scores. 
2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of SC IMP is equal to the 
date of last administration reported on the SC IMP administration CRF page.  If this date is 
missing, the exposure duration should be left as missing. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior and concomitant medication. 
Handling of AEs with missing or partial date/time of onset 
Missing or partial missing AE onset dates and times will be imputed so that if the partial AE onset 
date/time information does not indicate that the AE started prior to treatment or after the TEAE 
period, the AE will be classified as treatment-emergent.  No imputation of AE end dates/times 
will be performed.  These data imputations are for categorization purpose only and will not be 
used in listings.  No imputation is planned for date/time of AE resolution. 
Handling of AEs when date and time of first investigational medicinal product administration 
is missing 
When the date and time of the first IMP administration is missing, all AEs that occurred on or 
after the day of randomization should be considered as TEAE.  The exposure duration should be 
kept as missing. 
Handling of missing relationship of adverse events to investigational medicinal product 
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the AE considered as such in the frequency tables of possibly related AEs, but no 
imputation should be done at the data level. 
Handling of missing severity of AEs 
If the severity is missing for one of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences a “missing” category will be added in summary table. 


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Handling of PCSA  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
2.5.4 Windows for time points  
Visit windows based on days relative to the first IMP dose will be used to map the efficacy, lab, 
vital signs, PK and ADA measurements to each scheduled visit (see Appendix H). The following 
rule will be applied when mapping the measurements to the visit: 
• For the same parameter (i.e., efficacy, lab, or vital signs), if a patient has more than one 
measurement at different dates within the same visit window, the scheduled measurement 
that is closest to the target date will be used (in case of tie select the latest). If there is no 
scheduled measurement within the visit window, the unscheduled measurement that is 
closest to the target date will be used (in case of tie select the latest).  
• When a patient has more than one measurement on the same parameter on the same date, 
then the one with the later/largest sample ID will be used. 
• If there is no measurement for a given parameter in an analysis window, data will be 
considered missing for the corresponding visit. 
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory parameters and vital signs will be used for 
computation of baseline, the last on-treatment value, analysis according to PCSA analysis, and the 
shift summaries for safety. They will also be included in the by-visit summaries if they are re-
allocated to scheduled visits. 
2.5.6 Remote Assessment  
Due to the nature of the COVID-19 pandemic, related travel restrictions, and on-site visits 
limitations, some efficacy assessments and laboratory parameters have been taken remotely or 
locally. All the measurements will be used in the analyses. 


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2.5.7 Pooling of centers for statistical analyses  
Countries are pooled by region: Western countries, South American and Rest of the world. 
• Region 1 (Western countries): Australia, Belgium, Canada, Croatia, Denmark, Estonia, 
France, Germany, Hungary, Italy, Netherlands, Portugal, Slovenia, Spain, Sweden, 
Switzerland, United Kingdom, United States. 
• Region 2 (South American): Argentina. 
• Region 3 (Rest of the world): Russia, Israel. 
2.5.8 Statistical technical issues  
Not applicable. 


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3 
INTERIM ANALYSIS  
No interim analysis is planned for this study. 


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4 
DATABASE LOCK  
The database lock will occur approximately 4 weeks after the last patient has completed the EOS 
Visit.  


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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 


Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
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6 
REFERENCES  
 
1. 
J.H. Stone, K. Tuckwell, S. Dimonaco, et al. Trial of Tocilizumab in Giant-Cell Arteritis. The 
New England Journal of Medicine. 2017;377(4):317–328. 
2. 
Eli M. Miloslavsky, Ray P. Naden, Johannes W.J. Bijlsma, et al. Development of a 
Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. Annals of the 
rheumatic diseases. 2017;76(3):543–546. 
3. 
EurolQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199-208. 
 


Statistical Analysis Plan  
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7 
LIST OF APPENDICES  
 
Appendix A: 
Study flow chart 
Appendix B: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix C: 
Summary of statistical analyses 
Appendix D: 
SF-36 V2 Scoring 
Appendix E: 
FACIT-Fatigue scoring guidelines (Version 4) 
Appendix F: 
SAS code for EQ-5D-3L index utility scoring 
Appendix G 
SAS code for SF-36 scoring  
Appendix H 
Visit windows based on day ranges 
Appendix I 
Baseline glucocorticoid toxicity 
 


Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 57 
Appendix A 
Study flow chart  
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
V11 
V12 
(EOT) 
V13  
V14 (EOS) 
DAY 
D -42 to 
D -1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85 (±3) 
D113 (±3) 
D141 
(±3) 
D169 (±3) 
D225 (±3) 
D281 (±3) 
D365 (±3) 
D407 
(±3) 
D532 (±3)  
WEEK 
 
Wk 0 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 52 
Wk 58 
Wk 76 
Eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriaa 
Xa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical/smoking/alcohol 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family cardiovascular history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Targeted physical examinationb 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
Confirm eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Call IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial treatment kit assignment (IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administrationc 
 
X 
X 
X 
X 
X 
X 
X 
Xd 
Xd 
Xd 
X 
 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense patient diary (for study 
medications) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Compliance/review patient diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


Statistical Analysis Plan  
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Page 58 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
V11 
V12 
(EOT) 
V13  
V14 (EOS) 
DAY 
D -42 to 
D -1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85 (±3) 
D113 (±3) 
D141 
(±3) 
D169 (±3) 
D225 (±3) 
D281 (±3) 
D365 (±3) 
D407 
(±3) 
D532 (±3)  
WEEK 
 
Wk 0 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 52 
Wk 58 
Wk 76 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature, heart rate, blood 
pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCA clinical assessments (including 
disease flare) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PROse 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Physician Global Assessment (MD-
VAS) 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
GTI Assessment (excluding Bone 
Density assessment) 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
Bone density assessmentf 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE recording 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
QuantiFERON® 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-rayg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
 
Chemistryi 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
 
ANA 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 


Statistical Analysis Plan  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 59 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
V11 
V12 
(EOT) 
V13  
V14 (EOS) 
DAY 
D -42 to 
D -1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85 (±3) 
D113 (±3) 
D141 
(±3) 
D169 (±3) 
D225 (±3) 
D281 (±3) 
D365 (±3) 
D407 
(±3) 
D532 (±3)  
WEEK 
 
Wk 0 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 52 
Wk 58 
Wk 76 
Fasting lipids j, k/fasting glucose, 
fasting insulinj 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
 
HbA1c 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
 
CRPl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ESRl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysism 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virologyn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testo 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sarilumabj 
 
X 
X 
X 
 
X 
X 
Xp 
 
 
X 
X 
 
Anti-drug antibodyj 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
Genotyping and biomarkersj,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers-IL-6 and sIL-6R 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Blood for circulating immune cell 
phenotypingq 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
Future Use of Samples for 
Circulating proteins (serum/ 
plasma)r (optional) 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 


Statistical Analysis Plan  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 60 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
V11 
V12 
(EOT) 
V13  
V14 (EOS) 
DAY 
D -42 to 
D -1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85 (±3) 
D113 (±3) 
D141 
(±3) 
D169 (±3) 
D225 (±3) 
D281 (±3) 
D365 (±3) 
D407 
(±3) 
D532 (±3)  
WEEK 
 
Wk 0 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 52 
Wk 58 
Wk 76 
DNAs (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RNAs (optional) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
AE = Adverse event; ANA = Antinuclear antibodies; CRP = C-reactive protein; D = Day; DNA = Deoxyribonucleic acid; ECG = Electrocardiogram; EOT = End of treatment; EOS = End of study; EQ-5D-3L = 
EuroQol five-dimensional three-level questionnaire; ESR = Erythrocyte sedimentation rate; FACIT-Fatigue = Functional assessment of chronic illness therapy fatigue scale; GCA = Giant cell arteritis; GTI = 
Glucocorticoid toxicity index; HAQ-DI = Health assessment questionnaire disability index; HbA1c = Hemoglobin A1c; HBsAg = Hepatitis B surface antigen; HBcore Ab = Hepatitis B core antibodies; HCV = Hepatitis 
C virus; IL = Interleukin; IMP = Investigational medicinal product; IRT = Interactive response technology; MD-VAS = Physician global assessment of disease activity- visual analog scale; MRI = Magnetic resonance 
imaging; Pain VAS = Pain visual analog scale; PROs = Patient reported outcomes; Pt-VAS = Patient global assessment of disease activity – visual analog scale; RNA = Ribonucleic acid; SAE = Serious adverse 
event; SF-36v2 = Short form 36 version 2; TB = Tuberculosis; V = Visit; Wk = Week. 
a If ultrasound is being used as a diagnostic tool of GCA, the image needs to be submitted to the central reader for confirmation of eligibility. 
b Targeted physical examination: head, eyes, ears, neck and throat, skin, respiratory, cardiovascular, neurologic, lymphatic examinations and abdominal examination. 
c Last administration of sarilumab is at Week 50. 
d Where the visit interval exceeds 4 weeks, interim shipments of IMP to patients home may be performed using direct to patient (DTP) shipping (according to local regulations and logistics), in order to provide the 
patient with only 4 weeks IMP at a time in order to minimize compliance errors. 
e Patient Reported Outcomes include EQ-5D-3L, FACIT-Fatigue, SF-36v2, HAQ-DI (including Pain VAS and Pt-VAS). 
f 
Bone mineral density assessment must be performed during baseline if not already available within 12 weeks prior to screening visit. A ±2 week time window is allowed at baseline visit and -2 week time window is 
allowed at EOT visit. 
g Posterior-Anterior chest X-ray must be performed during screening if not already available within 12 weeks prior to screening visit.  
A standard PA chest X-ray (lateral view is also recommended but not required) is required during the screening period if no chest imaging (X-ray, Computed Tomography [CT], MRI) is available within the previous 
12 weeks of V1 that clearly documents the exclusion of TB (or >12 weeks, if appropriate according to local guidelines and requirements for screening of active TB). In countries for which a specific approval 
procedure for the X-ray is required by a different committee than the local ethics committee/Institutional review board (EC/IRB), a chest MRI between V1 and V2 can be performed.  
h Hematology (blood to be drawn before drug administration): Hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential, platelet count, 
absolute neutrophil count (ANC). 
i 
Chemistry(blood to be drawn before drug administration): Sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine and creatinine clearance, calcium, phosphate, total protein, albumin, 
alanine aminotransferase (ALT) (SGPT), aspartate aminotransferase (AST) (SGOT), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated bilirubin, lactate dehydrogenase (LDH), uric acid. 
j 
Blood to be drawn before drug administration. 
k Lipids: Triglycerides (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol.  
l 
CRP and ESR results will be blinded to Investigator (except screening and baseline). ESR kits will be provided by the central laboratory while the test will be performed locally at the site, results will be blinded to 
Investigator and staff directly involved in management of study patient, except safety assessor. 
m Urinalysis dipstick: specific gravity, pH, glucose, ketones, blood, protein, nitrite, leukocytes, urobilinogen and 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. 
n Human immunodeficiency virus antibodies (a separate local Informed Consent may need to be obtained if applicable); Hepatitis B: HBsAg, total HB core Ab, Hep B Surface Antibody, and Hep B viral DNA (if 
necessary); Hepatitis C: HCV-antibodies. 


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o In women of child-bearing potential. 
p Additional sample is to be drawn 4-7 days after Wk 24 dosing. 
q Immune cell phenotyping may be performed in only a subset of patients as determined by IRT system. 
r 
Future use Samples (for consented patients only). 
s Pharmacogenetic Research Informed Consent for collecting and sequencing DNA and RNA samples has to be obtained before any sampling. One DNA (at baseline) and RNA sample (predose) for sequencing 
sampling time point at baseline and V3 are needed. 
 


Statistical Analysis Plan  
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Appendix B 
Potentially clinically significant abnormalities (PCSA) criteria  
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Additional analysis*: 
>1 – 1.5 ULN 
>1.5 – 3 ULN 
>3 - 5 ULN 
>5 – 8 ULN 
> 8 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
AST 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Additional analysis*: 
>1 – 1.5 ULN 
>1.5 – 3 ULN 
>3 - 5 ULN 
>5 – 8 ULN 
> 8 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative  
First row is mandatory. Rows following one 
mentioning zero can be deleted. 


Statistical Analysis Plan  
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
 
Additional analysis*: 
>1.5 ULN 
>2 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
PCSA to be retrieved manually 
Unconjugated bilirubin 
Additional analysis*: 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 


Statistical Analysis Plan  
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
CPK** 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on the 
Cokcroft-Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR** (mL/min/1.73m2) 
(Estimate of GFR based 
on an MDRD equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 


Statistical Analysis Plan  
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
≥6.2 mmol/L* 
Threshold for therapeutic intervention. 
LDL 
≥4.1 mmol/L* 
≥4.9 mmol/L 
 
Triglycerides 
≥4.6 mmol/L 
≥5.6 mmol/L* 
Threshold for therapeutic intervention. 
Lipasemia** 
≥3 ULN 
 
Amylasemia** 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
<0.5 Giga/L* 
≥0.5 Giga/L - LLN* 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
<1.0 Giga/L* 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 


Statistical Analysis Plan  
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Page 66 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are 
more relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of 
Hb. 
Otherwise, consider FDA criteria. 
Platelets 
< 50 Giga/L* 
≥ 50 - 100 Giga/L* 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 


Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 67 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 


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Page 68 
Appendix C 
Summary of statistical analyses  
 
Analysis 
 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Population 
Primary Analysis 
Method 
Analysis* 
Analysis* 
Analyses* 
Primary Endpoint 
Patients who achieved 
sustained remission at 
Week 52 
ITT 
Proportion of patients achieving 
sustained remission at Week 52 
CMH test stratified 
by baseline 
prednisone dose for 
combined groups, 
and descriptive 
analysis for non-
combined groups. 
1) Sensitivity analysis;2) 
Analysis excluding 
patients who prematurely 
withdraw from the study 
due to early termination 
of the study 
No 
No 
Additional endpoint: 
Patients who achieved 
sustained remission at 
Week 24 
ITT 
Proportion of patients achieving 
sustained remission at Week 24 
CMH test stratified 
by baseline 
prednisone dose for 
combined groups, 
and descriptive 
analysis for non-
combined groups 
Sensitivity analysis 
No 
No 
Secondary Endpoints 
Patients who achieved of 
disease remission by Week 
12 
ITT 
Proportion of patients who achieved of 
disease remission by Week 12 
Descriptive 
No 
No 
No 
Patients who have absence 
of disease flare from Week 
12 through Week 24 and 
Week 52 
ITT 
Proportion of patients who have 
absence of disease flare from Week 
12 through Week 24 and Week 52 
Descriptive 
No 
No 
No 
Patients who have 
normalization of CRP 
(decrease to <10 mg/L) 
with sustained 
normalization from Week 
ITT 
Proportion of patients who have 
normalization of CRP (decrease to 
<10 mg/L) with sustained 
normalization from Week 12 through 
Week 24 and Week 52 
Descriptive 
No 
No 
No 


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Page 69 
 
Analysis 
 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Population 
Primary Analysis 
Method 
Analysis* 
Analysis* 
Analyses* 
12 through Week 24 and 
Week 52 
Patients who successfully 
adhere to the prednisone 
taper from Week 12 
through Week 24 and Week 
52 
ITT 
Proportion of patients who 
successfully adhere to the prednisone 
taper from Week 12 through Week 24 
and Week 52 
Descriptive 
No 
No 
No 
Total cumulative 
prednisone (or equivalent) 
dose 
ITT 
Total cumulative prednisone (or 
equivalent) dose over 52-week 
treatment period 
Descriptive 
No 
No 
No 
Time to the first GCA flare 
after clinical remission up to 
Week 52 
ITT 
Time (from randomization) to the first 
GCA flare after clinical remission up to 
Week 52  
Kaplan-Meier 
estimates and Cox 
proportional hazards 
model for combined 
groups, and 
descriptive analysis 
for non-combined 
groups. 
No 
No 
No 
Total composite GTI total 
score  
ITT 
Cumulative GTI scores (CWS and 
AIS) at Week 24 and Week 52 
Descriptive by 4 
treatment groups; 
and analysis of 
covariance 
(ANCOVA) model for 
combined groups. 
No 
No 
Summaries of domain 
specific scores and 
specific list events at 
Week 12, 24, 40 and 52. 
Safety 
 
 
 
 
 
 
Adverse Events 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
No 
Laboratory 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
No 
Vital signs and ECGs 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
No 


Statistical Analysis Plan  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 70 
 
Analysis 
 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Population 
Primary Analysis 
Method 
Analysis* 
Analysis* 
Analyses* 
PK 
 
 
 
 
 
 
Sarilumab serum 
concentration 
PK 
By visit 
Descriptive 
No 
No 
No 
Immunogenicity 
 
 
 
 
 
 
ADA positive patients 
ADA 
NA 
Descriptive 
No 
No 
No 
ADA negative patients 
ADA 
NA 
Descriptive  
No 
No 
No 
Persistent ADA response 
ADA 
NA 
Descriptive 
No 
No 
No 
Transient ADA response 
ADA 
NA 
Descriptive 
No 
No 
No 
 


Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 71 
Appendix D 
SF-36 V2 Scoring  
General Scoring information 
Items and scales are scored in 3 steps: 
• Step 1. Item recoding, for the 10 items that require recoding, 
• Step 2. Computing scale scores by summing across items in the same scale (raw scale 
scores); and, 
• Step 3. Transforming raw scale scores to a 0-100 scale (transformed scale). 
Item recoding 
• All 36 items should be checked for out-of-range values prior to assigning the final item 
value. All out-of-range values should be recoded as missing data. 
• The following tables show the recoding of response choice. 
How to treat missing data 
A scale score is calculated if a respondent answered at least half of the items in a multi-item scale 
(or half plus one in the case of scales with an odd number of items). 
The recommended algorithm substitutes a person-specific estimate for any missing item when the 
respondent answered at least 50 percent of the items in a scale. A psychometrically sound estimate 
is the average score, across completed items in the same scale, for that respondent. For example, if 
a respondent leaves one item in the 5-item mental Health scale blank, substitute the respondent’s 
average score (across the 4 completed mental health items) for that one item. When estimating the 
respondent’s average score, use the respondent’s final item values. 
Computing raw scale scores 
After item recoding, including handling of missing data, a raw score is computed for each scale. 
This score is a simple algebraic sum of responses for all items in that scale. 
If the respondent answered at least 50% of the items in a multi-items scale, the score can be 
calculated. If the respondent did not answer at least 50% of the items, the score for that scale 
should be set to missing. 


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Transformation of the scale scores 
The next step involves transforming each raw score to a 0 to 100 scale using the following 
formula: 
Transformed scale = [(actual raw score – lowest possible raw score) / possible raw score range] x 
100 
This transformation converts the lowest and highest possible scores to zero and 100, respectively. 
Table 8 - SF-36 V2 raw scores of eight domains  
Scale 
Lowest and highest possible raw scores 
Possible raw score range 
Physical Functioning 
10,30 
20 
Role-Physical 
4,20 
16 
Bodily pain 
2,12 
10 
General health 
5,25 
20 
Vitality 
4,20 
16 
Social Functioning 
2,10 
8 
Role-Emotional 
3,15 
12 
Mental Health 
5,25 
20 
 


Statistical Analysis Plan  
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Page 73 
Appendix E 
FACIT-fatigue scoring guidelines (version 4)  
Instructions:* 1. Record answers in "item response" column. If missing, mark with an X 
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by the 
number of items answered. This produces the subscale score. 
4. The higher the score, the better the QOL. 
Subscale 
         Item Code       Reverse item?            Item response         
 Item Score  
FATIGUE 
 
HI7 
      
4 
- 
________ 
 
=________ 
SUBSCALE 
 
HI12 
 
4 
- 
________ 
 
=________ 
    
 
 
An1 
 
4 
- 
________ 
 
=________ 
An2 
 
4 
- 
________ 
 
=________ 
An3 
 
4 
- 
________ 
 
=________ 
An4 
 
4 
- 
________ 
 
=________ 
An5 
 
0 
+ 
________ 
 
=________ 
An7 
 
0 
+ 
________ 
 
=________ 
An8 
 
4 
- 
________ 
 
=________ 
An12 
 
4 
- 
________ 
 
=________ 
An14 
 
4 
- 
________ 
 
=________ 
An15 
 
4 
- 
________ 
 
=________ 
An16 
 
4 
- 
________ 
 
=________ 
              Sum individual item scores:________   
 
 
 
                   Multiply by 13: ________ 
           Divide by number of items answered: ________=Fatigue Subscale score 
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring Guidelines in the manual or on-line 
at www.facit.org. 


Statistical Analysis Plan  
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Page 74 
Appendix F 
SAS code for EQ-5D-3L index utility scoring  
 
 
/*==================================================================*/; 
/* Aim : Derive the EQ5-D index (utility) */; 
/* Source for the algorithm : scoring EQ-5D health states (Rosalind Rabin */; 
/* (cf. G:\_HE\PRO questionnaire\EQ5D\scoring\YorkTariffx.doc) */; 
/* Note : UK based population (Dolan, 1997) */; 
/* Author : Elisheva Smadja */; 
/*==================================================================*/; 
 
data EUROQOL; set temp; 
profil= (10000*eqq1cd)+(1000*eqq2cd)+(100*eqq3cd)+(10*eqq4cd)+eqq5cd; 
eq5d=1; 
**********Mobility*********; 
if eqq1cd=2 then eq5d=eq5d-0.069; 
if eqq1cd=3 then eq5d=eq5d-0.314; 
********Self-care**********; 
if eqq2cd=2 then eq5d=eq5d-0.104; 
if eqq2cd=3 then eq5d=eq5d-0.214; 
******Usual activities*****; 
if eqq3cd=2 then eq5d=eq5d-0.036; 
if eqq3cd=3 then eq5d=eq5d-0.094; 
*****Pain/discomfort******; 
if eqq4cd=2 then eq5d=eq5d-0.123; 
if eqq4cd=3 then eq5d=eq5d-0.386; 
*****Anxiety/depression*****; 
if eqq5cd=2 then eq5d=eq5d-0.071; 
if eqq5cd=3 then eq5d=eq5d-0.236; 
 
if (eqq1cd ne 1 or eqq2cd ne 1 or eqq3cd ne 1 or eqq4cd ne 1 or eqq5cd ne 1) 
then eq5d=eq5d-0.081; 
 
if (eqq1cd=3 or eqq2cd=3 or eqq3cd=3 or eqq4cd=3 or eqq5cd=3) 
then eq5d=eq5d-0.269; 
 
if (eqq1cd=. or eqq2cd=. or eqq3cd=. or eqq4cd=. or eqq5cd=.) 
then eq5d=.; 
 
run; 


Statistical Analysis Plan  
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Page 75 
Appendix G 
SAS code for SF-36 scoring  
 
******************************************************************** 
*  PROGRAM: SF36 V2                                                * 
*  PURPOSE: SAS SCORING PROGRAM FOR THE SF-36 VERSION2             * 
*                                                                  * 
*******************************************************************; 
 
*****************************************************************; 
***               STEP 1: INPUT DATA                          ***; 
*****************************************************************; 
 
DATA SF36DATA; 
INFILE IN; 
INPUT ID $ 1-3 
      @ 5 (GH1 HT PF01-PF10 RP1-RP4 RE1-RE3 SF1 
      BP1-BP2 VT1 MH1 MH2 MH3 VT2 MH4 VT3 MH5 
      VT4 SF2 GH2 GH3 GH4 GH5) (1.); 
RUN; 
 
 
*****************************************************************; 
***               STEP 2: SF-36 SCALE CONSTRUCTION            ***; 
*****************************************************************; 
 
 
****************************************************************** 
*  USING THE SAS DATASET CREATED IN PART 1, CHANGE OUT-OF-RANGE 
*  VALUES TO MISSING FOR EACH ITEM.  RECODE AND RECALIBRATE ITEMS 
*  AS NEEDED.  AN 'R' PREFIX MEANS THE VARIABLE IS RECODED. 
*****************************************************************; 
 
DATA SF36SCAL; 
  SET SF36DATA; 
 
 
****************************************************************** 
*  THE SF-36 PHYSICAL FUNCTIONING INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM 
*  VALUE, THE BETTER THE PHYSICAL HEALTH. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE PHYSICAL FUNCTIONING. 
******************************************************************; 
 
ARRAY PFI(10) PF01-PF10; 
 
DO I = 1 TO 10; 
   IF PFI(I) < 1 OR PFI(I) > 3 THEN PFI(I) = .; 
END; 
 
PFNUM = N(OF PF01-PF10); 
PFMEAN = MEAN(OF PF01-PF10); 
 
DO I = 1 TO 10; 
  IF PFI(I)= . THEN PFI(I) = PFMEAN; 


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END; 
 
IF PFNUM GE 5 THEN RAWPF = SUM(OF PF01-PF10); 
PF = ((RAWPF - 10)/(30-10)) * 100; 
 
LABEL  PF = 'SF-36 PHYSICAL FUNCTIONING (0-100)' 
       RAWPF = 'RAW SF-36 PHYSICAL FUNCTIONING'; 
 
 
****************************************************************** 
*  THE SF-36 ROLE-PHYSICAL INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM VALUE, 
*  THE BETTER THE ROLE-PHYSICAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE ROLE-PHYSICAL. 
*****************************************************************; 
 
ARRAY RPA(4) RP1-RP4; 
 
DO I = 1 TO 4; 
   IF RPA(I) < 1 OR RPA(I) > 5 THEN RPA(I) = .; 
END; 
 
ROLPNUM = N(OF RP1-RP4); 
ROLPMEAN = MEAN(OF RP1-RP4); 
 
DO I = 1 TO 4; 
   IF RPA(I) = . THEN RPA(I) = ROLPMEAN; 
END; 
 
IF ROLPNUM GE 2 THEN RAWRP = SUM(OF RP1-RP4); 
RP = ((RAWRP - 4)/(20-4)) * 100; 
LABEL  RP = 'SF-36 ROLE-PHYSICAL (0-100)' 
       RAWRP = 'RAW SF-36 ROLE-PHYSICAL'; 
 
 
***************************************************************** 
*  THE SF-36 PAIN ITEMS. 
*  ITEM RECODING DEPENDS ON WHETHER BOTH PAIN1 AND PAIN2 
*  ARE ANSWERED OR WHETHER ONE OF THE ITEMS HAS MISSING DATA. 
*  AFTER RECODING, ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER 
*  THE SCORE, THE LESS PAIN (OR THE MORE FREEDOM FROM PAIN). 
* 
*   THIS SCALE IS POSITIVELY SCORED.  THE HIGHER THE 
*   SCORE THE LESS PAIN OR THE MORE FREEDOM FROM PAIN. 
*****************************************************************; 
 
IF BP1 < 1 OR BP1 > 6 THEN BP1 = .; 
IF BP2 < 1 OR BP2 > 5 THEN BP2 = .; 
 
*  RECODES IF NEITHER BP1 OR BP2 HAS A MISSING VALUE; 
 
IF BP1 NE . AND BP2 NE . THEN DO; 
 
   IF BP1 = 1 THEN RBP1 = 6; 


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   IF BP1 = 2 THEN RBP1 = 5.4; 
   IF BP1 = 3 THEN RBP1 = 4.2; 
   IF BP1 = 4 THEN RBP1 = 3.1; 
   IF BP1 = 5 THEN RBP1 = 2.2; 
   IF BP1 = 6 THEN RBP1 = 1; 
 
   IF BP2 = 1  AND BP1 = 1 THEN RBP2 = 6; 
   IF BP2 = 1  AND 2 LE BP1 LE 6 THEN RBP2 = 5; 
   IF BP2 = 2  AND 1 LE BP1 LE 6 THEN RBP2  = 4; 
   IF BP2 = 3  AND 1 LE BP1 LE 6 THEN RBP2  = 3; 
   IF BP2 = 4  AND 1 LE BP1 LE 6 THEN RBP2  = 2; 
   IF BP2 = 5  AND 1 LE BP1 LE 6 THEN RBP2  = 1; 
 
END; 
 
*  RECODES IF BP1 IS NOT MISSING AND BP2 IS MISSING; 
 
IF BP1 NE . AND BP2 = . THEN DO; 
   IF BP1 = 1 THEN RBP1 = 6; 
   IF BP1 = 2 THEN RBP1 = 5.4; 
   IF BP1 = 3 THEN RBP1 = 4.2; 
   IF BP1 = 4 THEN RBP1 = 3.1; 
   IF BP1 = 5 THEN RBP1 = 2.2; 
   IF BP1 = 6 THEN RBP1 = 1; 
   RBP2 = RBP1; 
 
END; 
 
*  RECODES IF BP1 IS MISSING AND BP2 IS NOT MISSING; 
 
IF BP1 = . AND BP2 NE . THEN DO; 
 
   IF BP2 = 1 THEN RBP2 = 6; 
   IF BP2 = 2 THEN RBP2 = 4.75; 
   IF BP2 = 3 THEN RBP2 = 3.5; 
   IF BP2 = 4 THEN RBP2 = 2.25; 
   IF BP2 = 5 THEN RBP2 = 1; 
   RBP1 = RBP2; 
 
END; 
 
BPNUM = N(BP1,BP2); 
 
IF BPNUM GE 1 THEN RAWBP = SUM(RBP1,RBP2); 
BP = ((RAWBP - 2)/(12-2)) * 100; 
 
LABEL  BP = 'SF-36 PAIN INDEX (0-100)' 
       RAWBP = 'RAW SF-36 PAIN INDEX'; 
 
 
****************************************************************** 
*  THE SF-36 GENERAL HEALTH PERCEPTIONS INDEX. 
*  REVERSE TWO ITEMS AND RECALIBRATE ONE ITEM.  AFTER RECODING 
*  AND RECALIBRATION, ALL ITEMS ARE POSITIVELY SCORED --  THE 
*  HIGHER THE SCORE, THE BETTER THE PERCEIVED GENERAL HEALTH. 
* 


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*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE HEALTH PERCEPTIONS. 
*****************************************************************; 
 
ARRAY GHP(5) GH1-GH5; 
 
DO I= 1 TO 5; 
  IF GHP(I) < 1 OR GHP(I) > 5 THEN GHP(I) = .; 
END; 
 
IF GH1 = 1 THEN RGH1 =   5; 
IF GH1 = 2 THEN RGH1 = 4.4; 
IF GH1 = 3 THEN RGH1 = 3.4; 
IF GH1 = 4 THEN RGH1 =   2; 
IF GH1 = 5 THEN RGH1 =   1; 
 
RGH3 = 6 - GH3; 
RGH5 = 6 - GH5; 
 
GHNUM = N(GH1,GH2,GH3,GH4,GH5); 
GHMEAN = MEAN(RGH1,GH2,RGH3,GH4,RGH5); 
 
ARRAY RGH(5) RGH1 GH2 RGH3 GH4 RGH5; 
 
DO I= 1 TO 5; 
  IF RGH(I) = . THEN RGH(I) = GHMEAN; 
END; 
 
IF GHNUM GE 3  THEN RAWGH = SUM(RGH1,GH2,RGH3,GH4,RGH5); 
GH = ((RAWGH - 5)/(25-5)) * 100; 
 
LABEL  GH = 'SF-36 GENERAL HEALTH PERCEPTIONS (0-100)' 
       RAWGH = 'RAW SF-36 GENERAL HEALTH PERCEPTIONS'; 
 
 
***************************************************************** 
*  THE SF-36 VITALITY ITEMS. 
*  REVERSE TWO ITEMS.  AFTER ITEM REVERSAL, ALL ITEMS ARE 
*  POSITIVELY SCORED -- THE HIGHER THE SCORE, THE LESS THE FATIGUE 
*  AND THE GREATER THE ENERGY. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE GREATER THE VITALITY. 
****************************************************************; 
 
ARRAY VI(4) VT1-VT4; 
 
DO I = 1 TO 4; 
  IF VI(I) < 1 OR VI(I) > 5 THEN VI(I) =.; 
END; 
 
RVT1 = 6-VT1; 
RVT2 = 6-VT2; 
 
VITNUM = N(VT1,VT2,VT3,VT4); 
VITMEAN = MEAN(RVT1,RVT2,VT3,VT4); 


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Page 79 
 
ARRAY RVI(4) RVT1 RVT2 VT3 VT4; 
 
DO I = 1 TO 4; 
  IF RVI(I) = . THEN RVI(I) = VITMEAN; 
END; 
 
IF VITNUM GE 2 THEN RAWVT= SUM(RVT1,RVT2,VT3,VT4); 
VT = ((RAWVT-4)/(20-4)) * 100; 
 
LABEL  VT = 'SF-36 VITALITY (0-100)' 
       RAWVT = 'RAW SF-36 VITALITY'; 
 
 
**************************************************************** 
*  THE SF-36 SOCIAL FUNCTIONING INDEX. 
*  REVERSE ONE ITEM SO THAT BOTH ITEMS ARE POSITIVELY SCORED -- 
*  THE HIGHER THE SCORE, THE BETTER THE SOCIAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE SOCIAL FUNCTIONING. 
*****************************************************************; 
 
ARRAY SOC(2) SF1-SF2; 
 
DO I = 1 TO 2; 
   IF SOC(I) < 1 OR SOC(I) > 5 THEN SOC(I) = .; 
END; 
 
RSF1 = 6 - SF1; 
SFNUM = N(SF1,SF2); 
SFMEAN = MEAN(RSF1,SF2); 
 
ARRAY RSF(2) RSF1 SF2; 
 
DO I = 1 TO 2; 
  IF RSF(I) = . THEN RSF(I) = SFMEAN; 
END; 
 
IF SFNUM GE 1 THEN RAWSF = SUM(RSF1,SF2); 
SF = ((RAWSF - 2)/(10-2)) * 100; 
 
LABEL  SF = 'SF-36 SOCIAL FUNCTIONING (0-100)' 
       RAWSF = 'RAW SF-36 SOCIAL FUNCTIONING'; 
 
 
****************************************************************** 
*  THE SF-36 ROLE-EMOTIONAL INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM VALUE, 
*  THE BETTER THE ROLE-EMOTIONAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE, THE BETTER THE ROLE-EMOTIONAL. 
*****************************************************************; 
 
ARRAY RM(3) RE1-RE3; 


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Page 80 
 
DO I = 1 TO 3; 
   IF RM(I) < 1 OR RM(I) > 5 THEN RM(I) = .; 
END; 
 
ROLMNUM = N(OF RE1-RE3); 
ROLMMEAN = MEAN(OF RE1-RE3); 
 
DO I = 1 TO 3; 
   IF RM(I) = . THEN RM(I) = ROLMMEAN; 
END; 
 
IF ROLMNUM GE 2 THEN RAWRE = SUM(OF RE1-RE3); 
RE = ((RAWRE - 3)/(15-3)) * 100; 
 
LABEL  RE = 'SF-36 ROLE-EMOTIONAL (0-100)' 
       RAWRE = 'RAW SF-36 ROLE-EMOTIONAL'; 
 
 
***************************************************************** 
*  THE SF-36 MENTAL HEALTH INDEX. 
*  REVERSE TWO ITEMS.  AFTER ITEM REVERSAL, ALL ITEMS ARE 
*  POSITIVELY SCORED -- THE HIGHER THE SCORE, THE BETTER THE 
*  MENTAL HEALTH. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE MENTAL HEALTH. 
****************************************************************; 
 
ARRAY MHI(5) MH1-MH5; 
 
DO I = 1 TO 5; 
   IF MHI(I) < 1 OR MHI(I) > 5 THEN MHI(I)=.; 
END; 
 
RMH3 = 6-MH3; 
RMH5 = 6-MH5; 
 
MHNUM=N(MH1,MH2,MH3,MH4,MH5); 
MHMEAN=MEAN(MH1,MH2,RMH3,MH4,RMH5); 
 
ARRAY RMH(5) MH1 MH2 RMH3 MH4 RMH5; 
 
DO I = 1 TO 5; 
   IF RMH(I) = . THEN RMH(I) = MHMEAN; 
END; 
 
IF MHNUM GE 3 THEN RAWMH = SUM(MH1,MH2,RMH3,MH4,RMH5); 
MH = ((RAWMH-5)/(25-5)) * 100; 
 
LABEL  MH = 'SF-36 MENTAL HEALTH INDEX (0-100)' 
       RAWMH = 'RAW SF-36 MENTAL HEALTH INDEX'; 
 
 
***************************************************************** 
*  THE SF-36 HEALTH TRANSITION ITEM. 


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*  THIS ITEM SHOULD BE ANALYZED AS CATEGORICAL DATA, 
*  PENDING FURTHER RESEARCH. 
****************************************************************; 
 
IF HT < 1 OR HT > 5 THEN HT = .; 
 
LABEL  HT='RAW SF-36 HEALTH TRANSITION ITEM'; 
RUN; 
 
 
*****************************************************************; 
***               STEP 3: SF-36 SCALE CONSTRUCTION            ***; 
*****************************************************************; 
 
 
 
DATA SF36INDX; 
  SET SF36SCAL; 
 
  
*******************************************************************; 
*  purpose: create physical and mental health index scores 
*           standardized but not normalized 
*           and standard deviations calculated with vardef=wdf 
*******************************************************************; 
 
         
/********************************************************************/ 
/* NORM-BASED SCORING OF SF-36, STANDARD RECALL (4 WEEKS)           */ 
/* USING  WEIGHTED MEANS AND SD'S FROM 1998 GENERAL US POPULATION   */ 
/* FROM COMBINED SAMPLES                                            */ 
/********************************************************************/ 
 
********************************************************** 
**********************1998 US NORMS*********************** 
**********************************************************; 
 
*CREATING SF-36 STANDARDIZED SCORES (0-100 Means/SD's from 1998 General 
Population)*; 
 
pf_z=(pf-83.29094)/23.75883; 
rp_z=(rp-82.50964)/25.52028; 
bp_z=(bp-71.32527)/23.66224; 
gh_z=(gh-70.84570)/20.97821; 
vt_z=(vt-58.31411)/20.01923; 
sf_z=(sf-84.30250)/22.91921; 
re_z=(re-87.39733)/21.43778; 
mh_z=(mh-74.98685)/17.75604; 
 
 
**************************************************************; 
*     COMPUTE SAMPLE RAW FACTOR SCORES                       *; 
*     Z SCORES ARE FROM ABOVE                                *; 
*     SCORING COEFFICIENTS ARE FROM U.S. GENERAL POPULATION  *; 
*     FACTOR ANALYTIC SAMPLE N=2393: HAVE ALL EIGHT SCALES   *; 
**********************************************************; 


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praw=(pf_z * .42402)+(rp_z * .35119)+(bp_z * .31754)+(sf_z * -.00753)+ 
     (mh_z * -.22069)+(re_z * -.19206)+(vt_z * .02877)+(gh_z * .24954); 
 
mraw=(pf_z * -.22999)+(rp_z * -.12329)+(bp_z * -.09731)+(sf_z * .26876)+ 
     (mh_z * .48581)+(re_z * .43407)+(vt_z * .23534)+(gh_z * -.01571); 
 
 
*COMPUTE AGGREGATE STANDARDIZED SUMMARY SCORES*; 
 
PCS = (praw*10) + 50; 
MCS = (mraw*10) + 50; 
 
label PCS='STANDARDIZED PHYSICAL COMPONENT SCALE-00' 
      MCS='STANDARDIZED MENTAL COMPONENT SCALE-00'; 
 
 
run;  
 


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Page 83 
Appendix H 
Visit windows based on day ranges  
Visit windows based on days relative to the first IMP dose will be used to map (see Table 9). 


Statistical Analysis Plan  
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Page 84 
Table 9 - Day range for each scheduled visit in the DB period for efficacy, lab, vital sign, PK and ADA summaries  
Visit Label 
Target 
Day 
Schedule Aa 
Schedule Bb 
Schedule Cc 
Schedule Dd 
Schedule Ee 
Schedule Ff 
Schedule 
Gg 
Schedule Hh 
Schedule Ii 
Schedule Ji 
Double-Blind Period 
 
Baseline 
1 
≤1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 2  
15 
>1*- 21 
 
 
 
 
 
>1*-21 
>1*-49 
 
Week 4  
29 
22-42 
 
 
>1*-56 
>1*-56 
>1*-42 
22 - 56 
 
>1*-98 
Week 8 
57 
43-70 
 
 
 
 
43 - 70 
 
 
 
Week 12 
85 
71-98 
>1*-126 
>1*-126 
 
57 - 126 
57 - 126 
71 - 98 
57 - 98 
50 - 126 
 
Week 16 
113 
99-126 
 
 
 
 
 
99 - 126 
99 - 140 
 
 
Week 20 
141 
127-154 
 
 
 
 
 
127 - 154 
 
 
 
Week 24 
169 
155-196 
127 - 224 
127 - 266 
 
127 - 224 
127 - 224 
155 - 196 
141 - 266 
127 - 266 
≥ 99 
Week 32 
225 
197-252 
 
 
 
 
 
197 - 252 
 
 
 
Week 40 
281 
253-322 
225 - 322 
 
 
225 - 322 
225 - 322 
253 - 322 
 
 
 
Week 52 
365 
≥323 
≥ 323 
≥ 267 
>1*  
≥ 323 
≥ 323 
≥ 323 
≥ 267 
≥ 267 
 
a Includes temperature, heart rate, blood pressure, GCA clinical assessments (including disease flare), CRP, ESR 
b Includes weight, glucocorticoid toxicity index (excluding bone density assessment) 
c Includes physician global assessments (MD-VAS), patient reported outcomes and antibodies to sarilumab/ADA 
d Includes bone density assessment, ANA 
e Includes hematology: hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential, platelet count, absolute neutrophil count (ANC) and chemistry: sodium, 
potassium, calcium, chloride, bicarbonate, total protein, creatinine and clearance, blood urea nitrogen (BUN), uric acid, lactate dehydrogenase (LDH), phosphate, albumin, ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP), 
total bilirubin, conjugated bilirubin, and unconjugated bilirubin 
f 
Includes HbA1c, fasting glucose, fasting lipids: triglycerides (TG), total cholesterol, HDL, LDL  
g Includes urine pregnancy test 
h Includes serum sarilumab 
i 
Includes biomarkers-IL-6 and sIL-6R 
j 
Includes immune cell phenotyping (whole blood) 
* Includes value measured on day 1 but after the first IMP dose 


Statistical Analysis Plan  
08-Jan-2021 
SAR153191-EFC15068 - sarilumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 85 
For PK and ADA, the follow-up (i.e., 6-week post-treatment) measurement will be defined based 
on the sample collected at the follow-up visit (ie, Visit 13). The rests of PK and ADA 
measurements will be mapped to each visit using the visit window defined in Table 9. 
 


Statistical Analysis Plan  
08-Jan-2021 
SAR153191-EFC15068 - sarilumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 86 
Appendix I 
Baseline glucocorticoid toxicity  
Approach to calculating the Baseline glucocorticoid toxicity score:  Toxicities assigned weighted scores 
from the Composite Index to establish a baseline glucocorticoid toxicity score 
Toxicity Domain 
 
Points 
Body Mass Index (BMI) 
BMI < 27 
0 
BMI > 27 but < 30 
21 
BMI > 30 
36 
Glucose Metabolism 
HgbA1c < 5.7 
0 
HgbA1c < 5.7 but on medication 
32 
Hgb A1c > 5.7    
32 
HgbA1c > 5.7 and on medication 
44 
Diabetic retinopathy, nephropathy, or neuropathy (count only one) 
44 
Lipid Metabolism 
LDL < targeta 
0 
LDL < targeta but on medications 
10 
LDL > targeta on no medications 
10 
LDL > targeta on treatment 
30 
Bone/Tendon 
Normal BMD or no known history of osteoporosis  
0 
Osteoporosis 
29 
Insufficiency fracture secondary to osteoporosis 
29 
Osteonecrosis 
29 
Tendon rupture while on corticosteroid 
29 
Glucocorticoid 
Myopathy 
No myopathy 
0 
Minor glucocorticoid myopathy 
9 
Moderate glucocorticoid myopathy 
63 
Severe glucocorticoid myopathy 
63 
Skin 
No skin toxicity 
0 
Minor skin toxicity (one or more than one minor skin item) 
8 
Moderate skin toxicity (one or more than one moderate skin item) 
26 
Severe skin toxicity (one or more than one moderate skin item) 
26 
Neuropsychiatric 
No neuropsychiatric toxicity 
0 
Minor (one or more than one minor NP item: insomnia, mania, 
depression, cognitive) 
11 
Moderate (one or more than one moderate NP item: insomnia, mania, 
depression, cognitive) 
74 
Severe (one or more than one severe NP item: insomnia, mania, 
depression, cognitive) 
74 
Psychosis 
74 
Glucocorticoid-induced violence 
74 
Infection 
No GTI-relevant infections within the pre-baseline GTI interval of the 
study  
0 
Oral or vaginal candidiasis or non-complicated zoster (<Grade3) within 
the pre-baseline GTI interval of the study 
19 


Statistical Analysis Plan  
08-Jan-2021 
SAR153191-EFC15068 - sarilumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 87 
Grade 3 or Grade 4 infection within the pre-baseline GTI interval of the 
study 
93 
Ocular 
Increased IOP 
33 
Posterior subcapsular cataract 
33 
Central serous retinopathy 
33 
Gastrointestinal 
GI perf absence of NSAIDs 
33 
PUD without H. pylori 
33 
Endocrine 
Adrenal insufficiency  
33 
a Target range of <70 mg/dL will be used for LDL domain. 


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