Clinical trial NCT03449758
Conditions: Rheumatoid Arthritis
Sponsor: Sanofi
Start date: 2018-03-05; Completion date: 2019-07-31
Enrollment: 84 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To assess the effect of sarilumab in combination with conventional synthetic Disease-Modifying Anti-Rheumatic Drug (csDMARD) and/or monotherapy on participant-reported impact of disease, using the rheumatoid arthritis impact of disease (RAID) questionnaire, in participants with moderately to severely active rheumatoid arthritis (RA) and inadequate response or intolerance to current csDMARD or tumor necrosis factor (TNF) inhibitors.

Secondary Objectives:

* To assess the change of the RAID score from baseline (to Week 4, Week 12, and Week 24) in participants with moderately to severely active RA and inadequate response or intolerance to current csDMARD or TNF inhibitors, treated with sarilumab in combination with csDMARD and/or monotherapy.
* To assess the effect of sarilumab in combination with csDMARD and/or monotherapy on other participant-reported outcomes (global assessment of disease activity, disability, morning stiffness, fatigue, anxiety/depression, mood disorders, and physical activities) in participants with moderately to severely active RA and inadequate response or intolerance to current csDMARD or TNF inhibitors.
* To assess the efficacy of sarilumab in combination with csDMARD and/or monotherapy using disease activity score-28 for RA with erythrocyte sedimentation rate (DAS28-ESR) and clinical disease activity index in participants with moderately to severely active RA and inadequate response or intolerance to current csDMARD or TNF inhibitors.
* To assess the safety of sarilumab in combination with csDMARD and/or monotherapy in participants with moderately to severely active RA and inadequate response or intolerance to current csDMARD or TNF inhibitors.

Detailed description:
The study duration per participant was approximately 32 weeks, with up to 4-week screening, 24 weeks treatment period, and 2-4 weeks post-treatment observations.

Arms: arm 1: Sarilumab 200 milligram (mg) subcutaneous (SC) injection every 2 weeks (q2w) from Day 1 of Week 0 up to Week 24 as monotherapy and/or in combination with methotrexate (MTX) or other csDMARD during the randomized 6-month (24 weeks) core treatment period. Participants completing 24 weeks period entered in a long-term extension treatment period and received sarilumab 200 mg q2w from Week 25 until the commercial availability of sarilumab in the country or maximum of up to Week 39.7.
Interventions: intervention 1: SARILUMAB intervention 2: Azathioprine intervention 3: Chloroquine intervention 4: Hydroxychloroquine intervention 5: Leflunomide intervention 6: Methotrexate intervention 7: Sulfasalazine
Intervention descriptions: intervention 1: Pharmaceutical form:Solution for injection in pre-filled syringe Route of administration: Subcutaneous intervention 2: Pharmaceutical form:Tablet Route of administration: Oral intervention 3: Pharmaceutical form:Tablet Route of administration: Oral intervention 4: Pharmaceutical form:Tablet Route of administration: Oral intervention 5: Pharmaceutical form:Tablet Route of administration: Oral intervention 6: Pharmaceutical form:Solution for injection Route of administration: Subcutaneous / Intramuscular intervention 7: Pharmaceutical form:Tablet Route of administration: Oral

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°15.0 (22-MAR-2017)
Page 1
CLINICAL TRIAL PROTOCOL
COMPOUND: SAR153191 (sarilumab)
Effect of sarilumab on patient-reported outcomes in patients with moderately to 
severely active rheumatoid arthritis and with inadequate response or intolerance 
to current conventional synthetic DMARDs or tumor necrosis factor inhibitors
STUDY NUMBER: SARILL08755
SariPRO
Version Number:
3.0
EudraCT 
2017-002951-27
IND Number(s)
Not applicable
Date:
06-06-2018
Total number of pages:
95
NCT03449758


Clinical Trial Protocol  
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Study Number: SARILL08755 - INN
Version number: 3.0
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NAMES AND ADDRESSES OF  
COORDINATING 
INVESTIGATOR


Clinical Trial Protocol  
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Study Number: SARILL08755 - INN
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Page 3 
MONITORING TEAM’S 
REPRESENTATIVE
  
Medical Advisor
Statistician
Clinical Project Leader  
Pharmacovigilance
CSU Sanofi France
SAE to be declared within 24 hours to :  
Fax: +33 (0) 1 57 63 30 45
Email PV: PV-URCFrance@sanofi.com
Contract Research Organization
ITEC  
3 Avenue Georges Clémenceau  
33150 CENON
Tel: 33 (0)5 57 77 85 00
Fax: 33 (0)5 57 77 85 01
Email: itec@itecservices.com


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SPONSOR
Company:
Address:
SANOFI AVENTIS FRANCE
82 Avenue Raspail
94255 GENTILLY Cedex
 
OTHER EMERGENCY 
TELEPHONE NUMBERS
Poison Control Center
CENTRE ANTI POISON LILLE
Tel : +33(0) 3 20 44 44 44 or 
+ 33 (0)8 25 812 822


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CLINICAL TRIAL SUMMARY
COMPOUND: Sarilumab
STUDY No.: SARILL08755
STUDY NAME: SariPRO
TITLE
Effect of sarilumab on patient-reported outcomes in 
patients with moderately to severely active rheumatoid 
arthritis and with inadequate response or intolerance to 
current conventional synthetic DMARDs or TNF 
inhibitors
INVESTIGATOR/TRIAL LOCATION
Mainland France
PHASE OF DEVELOPMENT
Phase IV
STUDY OBJECTIVES
STUDY DESIGN
SariPRO is a national, multicenter, open-label, single-
arm phase IV study.
Four study periods are defined for this study period:
x
Screening period: within 28 days prior to study 
treatment start (Baseline visit, Day 1), patient 
eligibility is determined at the Screening visit. At 
Baseline visit, patient’s inclusion in the study is 
established.
x
6-month core period: patients who fulfil the 
enrollment criteria received a SC injection of 
sarilumab 200 mg every 2 weeks as monotherapy 
and/or in combination with methotrexate (MTX) or 
csDMARD(s) (at investigator’s discretion) for 24 
weeks. Patient visits are scheduled at W4, W12, 
and W24.
x
LTE period: all the patients who will complete the 6-
month-core-period are allowed to continue the 
treatment with sarilumab, every 2 weeks for a
maximum of another 24 weeks or until the 
commercial availability of sarilumab in France, 
depending whichever comes first. Patient visits are 
scheduled every 12 weeks over the LTE period (at 
W36 and W48).
x
Post-treatment follow-up: each patient will have one 
follow-up visit, between 2 and 4 weeks after his/her 
last administration of sarilumab.
STUDY POPULATION 
Main selection criteria (6-month core 
period)
Inclusion criteria:
x
$GXOWSDWLHQWV\HDUVZLWKmoderately to 
severely active RA according to the American 
College of Rheumatology (ACR)/European League 
against Rheumatism (EULAR) 2010 Rheumatoid 
Arthritis Classification Criteria
x
Patients with moderate to severe disease activity of 


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RA defined as a DAS28-ESR >3.2 at Screening
x
Patients with inadequate response within at least 
the last 3 months or intolerance to current 
csDMARD or to at least one anti-TNF therapy (as 
defined by the investigator)
x
OUDOFRUWLFRVWHURLGVPJGay prednisone or 
equivalent) and NSAIDs or COX-2 (up to the 
maximum recommended dose) are allowed if at a 
stable dose for at least 4 weeks prior to Baseline
x
Permitted csDMARDs are allowed if at a stable dose 
for at least 4 weeks prior to Baseline
x
Females of childbearing potential can participate in 
this study only if using a reliable means of 
contraception during the study and for at least 3 
months following the last dose of sarilumab
x
Female of childbearing potential must have a 
negative pregnancy test at the Screening and 
Baseline visits
x
Patients must have signed a written informed 
consent prior to perform any study-related 
procedures.
Exclusion criteria:
x
Rheumatic autoimmune disease other than RA or 
prior history or current inflammatory joint disease 
other than RA
x
Treatment with any investigational agent within 4 
weeks of Screening 
x
Last RA treament prior to inclusion with any antiJAK 
or biologic DMARD other than anti-TNF
x
Patients treated with anti-TNF (e.i. adalimumab, 
infliximab, certolizumab, golimumab, etanercept) 
before the screening period, which are maintained 
within the 4 weeks before the inclusion (i.e.the first 
injection of sarilumab)
x
Intra-articular or parenteral corticosteroids within 4 
weeks prior to Baseline
x
History of severe allergic or anaphylactic reactions 
to human, humanized, or murine monoclonal 
antibodies (or to any of the excipients associated to 
sarilumab)
x
Stage III or IV cardiac failure according to the New 
York Heart Association classification
x
Evidence of active malignant disease, malignancies 
diagnosed within the previous 10 years (except 
basal and squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix uteri previously 
excised and cured)
x
Patient who is institutionalized due to regulatory or 
legal order or patient who is mentally disabled or 
educationally disadvantaged
x
History of previous gastrointestinal perforation or
diverticulitis
x
Known active current/ recurrent infections (including 


Clinical Trial Protocol
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B and C hepatitis)
NOTE:  in case of latent TB infection the patient may be 
included if a subsequent appropriate anti TB treatment 
is initiated since at least 3 weeks
x
Active tuberculosis or history of incompletely treated 
tuberculosis
x
Evidence of serious uncontrolled concomitant 
disease, including severe uncontrolled 
hypercholesterolemia or hypertriglyceridemia  at 
Screening
x
Hemoglobin <8.5 g/dL at Screening
x
Creatinine clearance <30 mL/min at Screening
x
White blood cells <3000/mm3 at Screening
x
Absolute neutrophil count <2000/mm3 at Screening
x
Absolute lymphocyte count <500/mm3 at Screening
x
Platelet count <150 000 cells/mm3 at Screening
x
AST or ALT >1.5 x ULN at Screening
x
Total bilirubin >ULN at Screening, unless Gilbert’s 
disease has been determined by genetic testing and 
has been documented
x
Total fasting cholesterol >3.50 g/L [9.1 mmol/L]) or 
triglycerides >5.00 g/L [5.6 mmol/L]) at Screening.
Total expected number of patients
140 patients enrolled in 35 university hospitals and
general hospitals centers are expected throughout 
mainland France.
STUDY TREATMENT(s)
Investigational medicinal product(s)
Sarilumab, anti-IL6R mAb (anti-interleukin 6 receptor 
monoclonal antibody)
Formulation:
Single-use prefilled glass syringes of sarilumab 200 mg
(and 150 mg in case of laboratory abnormalities)
Route(s) of administration:
Subcutaneous (SC) route, in abdomen, thigh, or upper 
arm
Dose regimen:
Sarilumab 200 mg is to be administered every 2 weeks 
(q2w) over the both treatment periods (as monotherapy 
or in combination with a csDMARD according to the 
investigator decision).
Non-investigational medicinal product(s)
Formulation:
NA
Route(s) of administration:
Dose regimen:
Post-trial access to study medication 
NA


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ENDPOINTS
Primary endpoint (6-month core period):
Change in the total RAID score from baseline to 
Week24
Secondary efficacy endpoints (6-month core 
period):
x
Values at each assessment visit and changes from 
baseline for the total RAID score, HADS, MAThys, 
FACIT-Fatigue, HAQ-DI, morning stiffness, 
International Physical Activity Questionnaire, and 
patient global assessment of disease activity
x
Values at each assessment visit and changes from 
baseline for ESR, DAS28-ESR, CDAI, and joint 
counts (TJC, SJC)
x
DAS28-ESR Low Disease Activity (LDA) and 
remission, CDAI LDA and remission, at W12 and 
W24
Safety endpoints (6-month core and long-term 
extension periods):
x
Incidence and severity of adverse events (AEs), 
serious and non-serious AEs, AESIs, AEs leading to 
dose modification or treatment withdrawal, AEs
leading to death
x
Physical examination, vital signs, and clinically 
significant laboratory abnormalities over time.
ASSESSMENT SCHEDULE
The study will consist of the following visits:
x
Visit 1 (D-28-D-1): screening
x
Visits of the 6-month core period: 
•
Visit 2 (D1): baseline, first sarilumab 
administration
•
Visit 3 to 5 at W4, W12, and W24, respectively: 
on treatment
x
Visits of the LTE period (if applicable)
•
Visits LTE 1 and LTE 2 at W36 and W48, 
respectively: on treatment
x
Visit PT: post treatment.
At screening and at 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. For an overview of the local laboratory tests, 
see the study flowchart below, which include 
hematology, chemistry, and lipids. A serum pregnancy 
test for women of childbearing potential will be obtained 
at Screening as well. 
PROs (RAID, HADS, MAThyS, FACIT-Fatigue, HAQ-DI, 
duration of morning stiffness, IPAQ, and patient global 
assessment of disease activity) will be assessed 
(completed by patients before all other assessments 
performed during the 6-month core study visits) at 
Baseline, Week 4, Week 12, and Week 24, as well as 
efficacy assessments (ESR, DAS28-ESR, CDAI, and 
joint counts (TJC, SJC, on 28 joints for both counts).


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Safety assessments are performed at each assessment 
visit during the 6-month core period (and over the LTE 
period if applicable) and at the post-treatment visit. They
include Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest including 
symptomatic overdose and pregnancy.
Patients and Investigators must respect the visit 
schedule per study flowchart. If a visit date is changed, 
the next visit should take place according to the original 
schedule.
STATISTICAL CONSIDERATIONS
Sample size determination:
According to the literature and previous studies having 
assessed sarilumab, the standard deviation (SD) of the 
RAID score could be estimated at 2.5 points. On this 
basis, a sample size of 140 included patients in order to 
have at least 112 evaluable patients (assuming almost 
20% of non-evaluable patients), produces a precision, 
two-sided 95% confidence interval (CI), with a distance 
from the mean to the limits that will be less than 0.5 
(considering 20% non-evaluable patients) when the 
estimated SD is 2.5, assuming that the change from 
baseline will be from 30% to 50% of baseline score.
Analysis populations:
x
Intent-to-treat (ITT) population: all patients who met 
the eligibility criteria and who are actually treated. 
x
Safety population: all patients who have signed the 
Informed Consent Form (ICF) and have been 
exposed to at least one dose or part of a dose of 
IMP. 
x
Per-protocol population: patients of ITT population 
without major protocol deviations.
Primary analysis:
The primary study objective is to assess the change in 
RAID score from baseline to W24.
The number of available data, mean, standard deviation, 
median and range (minimum, maximum) will be 
provided with the 95% confidence interval of the mean 
change from baseline to W24.  Main analysis will be 
performed on ITT population. Sensitivity analysis will be 
conducted in reproducing the same analysis using the 
per-protocol population.
In addition, multivariate analyses such as ANCOVA, 
Logistic Regressions and Multiple Correspondences 
analysis can be performed from baseline in order to 
exploratory explain patient profiles.
Analysis of secondary endpoints:
All secondary parameters will be described; 95% CI will 
be provided.


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DURATION OF STUDY PERIOD (per 
patient) 
The total duration of the core study period per patient is 
expected to be approximately 32 weeks:
x
Up to 4-week screening
x
24 weeks treatment 
x
2-4 week post-treatment observations.
For patients who will enter in the LTE period, a 
maximum of another 24 weeks is planned.








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2 TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL.......................................................................................................................1 
1 
FLOW CHARTS.............................................................................................................................11 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................11 
1.2 
STUDY FLOW CHART ..................................................................................................................12 
2 
TABLE OF CONTENTS ................................................................................................................14 
3 
LIST OF ABBREVIATIONS ..........................................................................................................19 
4 
INTRODUCTION AND RATIONALE.............................................................................................20 
4.1 
INTRODUCTION............................................................................................................................20 
4.1.1 
Background on rheumatoid arthritis and treatments......................................................................20 
4.1.2 
Sarilumab.......................................................................................................................................20 
4.1.3 
Patient Reported Outcomes (PROs)..............................................................................................22 
4.2 
STUDY RATIONALE......................................................................................................................23 
5 
STUDY OBJECTIVES ...................................................................................................................24 
5.1 
PRIMARY (6-MONTH CORE PERIOD).........................................................................................24 
5.2 
SECONDARY (6-MONTH CORE PERIOD) ..................................................................................24 
5.3 
EXPLORATORY ............................................................................................................................24 
6 
STUDY DESIGN ............................................................................................................................26 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................26 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................26 
6.2.1 
Duration of study participation for each patient .............................................................................26 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................27 
6.3 
INTERIM ANALYSIS......................................................................................................................27 
7 
SELECTION OF PATIENTS..........................................................................................................28 
7.1 
INCLUSION CRITERIA (6-MONTH CORE PERIOD) ...................................................................28 
7.2 
EXCLUSION CRITERIA (6-MONTH CORE PERIOD) ..................................................................28 
7.2.1 
Exclusion criteria related to study methodology ............................................................................28 


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7.2.2 
Exclusion criteria related to the current knowledge of Sanofi compound......................................29 
7.3 
SELECTION CRITERIA (LTE PERIOD)........................................................................................30 
8 
STUDY TREATMENTS .................................................................................................................31 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ...............................................................................31 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................31 
8.3 
BLINDING PROCEDURES............................................................................................................32 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................32 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING .............................32 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................32 
8.7 
RESPONSIBILITIES ......................................................................................................................33 
8.7.1 
Treatment accountability and compliance .....................................................................................33 
8.7.2 
Return and/or destruction of treatments ........................................................................................33 
8.8 
CONCOMITANT MEDICATION.....................................................................................................34 
8.8.1 
Prohibited medications...................................................................................................................34 
8.8.2 
Permitted medications ...................................................................................................................35 
8.8.3 
Drug interactions............................................................................................................................36 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................37 
9.1 
PRIMARY ENDPOINT ...................................................................................................................37 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................37 
9.2.1 
Secondary efficacy endpoints (6-month core period) ....................................................................37 
9.2.1.1 
Values at each assessment visit and changes from baseline for the total RAID score, 
HADS, MAThys, FACIT-Fatigue, HAQ-DI, morning stiffness, International Physical Activity 
Questionnaire, and patient global assessment of disease activity ................................................37 
9.2.1.2 
Values at each assessment visit and changes from baseline for ESR, DAS28-ESR, CDAI, 
and joint counts (TJC, SJC)...........................................................................................................38 
9.2.1.3 
DAS28-ESR Low Disease Activity (LDA) and remission, CDAI LDA and remission, at W12 
and W24.........................................................................................................................................39 
9.2.2 
Safety endpoints (6-month core and LTE periods)........................................................................39 
9.2.2.1 
Adverse events ..............................................................................................................................39 
9.2.2.2 
Laboratory safety variables............................................................................................................39 
9.2.2.3 
Vital signs.......................................................................................................................................40 
9.2.2.4 
Electrocardiogram variables ..........................................................................................................40 
9.2.2.5 
Other safety endpoints...................................................................................................................40 
9.3 
OTHER ENDPOINTS.....................................................................................................................40 
9.4 
FUTURE USE OF SAMPLES........................................................................................................40 


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9.5 
APPROPRIATENESS OF MEASUREMENTS..............................................................................40 
10 
STUDY PROCEDURES ................................................................................................................41 
10.1 
VISIT SCHEDULE..........................................................................................................................41 
10.1.1 
Screening (Visit 1: Day -28 to Day -1) ...........................................................................................41 
10.1.2 
Baseline examination (Visit 2: first IMP administration).................................................................42 
10.1.3 
Assessments during the 6-month core period (Visit 3 to Visit 5)...................................................43 
10.1.4 
.Assessments during the LTE period (Visit LTE1 and Visit LTE2) ................................................44 
10.1.5 
Assessments at early termination visit...........................................................................................45 
10.1.6 
Post-treatment observations (Visit PT) ..........................................................................................45 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................46 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................46 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product................................46 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................47 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................47 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................47 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................48 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................49 
10.4.1 
Definitions of adverse events.........................................................................................................49 
10.4.1.1 Adverse event ................................................................................................................................49 
10.4.1.2 Serious adverse event ...................................................................................................................49 
10.4.1.3 Adverse event of special interest...................................................................................................50 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................50 
10.4.3 
General guidelines for reporting adverse events...........................................................................50 
10.4.4 
Instructions for reporting serious adverse events..........................................................................51 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................52 
10.4.6 
Guidelines for management of specific laboratory abnormalities..................................................52 
10.4.7 
Guidelines for reporting product complaints (IMP) ........................................................................53 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................53 
10.6 
SAFETY INSTRUCTIONS.............................................................................................................54 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................56 
11 
STATISTICAL CONSIDERATIONS..............................................................................................57 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................57 


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11.2 
DISPOSITION OF PATIENTS .......................................................................................................57 
11.3 
ANALYSIS POPULATIONS...........................................................................................................58 
11.3.1 
Intent-to-treat population................................................................................................................58 
11.3.2 
Safety population ...........................................................................................................................58 
11.3.3 
Per-protocol population..................................................................................................................58 
11.4 
STATISTICAL METHODS .............................................................................................................58 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................58 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................58 
11.4.1.2 Demographic and baseline characteristics ....................................................................................58 
11.4.1.3 Compliance ....................................................................................................................................58 
11.4.1.4 Prior and concomitant treatments..................................................................................................59 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................59 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................59 
11.4.2.2 Secondary analyses.......................................................................................................................59 
11.4.2.3 Multiplicity considerations ..............................................................................................................60 
11.4.3 
Analyses of safety data..................................................................................................................60 
11.5 
INTERIM ANALYSIS......................................................................................................................60 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................61 
12.1 
ETHICAL AND REGULATORY STANDARDS..............................................................................61 
12.2 
INFORMED CONSENT .................................................................................................................61 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................61 
13 
STUDY MONITORING...................................................................................................................63 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................63 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................63 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................63 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................64 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................64 
14 
ADDITIONAL REQUIREMENTS...................................................................................................65 
14.1 
CURRICULUM VITAE....................................................................................................................65 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................65 
14.3 
CONFIDENTIALITY .......................................................................................................................65 


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14.4 
PROPERTY RIGHTS.....................................................................................................................66 
14.5 
DATA PROTECTION.....................................................................................................................66 
14.6 
INSURANCE COMPENSATION....................................................................................................66 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................66 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................67 
14.8.1 
By the Sponsor...............................................................................................................................67 
14.8.2 
By the Investigator .........................................................................................................................67 
14.9 
CLINICAL TRIAL RESULTS..........................................................................................................68 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................68 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................69 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................70 
17 
APPENDICES................................................................................................................................74 
APPENDIX A 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................75 
APPENDIX B 
DOCUMENT(S) RELATED TO THE ASSESSMENT OF 1 (OR MORE) 
ENDPOINT(S)................................................................................................................................77 
APPENDIX C 
OTHER SPECIFIC APPENDICES FOR A GIVEN CLINICAL TRIAL .................................93 
LIST OF TABLES
Table 1 - Summary of adverse event reporting instructions..........................................................................53 


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3 LIST OF ABBREVIATIONS
AE:
adverse event
AESI:
adverse event of special interest
DME:
drug metabolizing enzymes
DTP:
direct-to-patient
ECG:
electrocardiogram
IEC:
independent ethics committee
IMP:
investigational medicinal product
INN:
international nonproprietary name
IRB:
institutional review board
IRT:
interactive response technology
NIMP:
noninvestigational medicinal product
PRO:
patient reported outcome
PV:
pharmacovigilance
SAE:
serious adverse event
WOCBP:
woman of child-bearing potential


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4 INTRODUCTION AND RATIONALE
4.1
INTRODUCTION
4.1.1
Background on rheumatoid arthritis and treatments
Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disease characterized by 
inflammation of the synovium leading to irreversible destruction and disability of the joints (1).
The inflammatory process can also target other organs, characteristically bone marrow (anemia), 
eye (scleritis, episcleritis), lung (interstitial pneumonitis, pleuritis), cardiac (pericarditis) and skin 
(nodules, leukocytoclastic vasculitis). 
It is estimated that approximately 0.5-1% of the adult population in North America and Europe is 
affected by RA (2) with 65-70% of RA patients having progressive disease that leads to joint 
destruction, disability and premature death (3, 4, 5). RA affects three times more women than 
men and the incidence is highest among women over 40 years of age (6).
Apart from symptomatic treatments as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs),
conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) were shown to
maintain or improve physical function and retard radiographic joint damage (7). More recently, 
biological compounds including those targeting tumor necrosis factor (TNF) alpha, B-cells, or T-
cells, have been used successfully to treat RA, and demonstrate greater efficacy in combination 
with the reference csDMARD, methotrexate (MTX). However, about 30-40% of patients fail to 
respond to these therapies (8, 9) and 50-60% fail to achieve a major clinical response (by
American College of Rheumatology [ACR] criteria or good response by European League 
Against Rheumatism [EULAR] criteria).
These limitations have prompted the development of therapies with alternative mechanisms of 
action. Interleukin 6 (IL-6) is a key cytokine involved in the RA pathogenesis causing 
inflammation and joint destruction (10, 11). Inhibition of IL-6 signaling through blockade of the 
IL-6 receptor (IL-6R) was first demonstrated to be effective by tocilizumab, a humanized 
monoclonal antibody (mAb) to the IL-6 receptor, with intravenous (IV) and newly subcutaneous 
(SC) formulations (12-18).
4.1.2
Sarilumab
Sarilumab, a fully human IgG1 mAb produced using a novel technology Velocimmune®
developed by Regeneron, targets IL-6R and inhibits IL-6 signaling. Its binding affinity relative to 
tocilizumab is approximately 20-fold greater (19). Sarilumab has been developed for SC
administration.
In combination with MTX or another csDMARDs, sarilumab demonstrated strong efficacy 
results compared to placebo, from previous pivotal phase III studies conducted by Sanofi and 
Regeneron (20, 21):


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MOBILITY (20)
Sarilumab 200 mg q2w + 
MTX vs. placebo + MTX 
(n=399)
TARGET (21)
Sarilumab 200 mg q2w + 
csDMARD vs. placebo + 
MTX (n=184)
ACR response at Week 24
ACR20 
66.4% vs. 33.4% *
60.9% vs. 33.7% *
ACR50
45.6% vs. 14.6% *
40.8% vs. 18.2% *
ACR70
24.8% vs. 7.3% *
16.3% vs. 7.2% *
HAQ-QI
Mean change from baseline
-0.55 vs. -0.29 at week 16 * 
-0.47 vs. -0.26 at week 12 **
DAS28-CRP at Week 24
/RZGLVHDVHDFWLYLW\
49.1% vs. 16.8% *
40.2% vs. 13.8% ***
Remission (<2.6)
34.1% vs. 10.1% *
28.8% vs. 7.2% ****
* p <0.0001; ** p=0.0004; *** nominal p <0.05; ****p <0.025
At week 24, improvement was stronger in patients treated with sarilumab (200 mg q2w) as 
monotherapy than those receiving adalimumab (40 mg q2w) (21):
MONARCH (21)
Sarilumab 200 mg q2w 
(n=184) vs. adalimumab 40 
mg q2w (n=185)
p value
ACR response at Week 24
ACR20 
71.7% vs. 58.4%
0.0074
ACR50
45.7% vs. 29.7%
0.0017
ACR70
23.4% vs. 11.9%
0.0036
HAQ-QI
Mean change from baseline 
at Week 24
-0.61 vs. -0.43
0.0037
DAS28-ESR at Week 24
Mean change from baseline
-3.28 vs. -2.20
<0.0001
Remission (<2.6)
26.6 % vs. 7.0%
<0.0001
Based on data from previous clinical trials, the most frequent adverse reactions occurred under 
sarilumab treatment were consistent with previous biologic studies: infections, neutropenia,
thrombocytopenia, elevation in lipids, transaminases increased, and injection site reactions; the 
most frequent serious adverse reactions were infections (23).
On the basis of previous development program, sarilumab (Kevzara®) was approved by the 
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in adult patients who responded inadequately or were intolerant to csDMARDs or biologic
DMARDs (23).
Kevzara® is expected to be available commercially in the second half of 2018 in France.
4.1.3
Patient Reported Outcomes (PROs)
Although disease status has been globally improved in RA, and inflammation is better controlled 
since the wide access to biologics, there remain some unmet needs as identified by patients’ 
residual patient burden of disease and comorbidities. 
Over the last 20 years, there has been a growing interest for subjective data and patients’ health 
care perception (self-reported health assessment, quality of life, and satisfaction with health care 
and medication), especially in chronic diseases. Apart from preventing joint destruction and 
disability in RA patients, treatments aim to provide them better health-related quality of life (24-
26) which leads to assess patient’s perspective on outcomes since it is often different from 
physician’s perspective. 
PRO incorporation into clinical practice and in research in RA is widely supported by 
international organizations and professional bodies including the European Patients’ Academy 
on Therapeutic Innovations (EUPATI; http://www.patientsacademy.eu/index.php/en/) and the 
EULAR (25) in Europe, and the Patient-Centered Outcomes Research Institute (PCORI; 
http://www.pcori.org/research-results) and the ACR (27) in the United States; all of whom 
recognize the patients’ unique position in providing direct feedback on their disease.
Regarding RA treatments, PROs include overall disease burden assessment measured by generic 
or specific patient self-reported questionnaires, which assess domains such as pain or physical 
function, but may also include anxiety/ depression, fatigue, sleep and physical activities (28, 29).
Depression is the most frequent comorbidity in RA (30). Such outcomes are of utmost 
importance to patients (31). In fact, patients strive for what they consider to be remission, which 
is normalization of patients’ lives which includes also normal social life, normal physical 
activities etc. Although not all outcomes appear similarly accessible to disease-modifying 
therapies or biologics; since mental well-being is multi-factorial, levels of efficacy on such 
outcomes would be useful information for both patients and caregivers, and could help guide 
prescriptions.
PROs were assessed in RA patients treated with sarilumab in previous phase III studies [in 
combination with MTX or other csDMARD (32, 33) and as monotherapy (21)] showing an 
improvement from baseline by week 24 in patient global assessment of disease activity, pain, 
Health assessment questionnaire disability index (HAQ-DI), Short Form-36 (SF-36) physical 
score, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). 
The Rheumatoid Arthritis Impact of Disease (RAID) scale is a patient-derived score developed 
by EULAR a few years ago (29). This specific composite index comprises the seven most 
important dimensions (measured with a numerical rating scale from 0 to 10) shown as useful for 
the assessment of PROs in RA patients: pain, functional disability, fatigue, emotional and 
physical well-being, sleep disturbance, and coping (29, 34). The RAID was assessed in the 


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international MONARCH and TARGET trials (21, 33), with greater improvement under 
sarilumab compared to placebo, but findings were not conclusive due to adjustment for 
multiplicity of tests. Furthermore, these randomized trials were conducted with the usual caveats 
associated to patient selection and patient characteristics.
In addition, few data are available regarding PROs in French RA patients (29, 35, 36). In 
particular, no French patients were included in the recent interventional comparative study 
aiming to assess PROs (including the RAID scale) in RA patients receiving sarilumab or placebo 
in combination or not with csDMARD (21, 33). Thus, knowing that the Outcome Measures in 
rheumatology (OMERACT) Equity Working Group suggested some heterogeneity in the PROs
according to population characteristics (37), detection for PRO improvement is currently an 
important meaning for France besides efficacy criteria.
4.2
STUDY RATIONALE
This French study will permit data collection from an moderately to severely active RA patient 
population with the aim to analyze relevant data derived from PRO instruments in order to gain 
further insights into efficacy of sarilumab. This is all the more important given that some PROs 
domains were previously scarcely collected while being of great importance for RA patients.
Furthermore they must be taken into account in the shared decision-making process for RA 
treatment (38). 
More specifically, the main objective of this French single-arm, open-label phase IV study is to 
assess the effect of sarilumab on PROs including important but previously little assessed 
domains in particular in France, in patients with moderately to severely active RA and 
inadequate response or intolerance to current csDMARDs or TNF inhibitors.
Among all the studied PROs [RAID, Hospital Anxiety and Depression Scale, HADS (39);
FACIT-F (40); HAQ-DI (41); International Physical Activity Questionnaire, IPAQ (42);
Multidimensional Assessment of Thymic States, MAThyS (43), and patient global assessment of 
disease activity], RAID change from baseline to week 24 is chosen as primary criterion as this 
scale comprises the seven most important dimensions shown as useful for the PRO assessment in 
RA patients (29, 34).
Included patients will receive SC sarilumab 200 mg q2w, in accordance with the Summary of 
Product Characteristics (23). In addition to the efficacy of the product as previously shown, this 
limited number of injections, as done in this phase IV study with patient management closer to 
real-life clinical practice than in previous international clinical trials, may lead to provide a 
positive impact on patients’ perceptions, and then to PROs improvement under treatment.
The 6-month-core period of the SariPRO study will be completed by another maximum 24-week
period to assess long-term safety of sarilumab and to allow patients to pursue their treatment 
until sarilumab is commercially available in France.


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5 STUDY OBJECTIVES
5.1
PRIMARY (6-MONTH CORE PERIOD)
The primary objective of this study is to describe the evolution of the perception of patients 
regarding the effect of sarilumab in combination with conventional synthetic Disease-Modifying 
Anti-Rheumatic Drug (csDMARD) and/or monotherapy on patient-reported impact of disease, 
using the rheumatoid arthritis impact of disease (RAID) questionnaire, in patients with 
moderately to severely active RA and inadequate response or intolerance to current csDMARD 
or TNF inhibitors.
5.2
SECONDARY (6-MONTH CORE PERIOD)
x
To assess the change of the RAID score from baseline (to W4, W12, and W24) in 
patients with moderately to severely active RA and inadequate response or intolerance to 
current csDMARD or TNF inhibitors, treated with sarilumab in combination with 
csDMARD and/or monotherapy.
x
To assess the effect of sarilumab in combination with csDMARD and/or monotherapy on 
other patient-reported outcomes (global assessment of disease activity, disability, 
morning stiffness, fatigue, anxiety/ depression, mood disorders, and physical activities), 
in patients with moderately to severely active RA and inadequate response or intolerance 
to current csDMARD or TNF inhibitors.
x
To assess the efficacy of sarilumab in combination with csDMARD and/or monotherapy 
using DAS28-ESR and CDAI in patients with moderately to severely active RA and
inadequate response or intolerance to current csDMARD or TNF inhibitors.
x
To assess the safety of sarilumab in combination with csDMARD and/or monotherapy in 
patients with moderately to severely active RA and inadequate response or intolerance to 
current csDMARD or TNF inhibitors.
5.3
EXPLORATORY
x
Over the 6-month core period
o
To describe the associations between changes in RAID score and composite disease 
activity scores (DAS28-ESR and CDAI).
o
To describe the associations between changes in HADS score and in composite 
disease activity scores (DAS28-ESR and CDAI)
o
To explore patient profiles (using multivariate method such as multiple 
correspondences analysis).
x
Over the long-term extension period (maximum 24 weeks)


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o
To assess the safety of sarilumab in combination with csDMARD and/or 
monotherapy in patients with moderately to severely active RA and inadequate 
response or intolerance to current csDMARD or TNF inhibitors over the LTE period.
All other analyses that could give interesting information with respect of study objectives will be 
performed after agreement of the Scientific Committee of the study. 


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6 STUDY DESIGN
6.1
DESCRIPTION OF THE STUDY
This is a national, multicenter, open-label, single-arm phase IV study designed to assess the 
effect of sarilumab on patient-reported impact of disease, using the rheumatoid arthritis impact of 
disease (RAID) questionnaire, in patients with moderately to severely active RA and inadequate 
response or intolerance to current csDMARD or TNF inhibitors.
Four study periods are defined for this study:
x
Screening period: within 28 days prior to study treatment start (Baseline visit, Day 1), 
out-patient eligibility is determined at the Screening visit. At Baseline visit, patient’s 
inclusion in the study will be established.
x
6-month core period: patients who fulfil the enrolment criteria will start the 
investigational medicinal product (IMP), SC injection of sarilumab 200 mg every 2 
weeks as monotherapy and/or in combination with methotrexate (MTX) or other
csDMARD (at investigator’s discretion) for 24 weeks. Patient visits are scheduled at 
Baseline, W4, W12, and W24.
x
Long-term extension period: all patients who will complete the 6-month-core-period will 
be allowed to continue the treatment with sarilumab, every 2 weeks for a maximum of 
another 24 weeks or until the commercial availability of sarilumab, depending whichever 
comes first. Patient visits are scheduled every 12 weeks over the LTE period (at W36 and 
W48).
x
Post-treatment follow-up: each patient will have one follow-up visit, between 2 and 4 
weeks after his/her last administration of sarilumab.
Around 140 patients enrolled in 35 university hospital and general hospital centers are expected 
throughout mainland France.
6.2
DURATION OF STUDY PARTICIPATION
6.2.1
Duration of study participation for each patient
The total duration of the 6-month core study period per patient is expected to be approximately 
32 weeks:
x
Up to 4-week for screening
x
24 weeks for the treatment period (sarilumab 200 mg q2w)
x
Between 2 and 4 week for post-treatment observations.
For patients who will enter in the LTE period, a maximum of another 24 weeks is planned.


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6.2.2
Determination of end of clinical trial (all patients)
The end of the clinical trial in all participating sites is reached when the last patient last visit is 
completed per protocol. The last patient last visit will occur 2 to 4 weeks after the last sarilumab 
administration (i.e. at between Week 26 and Week 28 for patients who will not enter the LTE 
study and between Week 50 and Week 52 at a maximum for patients who will enter the LTE 
study).
6.3
INTERIM ANALYSIS
No interim analysis is planned.


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7 SELECTION OF PATIENTS
7.1
INCLUSION CRITERIA (6-MONTH CORE PERIOD)
I 01.
Patient with moderately to severely active RA according to the 2010 EULAR/ACR 
criteria (see Appendix A)
I 02.
Patient with moderate to severe disease activity defined as a DAS28-ESR >3.2 at 
Screening
I 03.
Patient with inadequate response within at least the last 3 months or intolerance to current 
csDMARD or to at least one anti-TNF therapy (as defined by the investigator)
I 04.
OUDOFRUWLFRVWHURLGVPJGD\SUHGQLVRQHRUHTXLYDOHQWDQGnon-steroidal anti-
inflammatory drugs (NSAID) and cyclo-oxygenase-2 inhibitors (COX-2) (up to the 
maximum recommended dose) are allowed if at a stable dose for at least 4 weeks prior to 
Baseline
I 05.
Permitted csDMARDs are allowed if at a stable dose for at least 4 weeks prior to Baseline
I 06.
Patient able and willing to give written informed consent and to comply with the 
requirements of the study protocol.
7.2
EXCLUSION CRITERIA (6-MONTH CORE PERIOD)
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 two subsections.
7.2.1
Exclusion criteria related to study methodology
<18 years of age 
E 01.
Patient unable to understand and write adequately to complete the study PRO assessments
E 02.
Exposure to sarilumab at any time prior to Baseline
E 03.
Use of intra-articular or parenteral corticosteroids within 4 weeks prior to Baseline
E 04.
Treatment with any investigational agent within the 4 weeks of Screening
E 05.
Last RA treament prior to inclusion with any antiJAK or biologic DMARD other than 
E 06.
anti-TNF


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Patients treated with anti-TNF (e.i. adalimumab, infliximab, certolizumab, golimumab, 
E 07.
etanercept) before the screening period, which are maintained within the 4 weeks before 
the inclusion (i.e.the first injection of sarilumab)
Rheumatic autoimmune disease other than RA or prior history or current inflammatory 
E 08.
joint disease other than RA
Evidence of active malignant disease, malignancies diagnosed within the previous 10 
E 09.
years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the 
cervix uteri previously excised and cured)
Patient who is institutionalized due to regulatory or legal order or patient who is mentally 
E 10.
disabled or educationally disadvantaged
7.2.2
Exclusion criteria related to the current knowledge of Sanofi 
compound 
Pregnant or breastfeeding woman
E 11.
Women of childbearing potential not protected by highly-effective contraceptive 
E 12.
method(s) of birth control (as defined in the informed consent form and/or in a local 
protocol addendum/amendment) over the study period and for at least 3 months following 
the last dose of sarilumab, and/or who are unwilling or unable to be tested for pregnancy
History of severe allergic or anaphylactic reactions to human, humanized, or murine 
E 13.
monoclonal antibodies (or to any of the excipients associated to sarilumab)
Immunization with a live/attenuated vaccine within 4 weeks prior to Baseline
E 14.
Stage III or IV cardiac failure according to the New York Heart Association classification
E 15.
History of previous gastrointestinal perforation or diverticulitis
E 16.
Known active current/ recurrent infections (including but not limited to active
E 17.
tuberculosis [TB] or history of incompletely treated TB and atypical mycobacterial 
disease, hepatitis B and C, and herpes zoster)
NOTE:  in case of latent TB infection the patient may be included if a subsequent 
appropriate anti TB treatment is initiated since at least 3 weeks
Positive hepatitis B surface antigen (HbsAg), and/or positive total hepatitis B core 
E 18.
antibody, and/or positive hepatitis C antibody (HCV) at the Screening visit
Evidence of serious uncontrolled concomitant disease, including severe uncontrolled 
E 19.
hypercholesterolemia or hypertriglyceridemia 
Patients with any of the following laboratory abnormalities at the Screening or Baseline 
E 20.
visit:


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x
Hemoglobin <8.5 g/dL 
x
White blood cells <3000/mm3
x
Absolute neutrophil count <2000/mm3
x
Absolute lymphocyte count <500/mm3
x
Platelet count <150 000 cells/mm3
x
Creatinine clearance <30 mL/min
x
AST or ALT >1.5 x ULN.
x
Bilirubin (total) >ULN, unless Gilbert’s disease has been determined by genetic testing 
and has been documented
x
Total fasting cholesterol >3.50 g/L [9.1 mmol/L]) or triglycerides >5.00 g/L [5.6 
mmol/L])
7.3
SELECTION CRITERIA (LTE PERIOD)
All the patients who will complete the 6-month-core period will be allowed to enter the LTE 
period, if sarilumab is not yet commercially available in France (as monotherapy or in 
combination with csDMARDs).


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8 STUDY TREATMENTS
8.1
INVESTIGATIONAL MEDICINAL PRODUCT
The investigational medicinal product (IMP) is sarilumab (Kevzara®) that is expected to be
available commercially in the second half of 2018 in France.
Sarilumab will be supplied by the Sponsor in 1.14 mL ready-to-use, single-use prefilled glass
syringes delivering 200 mg (175 mg/mL) of sarilumab for subcutaneous (SC) injections. A 
patient will use one prefilled syringe for each dosing. In case of specific laboratory abnormalities
over the treatment period (see section 10.4.6 for more details), the Sponsor will supply 1.14 mL 
ready-to-use, single-use prefilled glass syringes delivering 150 mg (131.6 mg/mL) of sarilumab 
for SC injections, using the Intreractive Voice Response System (IVRS).
During the treatment period, the IMP should be administered every 14 days; however an IMP 
administration window of ±3 days is permitted per protocol to accommodate exceptional 
circumstances, eg, laboratory test result pending), ongoing adverse event, or patient scheduling 
difficulty.
Patients and/or their non-professional caregivers will be trained to administer IMP at the start of 
the treatment period. This training must be documented in the patients’ study file. The study 
coordinator or designee may administer the first injection, or allows the patient to self-inject, 
under observation, and provide feedback on technique, thus combining the initial dose 
administration as part of the training procedure on Treatment Period Day 1 (Visit 2). If SC 
injections have to be done on days when the patient has a study visit, the IMP will be 
administered following clinic procedures and blood collection. For doses not given at the study 
site, a diary card will be provided to record information pertaining to these injections; these 
diaries will be kept as source data in the patients’ study file. 
If a patient or non-professional caregiver is completely unable to administer sarilumab at home,
it is permitted that the dose will be administered as described above by a home nurse as 
scheduled.
Sarilumab is administered as subcutaneous injection in the abdomen (except for the 2-inch area 
surrounding the navel), the front of the thigh or in upper arm. The site for each injection should 
be rotated. Injections should not be administered into skin that is sore (tender), bruised, red, hard, 
scarred or damaged. The injection sites will be inspected by the site personnel at each visit and 
any injection site reactions (ISRs) should be documented appropriately on the AE electronic 
Case Report Form (eCRF) page.
8.2
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S)
Not applicable.


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8.3
BLINDING PROCEDURES
Not applicable.
8.4
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP
Not applicable.
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. In particular, study drug 
packaging will be overseen by the Sponsor clinical trial supplies department and bear a label 
with the identification required by local law, the protocol number, drug identification and 
dosage.
The primary treatment supply shall contain two kits of one prefilled syringe per patient in each,
the first for the IMP injection at the inclusion visit and the second for the second injection to be 
done at home. Following kits of one prefilled syringe will be provided for each patient, using the 
IVRS.
Additional treatment kits to provide medication under circumstances as damaged kit or unusable 
kit will be allocated by IVRS.
8.6
STORAGE CONDITIONS AND SHELF LIFE
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in 
a secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures. 
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.
All sarilumab PFS must be stored at a controlled temperature of 2-8qC (with no freezing), and in 
the original carton in order to protect from light. After removing the PFS from the refrigerator, it 
should be allowed to warm up at room temperature before injecting sarilumab (for at least 30 
minutes before using), and it should be administered within 14 days and should not be stored 
above 25ºC.


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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.
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 patients 
enrolled in the study), 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:
x
Proper recording of treatment kit number or packaging number as required on appropriate 
electronic case report form (e-CRF) page for accounting purposes.
x
A diary card will be provided to patients to record home injections. Patients will be asked 
to return all empty drug supply boxes, unused PFS, and diary cards to the clinic at each 
visit as a measure of drug accountability and patient compliance. Sharps containers for 
any used PFS will be provided locally to patients for home usage. After home injections, 
the used syringes must be placed into the sharps containers immediately. The sharps 
containers should be returned to sites and discarded by the site staff at the frequency per 
local schedule. So, sharps containers for used syringes, back-pack and insulated cooling 
bag for transport from sites to patient’s home will be provided by the sponsor to the site 
for the patients.
x
The study coordinator tracks treatment accountability/compliance, either by diary, or by 
counting the number of unused/used treatment kits 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
All partially used or unused treatments will be retrieved by the Sponsor or destroyed at study 
site.


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A detailed treatment log of the returned/destroyed IMP will be established with the Investigator 
(or the pharmacist) and countersigned by the Investigator and the monitoring team. The 
Investigator will not destroy the unused IMP unless the Sponsor provides written authorization.
In this case, written documentation of destruction must contain the following:
x
Identity (kit or packaging numbers and subject numbers) of IMP destroyed
x
Quantity of IMP destroyed
x
Date of destruction
x
Method of destruction
x
Name and signature of responsible person who destroyed IMP.
In case of PFS failure, or if there are any issues with the drug, the syringe should not be 
destroyed, and instead should be returned to the appropriate Sponsor clinical trial supplies 
department for further assessment.
8.8
CONCOMITANT MEDICATION
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s).
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements) used by a patient from 7 days prior to 
Screening to the study completion/early termination visit. All concomitant medications should be 
reported to the Investigator and recorded on the corresponding pages of the patient e-CRF, along 
with a description of the type of drug or procedure, the amount, duration, reason for 
administration of drug, and the outcome of any procedure.
8.8.1
Prohibited medications
The use of any biologic DMARDs, including but not limited to etanercept, infliximab, anakinra,
rituximab, abatacept, tocilizumab, certolizumab, golimumab, adalimumab and any targeted 
synthetic DMARDs such as tofacitinib, as well as any biologic DMARDs or JAK inhibitors 
approved during the study are not permitted throughout the study treatment and until 4 weeks 
following the End-of-Treatment visit. If any of these treatments are used, the patient should be 
discontinued but the patient will continue to be followed up for safety for at least 4 additional 
weeks.
The use of intramuscular (IM), IV and more than one intra-articular glucocorticoid 
injection is not permitted throughout the study treatment and until 4 weeks following the End-
of-Treatment visit. In cases where IM, IV, or more than intra-articular corticosteroids are needed, 
patient’s withdrawal should be considered.
Immunization with a live or attenuated vaccine is prohibited within 4 weeks prior to Baseline, 
for the duration of study participation and 12 weeks after administration of the last dose of IMP.
Treatment with any investigational medicinal product other than sarilumab is not permitted.


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8.8.2
Permitted medications
DMARDs: Treatment with csDMARDs (azathioprine, chloroquine, hydroxychloroquine, 
leflunomide, MTX, sulfasalazine), at a stable dose initiated at least 4 weeks prior to Baseline, is 
permitted during the study. If applicable, DMARDs can be used alone or in combination except 
for the combination of MTX and leflunomide. If applicable, patients should remain on the same 
background csDMARD(s) throughout the study. 
The dose and route of administration of csDMARDs at entry in the study should be continued 
without change during the study period unless an adjustment is necessary for safety reasons. All 
biologic DMARDs are prohibited during the study and must be discontinued and washed out 
prior to the initiation of study treatment. The use of prohibited medications will require the 
patients to be withdrawn from the study.
Folic Acid: In order to minimize MTX toxicity, all patients treated with MTX will receive folic 
acid or equivalent at a dose of at least 5 mg/week. This can either be given as a single weekly 
dose usually 48 hours after MTX administration or be divided into daily doses to achieve at least 
5 mg folic acid per week. It is the Investigator’s decision as to which dosing regimen is used.
Oral corticosteroids: Patients may receive oral corticoVWHURLGVDWGRVHRImg/day 
prednisone or equivalent during the study, if initiated at least 4 weeks prior to Baseline. To treat 
AE for a condition not related to RA that requires a corticosteroid dose modification, increased
doses of oral corticosteroids during the study will be permitted.
Corticosteroids can be stepwise discontinued at the investigator's discretion in eligible patients in
order to achieve a steroid-free condition. After a potential increased dose of oral corticosteroids, 
up to 15 mg of prednisone daily (or equivalent), the corticosteroid dose should be tapered down 
to the previous level as rapidly as medically possible. In cases where increased corticosteroids 
doses for RA conditions can’t be tapered down during the study, patient maintenance in the study 
should be reevaluated based on the investigator’s judgment.
Intranasal, inhaled, or topical corticosteroids as per label are permitted, as needed throughout the 
course of the study.
NSAIDs: Patients may be treated with NSAIDs or cyclo-oxygenase-2 inhibitors (COX-2) at a 
stable dose that was initiated at least 4 weeks prior to Baseline, up to the maximum 
recommended dose during the study. The dose should remain stable during the study, unless dose 
reduction is required for safety reasons. The choice and doses of NSAIDs and COX-2are at the 
discretion of the Investigator. The addition of new NSAIDs during the study treatment period is 
not permitted.
Analgesics (other than NSAIDs) and opioids: Analgesics and opioids up to the maximum 
recommended doses may be used for pain as required. However, patients should not take 
analgesics or opioids within 12 hours prior to a visit where clinical efficacy assessments are 
performed.
Lipid-lowering agents: Lipid lowering drugs are permitted. Dose should be stable for at least 6 
weeks prior to screening. Anti-IL-6 drugs, including sarilumab, are known to increase serum 


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cholesterol levels and this effect will be closely monitored during the study. Use of lipid-
lowering agents in patients with elevated lipids at any time during the study are strongly 
encouraged in conjunction with the treating physician’s clinical judgment and guidelines such as 
National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III, see 
Appendix C).
8.8.3
Drug interactions
In vitro studies demonstrate that IL-6 reduces cytochrome CYP1A2, CYP2C9, CYP2C19, and
CYP3A4 enzyme expression. Caution should be exercised in patients who will start sarilumab
treatment while on therapy with CYP3A substrates (e.g. oral contraceptives or statins).
Sarilumab or tocilizumab, which antagonize IL-6, may normalize the formation of CYP450 
enzymes. As a result, the therapeutic effect of drugs that are metabolized by these CYP450 
isoforms may decrease when RA patients start receiving sarilumab. CYP450 substrates with a 
narrow therapeutic index should be monitored in patients that enter the treatment period. Some 
examples of CYP450 substrates with a narrow therapeutic index that require therapeutic 
monitoring (pharmacodynamics and/or drug concentration) include: warfarin, cyclosporine, 
theophylline, digoxin, antiepileptics like carbamazepine (Carbatrol®, Tegretol®), divalproex 
(Depakote®), phenytoin (Dilantin®), or valproic acid (Depakene®); or antiarrhythmics, like 
disopyramide (Norpace®), procainamide (Procan®, Pronestyl®), or quinidine (Quinidex®, Quin-
Release Quin-G®).


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9 ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT
9.1
PRIMARY ENDPOINT
x
Change in the total RAID score from baseline to Week24.
The Rheumatoid Arthritis Impact of Disease (RAID) is a patient-reported outcome measure 
evaluating the impact of RA on patient quality of life which comprises 7 domains: pain, function, 
fatigue, physical and psychological wellbeing, sleep disturbance and coping. 
Each domain is evaluated using a single question answered by a 0 to 10 numerical rating scale. 
Each domain also has a specific weight assigned by a patient survey. The RAID score is a 
continuous variable ranging from 0 (best) to 10 (worst) (see Appendix B).
The RAID score will be assessed at each assessment visit over the treatment period, from V2 (at 
first IMP administration) to V5 (at Week 24).
9.2
SECONDARY ENDPOINTS
9.2.1
Secondary efficacy endpoints (6-month core period)
9.2.1.1Values at each assessment visit and changes from baseline for the 
total RAID score, HADS, MAThys, FACIT-Fatigue, HAQ-DI, morning 
stiffness, International Physical Activity Questionnaire, and patient 
global assessment of disease activity
All the studied PROs will be assessed at each visit over the treatment period (from V2 to V5).
Questionnaires used are all valid and self-rating reliable scales.
The Hospital Anxiety and Depression Scale (HADS) measures anxiety and depression in both 
hospital and community settings. This questionnaire comprises 14 items divided into two 
subscales: anxiety and depression (see Appendix B). Each item is answered by a 0 to 3 rating 
scale, leading to maximum scores of 21 points for anxiety and depression. A total score up to 19 
indicates a major depressive episode; a total score up to 13 indicates adjustment disorders and 
minor depression.
The Multidimensional Assessment of Thymic States (MAThys) is a multi-dimensional 
assisted self-administered questionnaire comprising five dimensions (emotional reactivity, 
cognition speed, psychomotor function, motivation and sensory perception) divided into 20 items
relating to individual states as perceived by patients for the preceding week (see Appendix B).
Each item is set out as a continuous measure in the form of a visual analogic scale of 10 cm on 
which the subject is asked to make a mark to indicate where he/she is positioned between the two 
predefined extreme propositions.


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The Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) is a symptom-
specific scale that measures fatigue in patients assess with chronic illness therapy over the 7 
preceding days. This scale comprises 13 items scored on a 5-point Likert scale, from 0 (not at 
all) to 4 (very much) (see Appendix B). The figures are reversed during score calculations, so 
that higher score values indicate more favorable conditions. Total scores then range from 0 to 52, 
with lower scores representing greater fatigue.
The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient-oriented 
outcome assessment questionnaire specifically developed to assess the extent of a RA patient’s 
functional ability. It consists of 20 questions referring to eight component sets: dressing/
grooming, arising, eating, walking, hygiene, reach, grip, and activities (see Appendix B).
Knowing that here are 2 or 3 questions for each section, scoring within each section is from 0 
(without any difficulty) to 3 (unable to do). The eight category scores are averaged into an 
overall HAQ-DI score on a scale from zero (no disability) to three (completely disabled). It is not 
truly continuous but has 25 possible values.
The duration of morning stiffness (in minutes) will be self-reported by RA patients.
The International Physical Activity Questionnaire (IPAQ) is a 27-item self-reported 
questionnaire designed to measure physical activity of patient. It comprises several parts (job-
related, transport-related, domestic and leisure-time physical activity) and intensities (moderate, 
vigorous, walking) and includes sitting time (see Appendix B). Based on frequency, duration and
intensity of self-reported physical activity, individuals are categorized into low, moderate and 
high physical activity groups.
The patient global assessment of disease activity measures RA activity as perceived by the 
patient, using a 100 mm horizontal visual analog scale (VAS).
9.2.1.2Values at each assessment visit and changes from baseline for ESR, 
DAS28-ESR, CDAI, and joint counts (TJC, SJC)
At each visit, all the efficacy parameters will be assessed.
The erythrocyte sedimentation rate (ESR) is measured in mm/hr. This laboratory test will be 
performed in a local medical laboratory.
The DAS28 is a combined index for measuring disease activity in RA. The index includes the 
assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP), and 
general health status. For this study, ESR will be used to calculate the DAS28 score. The index is 
calculated using the following formula:
DAS28-ESR  î¥7-&î¥6-&îOQ(65îPtGA
where TJC28 is the tender joint count on 28 joints, SJC28 is the swollen joint count on 28 
joints, ln is the natural log, ESR is the erythrocyte sedimentation rate (mm/hour), i.e., patient’s 
global assessment of disease activity (PtGA using a 100 mm VAS). The 28 joints to be assessed 
are detailed in Appendix B.


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The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
The CDAI is a combined index for measuring disease activity in RA that does not include a 
laboratory test. It is calculated as follows:
CDAI = TJC28 + SJC28 + PtGA (in cm) + PhGA (in cm)
where TJC28 is the tender joint count on 28 joints, SJC28 is the swollen joint count on 28 joints, 
PtGA is patient’s global assessment of disease activity (100mm VAS), and PhGA is the 
physician’s global assessment of disease activity (100mm VAS). The 28 joints to be assessed are 
detailed in Appendix B.
9.2.1.3DAS28-ESR Low Disease Activity (LDA) and remission, CDAI LDA and 
remission, at W12 and W24
A DAS28-(65VFRUHRIUHSUHVHQWVFOLQLFDOUHPLVVLRQDQGDVFRUHRIUHSUHVHQWVORZ
disease activity. 
A CDAI score of 2.8 represents clinical remission and a score of UHSUHVHQWVORZGLVHDVH
activity. 
For both indexes, clinical remission is included in low disease activity.
9.2.2
Safety endpoints (6-month core and LTE periods)
Safety will be assessed, according to the Schedule of Assessment (see Section 1.2), based on
reporting of adverse events (AEs), clinical laboratory results, physical examination, and vital 
signs.
9.2.2.1Adverse events
All AES, including serious AEs (SAEs) and AEs of special interest (AESIs) will be collected at 
every visit. Refer to Section 10.4 to Section 10.7 for details.
9.2.2.2Laboratory safety variables
The clinical laboratory data consist of blood analysis (including hematology, serum 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 analyses will be performed locally, according to the Schedule of 
Assessment (see Section 1.2):
x
Hematology: hemoglobin, platelet count, and complete blood count (CBC)
x
Serum chemistry and liver profile: creatinine clearance, serum iron and 25OHD (at 
Screening and Week 24 only), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and total bilirubin


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x
Serum lipids: total fasting cholesterol, triglycerides, high density lipoprotein (HDL) 
cholesterol, low density lipoprotein (LDL) cholesterol
x
Serology: HbsAg, hepatitis B antibody, and hepatitis C virus antibody (at Screening only 
unless clinically indicated during the trial)
x
Pregnancy test: Local pregnancy tests will be conducted for female patients of child-
bearing potential. Pregnancy test at Screening will be a serum test. All following 
pregnancy tests will be urine tests. If a urine test is positive it must be confirmed by a 
serum pregnancy test
x
TB test at Screening (or within the prior 90 days with no abnormality) unless clinically 
indicated during the trial.
Overnight fasting (>8 hours) prior to blood sampling is required for fasting samples. Patients will 
only be allowed to drink water during this time. Unscheduled laboratory assessments for safety 
issues are permitted at any time.
9.2.2.3Vital signs
Vital signs include pulse rate, systolic and diastolic blood pressure, body weight, and waist 
circumference, according to the Schedule of Assessment (see Section 1.2). The blood pressures 
should be taken after the patient has been seated for at least 5 minutes.
9.2.2.4Electrocardiogram variables
A standard 12-lead electrocardiogram (ECG) will be performed at the Screening visit.
9.2.2.5Other safety endpoints
Not applicable.
9.3
OTHER ENDPOINTS
Not applicable.
9.4
FUTURE USE OF SAMPLES
Not applicable.
9.5
APPROPRIATENESS OF MEASUREMENTS 
The assessments used in this study are standard for the evaluation of therapy in RA patients.


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10 STUDY PROCEDURES
10.1
VISIT SCHEDULE
The visit schedule consists of the following visits:
x
Screening Visit (V1). This visit will be performed over a 28-day period prior to Visit 2. 
No IMP will be administered during this period
x
6-month core period (D1 to Week 24). Four visits are planned after screening: V2 
(baseline, first sarilumab injection at D1), V3 (Week 4 ± 3 days), V4 (Week 12 ± 7 days),
and V5 (Week 24 ± 7 days)
x
LTE period for patients who will complete the 6-month core period: V LTE1 (Week 36 ±
7 days) and V LTE2 (Week 48 ± 7 days) or until the commercial availability of sarilumab 
in France
x
Post-treatment observations (V6). One visit is planned between two and four weeks after 
the last IMP administration.
In case of premature withdrawal, the patient should perform a specific visit as soon as possible
after the last IMP dose administration.
The visits’ schedule is detailed in section 1.2. If a visit date is changed, the next visit should take 
place according to the original schedule.
The patients will be requested to complete PROs questionnaires during their clinical visits (at 
each visit over the 6-month core period and at premature withdrawal if applicable), before any 
other assessments. Over the treatment period, when IMP administration is performed at the time 
of an assessment visit, the injection should be done after all study assessments.
10.1.1 Screening (Visit 1: Day -28 to Day -1)
Written informed consent for participation in the study must be obtained before performing 
any study-specific Screening tests or evaluations. Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.  
Screening tests and evaluations will be performed within 28 days prior to Baseline (see details in 
Section 1.2). Patients must fulfill all entry criteria specified in Section 7 and provide background 
clinical information in order to participate in the study. If a patient fails any inclusion/exclusion 
criteria at Screening, the patient may be re-screened depending on the inclusion/exclusion 
criteria he/she failed and upon authorization by the Sponsor.
An Eligibility Screening Form documenting the Investigator’s assessment of each screened 
patient with regard to the protocol’s inclusion and exclusion criteria is to be completed by the 
Investigator. A screen failure log must be maintained by the Investigator.


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The following items will be checked and recorded by the Investigator or designee:
x
Assess eligibility by review of inclusion/exclusion criteria. Patients who do not meet 
these inclusion/exclusion criteria should not continue the screening process.
x
Record patient’s demography, previous medical and surgical history. Medical history 
should include RA history to confirm the diagnosis and TB history in particular.
x
A general physical examination should be performed during the Screening period 
(between D-28 and D-1). 
x
Record the size of the largest rheumatoid nodule (if applicable), considering that the 
effect of DMARD on rheumatoid nodules are still being debated
x
If at Baseline a chest X-ray has been performed within 90 days that shows no clinically 
significant abnormality, a further chest X-ray is not required. A 12-lead ECG should be 
performed during the Screening period.
x
Record vital signs [pulse rate, systolic and diastolic blood pressure (while seated)].
x
If a tuberculosis assessment (QUANTIFERON, performed locally) has been performed
within 90 days that shows no abnormality, a further tuberculosis assessment is not 
required over the Screening period and at the following study visits, unless clinically 
indicated during the trial.
x
Obtain blood sample serum for female patients of child-EHDULQJSRWHQWLDOIRUȕ-HCG
pregnancy test 
x
Obtain fasting blood samples during the Screening period (performed locally) including
hematology [hemoglobin, complete blood count (CBC), platelet count, and erythrocyte 
sedimentation rate (ESR)], serum chemistry [creatinine clearance, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin count], serum 
iron, 25OHD, fasting lipids [total fasting cholesterol, high density lipoprotein (HDL) 
cholesterol, low density lipoprotein (LDL) cholesterol], and serology (hepatitis B surface 
antigen, hepatitis B antibody, and hepatitis C antibody) during the Screening period only 
unless clinically indicated during the trial). Hematology, serum chemistry, and fasting 
lipid tests have to be performed over the 7-day period before inclusion.
x
Any clinically significant abnormalities should be recorded and documented in 
medical/surgical history
x
Complete the ACR core set assessments including ESR, DAS28-ESR, CDAI, and joint
counts (TJC and SJC on 28 joints). 
x
Patients who meet all the inclusion criteria and none of the exclusion criteria will be 
eligible for the baseline visit.
10.1.2 Baseline examination (Visit 2: first IMP administration)
All Baseline investigations will be performed according to the Schedule of Assessments (see 
details in Section 1.2). 


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All PROs and efficacy assessments performed at the Baseline visit should occur the same day 
and before the first administration of sarilumab. 
The investigator or designee will:
x
Assess eligibility by review of inclusion/exclusion criteria. Patients who do not meet 
these inclusion/exclusion criteria should be excluded from the study prior any study 
treatment administration.
x
Record the general physical examination performed during the Screening period 
(between D-28 and D-1), and reported V2 body weight and waist circumference.
x
Record Baseline chest X-ray and 12-lead ECG.
x
Record vital signs.
x
Ask the patient to complete the following self-assessments: RAID, HADS, MAThyS, 
FACIT-Fatigue, HAQ-DI, duration of morning stiffness, IPAQ, and patient global 
assessment of disease activity (VAS)
x
For female patients of child-bearing potential performed a urine pregnancy test. If the 
urine test is positive it must be confirmed by a serum pregnancy test. 
x
Record the results of hematology, serum chemistry, serum iron, 25OHD, fasting lipids, 
and serology tests results
x
Complete the ACR core set assessments including ESR, DAS28-ESR, CDAI, and joint 
counts (TJC and SJC on 28 joints). 
x
Review concomitant medications
x
Inquire about and record any adverse events/SAEs that could have occurred since the 
signature of the written consent form.
x
If the patient meet all the inclusion criteria and none of the exclusion criteria, proceed to 
the first SC administration of the IMP 
x
For patients able to perform SC injections at home, the investigator or delegate will 
provide training regarding the preparation and injections (at Baseline). For patients and/or 
non-professional caregivers completely unable to perform such injections at home, a 
home nursing will be needed and arrangements must be made to administer IMP at 2-
week intervals.
x
Deliver IMP for the next study period.
x
Schedule an appointment for the next visit. 
For all subsequent visits, the scheduled day should be followed (see details in Section 1.2).
10.1.3 Assessments during the 6-month core period (Visit 3 to Visit 5)
All assessments must be performed on the day of the specified visit (see details in Section 1.2). 
For local laboratory tests required at a given visit (results should be available at this study time-
point), a time window of 3 days prior the visit is allowed.


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The investigator or designee will:
x
Body weight and waist circumference have to be reported only at V5.
x
Record vital signs.
x
Record the size of the largest rheumatoid nodule (if applicable), only at V5.
x
Ask the patient to complete the following self-assessments: RAID, HADS, MAThyS, 
FACIT-Fatigue, HAQ-DI, duration of morning stiffness, IPAQ, and patient global 
assessment of disease activity (VAS)
x
For female patients of child-bearing potential performed a urine pregnancy test. If the 
urine test is positive it must be confirmed by a serum pregnancy test. 
x
Record the results of hematology, serum chemistry, and fasting lipids results at each visit; 
serum iron and 25OHD at the V5 visit only
x
Complete the ACR core set assessments including: ESR, DAS28-ESR, CDAI, and joint 
counts (TJC and SJC on 28 joints). 
x
Review concomitant medications
x
Assess IMP compliance / review patient diary
x
Inquire about and record any adverse events/SAEs.
x
Deliver IMP for the next study period
x
Schedule an appointment for the next visit. 
10.1.4 .Assessments during the LTE period (Visit LTE1 and Visit LTE2)
All the patients who will complete the 6-month-core period are allowed to enter the LTE period
in order to continue the treatment with sarilumab (as monotherapy or in combination) for a 
maximum of another 24 weeks or until the commercial availability of sarilumab in France
All assessments must be performed on the day of the specified visit (see details in Section 1.2). 
For local laboratory tests required at a given visit (results should be available at this study time-
point), a time window of 3 days prior the visit is allowed.
The investigator or designee will:
x
Record vital signs.
x
For female patients of child-bearing potential performed a urine pregnancy test. If the 
urine test is positive it must be confirmed by a serum pregnancy test. 
x
Record the results of hematology, serum chemistry, and fasting lipids results
x
Review concomitant medications
x
Assess IMP compliance / review patient diary
x
Inquire about and record any adverse events/SAEs.


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x
Deliver IMP for the next study period
x
Schedule an appointment for the next visit. 
10.1.5 Assessments at early termination visit
If a patient withdraws from the study at any time point, an early withdrawal visit must be 
completed as soon as possible after the last dose of study drug. If a patient withdraws at a visit, 
this visit should proceed as an early withdrawal visit. In this case, only the withdrawal visit 
assessments should be conducted.
The investigator or designee will:
x
Record body weight and waist circumference.
x
A general physical examination should be performed.
x
Record vital signs.
x
Record the size of the largest rheumatoid nodule (if applicable).
x
Ask the patient to complete the following self-assessments: RAID, HADS, MAThyS, 
FACIT-Fatigue, HAQ-DI, duration of morning stiffness, IPAQ, and patient global 
assessment of disease activity (VAS)
x
For female patients of child-bearing potential performed a urine pregnancy test. If the 
urine test is positive it must be confirmed by a serum pregnancy test. 
x
Record the results of hematology, serum chemistry, serum iron, 25OHD, and fasting 
lipids results.
x
Complete the ACR core set assessments including: ESR, DAS28-ESR, CDAI, and joint 
counts (TJC and SJC on 28 joints). 
x
Review concomitant medications
x
Assess IMP compliance / review patient diary
x
Inquire about and record any adverse events/SAEs.
x
Record the reason(s) for early termination.
10.1.6 Post-treatment observations (Visit PT)
Between 2 and 4 weeks after the last IMP administration (Visit PT), the patient will be required 
to perform a follow-up visit as detailed in Section 1.2.
The investigator or designee will:
x
Record vital signs.
x
For female patients of child-bearing potential performed a urine pregnancy test. If the 
urine test is positive it must be confirmed by a serum pregnancy test. 
x
Review concomitant medications.


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x
Assess IMP compliance / review patient diary
x
Inquire about and record any adverse events/SAEs.
10.2
DEFINITION OF SOURCE DATA
Source documents are defined as original documents, data, and records. They include, but are not 
limited to, hospital records, clinical and office charts, laboratory notes, patient-reported 
outcomes, evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, photographic negatives, microfilm or magnetic media, X-rays and ECG tracings,
patient files, and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
For this study, source documents notably include: 
x
PROs assessments completed par patients (RAID, HADS, MAThyS, FACIT-Fatigue, 
HAQ-DI, duration of morning stiffness, IPAQ, and patient global assessment of disease 
activity)
x
Physician global assessment of disease activity
x
TJC and SJC
x
Patient Home Dosing Diaries.
10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation must be fully documented in the eCRF. In any case, the
patient should remain in the study as long as possible.
10.3.1 Temporary treatment discontinuation with investigational medicinal 
product
Temporary treatment discontinuation decided by the Investigator corresponds to more than one 
sarilumab injection not administered to the patient. A temporary treatment discontinuation
greater than 31 days has to be considered as permanent.
Temporary treatment discontinuation may be considered by the Investigator because of 
suspected or confirmed AEs. Re-initiation of treatment with the IMP will be done under close 
and appropriate clinical/and or laboratory monitoring once the Investigator will have considered 
according to his/her best medical judgment that the responsibility of the IMP in the occurrence of 
the concerned event was unlikely and if the selection criteria for the study are still met (refer to 
the Section 7).


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For all temporary treatment discontinuations, duration must be recorded by the Investigator in 
the appropriate pages of the eCRF.
10.3.2 Permanent treatment discontinuation with investigational medicinal
product(s)
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to re-expose the patient to the IMP at any time
during the study, or from the patient not to be re-exposed to the IMP whatever the reason.
10.3.3 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.
Patients must discontinue sarilumab if they experience any of the following:
x
Pregnancy in female patients
x
Opportunistic infections (including but not limited to tuberculosis and disseminated
herpes zoster) and serious infections 
x
Gastro-intestinal perforations or diverticulitis
x
Neutropenia (ANC <500 cells/mm3)
x
Thrombocytopenia (platelet count <50,000 cells/mm3)
x
ALT or AST elevation of >5 times ULN 
x
Malignancies (with the exception of local basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix uteri that have been excised and cured)
x
Signs/symptoms of anaphylaxis or hypersensitivity following SC administration of 
sarilumab
x
Use of biologic DMARD other than sarilumab
x
Any AEs, per Investigator’s judgment, that may jeopardize the patient’s safety.
Any abnormal laboratory value will be immediately rechecked for confirmation before deciding 
of permanent discontinuation of IMP treatment.
10.3.4 Handling of patients after permanent treatment discontinuation
Patients will be followed-up according to the study procedures 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.


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If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IMP (see Section 1.2).
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed.
10.3.5Procedure 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 without any effect on their care. However, if patients no 
longer wish to take the IMP, they will be encouraged to remain in the study.
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public 
health value of the study.
Patients who withdraw from the study treatment should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals must be recorded by the Investigator in the appropriate screens of the 
eCRF and in the patient’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented.
In addition, a patient may withdraw his/her consent to stop participating in the study. Withdrawal 
of consent for treatment should be distinguished from withdrawal of consent for follow-up visits 
and from withdrawal of consent for non-patient contact follow-up, eg, medical record checks. 
The site should document any case of withdrawal of consent.
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator must make the best effort to re-contact 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 retreated in the study. Their inclusion and 
treatment numbers must not be reused. 


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10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY 
REPORTING
10.4.1 Definitions of adverse events 
10.4.1.1 Adverse event
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.
10.4.1.2 Serious adverse event
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
x
Results in death, or
x
Is life-threatening, or
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.
x
Requires inpatient hospitalization or prolongation of existing hospitalization, or
x
Results in persistent or significant disability/incapacity, or
x
Is a congenital anomaly/birth defect
x
Is a medically important event
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require medical or surgical intervention (ie, specific measures or 
corrective treatment) to prevent one of the other outcomes listed in the definition above.
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:
x
Intensive treatment in an emergency room or at home for:
-
Allergic bronchospasm 
-
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.),
-
Convulsions (seizures, epilepsy, epileptic fit, absence, etc.).
x
Development of drug dependence or drug abuse
x
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN
x
Suicide attempt or any event suggestive of suicidality


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x
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling)
x
Bullous cutaneous eruptions
x
Cancers diagnosed during the study or aggravated during the study 
x
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
x
Suspected transmission of an infectious agent.
10.4.1.3 Adverse event of special interest
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor 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.
Any AESIs will be reported to the Sponsor in the same timeframe as SAEs, ie, within 24 hours, 
as detailed in Section 10.4.5.
For this study, AESIs are defined as:
x
Pregnancy of a female subject in the study
-
It will be qualified as a SAE only if it fulfills one of the seriousness criteria (see 
Section 10.4.1.2)
-
In the event of pregnancy in a female participant, IMP should be discontinued
-
Follow-up of the pregnancy in a female participant is mandatory until the outcome 
has been determined (see Appendix A).
x
Symptomatic overdose (serious or non-serious) with IMP
-
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as at least twice the dose during the planned intervals.
Of note, asymptomatic overdose has to be reported as a standard AE.
10.4.2 Serious adverse events waived from expedited regulatory reporting to 
regulatory authorities
Not applicable.
10.4.3 General guidelines for reporting adverse events
x
All AEs, regardless of seriousness or relationship to IMP, 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.


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x
Whenever possible, diagnosis or single syndrome should be reported instead of 
symptoms. The Investigator should specify the date of onset, intensity, action taken with 
respect to IMP, corrective treatment/therapy given, additional investigations performed, 
outcome, and his/her opinion as to whether there is a reasonable possibility that the AE 
was caused by the IMP or by the study procedure(s). 
x
The Investigator should take appropriate measures to follow all AEs until clinical 
recovery is complete and laboratory results have returned to normal, or until progression 
has been stabilized, or until death, in order to ensure the safety of the patients. This may 
imply that observations will continue beyond the last planned visit per protocol, and that 
additional investigations may be requested by the monitoring team up to as noticed by the 
Sponsor. 
x
When treatment is prematurely discontinued, the patient’s observations will continue 
until the end of the study as defined by the protocol for that patient.
x
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.
Instructions for AE reporting are summarized in Table 1.
10.4.4 Instructions for reporting serious adverse events
In the case of occurrence of an SAE, the Investigator or any designees must immediately:
x
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.
x
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the 
monitoring team whose name, fax number, and 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.
x
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.


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x
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.
10.4.5 Guidelines for reporting adverse events of special interest 
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the corresponding screens in the eCRF.
Instructions for AE reporting are summarized in Table 1.
10.4.6 Guidelines for management of specific laboratory abnormalities
Recommended dose modifications in case of neutropenia, thrombocytopenia, or liver enzyme 
elevations are provided in the following tables.
Low Absolute Neutrophil Count
Lab Value (cells x 109/L) 
Recommendation
ANC greater than 1
Current dose of sarilumab should be maintained.
ANC 0.5-1
Treatment with sarilumab should be withheld until >1 x 109/L.
Sarilumab can then be resumed at 150 mg every 2 weeks and increased 
to 200 mg every 2 weeks as clinically appropriate.
ANC less than 0.5
Discontinue sarilumab.
Low Platelet Count
Lab Value (cells x 103/μL) 
Recommendation
50 to 100
Treatment with sarilumab should be withheld until >100 x 103ȝ/
Sarilumab can then be resumed at 150 mg every 2 weeks and increased to
200 mg every 2 weeks as clinically appropriate.
Less than 50
If confirmed by repeat testing, discontinue sarilumab.
Liver Enzyme Abnormalities
Lab Value
Recommendation
$/7!WR[8/1
Consider dose modification of concomitant DMARDs as clinically
appropriate.


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Liver Enzyme Abnormalities
Lab Value
Recommendation
ALT >3 x and 5 x ULN
Treatment with sarilumab should be withheld until < 3 x ULN.
Sarilumab can then be resumed at 150 mg every 2 weeks and increased to
200 mg every 2 weeks as clinically appropriate.
ALT >5 x ULN
Treatment with sarilumab should be discontinued.
10.4.7 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.
Table 1 - Summary of adverse event reporting instructions
Event 
category
Reporting 
timeframe
Specific events in this 
category
Case Report Form completion
AE form 
Safety  
Complementary 
Form 
Other 
specific 
forms 
Adverse Event 
(non-SAE, non-
AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI 
or AESI) 
Expedited 
(within 24 hours) 
Any AE meeting seriousness 
criterion per Section 10.4.1.2 
Yes 
Yes 
No 
 
 
 
 
 
 
Adverse Event of 
Special Interest  
Expedited 
(within 24 hours) 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
10.5
OBLIGATIONS OF THE SPONSOR
During the course of the study, the Sponsor will report in an expedited manner:
x
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), 
to the regulatory authorities, independent ethics committee (IRB/IEC) as appropriate and 
to the Investigators.  
x
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations.


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x
The AESIs (listed in section 10.4.5) to those regulatory authorities who require such 
reporting.
In this study, some AEs are considered related to the underlying condition and thus will not be
considered unexpected. RA flares are not considered as AEs. Any other AE not listed as an
expected event in the summary of product characteristics or in this protocol will be considered 
unexpected.
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report.
10.6
SAFETY INSTRUCTIONS
Please refer to serious adverse events reporting (see Section 10.4.4), adverse event of special
interest (see Section 10.4.5) definitions and reporting, and guidelines for management of specific
laboratory abnormalities (Section 10.4.6).
Infections
Biologics including sarilumab have been associated with an increased risk of infections. 
Physicians should then exercise caution when considering the use of sarilumab in patients with a 
history of recurring infections or with underlying conditions (e.g., diabetes mellitus) which may 
predispose patients to infections. Sarilumab should not be administered in patients with active 
infection. Therefore patients with active current infection or a history of recurring infection 
(including but not limited to active TB or history of incompletely treated TB and atypical 
mycobacterial disease, hepatitis B and C, and herpes zoster) will be excluded from the study.
The effects of sarilumab on acute reactants, neutrophils, and the signs and symptoms of infection 
should be considered when evaluating a patient for a potential infection. Any infection should be 
reported by the Investigator as an adverse event and a corresponding eCRF form should be filled 
in (type of infection, treatment with antibiotics if any with route of administration).
As all biologics, sarilumab may induce immunosuppression, increasing the risk of reactivation of 
latent TB. As a precautionary measure, patients with active 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, notably based on physical examination, 
negative chest X-ray and TB test over the Screening period.
NOTE:  in case of latent TB infection the patient may be included if a subsequent appropriate 
anti TB treatment is initiated since at least 3 weeks


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Systemic hypersensitivity reactions/anaphylaxis
As infrequent, mild-moderate, systemic hypersensitivity reactions have been observed with 
sarilumab, the patient should be monitored for 30 minutes after the IMP injection when given at 
the study site. Also patient should be advised, when IMP is administered at home, to self-monitor 
for potential signs and symptoms that may suggest a hypersensitive reaction for 30 minutes after 
administration. Any problems should be documented in the patient’s Home 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 (e.g., hospitalization, life 
threatening, etc.; see Section 10.4.1.2) should be reported as SAEs. 
Signs of a possible hypersensitivity reaction include but are not limited to: 
x
Fever, chills, pruritus, urticaria, angioedema, and skin rash.
x
Cardiopulmonary reactions, including chest pain, dyspnea, hypotension, or hypertension.
If clinical criteria for anaphylaxis are met, appropriate treatment should be administered 
immediately and the event should be reported as a SAE.
Diverticulitis and gastrointestinal perforation
Symptomatic diverticulosis, diverticulitis, or chronic ulcerative lower GI disease such as Crohn’s 
disease, ulcerative colitis, or other chronic lower GI conditions might predispose to perforations. 
Therefore patients with a history of previous gastrointestinal perforation or diverticulitis will be
excluded from the study.
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 is known to increase the risk of gastrointestinal perforations. The Investigator 
should be aware of this potential risk and monitor any sign of diverticulitis.
Gastro-intestinal perforation is an AESI with immediate notification to be reported as SAE (see
Section 10.4.4). Confirmed diverticulitis or gastrointestinal ulceration should be reported as AEs.
Management of dyslipidemia
Patients treated with sarilumab have been observed to have increased elevations of all lipid 
parameters, and RA is a known independent risk factor for cardiovascular events. Therefore, as a 
precautionary measure, patients with severe uncontrolled fasting hypercholesterolemia (>3.5 g/L 
[9.1 mmol/L]) or hypertriglyceridemia (>5.00 g/L [5.6 mmol/L]) will be excluded from the 
study.
Patients who are found to have dyslipidemia during the course of the study should be treated 
according to the National Cholesterol Education Program (NCEP)/Adult Treatment Panel 3 
(ATP3; See Appendix C) or applicable local guideline. Also see Section 8.8.2 under concomitant 
medication rules for lipid-lowering therapy.


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Local injection site reactions
In previous clinical trials, no clinically significant injection site reactions (ISRs) were observed. 
Local ISRs, including but not limited, to erythema, induration, pain, and SC emphysema, should 
be reported as an AE, with the event term recorded in AE eCRF as the symptom followed by ‘at 
injection site’ (i.e. ‘erythema at injection site’). If needed, ISRs should be treated topically and 
the treatment(s) should be reported in the eCRF.
10.7
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 primary study objective is to assess the change in RAID score from baseline to W24. A 
sufficient precision (half-length of the 95% confidence interval) is required. According to the 
literature (44, 45, 46) and findings from the MONARCH and TARGET studies (22, 33), the 
standard deviation (SD) of the RAID score could be estimated at 2.5 points. On this basis, a 
sample size of 140 patients (122 evaluable, if 20% non-evaluable patients) produces a 
precision, two-sided 95% confidence interval (CI), with a distance from the mean to the limits 
that will be less than 0.5 when the estimated SD is 2.5. Table below gives the 95% CI of change
from baseline to W24 of RAID score with this precision (0.44), assuming that the change from 
baseline will be from 30% to 50% (MCII defined by Dougados in 2012; 47) of baseline score.
Expected change from baseline 
to W24 of RAID score
(Relative to baseline %)
RAID score at 
Baseline
Expected change from 
baseline to W24 of 
RAID score 
(Absolute value)
 
95% CI
(precision =0.5)
30%
65
2,0
[1,5 ; 2,5]
5
1,5
[1,0 ; 2,0]
3,5
1,1
[0,6 ; 1,6]
50%
6,5
3,3
[2,8; 3,8]
5
2,5
[2,0 ; 3,0]
3,5
1,8
[1,3 ; 2,3]
Note that on MONARCH study (22), the % of change from baseline was 49.6% (3.32/6/69) and in 
TARGET study (33) 47.4% (3.24/6.83).
11.2
DISPOSITION OF PATIENTS
Disposition of patients will be depicted for patient status and patient analysis populations. The
total number of patients for each of the following categories will be described:
x
Enrolled patients
x
Patients failed to be enrolled and the reason for non-enrollment
x
Safety population
x
ITT population
x
Per-Protocol population.


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11.3
ANALYSIS POPULATIONS
11.3.1 Intent-to-treat population
Intent-to-treat (ITT) population: all patients who met all the eligibility criteria and who are 
actually treated.
11.3.2 Safety population
Safety population: all patients who have signed the Informed Consent Form (ICF) and have been 
exposed to at least one dose or part of a dose of IMP.
11.3.3 Per-protocol population
Per-protocol population: patients of ITT population without major protocol deviations. Major 
deviations will be defined in the statistical analyses plan before database frozen. 
11.4
STATISTICAL METHODS
11.4.1 Extent of study treatment exposure and compliance
The extent of study treatment exposure and compliance will be assessed and summarized within 
the safety population.
11.4.1.1 Extent of investigational medicinal product exposure
The duration of IMP exposure is defined as follows last dose date – first dose date + 14 days
regardless of unplanned intermittent discontinuations. 
The IMP dose as well as temporary and permanent discontinuations of the IMP will be described 
(with reasons).
11.4.1.2 Demographic and baseline characteristics
All demographic and baseline characteristics will be summarized in the ITT population using
descriptive statistics.
11.4.1.3 Compliance 
A given administration will be considered non-compliant 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. 
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 <80% will be summarized. 


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11.4.1.4 Prior and concomitant treatments
The prior and concomitant medications will be presented for the Safety population.
Medications will be summarized according to the WHO-DD dictionary, considering the first 
digit of the ATC class (anatomic category) and the first three digits of the ATC class (therapeutic
category). All ATC codes corresponding to a medication will be summarized. Patients will be
counted once in each ATC categories (anatomic or therapeutic) linked to the medication, 
therefore patients may be counted several time for the same medication.
The table for prior and concomitant medications will be sorted by decreasing frequency of
anatomic category followed by all other therapeutic classes. In case of equal frequency regarding
anatomic categories, alphabetical order will be used.
11.4.2 Analyses of efficacy endpoints
11.4.2.1 Analysis of primary efficacy endpoint
The primary study objective is to assess the change in RAID score from baseline to W24. The 
number of available data, mean, standard deviation, median and range (minimum, maximum) 
will be provided with the 95% confidence interval of mean change from baseline to W24. 
Main analysis will be done on ITT population. Sensitivity analysis will be conducted in 
reproducing the same analysis using the per-protocol population.
In addition, multivariate analyses such as ANCOVA (Analyze of Covariance), Logistic 
Regression and Multiple Correspondences analysis can be performed from baseline in order to 
exploratory explain different profiles of patients. The details of theses analyses will be described 
on the statistical analyses plan before database frozen. 
In case of any event mentioned below, the last available endpoint before the considered event 
will be taken in account (for RAID score for primary endpoint and for all other secondary 
endpoints):
x
Lack of efficacy
o
More than one glucocorticoid infiltration per articulation  
o
Dose increase of an ongoing glucocorticoid or start of systemic glucocorticoid 
treatment
o
Change in NSAID due to lack of efficacy or adverse event considered as related 
to treatment by the investigator
x
Missing data
o
Treatment discontinuation due to lack of efficacy or adverse event (except for 
AEs due to NSAID). For all other cases, missing data will not be replaced.
11.4.2.2 Secondary analyses
All secondary parameters will be described. For continuous variables, the number of available 
data, mean, standard deviation, median and range (minimum, maximum) will be provided. 
Categorical variables will be summarized using number and percentage of patients. Patients with 
missing data will not be included in the calculation of percentages. 95% CI will be provided.


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11.4.2.3 Multiplicity considerations
Not applicable: all analyses are descriptive without test.
11.4.3 Analyses of safety data
All safety analyses will be performed on the safety population using the following common 
rules:
The following definitions will be applied to laboratory parameters and vital signs 
x
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs. These abnormal values will be detailed in the Statistical 
Analysis Plan that will be validated before the database freezing.
x
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. 
Death. The following deaths summaries will be generated:
x
Number (%) of patients who died by study period (treatment-emergent AEs, on-study) 
and reasons for death summarized on the safety population 
x
All AEs leading to death (death as an outcome on the AE CRF/eCRF 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 
x
TEAE leading to death (death as an outcome on the AE CRF/eCRF 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. 
11.5
INTERIM ANALYSIS
Not applicable


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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 Sub-investigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the 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 ICF should be signed, name filled 
in and personally dated by the patient or by the patient’s legally acceptable representative, and by 
the person who conducted the informed consent discussion. A copy of the signed and dated 
written ICF will be provided to the patient. 
The ICF 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.
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, labeling documents (summary of product characteristics, 
package insert), Investigator’s curriculum vitae, etc.] and the date of the review should be clearly 
stated on the written IRB/IEC approval/favorable opinion.


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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 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 e-CRF, Discrepancy Resolution Form [DRF] or other appropriate
instrument) in an accurate and legible manner according to the instructions provided and to 
ensure direct access to source documents by Sponsor representatives.
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred.
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub-
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The Sub-
investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information.
13.2
RESPONSIBILITIES OF THE SPONSOR
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the 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 pre-identified 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 curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial.
14.2
RECORD RETENTION IN STUDY SITES
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents.
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial.
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required.
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation.
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
14.3
CONFIDENTIALITY
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, and the results obtained during the 
course of the clinical trial, is confidential, prior to the publication of results. The Investigator and 
any person under his/her authority agree to undertake to keep confidential and not to disclose the 
information to any third party without the prior written approval of the Sponsor.
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality.
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial.
The Investigator and the Sub-investigators shall use the information solely for the purposes of 
the clinical trial, to the exclusion of any use for their own or for a third party's account.


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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 /Sub-investigator not to 
mention any information or the Product in any application for a patent or for any other 
intellectual property rights.
All the results, data, documents and inventions, which arise directly or indirectly from the 
clinical trial in any form, shall be the immediate and exclusive property of the Sponsor.
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial.
As the case may be, the Investigator and/or the Sub-investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents.
14.5
DATA PROTECTION
x
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations
x
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access 
to this data by any unauthorized third party
x
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all 
applicable laws and regulations.
14.6
INSURANCE COMPENSATION
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
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.


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The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information.
The Investigator will make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data, and documents.
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection.
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections.
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor.
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections.
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE 
CLOSE-OUT OF A SITE
14.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 
x
The information on the product leads to doubt as to the benefit/risk ratio
x
Patient enrollment is unsatisfactory
x
The Investigator has received from the Sponsor all IMP, means, and information 
necessary to perform the clinical trial and has not included any patient after a reasonable 
period of time mutually agreed upon
x
Noncompliance of the Investigator or Sub-investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach 
of the ICH GCP
x
The total number of patients are included earlier than expected.
In any case the Sponsor will notify the Investigator of its decision by written notice.
14.8.2 By the Investigator
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial. 


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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 twelve (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 re-
collected if necessary.


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16 BIBLIOGRAPHIC REFERENCES
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17 APPENDICES


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Appendix A
Contraceptive guidance and collection of pregnancy information
DEFINITIONS
Woman of childbearing potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy.
3. Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) 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 measurement is insufficient. 
-
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the non-hormonal 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 
enrollment.
CONTRACEPTION GUIDANCE
Female participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the following 
Table.
Table 2: Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly
x
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb
 oral


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 intravaginal
 transdermal
x
Progestogen-only hormone contraception associated with inhibition of ovulation
 oral
 injectable
Highly Effective Methods That Are User Independenta
x
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb
-
Intrauterine device (IUD)
-
Intrauterine hormone-releasing system (IUS)
x
Bilateral tubal occlusion
Vasectomized partner
A vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.
NOTES:
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may 
reduce the efficacy of the contraceptive method. In this case TWO highly effective methods of 
contraception should be utilized during the treatment period and for up to 3 months after treatment
after the last dose of study treatment.


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Appendix B
Document(s) related to the assessment of 1 (or more) endpoint(s)
2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis


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APPENDIX
The 28 joints to be assessed are as followed.


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APPENDIX
RAID (Rheumatoid Arthritis Impact of Disease)


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APPENDIX
HADS (Hospital Anxiety and Depression Scale)


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APPENDIX
FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy – Fatigue) – Version 4


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APPENDIX
HAQ-DI (Health Assessment Questionnaire – Disability Index)


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Clinical Trial Protocol
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Page 84


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APPENDIX
IPAQ (International Physical Activity Questionnaire))


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Page 87


Clinical Trial Protocol
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Page 88


Clinical Trial Protocol
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Page 89


Clinical Trial Protocol  
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Page 90
APPENDIX


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Page 91


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Study Number: SARILL08755 - INN
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APPENDIX
Patient global assessment of disease activity
Considering all the ways that your rheumatoid arthritis affects you, rate how you are doing on the 
following scale by placing a vertical mark on the line:
 
Physician global assessment of disease activity
Place a vertical mark on the line for how you would assess your patient’s current activity


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Appendix C
Other specific appendices for a given clinical trial
New York Heart Association Classification of Heart Failure


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APPENDIX
National Cholesterol Education Program Adult Treatment Panel III


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APPENDIX 
SmPC sarilumab

SAP_001.pdf: 
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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 
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Appendix A: Derived data 
34 
Appendix B: Decision tables 
40 
Appendix C: Rheumatoid Arthritis Impact of Disease - RAID questionnaire 
43 
Appendix D: Hospital Anxiety and Depression Scale (HADS) 
44 
Appendix E: FACIT Fatigue Scale (Version 4) 
45 
Appendix F: Health Assessment Questionnaire – Disability Index (HAQ-DI) 
46 
Appendix G: International Physical Activity Questionnaire (IPAQ) 
49 
Appendix H: Multidimensional Assessment of Thymic States (MAThys) 
53 
Appendix I: Global assessment of disease activity 
55 
Appendix J:  Potentially clinically significant abnormalities (PCSA) criteria 
56 
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