Clinical trial NCT01146652
Conditions: Rheumatoid Arthritis
Sponsor: Sanofi
Start date: 2010-06-21; Completion date: 2020-12-31
Enrollment: 2023 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Main Study:

Primary Objective:

Assess the long term safety of sarilumab in participants with rheumatoid arthritis (RA).

Secondary Objective:

Assess the long term efficacy of sarilumab in participants with RA.

Sub-Study:

This phase 3, open label sub-study was aimed to assess the usability of PFS-S when used by participants with moderate or severe RA, or their professional or non-professional healthcare providers in an unsupervised real-world situation. To mimic the real-world practice, the sub-study was incorporated into the LTS11210 study without additional visits compared to the scheduled visits in the main study. The duration of this sub-study was 12 weeks.

Detailed description:
The maximum duration of the study was up to 523 weeks:

* Up to 1-week of screening, if any.
* At least 264 weeks of open label treatment phase and up to 516 weeks as maximum.
* 6-week post-treatment follow-up as required per protocol.

Arms: arm 1: Participants who completed any of initial studies:Part A or B of EFC11072, ACT11575, EFC10832 or SFY13370 were enrolled in LTS11210 and received sarilumab 150 milligrams (mg) subcutaneously (SC) once weekly (qw). Dose could be reduced to 150 mg every 2 weeks (q2w) due to neutropenia, thrombocytopenia or increase in liver enzymes (alanine aminotransferase \[ALT\]). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), participants already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per participant was at least 264 weeks from first study drug administration in LTS11210. Participants continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Participants who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking. arm 2: Participants who completed study EFC13752 were enrolled in LTS11210 and received sarilumab 200 mg q2w. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). Treatment duration per participant was at least 264 weeks from first study drug administration in LTS11210. Participants continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks).
Interventions: intervention 1: SAR153191 (REGN88)
Intervention descriptions: intervention 1: Pharmaceutical form: solution

Route of administration: subcutaneous

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°2.0 (04-DEC-2009) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 9 
COMPOUND:  Sarilumab (SAR153191) 
A multi-center, uncontrolled extension study evaluating the efficacy and safety of 
sarilumab in patients with active Rheumatoid Arthritis (RA) 
STUDY NUMBER:  LTS11210 
STUDY NAME: SARIL-RA-EXTEND 
VERSION DATE / STATUS:  31-Aug-2015 / Approved 
CLINICAL STUDY DIRECTOR:  
 
Protocol Amendment 9  
Version number: 1 (electronic 1.0) 
Date: 31-Aug-2015 
Amended Clinical Trial Protocol 8  
Version number: 1 (electronic 10.0) 
Date: 17-Jul-2014 
Protocol Amendment 8 (includes local 
amendments 6 and 7) 
Version number: 1 (electronic 2.0) 
Date: 17-Jul-2014 
Amended Clinical Trial Protocol 7 
(Local-UK) 
Version number: 1 (electronic 6.0) 
Date: 01-Jul-2013 
Protocol Amendment 7 (Local-UK) 
Version number: 1 (electronic 1.0) 
Date: 01-Jul-2013 
Amended Clinical Trial Protocol 6 
(Local-Portugal) 
Version number: 1 (electronic 2.0) 
Date: 27-Mar-2013 
Protocol Amendment 6 (Local-
Portugal) 
Version number: 1 (electronic 1.0) 
Date: 27-Mar-2013 
Amended Clinical Trial Protocol 5 
Version number: 2 (electronic 2.0) 
Date: 28-Jan-2013 
Protocol Amendment 5 
Version number: 1 (electronic 1.0) 
Date: 31-Oct-2012 
Amended Clinical Trial Protocol 4 
Version number: 1 (electronic 6.0) 
Date: 08-Aug-2012 
Protocol Amendment 4 
Version number: 1 (electronic 1.0) 
Date: 08-Aug-2012 
Amended Clinical Trial Protocol 3 
Version number: 1 (electronic 5.0) 
Date: 24-Jan-2012 
Protocol Amendment 3 
Version number: 1 (electronic 1.0) 
Date: 24-Jan-2012 
Amended Clinical Trial Protocol 2 
Version number: 3 (electronic 4.0) 
Date: 26-May-2011 
Protocol Amendment 2 
Version number: 1 (electronic 2.0) 
Date: 26-May-2011 
Amended Clinical Trial Protocol 1 
Version number: 2 (electronic 2.0) 
Date: 10-Jan-2011 
Protocol Amendment 1 
Version number: 2 (electronic 2.0) 
Date: 10-Jan-2011 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date: 16-Feb-2010 
EudraCT or IND number:  2010-019262-86 / 100,632 
(electronic 1.0)
NCT01146652


Amended Clinical Trial Protocol 9 
31-Aug-2015
SAR153191-LTS11210  
Version number:  1
Property of the Sanofi group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
Tel: 
Fax: 
E-mail:
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail:
SPONSOR 
Company: 
Address: 
Sanofi recherche & développement  
1 avenue Pierre Brossolette 
91380 Chilly-Mazarin Cedex 
FRANCE 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
(electronic 
 
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Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
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Page 3 
 
CLINICAL TRIAL SUMMARY 
COMPOUND:  Sarilumab 
STUDY No.:  LTS11210 
TITLE 
A multi-center, uncontrolled extension study evaluating the efficacy 
and safety of sarilumab in patients with active Rheumatoid Arthritis 
(RA). 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
STUDY OBJECTIVE(S) 
To document the long term safety and efficacy of sarilumab. 
STUDY DESIGN 
An uncontrolled open label extension study of sarilumab 200 mg 
every other week (q2w); lasting 264 weeks from the first IMP 
administration in LTS11210. In addition the patients will continue to 
be treated beyond 264 weeks until sarilumab is commercially 
available in their country or until 2020 at the latest when the study 
will be closed. (In the UK the duration of treatment will be 264 weeks 
from the first study drug administration in LTS11210). At the time of 
inclusion in this long-term extension, patients may have been 
exposed to sarilumab or placebo or active comparator for 2 to 52 
weeks, depending on the study in which they were initially included. 
The sarilumab dose is reduced to 150 mg q2w in case of 
neutropenia, thrombocytopenia, or an increase in liver enzymes 
(alanine aminotransferase (ALT).  
A 12-week optional sub-study to evaluate the usability of pre-filled 
syringe with safety system (PFS-S) will be conducted in some 
countries. Patients in selected sites in those countries may be 
offered the opportunity to participate in this PFS-S sub-study.  
STUDY POPULATION  
Main selection criteria: 
Inclusion criteria 
Patients with RA who were randomized:  
• in the study EFC11072 (a randomized, double-blind, placebo-
controlled study in patients with active rheumatoid arthritis who 
are inadequate responders to MTX therapy) 
- 
and who have completed Part A (12 weeks) or Part B 
(52 weeks) of the study EFC11072. 
- 
or patients randomized in Part B of EFC11072 to a 
treatment arm subsequently not retained following 
pivotal dose selection. 
• in the study ACT11575 and completed the treatment period. 
• in the study EFC10832 
- 
and completed the 24-week study treatment period. 
- 
or patients from 12 weeks onward with per protocol-
defined  lack of efficacy 
• in the study SFY13370 and completed the treatment period 
• in the study EFC13752 and completed the treatment period  
Exclusion criteria 
− 
Patients with any adverse event leading to permanent 
study drug (active or placebo) discontinuation in a prior 
study 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
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Property of the Sanofi group - strictly confidential 
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− 
Patients with an abnormality(ies) or adverse event(s) that 
per investigator judgment would adversely affect 
participation of the patient in the study 
Total expected number of patients: 
Maximum number of patients = Approximately 2000 patients. 
Expected number of sites: 
Approximately 400 sites 
STUDY TREATMENT(s) 
 
Investigational Medicinal Product(s) 
 
Formulation 
Sarilumab (anti-Interleukin 6Rα monoclonal antibody (Anti-IL6Rα 
mAb)   
Two different pharmaceutical forms are used in the study: C1F2 
used in vials and C2F3 (pivotal formulation) used in prefilled 
syringes. 
Before Phase 3 pivotal dose selection decision:  vials 150 mg 
(75 mg/ml)  
After Phase 3 pivotal dose selection decision, and prior to 
availability of prefilled syringes: vials 150 mg (75 mg/mL), and 
200 mg (100 mg/mL)  
After Phase 3 pivotal dose selection decision, upon availability 
of prefilled syringes:   prefilled syringes filled with 150 mg 
(131.6 mg/ml) or 200 mg (175 mg/ml) of drug product 
In the sub-study: prefilled syringes with a needle safety shield 
(PFS-S) with exactly the same IMP formulation as the PFS used in 
the main study  
Route(s) of administration: 
Subcutaneous (SC) injection in the abdomen, thigh, or upper arm 
Injection volume: 2 mL (vials); 1.14 mL (prefilled syringes) 
Dose regimen: 
Before the phase 3 pivotal dose selection decision, the sarilumab 
dose was 150 mg weekly (qw) (dose reduction to 150 mg q2w in 
case of neutropenia, thrombocytopenia, or an increase in liver 
enzymes (ALT). 
After the phase 3 pivotal doses were selected; the sarilumab dose is 
200 mg q2w and the reduced dose is 150 mg q2w.  
Note: Patients enrolled in the study prior to the dose selection 
decision and receiving 150 mg qw were switched to 200 mg q2w. 
Patients who prior to the dose selection decision were assigned to 
the step-down dose of 150 mg q2w because of a safety issue 
continued to receive sarilumab 150 mg q2w. 
Noninvestigational Medicinal Products 
(except EFC13752 patients) 
One or a combination of non-biologic disease modifying drugs 
(DMARDs). 
Folic/Folinic acid in patients using MTX. 
Formulation, route of administration and dose regimen should follow 
the applicable local labeling information. 
PRIMARY AND SECONDARY 
ENDPOINT(S) 
 
Primary endpoint:  
Safety assessment of sarilumab over time. 
Secondary Endpoint(s): 
• 
The proportion of patients who achieve American College 
of Rheumatology criteria ACR20/ACR50/ACR70, DAS28 
(Disease activity score) Remission, and EULAR (European 
League against Rheumatism) Response over time. 
• 
DAS28-CRP over time 
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Amended Clinical Trial Protocol 9  
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• 
HAQ-Dl (Health assessment questionnaire – Disability 
index) results over time. 
• 
Van der Heijde modified total Sharp score over time and 
incidence of radiographic progression of the van der Heijde 
modified total Sharp score for the subset of patients who 
previously completed study EFC11072, Part B (Cohort 2 
and Cohort 1 selected dose arms).  
• 
Each component of the ACR over time. 
• 
Health economic endpoints and Patient reported 
outcomes: patients will continue in evaluation of the health 
economic endpoints as per the initial study.  
ASSESSMENT SCHEDULE 
The last visit (EOT visit) of EFC11072, ACT11575, EFC10832, 
SFY13370, or EFC13752 will be used as the initial LTS11210 visit. 
All patients who agree to participate in the LTS11210 will need to 
sign a new informed consent form specific for this study.  At D1, after 
confirmation of eligibility, patients will be enrolled in the LTS11210 
study.  
Patients will have site visits at weeks 4, 8, and 12, then every 
12 weeks until the 2nd year of treatment in the study (Week 96). 
After 2 years of study participation, safety assessment and 
laboratory tests will take place at 24-week intervals. In addition, there 
will be visits at 24-week intervals in between regular study visits for 
distribution of IMP kits and recording of AEs only (in Portugal and 
Sweden, hematology and liver function test evaluations will be 
performed at all IMP dispensing visits until end of treatment) . After 
264 weeks in LTS11210, some assessments will no longer be 
required in either scheduled visits or EOT visit (see Section 1.2).  
Additional laboratory testing (central) including hematology and liver 
function tests will be performed at week 2, week 6, and week 10 (site 
or home visits). 
Efficacy assessments will be performed at Weeks 0, 4, 8, 12 and 
then every 12 weeks up to Week 96 and then every 24 weeks until 
the end of treatment. 
Health economic assessments and Patient Reported outcomes 
(PROs) defined per initial study will be performed every 12 weeks up 
to Week 96 and then every 24 weeks until Week 264.  PROs will not 
be assessed after Week 264, including EOT if EOT is after Week 
264. 
Patients who completed EFC11072 Part B will have an additional 
X-ray evaluation at week 48, 96, 144, 192 (±14 days for each 
evaluation) or at EOT if EOT prior to Week 192.  
Electrocardiograms (ECGs) will be performed at the initial visit, week 
48, 96, 144, 192, 240 and 264 or EOT. ECGs will not be performed 
after Week 264, including EOT if EOT is after Week 264. 
Adverse events will be collected throughout the study. 
Pharmacokinetic samples will be collected at V1 or V1/V2, V4 
(Week 4), V7 (Week 12),  every 12 weeks thereafter through year 2 
and then every 24 weeks until the end of treatment and at the 
Post-Treatment follow-up visit 6 weeks after the end of treatment. 
(electronic 
 
 
 
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31-Aug-2015 
SAR153191-LTS11210  
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Specific serum samples will be taken during the study to test for anti-
drug antibody to sarilumab at week 12, every 12 weeks thereafter 
through year 2 and then every 24 weeks until the end of treatment 
and at the Post-Treatment follow-up visit 6 weeks after the end of 
treatment. 
Serum samples to store for future biomarker analyses will be 
collected at the initial visit, week 2, 12, and 48 (except for EFC13752 
patients). Whole blood to store for future ribonucleic acid (RNA) 
expression analysis will be collected at week 0 (baseline) and week 
2, except for patients from study SFY13370 and EFC13752. 
There will be a 6-week post treatment observation period for patients 
with early discontinuation and for patients who completed the 
planned treatment period. In patients who complete sarilumab 
treatment per protocol in countries where sarilumab is commercially 
available the post treatment follow-up visit may be cancelled if the 
patient initiates treatment with commercial sarilumab during the post 
treatment follow-up period. However, in this case, a telephone 
contact must be established with the patient to capture all AEs 
occurring up to the 1st administration of commercial sarilumab. 
STATISTICAL CONSIDERATIONS 
 
Patient Population: 
The primary analysis population will be safety population which is 
defined as all patients who have received at least one dose of 
treatment.   
Analysis Methods: 
The safety analyses will be based on the reported adverse events, 
clinical laboratory evaluations, vital signs, and 12-lead ECGs. The 
number and proportion of patients who experience an adverse event 
will be summarized by treatment group.  Other categorical variables 
will be described in the same way.  Continuous variables will be 
described using the mean, standard deviation, median, minimum 
and maximum.  All summaries will be based on observed cases only; 
missing response data will not be imputed. 
For efficacy variables, descriptive statistics will be provided and 95% 
confidence intervals will be calculated if appropriate. 
Descriptive statistics will be provided for the van der Heijde modified 
total Sharp score for the subset of patients who previously 
completed study EFC11072, Part B. 
Data analysis results for patients who roll over from the EFC13752 
study will be presented separately as sarilumab is administered as 
monotherapy in the EFC13752 and these patients will continue to be 
on sarilumab monotherapy in the LTS11210 study. 
DURATION OF STUDY PERIOD (per 
patient)  
Duration of the study treatment will be at least 264 weeks from the 
first study drug administration in LTS11210, or until sarilumab is 
commercially available in the patient’s country whichever later, but 
no later than 2020 when the study will be closed. (In the UK the 
duration of treatment will be 264 weeks from the first study drug 
administration in LTS11210).  
The maximum duration of the study is expected to be approximately 
523 weeks: 
Up to 1-week of screening, if any 
 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
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Up to 516-week open label treatment phase (for the earliest patients 
enrolled in LTS11210 in 2010 if sarilumab is not commercialized by 
2020) 
6-week post-treatment follow-up as required by the protocol 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
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Page 8 
1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
1.1.1 Graphical Study Design for Patients in ACT11575 and EFC11072 Part A or Part B Cohort 1 
 
Last treatment visit of 
ACT11575 and EFC11072 
Part A or Part B Cohort 1 
Initial LTS11210 visit
Screening 
period
Treatment Period
D-7
D1 
SAR153191 (200mg q2w)
Duration of the study treatment will be at least 264 
weeks from the first study drug administration in 
LTS11210, or until sarilumab is commercially available 
in the patient’s country whichever later, but no later than 
2020 when the study will be closed. 
  
The dose regimen will change 
at the time of the dose 
selection for phase 3 if 
patients have been included 
before.
SAR153191 (150mg qw)
Wk 264
Year 2020
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1.1.2 Graphical Study Design for Patients in EFC11072 Part B Cohort 2, EFC10832, SFY13370, and EFC13752 
 
 
Treatment Period
D1
SAR153191 (200mg q2w)
Duration of the study treatment will be at least 264 weeks 
from the first study drug administration in LTS11210, or 
until sarilumab is commercially available in the patient’s 
country whichever later, but no later than 2020 when the 
study will be closed. 
  
Wk 264 
Year 2020
Last treatment visit of  
EFC11072 Part B Cohort 2, 
EFC10832, SFY13370, or 
EFC13752 
Initial LTS11210 visit 
In the UK the duration of treatment will be 264 weeks 
from the first study drug administration in LTS11210. 
(electronic 
 
 
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Page 10 
1.2 
STUDY FLOWCHART 
1.2.1 Study Flow Chart for Patients Enrolling From ACT11575 and EFC11072 Part A or Part B Cohort 1 
 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 
15 
 
 
Wk 2
Day 29
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71
 
 
Wk 10
D85 
 
 
Wk 12
Wk 24-96  
(every 
12  wks)  
 
Wk24, 36, 
48, 60, 72, 
84, 96 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a 
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 
312, …, 504a
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days)
V 4 
(±3 
days)
HV 5c
(±3 
days)
V 6 
(±3 
days)
HV 
6.1c
(±3 
days)
V 7 
(±3 
days)
V 8 to V 14 
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days) 
V49 (±3 days)
V50(±3 days) 
Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Previous 
medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking, alcohol, 
and illicit drug use 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 
15 
 
 
Wk 2
Day 29
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71
 
 
Wk 10
D85 
 
 
Wk 12
Wk 24-96  
(every 
12  wks)  
 
Wk24, 36, 
48, 60, 72, 
84, 96 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a 
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 
312, …, 504a
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days)
V 4 
(±3 
days)
HV 5c
(±3 
days)
V 6 
(±3 
days)
HV 
6.1c
(±3 
days)
V 7 
(±3 
days)
V 8 to V 14 
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days) 
V49 (±3 days)
V50(±3 days) 
Detail history for 
tuberculosis (TB) 
and opportunistic 
infection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examinatione 
Xd 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Confirm eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
dispensingb   
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Study drug 
complianceb 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature, 
heart rate, blood 
pressure 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Weight in Kg 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
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Amended Clinical Trial Protocol 9  
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Page 12 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 
15 
 
 
Wk 2
Day 29
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71
 
 
Wk 10
D85 
 
 
Wk 12
Wk 24-96  
(every 
12  wks)  
 
Wk24, 36, 
48, 60, 72, 
84, 96 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a 
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 
312, …, 504a
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days)
V 4 
(±3 
days)
HV 5c
(±3 
days)
V 6 
(±3 
days)
HV 
6.1c
(±3 
days)
V 7 
(±3 
days)
V 8 to V 14 
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days) 
V49 (±3 days)
V50(±3 days) 
Efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACR disease core 
seth 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X-ray (hand, feet)g 
Xd 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Health Economic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 
Xd 
 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
WPAI  
Xd 
 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
FACIT-Fatigue, 
Sleep 
questionnaire 
Xd 
 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis 
assessments 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
AE/SAE recording 
(if any) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High sensitive- C- 
Reactive protein 
(hs-CRP) 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
Property of sanofi - strictly confidential 
Page 13 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 
15 
 
 
Wk 2
Day 29
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71
 
 
Wk 10
D85 
 
 
Wk 12
Wk 24-96  
(every 
12  wks)  
 
Wk24, 36, 
48, 60, 72, 
84, 96 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a 
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 
312, …, 504a
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days)
V 4 
(±3 
days)
HV 5c
(±3 
days)
V 6 
(±3 
days)
HV 
6.1c
(±3 
days)
V 7 
(±3 
days)
V 8 to V 14 
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days) 
V49 (±3 days)
V50(±3 days) 
Hematology: CBC 
and differentiali 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Liver Function 
Tests (LFTs)j 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Lipids (fasting)k 
Xd 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
Clinical  chemistry 
(fasting)l 
Xd 
 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
ANA/Anti-ds-
DNAm 
Xd 
 
 
 
 
 
 
 
X  
 
X  
X 
X 
 
Dipstick urinalysis 
n 
Xd 
 
 
 
 
X 
 
X 
X 
 
X 
 
Xf 
 
Urine pregnancy 
test (for women of 
childbearing 
potential) o 
Xd 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Dispense urine 
pregnancy kits o 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
 
12-lead 
electrocardiogram 
p 
Xd 
 
 
 
 
 
 
 
X 
 
X 
 
Xf 
 
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
Property of sanofi - strictly confidential 
Page 14 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 
15 
 
 
Wk 2
Day 29
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71
 
 
Wk 10
D85 
 
 
Wk 12
Wk 24-96  
(every 
12  wks)  
 
Wk24, 36, 
48, 60, 72, 
84, 96 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a 
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 
312, …, 504a
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days)
V 4 
(±3 
days)
HV 5c
(±3 
days)
V 6 
(±3 
days)
HV 
6.1c
(±3 
days)
V 7 
(±3 
days)
V 8 to V 14 
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days) 
V49 (±3 days)
V50(±3 days) 
Other analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rheumatoid 
factorq 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Xf 
 
Serum IL-6 v 
Xd 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
Pharmacokinetics 
r 
Xd 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
Anti-sarilumab 
antibody 
Xd 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
Serum sample to 
be stored  for 
future biomarkers 
s 
Xd 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
Expression RNA t 
 
Xd 
X 
 
 
 
 
 
 
 
 
 
 
 
a EOT visit and follow up visit 6 weeks later should be completed for all patients at the end of treatment (in patients who complete sarilumab treatment per protocol in countries where sarilumab is commercially 
available the post treatment follow-up visit may be cancelled if the patient initiates treatment with commercial sarilumab during the post treatment follow-up period; however, in this case, a telephone contact must 
be established with the patient to capture all AEs occurring up to the 1st administration of commercial sarilumab). EOT visit may occur when the patients complete 264 weeks of sarilumab treatment from the 
LTS11210, or at any visit thereafter when sarilumab is commercialized in their country, but no later than 2020 when the study will be closed. In case of permanent discontinuation of treatment, the patients will be 
assessed using the procedures normally planned for the EOT visit and the 6 week follow up visit 6 weeks later.  
b From Week 24, patients at limited sites in selected countries may participate in PFS-S sub-study. If the patient enters the sub-study, then the sub-study IMP will be dispensed instead of the main study IMP at the 
entry into sub-study and IMP compliance with sub-study IMP will be reviewed at the end of sub-study. Full details of the sub-study are provided in Appendix R  
c HV: Visit can be home visit or clinic visit to draw and collect the blood sample only for hematology and LFTs using the designated central laboratory.  
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
Property of sanofi - strictly confidential 
Page 15 
d Last treatment visit from the study EFC11072 or ACT11575. Please note that the SF-36 must be completed at the screening visit of the LTS11210 study for patients rolling over from EFC11072 Part A and 
ACT11575 studies.  Please note that the RNA sample must be collected at V2 of the LTS11210 study for patients rolling over from EFC11072. 
e Physical examination to be done at Week 48, 96, 144, 192, 240, 264, 288, 336, 384, 432, 480 and EOT visit.  
f 
Assessment is NOT required when EOT visit is after Week 264. 
g X-ray of hand and feet (only for patients who completed Part B of the study EFC11072 (not performed for Part A patients, or patients from Part B non-selected dose arms) will be done at Weeks 48, 96, 144, 192 
(±14 days for each assessment), and EOT; No X-ray evaluation will be performed after Week 192 including EOT if EOT is after Week 192. Required x-ray must be done after confirmation of negative urine 
pregnancy test in women of child bearing potential. 
h After Week 264, only DAS28 components of ACR core set will be assessed (TJC & SJC for 28 joints, patient´s global assessment of disease activity). 
i 
Hematology:  Hemoglobin, hematocrit, red blood cell (RBC) morphology (if blood cell count is abnormal), white blood cell (WBC) with differential, platelets count. For all patients, a CBC test must be performed 
before or at Visit 3 (using either designated central lab or a local laboratory facility), but not earlier than the 12th day after the first dose of IMP administration in order to confirm that the neutrophil count and platelet 
count are not within the protocol-defined limits for temporary or permanent discontinuation of study drug. 
j 
Liver Function Tests (LFTs): Prothrombin Time (PT), Albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated 
bilirubin. PT is NOT required at any visit after Week 264. 
k Lipids (fasting): Total cholesterol (TC), High-Density Lipoprotein (HDL) cholesterol, Low-Density Lipoprotein (LDL) cholesterol, triglycerides, Apolipoprotein A, and Apolipoprotein B. After Week 264, lipids 
(excluding Apolipoprotein A, and Apolipoprotein B ) will only be assessed at Weeks 288, 336, 384, 432, 480 (including EOT if EOT is after Week 264)  
l 
Clinical chemistry (fasting): fasting glucose, total proteins, calcium, sodium, potassium, Lactate Dehydrogenase, (LDH), urea nitrogen and creatinine. Creatinine clearance will be calculated during the study if 
clinical indicated.  
m ANA titer will be done at screening, at Week 48, 96, 144, 192, 240, 264, 288, 336, 384, 432, 480 and EOT visit or sooner if clinical indicated (Anti-ds-DNA only if ANA titer is >1:160) 
n Dipstick urinalysis for:  specific gravity, pH, glucose, blood, ketones, proteins, bilirubin, urobilinogen, nitrite, leukocytes. If any parameter is abnormal, a urinalysis sample should be sent to central laboratory for 
testing. If positive for proteins, microscopic analysis will be performed by central laboratory. 
o After Visit 7 (Week 12) between study visits the patient will have a urine pregnancy test at home on a monthly basis.  Patients will be given sufficient urine pregnancy kits to take home at each successive visit for 
monthly testing up until the final treatment visit. When the testing coincides with a clinical visit as indicated in the flow chart, the results should be reported in the eCRF. No pregnancy test kits will be dispensed at 
EOT.  
p ECG to be done at Weeks 48, 96, 144, 192, 240, 264 or EOT; No ECG will be done after Week 264 including EOT if EOT is after Week 264. 
q Rheumatoid factor only at baseline Visit 2 (Week 0) and at Weeks 48, 96, 144, 192, 240, 264 or EOT. No Rheumatoid factor will be assessed after Week 264 including EOT if EOT is after Week 264. 
r 
If throughout the study a serious adverse event (SAE) occurs in a patient, blood samples should be collected for sarilumab at or near the onset and completion of the occurrence of the event, if possible.  The exact 
date of sample collection and last dose must be recorded on the e-CRF.  
s Serum sample for biomarkers to be collected at screening (ie, the last treatment visit from the EFC11072 or ACT11575), Week 2, Week 12, and Week 48. 
t 
Blood sample for RNA to be collected at Week 0 (baseline, prior to administration of study drug) and Week 2 (at site visit only; cancel RNA collection if home visit). 
u Deleted. 
v Samples for IL-6 to be collected at Screening (ie the last treatment visit from EFC11072 or ACT11575) and at V4 (Week 4), V7 (Week 12), V8 (Week 24), V9 (Week 36), and V10 (Week 48).  
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
Property of sanofi - strictly confidential 
Page 16 
1.2.2 Study Flow Chart for Patients Enrolling From EFC10832, EFC11072 Part B Cohort 2, SFY13370, and EFC13752 
 
Evaluation 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY and/or WEEK 
 
 
 
Day 1 
 
 
WK0 
Day 15 
 
 
Wk 2 
Day 29 
 
 
Wk 4 
Day 43 
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71 
 
 
Wk 10 
D85 
 
 
Wk 12 
Wk 24-96  
 
(every 
12  wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
Wk 108-
492IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228… 492a 
Wk120 – 
264 
(every 24 
weeks) 
 
 
Wk120, 144, 
168, 192, 
216, 240, 
264a 
Wk288 – 
504 
(every 24 
weeks) 
 
 
Wk288, 
312,…, 
504a  
EOT visita 
 
 
6 weeks 
after end 
of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V1/V 2 
HV 3c 
(± 3 
days) 
V 4 
(±3 days)
HV 5c
(±3 
days) 
V 6 
(±3 
days) 
HV 6.1c
(±3 days)
V 7 
(±3 days) 
V 8 to V1428
(±3 days) 
V15, V17, 
V19, V21, 
V23, V25… 
V47 (±3 days)
V16, V18, 
V20, V22, 
V24, V26, 
V28 (±3 
days) 
V30, V32, 
V34, V36, 
V38, … , 
V48 (±3 
days) 
V49 (±3 
days) 
V50(±3 
days) 
Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Previous medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking, alcohol, and illicit 
drug use history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Detail history for tuberculosis 
(TB) and opportunistic 
infection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
Xd 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Confirm eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
Property of sanofi - strictly confidential 
Page 17 
Evaluation 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY and/or WEEK 
 
 
 
Day 1 
 
 
WK0 
Day 15 
 
 
Wk 2 
Day 29 
 
 
Wk 4 
Day 43 
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71 
 
 
Wk 10 
D85 
 
 
Wk 12 
Wk 24-96  
 
(every 
12  wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
Wk 108-
492IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228… 492a 
Wk120 – 
264 
(every 24 
weeks) 
 
 
Wk120, 144, 
168, 192, 
216, 240, 
264a 
Wk288 – 
504 
(every 24 
weeks) 
 
 
Wk288, 
312,…, 
504a  
EOT visita 
 
 
6 weeks 
after end 
of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V1/V 2 
HV 3c 
(± 3 
days) 
V 4 
(±3 days)
HV 5c
(±3 
days) 
V 6 
(±3 
days) 
HV 6.1c
(±3 days)
V 7 
(±3 days) 
V 8 to V1428
(±3 days) 
V15, V17, 
V19, V21, 
V23, V25… 
V47 (±3 days)
V16, V18, 
V20, V22, 
V24, V26, 
V28 (±3 
days) 
V30, V32, 
V34, V36, 
V38, … , 
V48 (±3 
days) 
V49 (±3 
days) 
V50(±3 
days) 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensingb  
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Study drug complianceb 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature, heart rate, 
blood pressure 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Weight in Kg 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
ACR disease core seth 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X-ray (hand, feet)g 
Xd 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Health Economic 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 (EFC11072, 
EFC10832) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
WPAI (EFC11072) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
FACIT-Fatigue (EFC11072, 
EFC10832) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
Sleep questionnaire 
(EFC11072) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
Property of sanofi - strictly confidential 
Page 18 
Evaluation 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY and/or WEEK 
 
 
 
Day 1 
 
 
WK0 
Day 15 
 
 
Wk 2 
Day 29 
 
 
Wk 4 
Day 43 
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71 
 
 
Wk 10 
D85 
 
 
Wk 12 
Wk 24-96  
 
(every 
12  wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
Wk 108-
492IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228… 492a 
Wk120 – 
264 
(every 24 
weeks) 
 
 
Wk120, 144, 
168, 192, 
216, 240, 
264a 
Wk288 – 
504 
(every 24 
weeks) 
 
 
Wk288, 
312,…, 
504a  
EOT visita 
 
 
6 weeks 
after end 
of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V1/V 2 
HV 3c 
(± 3 
days) 
V 4 
(±3 days)
HV 5c
(±3 
days) 
V 6 
(±3 
days) 
HV 6.1c
(±3 days)
V 7 
(±3 days) 
V 8 to V1428
(±3 days) 
V15, V17, 
V19, V21, 
V23, V25… 
V47 (±3 days)
V16, V18, 
V20, V22, 
V24, V26, 
V28 (±3 
days) 
V30, V32, 
V34, V36, 
V38, … , 
V48 (±3 
days) 
V49 (±3 
days) 
V50(±3 
days) 
WPS-RA (EFC10832) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis assessments 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
AE/SAE recording (if any) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
High sensitive- C- Reactive 
protein (hs-CRP)  
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
Hematology: CBC and 
differentiali  
Xd 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Liver Function Tests (LFTs)j  
Xd 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Lipids (fasting)k 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
Clinical  chemistry (fasting)l 
Xd 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
ANA/Anti-ds-DNA n 
Xd 
 
 
 
 
 
 
X  
 
X 
X 
X 
 
Dipstick urinalysis o 
Xd 
 
 
 
X 
 
X 
X 
 
X 
 
Xf 
 
Urine pregnancy test (for 
women of childbearing 
potential)p 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
Property of sanofi - strictly confidential 
Page 19 
Evaluation 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY and/or WEEK 
 
 
 
Day 1 
 
 
WK0 
Day 15 
 
 
Wk 2 
Day 29 
 
 
Wk 4 
Day 43 
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71 
 
 
Wk 10 
D85 
 
 
Wk 12 
Wk 24-96  
 
(every 
12  wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
Wk 108-
492IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228… 492a 
Wk120 – 
264 
(every 24 
weeks) 
 
 
Wk120, 144, 
168, 192, 
216, 240, 
264a 
Wk288 – 
504 
(every 24 
weeks) 
 
 
Wk288, 
312,…, 
504a  
EOT visita 
 
 
6 weeks 
after end 
of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V1/V 2 
HV 3c 
(± 3 
days) 
V 4 
(±3 days)
HV 5c
(±3 
days) 
V 6 
(±3 
days) 
HV 6.1c
(±3 days)
V 7 
(±3 days) 
V 8 to V1428
(±3 days) 
V15, V17, 
V19, V21, 
V23, V25… 
V47 (±3 days)
V16, V18, 
V20, V22, 
V24, V26, 
V28 (±3 
days) 
V30, V32, 
V34, V36, 
V38, … , 
V48 (±3 
days) 
V49 (±3 
days) 
V50(±3 
days) 
Dispense urine pregnancy 
kitsp 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
 
12-lead electrocardiogramq 
Xd 
 
 
 
 
 
 
X 
 
X 
 
Xf 
 
Other analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rheumatoid factorr 
Xd 
 
 
 
 
 
 
X 
 
X 
 
Xf 
 
Serum IL-6 w 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
Pharmacokineticss 
Xd 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
Anti-sarilumab antibody 
Xd 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
Serum sample to be stored  
for future biomarkers t 
Xd 
X 
 
 
 
 
X 
X 
 
 
 
 
 
Expression RNAu 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
a EOT visit and follow up visit 6 weeks later should be completed for all patients at the end of treatment (in patients who complete sarilumab treatment per protocol in countries where sarilumab is commercially 
available the post treatment follow-up visit may be cancelled if the patient initiates treatment with commercial sarilumab during the post treatment follow-up period; however, in this case, a telephone contact 
must be established with the patient to capture all AEs occurring up to the 1st administration of commercial sarilumab). EOT visit may occur when the patients complete 264 weeks of sarilumab treatment from 
LTS11210, or any visit thereafter when sarilumab is commercialized in their country, but no later than 2020 when the study will be closed. (In UK, the duration of treatment will be 264 weeks from the first study 
drug administration in LTS11210).  In case of permanent discontinuation of treatment, the patients will be assessed using the procedures normally planned for the EOT visit and the 6 week follow up visit 6 
weeks later.  
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 9  
31-Aug-2015 
SAR153191-LTS11210  
Version number:  1 
Property of sanofi - strictly confidential 
Page 20 
b From Week 24, patients at limited sites in selected countries may participate in PFS-S sub-study. If the patient enters the sub-study, then the sub-study IMP will be dispensed instead of the main study IMP at 
the entry into sub-study and IMP compliance with sub-study IMP will be reviewed at the end of sub-study. Full details of the sub-study are provided in Appendix R  
c HV: Visit can be home visit or clinic visit to draw and collect the blood sample only for hematology and LFTs using the designated central laboratory.  
d Last treatment visit from the study EFC11072, EFC10832, SFY13370, or EFC13752.   
e Physical examination to be done at Week 48, 96, 144, 192, 240, 264, 288, 336, 384, 432, 480 and EOT visit 
f 
The assessment is NOT required when EOT visit is after Week 264. 
g X-ray of hands and feet (only for patients who completed Part B of the study EFC11072 will be done at Weeks 48, 96, 144, 192 (±14 days for each assessment), and EOT; No X-ray evaluation will be performed 
after Week 192 including EOT if EOT is after Week 192. Required x-ray must be done after confirmation of negative urine pregnancy test in women of child bearing potential. 
h After Week 264, only DAS28 components of ACR core set will be assessed (TJC & SJC for 28 joints, patient´s global assessment of disease activity). 
i 
Hematology:  Hemoglobin, hematocrit, red blood cell (RBC) morphology (if blood cell count is abnormal), white blood cell (WBC) with differential, platelets count. For all patients, a CBC test must be performed 
before or at Visit 3 (using either designated central or a local laboratory facility) but not earlier than the 12th day after the first dose of IMP administration in order to confirm that the neutrophil count and platelet 
count are not within the protocol-defined limits for temporary or permanent discontinuation of study drug. 
j 
Liver Function Tests (LFTs): Prothrombin Time (PT), Albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated 
bilirubin. PT is NOT required at any visit after Week 264. 
k Lipids (fasting): Total cholesterol (TC), High-Density Lipoprotein (HDL) cholesterol, Low-Density Lipoprotein (LDL) cholesterol, triglycerides, Apolipoprotein A, and Apolipoprotein B. After Week 264, lipids 
(excluding Apolipoprotein A, and Apolipoprotein B ) will only be assessed at Weeks 288, 336, 384, 432, 480 (including EOT if EOT is after Week 264) 
l 
Clinical chemistry (fasting): fasting glucose, total proteins, calcium, sodium, potassium, Lactate Dehydrogenase, (LDH), urea nitrogen and creatinine.  Creatinine clearance will be calculated during the study if 
clinical indicated.  
m Deleted. 
n ANA titer will be done at V1/V2 ( ie the last treatment visit from the initial study),  at Week 48, 96,  144, 192, 240, 264, 288, 336, 384, 432, 480 and EOT visit , or sooner if clinical indicated (Anti-ds-DNA only if 
ANA titer is >1:160) 
o Dipstick urinalysis for:  specific gravity, pH, glucose, blood, ketones, proteins, bilirubin, urobilinogen, nitrite, leukocytes. If any parameter is abnormal, a urinalysis sample should be sent to central laboratory for 
testing. If positive for proteins, microscopic analysis will be performed by central laboratory.  
p After Visit 7 (Week 12) between study visits the patient will have a urine pregnancy test at home on a monthly basis.  Patients will be given sufficient urine pregnancy kits to take home at each successive visit 
for monthly testing up until the final treatment visit. When the testing coincides with a clinical visit as indicated in the flow chart, the results should be reported in the e-CRF. No pregnancy test kits will be 
dispensed at EOT. 
q ECG to be done at Weeks 48, 96, 144, 192, 240, 264 or EOT; No ECG will be done after Week 264 including EOT if EOT is after Week 264  
r 
Rheumatoid factor only at Weeks 48, 96, 144, 192, 240, 264 or EOT; No Rheumatoid factor will be assessed after Week 264 including EOT if EOT is after Week 264 
s If throughout the study a serious adverse event (SAE) occurs in a patient, blood samples should be collected for sarilumab at or near the onset and completion of the occurrence of the event, if possible.  The 
exact date of sample collection and last dose must be recorded on the eCRF.  
t 
Serum sample for biomarkers to be collected for all patients except EFC13752: at V1/V2 (ie, the last treatment visit from the initial study), as well as Week 2, Week 12, and Week 48. 
u Blood sample for RNA except for SFY13370 and EFC13752 patients: to be collected at V1/V2 (Week 0) (baseline prior to administration of study drug) and V3 (Week 2) at site visit only (cancel RNA collection if 
home visit).  
v Deleted 
w Samples for IL-6 to be collected at V1/V2 for EFC11072 patients only (ie the last treatment visit) and for all patients at V4 (Week 4), V7 (Week 12), V8 (Week 24), V9 (Week 36), and V10 (Week 48). 
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TABLE OF CONTENT 
AMENDED CLINICAL TRIAL PROTOCOL 9 ................................................................................................1 
1 
FLOW CHARTS...............................................................................................................................8 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................8 
1.1.1 
Graphical Study Design for Patients in ACT11575 and EFC11072 Part A or Part B Cohort 
1 .......................................................................................................................................................8 
1.1.2 
Graphical Study Design for Patients in EFC11072 Part B Cohort 2, EFC10832, SFY13370, 
and EFC13752.................................................................................................................................9 
1.2 
STUDY FLOWCHART ...................................................................................................................10 
1.2.1 
Study Flow Chart for Patients Enrolling From ACT11575 and EFC11072 Part A or Part B 
Cohort 1 .........................................................................................................................................10 
1.2.2 
Study Flow Chart for Patients Enrolling From EFC10832, EFC11072 Part B Cohort 2, 
SFY13370, and EFC13752............................................................................................................16 
2 
TABLE OF CONTENT...................................................................................................................21 
3 
LIST OF ABBREVIATIONS ..........................................................................................................30 
4 
INTRODUCTION AND RATIONALE.............................................................................................32 
4.1 
SARILUMAB ..................................................................................................................................32 
4.1.1 
Summary of nonclinical studies .....................................................................................................32 
4.1.2 
Summary of previous human experience ......................................................................................33 
5 
STUDY OBJECTIVES ...................................................................................................................35 
5.1 
PRIMARY.......................................................................................................................................35 
5.2 
SECONDARY ................................................................................................................................35 
6 
STUDY DESIGN ............................................................................................................................36 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................36 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................36 
6.3 
OPTIONAL PFS-S SUB-STUDY ...................................................................................................37 
6.4 
STUDY COMMITTEES..................................................................................................................37 
6.4.1 
Data Monitoring Committee ...........................................................................................................37 
6.4.2 
Cardiovascular Adjudication Committee........................................................................................37 
7 
SELECTION OF PATIENTS..........................................................................................................39 
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7.1 
NUMBER OF PATIENTS PLANNED.............................................................................................39 
7.2 
INCLUSION CRITERIA..................................................................................................................39 
7.3 
EXCLUSION CRITERIA ................................................................................................................39 
8 
STUDY TREATMENTS .................................................................................................................41 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ...............................................................................41 
8.2 
NON INVESTIGATIONAL PRODUCTS.........................................................................................42 
8.3 
DELETED.......................................................................................................................................43 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................43 
8.5 
PACKAGING AND LABELING ......................................................................................................43 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................43 
8.7 
RESPONSIBILITIES ......................................................................................................................43 
8.7.1 
Access to the randomization code during the study ......................................................................44 
8.8 
CONCOMITANT MEDICATION.....................................................................................................44 
8.8.1 
Prohibited concomitant medication................................................................................................44 
8.8.2 
Permitted concomitant medication.................................................................................................45 
8.9 
CONCOMITANT TREATMENT .....................................................................................................46 
8.10 
TREATMENT ACCOUNTABILITY AND COMPLIANCE ...............................................................46 
8.11 
RETURN AND/OR DESTRUCTION OF TREATMENTS ..............................................................47 
9 
ASSESSMENT OF INVESTIGATIONAL PRODUCT ...................................................................48 
9.1 
ENDPOINTS ..................................................................................................................................48 
9.1.1 
Primary endpoint............................................................................................................................48 
9.1.2 
Secondary endpoints .....................................................................................................................48 
9.1.2.1 
ACR20/ACR50/ACR70 ..................................................................................................................48 
9.1.2.2 
DAS28-CRP...................................................................................................................................49 
9.1.2.3 
EULAR response ...........................................................................................................................49 
9.1.2.4 
Van der Heijde modified Total Sharp Score ..................................................................................50 
9.1.2.5 
Physical Function...........................................................................................................................50 
9.1.2.6 
ACR Components ..........................................................................................................................50 
9.1.2.7 
Health economic assessment and Patient reported outcomes (PROs) ........................................50 
9.2 
DELETED.......................................................................................................................................52 
9.3 
PHARMACOKINETICS AND IMMUNOGENICITY........................................................................52 
9.3.1 
Sampling time ................................................................................................................................52 
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9.3.2 
Pharmacokinetic handling procedure.............................................................................................53 
9.3.3 
Bioanalytical method......................................................................................................................54 
9.4 
SERUM AND RNA BIOMARKERS................................................................................................54 
9.4.1 
Serum for future biomarker analysis..............................................................................................54 
9.4.2 
RNA for future biomarker analysis.................................................................................................54 
10 
PATIENT SAFETY.........................................................................................................................55 
10.1 
SAFETY PARAMETERS ASSESSED IN THIS TRIAL..................................................................55 
10.2 
SAFETY INSTRUCTIONS .............................................................................................................57 
10.2.1 
Infections........................................................................................................................................57 
10.2.2 
Demyelinating / Neurological events..............................................................................................58 
10.2.3 
Autoimmunity and Lupus-like syndrome........................................................................................58 
10.2.4 
Liver Function.................................................................................................................................58 
10.2.5 
Neutrophils .....................................................................................................................................59 
10.2.6 
Platelets .........................................................................................................................................60 
10.2.7 
Systemic Hypersensitivity reactions / Anaphylaxis........................................................................61 
10.2.8 
Diverticulitis and Gastrointestinal perforation ................................................................................62 
10.2.9 
Acute renal failure ..........................................................................................................................62 
10.2.10 Management of dyslipidaemia, cardiovascular events, and deaths ..............................................62 
10.3 
ADVERSE EVENTS MONITORING..............................................................................................63 
10.4 
DEFINITIONS OF ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE)...............63 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................64 
10.5.1 
Adverse Events..............................................................................................................................64 
10.5.2 
Serious Adverse Events.................................................................................................................65 
10.5.3 
Deleted...........................................................................................................................................65 
10.5.4 
Adverse events of special interest/Adverse events with pre-specified monitoring 
(AESI/AEPM) .................................................................................................................................65 
10.6 
OBLIGATIONS OF THE SPONSOR .............................................................................................71 
11 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION......................................72 
11.1 
TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
PRODUCT(S).................................................................................................................................72 
11.2 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
PRODUCT(S).................................................................................................................................73 
11.2.1 
List of criteria for definitive treatment discontinuation....................................................................73 
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11.2.2 
Handling of patients after permanent treatment discontinuation ...................................................74 
11.3 
PROCEDURE AND CONSEQUENCE FOR PATIENT WITHDRAWAL FROM STUDY ..............74 
12 
STUDY PROCEDURES ................................................................................................................75 
12.1 
VISIT SCHEDULE..........................................................................................................................75 
12.1.1 
Visit 1:  Screening Visit (D-7 to D-1) ..............................................................................................76 
12.1.2 
Baseline (D1) (WK0) ......................................................................................................................77 
12.1.2.1 Visit 2: Patients enrolling from ACT11575 or EFC11072 Part A or Part B Cohort 1 .....................77 
12.1.2.2 Visit 1/Visit 2: Patients enrolling From EFC10832, SFY13370, EFC13752 and EFC11072 
Part B Cohort 2 ..............................................................................................................................79 
12.1.3 
Visit 3:  Home visit On-treatment/Week 2 (D15 ±3D) ....................................................................81 
12.1.4 
Visit 4:  On-treatment/Week 4 (D29, ±3D) .....................................................................................81 
12.1.5 
Visit 5, Home Visit: On-treatment/Week 6 (D43 ±3D)....................................................................82 
12.1.6 
Visit 6, on-treatment/Week 8 (D57±3D).........................................................................................82 
12.1.7 
Visit 6.1, Home Visit: On-treatment/Week 10 (D71 ±3D)...............................................................83 
12.1.8 
Visit 7:  On-treatment/ Week 12 (D85±3D) ....................................................................................83 
12.1.9 
Visit 8 (Week 24) to Visit 14 (Week 96) and Visit 16 (Week 120), Visit 18 (Week 144), Visit 
20 (Week 168), Visit 22 (Week 192), Visit 24 (Week 216), Visit 26 (Week 240), Visit 28 
(Week 264): On treatment visit from Week 24 to Week 264 .........................................................84 
12.1.10 Visit 15 (Week 108), Visit 17 (Week 132), Visit 19 (Week 156), Visit 21 (Week 180), Visit 
23 (Week 204), Visit 25 (Week 228), Visit 27 (Week 252), Visit 29 (Week 276), Visit 31 
(Week 300), Visit 33 (Week 324), Visit 35 (Week 348), Visit 37 (Week 372), Visit 39 (Week 
396), Visit 41 (Week 420), Visit 43 (Week 444), Visit 45 (Week 468), Visit 47 (Week 492): 
IMP dispensing visits in between every 24-week on-treatment visits (after Week 96)..................86 
12.1.11 Visit 30 (Week 288), Visit 32 (Week 312), Visit 34 (Week 336), Visit 36 (Week 360), Visit 
38 (Week 384), Visit 40 (Week 408), Visit 42 (Week 432), Visit 44 (Week 456), Visit 46 
(Week 480), Visit 48 (Week 504): On treatment visit from Week 288 to week 504 ......................86 
12.1.12 Visit 49: End of treatment (EOT)....................................................................................................87 
12.1.13 Visit 50: Post Treatment safety follow-up visit ...............................................................................89 
12.2 
DEFINITION OF SOURCE DATA..................................................................................................89 
13 
STATISTICAL CONSIDERATIONS..............................................................................................91 
13.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................91 
13.2 
ANALYSIS ENDPOINTS ...............................................................................................................91 
13.2.1 
Demographic and baseline characteristics ....................................................................................91 
13.2.1.1 Demographic and baseline characteristics ....................................................................................91 
13.2.1.2 Concomitant medications...............................................................................................................92 
13.2.2 
Safety endpoints ............................................................................................................................92 
13.2.2.1 Adverse events ..............................................................................................................................92 
13.2.2.2 Laboratory safety variables............................................................................................................92 
13.2.2.3 Vital signs.......................................................................................................................................92 
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13.2.2.4 Electrocardiogram variables ..........................................................................................................92 
13.2.3 
Efficacy endpoints..........................................................................................................................93 
13.2.4 
Pharmacokinetic and immunogenicity variables............................................................................93 
13.2.5 
Pharmacodynamic/genomics variables .........................................................................................93 
13.2.6 
Health economic variables.............................................................................................................93 
13.3 
DISPOSITION OF PATIENTS .......................................................................................................94 
13.4 
ANALYSIS POPULATIONS...........................................................................................................94 
13.5 
STATISTICAL METHODS .............................................................................................................94 
13.5.1 
Demographic and baseline characteristics ....................................................................................95 
13.5.2 
Concomitant medications...............................................................................................................95 
13.5.3 
Extent of study treatment exposure and compliance.....................................................................95 
13.5.3.1 Extent of investigational product exposure ....................................................................................95 
13.5.3.2 Compliance ....................................................................................................................................96 
13.5.4 
Analyses of safety data..................................................................................................................96 
13.5.4.1 Adverse events ..............................................................................................................................96 
13.5.4.2 Liver Function Tests.......................................................................................................................97 
13.5.4.3 Clinical laboratory evaluations .......................................................................................................98 
13.5.4.4 Vital signs.......................................................................................................................................98 
13.5.4.5 Electrocardiogram..........................................................................................................................98 
13.5.5 
Analyses of efficacy endpoints.......................................................................................................99 
13.5.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................99 
13.5.6.1 Pharmacokinetic descriptive analysis ............................................................................................99 
13.5.6.2 Immunogenicity variables ............................................................................................................100 
13.5.6.3 Pharmacodynamic descriptive analysis.......................................................................................100 
13.5.7 
Analyses of quality of life/health economics variables.................................................................100 
13.6 
DATA HANDLING CONVENTIONS ............................................................................................100 
13.7 
X-RAY DATA SUMMARY ............................................................................................................101 
13.8 
INTERIM ANALYSIS....................................................................................................................101 
14 
ETHICAL AND REGULATORY STANDARDS...........................................................................102 
14.1 
ETHICAL PRINCIPLES ...............................................................................................................102 
14.2 
LAWS AND REGULATIONS .......................................................................................................102 
14.3 
INFORMED CONSENT ...............................................................................................................102 
14.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ............102 
15 
STUDY MONITORING.................................................................................................................104 
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15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................104 
15.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................104 
15.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................105 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST....................................................................................................................................105 
15.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................105 
16 
ADMINISTRATIVE RULES .........................................................................................................106 
16.1 
CURRICULUM VITAE..................................................................................................................106 
16.2 
RECORD RETENTION IN STUDY SITES ..................................................................................106 
17 
CONFIDENTIALITY.....................................................................................................................107 
18 
PROPERTY RIGHTS...................................................................................................................108 
19 
DATA PROTECTION...................................................................................................................109 
20 
INSURANCE COMPENSATION .................................................................................................110 
21 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES..............................111 
22 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................112 
22.1 
DECIDED BY THE SPONSOR IN THE FOLLOWING CASES:..................................................112 
22.2 
DECIDED BY THE INVESTIGATOR...........................................................................................112 
23 
CLINICAL TRIAL RESULTS.......................................................................................................113 
24 
PUBLICATIONS AND COMMUNICATIONS ..............................................................................114 
25 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................115 
26 
BIBLIOGRAPHIC REFERENCES...............................................................................................116 
27 
APPENDICES..............................................................................................................................118 
APPENDIX A 
ARA & ACR CRITERIA......................................................................................................119 
APPENDIX B 
ACR SCORE......................................................................................................................120 
APPENDIX C SHARP VAN DER HEIJDE METHOD...............................................................................122 
APPENDIX D SUBJECT’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY......................................123 
APPENDIX E 
SUBJECT’S ASSESSMENT OF PAIN..............................................................................124 
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APPENDIX F FACIT-FATIGUE SCALE...................................................................................................125 
APPENDIX G 
WPAI QUESTIONNAIRE ..................................................................................................126 
APPENDIX H SLEEP QUESTIONNAIRE (VAS)......................................................................................128 
APPENDIX I 
SF-36 HEALTH SURVEY ...................................................................................................129 
APPENDIX J 
HAQ-DI – HEALTH ASSESSMENT QUESTIONNAIRE....................................................134 
APPENDIX K 
PROHIBITED LIVE (ATTENUATED) VACCINE LIST.......................................................136 
APPENDIX L GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI-AVENTIS...................................................................................137 
APPENDIX M 
LIST OF POTENTIAL OPPORTUNISTIC INFECTIONS..................................................141 
APPENDIX N DELETED ..........................................................................................................................142 
APPENDIX O 
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS .............................................143 
APPENDIX P 
DELETED ..........................................................................................................................144 
APPENDIX Q 
WPS-RA QUESTIONNAIRE .............................................................................................145 
APPENDIX R ABBREVIATED PROTOCOL OF PFS-S SUB-STUDY.....................................................147 
1 
FLOW CHARTS...........................................................................................................................148 
1.1 
GRAPHICAL STUDY DESIGN ....................................................................................................148 
1.2 
STUDY FLOW CHART ................................................................................................................149 
2 
TABLE OF CONTENTS ..............................................................................................................150 
3 
LIST OF ABBREVIATIONS ........................................................................................................151 
4 
INTRODUCTION AND RATIONALE...........................................................................................152 
4.1 
PRE-FILLED SYRINGE WITH SAFETY SYSTEM (PFS-S)........................................................152 
4.2 
SUB-STUDY RATIONALE...........................................................................................................153 
5 
STUDY OBJECTIVES .................................................................................................................154 
5.1 
PRIMARY.....................................................................................................................................154 
5.2 
SECONDARY ..............................................................................................................................154 
6 
STUDY DESIGN ..........................................................................................................................155 
6.1 
DESCRIPTION OF THE PROTOCOL.........................................................................................155 
6.2 
DURATION OF STUDY PARTICIPATION ..................................................................................156 
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6.2.1 
Duration of study participation for each patient ...........................................................................156 
6.2.2 
Determination of end of sub-study (all patients) ..........................................................................156 
6.3 
INTERIM ANALYSIS....................................................................................................................156 
6.4 
STUDY COMMITTEES................................................................................................................156 
7 
SELECTION OF PATIENTS........................................................................................................157 
7.1 
INCLUSION CRITERIA................................................................................................................157 
7.2 
EXCLUSION CRITERIA ..............................................................................................................157 
8 
STUDY TREATMENTS ...............................................................................................................158 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ........................................................................158 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ................................................................158 
8.3 
BLINDING PROCEDURES..........................................................................................................158 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ............................................159 
8.5 
PACKAGING AND LABELING ....................................................................................................159 
8.6 
STORAGE CONDITIONS AND SHELF LIFE..............................................................................159 
8.7 
RESPONSIBILITIES ....................................................................................................................159 
8.7.1 
Treatment accountability and compliance....................................................................................159 
8.7.2 
Return and/or destruction of treatments ......................................................................................160 
8.8 
CONCOMITANT MEDICATION...................................................................................................160 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ............................................161 
9.1 
PRIMARY ENDPOINT .................................................................................................................161 
9.2 
SECONDARY ENDPOINTS ........................................................................................................162 
9.2.1 
Device related endpoints .............................................................................................................162 
9.2.2 
Safety endpoints ..........................................................................................................................162 
9.2.3 
EXPLORATORY ENDPOINT OF pk............................................................................................162 
9.2.4 
PHARMACOKINETICS AND IMMUNOGENICITY......................................................................162 
9.2.4.1 
Sampling time ..............................................................................................................................162 
9.2.4.2 
Sample handling procedure .........................................................................................................163 
10 
STUDY PROCEDURES ..............................................................................................................164 
10.1 
VISIT SCHEDULE........................................................................................................................164 
10.1.1 
Visit 101: Entry of sub-study / Day 1............................................................................................164 
10.1.2 
Visit 102: End of sub-study / Day 85............................................................................................164 
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10.2 
DEFINITION OF SOURCE DATA................................................................................................165 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION DURING THE SUB-STUDY AND OF PATIENT STUDY 
DISCONTINUATION....................................................................................................................165 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................165 
10.4.1 
Instructions for reporting PTC and adverse events related to PTC.............................................165 
11 
STATISTICAL CONSIDERATIONS............................................................................................166 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................166 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................166 
11.3 
ANALYSIS POPULATIONS.........................................................................................................166 
11.4 
STATISTICAL METHODS ...........................................................................................................166 
11.4.1 
Extent of study treatment exposure and compliance...................................................................166 
11.4.2 
Analyses of endpoints..................................................................................................................167 
11.4.2.1 Analysis of primary endpoint(s)....................................................................................................167 
11.4.2.2 Analyses of secondary and exploratory endpoints ......................................................................167 
11.4.2.3 Multiplicity considerations ............................................................................................................167 
11.5 
INTERIM ANALYSIS....................................................................................................................168 
12 
HANDLING PROCESS FOR PRODUCT TECHNICAL COMPLAINT REPORTING.................169 
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3 
LIST OF ABBREVIATIONS 
 
ACR: 
American College of Rheumatology 
ADA: 
anti-drug antibody 
AE: 
Adverse Event 
AEPM: 
Adverse Event of Pre-specified Monitoring 
AESI: 
Adverse Event of Special Interest 
ALP: 
Alkaline Phosphatase 
ALT: 
Alanine Aminotransferase 
ANA: 
Anti Nuclear Auto antibody 
Anti-ds DNA: 
Anti double stranded DNA 
AST: 
Aspartate Aminotransferase 
ATC: 
Anatomic Category 
CAC: 
Cardiovascular Adjudication Committee  
CBC: 
Complete Blood Count 
CIB: 
Clinical Investigators Brochure 
CV%: 
Coefficient of Variation 
CYP: 
Cytochrome P450 
DAS28: 
disease activity score 
DMARDs: 
Disease Modifying Anti-Rheumatic Drugs 
DNA: 
DeoxyriboNucleic Acid 
DRF: 
Discrepancy Resolution Form 
ds-DNA: 
double-standard DNA 
ECG: 
Electrocardiogram 
e-CRF: 
electronic Case Report Form 
EULAR: 
European League against Rheumatism 
FACIT-Fatigue: Functional Assessment of Chronic Illness Therapy Fatigue scale 
FDD: 
failed drug deliveries 
HDL: 
High Density Lipoprotein  
HLGT: 
High Level Group Term 
HLT: 
High Level Term 
hs-CRP: 
high sensitivity C-reactive protein, high sensitivity C-reactive protein 
ICH: 
International Conference on Harmonisation 
IECs/IRBs: 
Independent Ethic Committees/Institutional Review Board 
IL-6: 
interleukin 6 
IL6 R mAB: 
Interleukin 6 Receptor monoclonal Antibody 
IMP: 
investigational medicinal product 
IUD: 
Intra Uterine Device 
IVRS: 
Interactive Voice Response System 
IWRS: 
Interactive Web Response System 
kDa: 
Kilodalton 
LDH: 
Lactacte Dehydrogenase 
LDL: 
Low Density Lipoprotein  
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LLN: 
Lower Limit of Normal 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NIMP: 
noninvestigational medicinal product 
NSAIDs: 
Non Steroidal Anti-Inflammatory Drugs 
PCSA: 
Potentially Clinically Significant Abnormality 
PFS-S: 
pre-filled syringe with safety system, pre-filled syringe with safety system 
PK: 
Pharmacokinetic 
PML: 
Progressive Multifocal Leukoencephalopathy 
PROs: 
Patient Reported Outcomes, Patient Reported Outcomes 
PT: 
Preferred Term, Prothrombin Time 
PTC: 
product technical complaint 
PTF: 
product technical failure 
q2w: 
bi-weekly (every-other-week) 
qw: 
weekly 
RA: 
Rheumatoid Arthritis 
RBC: 
Red Blood Cells 
RF: 
Rheumatoid Factor 
RNA: 
Ribonucleic Acid 
SAE: 
Serious Adverse Event 
SD: 
Standard Deviation 
SEM: 
Standard Error of the Mean 
SF-36: 
Short Form 36 
SJC: 
Swollen Joints Count 
SLE: 
Systemic Lupus Erythematosus 
SMQ: 
Standardized MedDRA Query 
SOC: 
System Organ Class 
SUSAR: 
Suspected Unexpected Serious Adverse Reaction 
TB: 
Tuberculosis 
TC: 
total cholesterol 
TEAEs: 
Treatment Emergent Adverse Events 
TJC: 
Tender Joints Count 
ULN: 
Upper limit of normal 
VAS: 
Visual Analog Scale 
WBC: 
White Blood Cells 
WICF: 
Written Informed Consent Form, Written Informed Consent Form 
WOCBP: 
Women of Childbearing Potential 
WPAI: 
Work Productivity and Activity Impairment 
WPS: 
work productivity survey 
WPS-RA: 
Rheumatoid Arthritis-Work Productivity Survey 
 
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4 
INTRODUCTION AND RATIONALE 
Rheumatoid arthritis (RA) is a chronic, debilitating disease that primarily affects the synovial 
membrane of diarthrodial joints. 
Currently, treatment of RA involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs), 
glucocorticoids and disease modifying anti-rheumatic drugs (DMARDs). Methotrexate, 
sulfasalazine, hydroxychloroquine and leflunomide are DMARDs that have been used by 
rheumatologists for many years (1)(2)(3). 
Introduction of biologic agents, especially inhibitors of TNF-α, has greatly improved the 
therapeutic options available for treating RA (4)(5)(6)(7)(8)(9); however, no therapeutic modality 
provides either universal or complete control of disease and safety remains one of the key issues 
with anti-TNF-α treatment (10)(11). 
Besides early benefit/risk of biologics, the long term outcome of RA remain a critical question: 
long term use of biologics have been associated with immunosuppression and effects on the 
development of infections, malignancies, demyelinating events, lupus like events, etc.  
Consequently, long-term data are needed to investigate the risks associated with the long-term use 
of these drugs. 
This LTS11210 study is intended to identify potential late onset adverse events associated with 
long-term use of sarilumab with or without concomitant non-biologic DMARD(s), including 
MTX, as well as to assess long-term efficacy. 
4.1 
SARILUMAB 
Sarilumab is a fully human immunoglobulin (Ig) G1 monoclonal antibody directed against the IL-
6Rα receptor produced using VelocImmune® technology developed by Regeneron. Sarilumab 
blocks the IL6 receptor and inhibits IL-6 signaling. Sarilumab is under development for the 
treatment of patients with moderate to severe RA. 
Sarilumab is a covalent heterotetramer consisting of two, disulfide linked human heavy chains, 
each covalently linked through disulfide bonds to a fully human kappa light chain. The antibody 
possesses a protein molecular weight of approximately 155 kDa, with a single N-linked 
glycosylation site in each heavy chain, located within the constant region in the Fc portion of the 
molecule.  The sarilumab heavy chain has an IgG1 isotype constant region (an allotype). The 
variable domains of the heavy and light chains combine to form the IL-6Rα binding site within 
the antibody. 
4.1.1 Summary of nonclinical studies 
See the clinical investigator’s brochure (CIB) for detailed information.  
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4.1.2 Summary of previous human experience 
See the Clinical Investigator’s Brochure for detailed information. 
Prior to entering LTS11210 patients were included in ACT11575, EFC11072, EFC10832, 
SFY13370, or EFC13752.   
In the initial studies patients were exposed to IMP for: 
• 12 weeks if they were initially randomized in EFC11072 Part A or ACT11575;  
• between 2 and 52 weeks, if initially randomized in EFC11072 Part B;  
• between 12 and 24 weeks, if initially randomized in EFC10832;  
• 24 weeks, if initially randomized in SFY13370 or EFC13752. 
These studies are described briefly below: 
EFC11072:  A randomized, double-blind, placebo-controlled, multi-centre, two-part, dose 
ranging (Part A) and confirmatory (Part B) study with an operationally seamless design, 
evaluating efficacy and safety of sarilumab added to methotrexate (MTX) in patients with active 
rheumatoid arthritis who are inadequate responders to MTX therapy. The study is completed.  
In the dose ranging part of the study (Part A), five doses (100 mg weekly [qw], 150 mg qw, 
100 mg every other week [q2w], 150 mg q2w, and 200 mg q2w) and placebo were tested in 
combination with methotrexate (MTX).  Two doses (150 mg every two weeks [q2w] and 200 mg 
q2w) were selected for the pivotal phase 3 studies. In the Phase 3 confirmatory part (Part B) both 
sarillumab arms showed clinically relevant and statistically significant (p<0.0001) improvements 
compared with placebo in all 3 co-primary efficacy endpoints (signs and symptoms [American 
College of Rheumatology criteria, ACR20], physical function [Health Assessment Questionnaire 
Disability Index, HAQ-DI], and radiographic progression [modified van der Heijde total Sharp 
score, vdH-mTSS]).  In this study, the safety profile was consistent with previous studies showing 
higher incidence of infections including serious infections, in the sarilumab treated groups 
compared to placebo, along with the expected laboratory data: a decrease in neutrophil count, 
elevated alanine aminotransferase, elevated serum LDL-cholesterol and injection site reactions 
(i.e., erythema, pruritus and rash). The incidence of treatment emergent anti-drug antibody (ADA) 
in the sarilumab 150 mg q2w, 200 mg q2w, and placebo groups were 19.8%, 14.6%, and 4.2%, 
with 3.5%, 2.4% and 0.2% of neutralizing ADA, respectively.  No notable differences have been 
observed with regards to loss or lack of efficacy or hypersensitivity reactions, including systemic 
and local, between those patients who were ADA positive and ADA negative (see the Investigator’s 
Brochure for details). 
ACT11575:  A randomized, double-blind, parallel-group, placebo- and active calibrator-
controlled study assessing the clinical benefit of sarilumab on top of MTX in patients with active 
RA who have failed previous TNF-α antagonists was terminated by the Sponsor due to 
administrative reasons with only 16 patients enrolled.   
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The objective of ACT11575 was to demonstrate that sarilumab added to MTX is superior in 
efficacy to placebo, for the relief of signs and symptoms of RA, in patients with active RA who 
have failed up to 2 TNF-α antagonists.  
EFC10832: A randomized, double-blind, parallel-group, placebo-controlled study assessing the 
efficacy and safety of sarilumab added to DMARD therapy in patients with active rheumatoid 
arthritis (RA) who are inadequate responders or intolerant to tumor necrosis factor-alpha (TNF-α) 
antagonists. The study is completed. 
The objective of EFC10832 was to demonstrate that sarilumab added to DMARD therapy is 
superior in efficacy to placebo for the relief of signs and symptoms of RA at Week 24 in patients 
with active RA who are inadequate responders or intolerant to TNF-α antagonists. 
SFY13370:  A randomized, double-blind, double-dummy study assessing the safety and 
tolerability of sarilumab and tocilizumab in patients with rheumatoid arthritis who are inadequate 
responders to or intolerant of TNF antagonists. The study is completed. 
The primary objective of SFY13370 was to assess, in the same study, the safety of sarilumab and 
tocilizumab in patients with rheumatoid arthritis (RA) who are inadequate responders to or 
intolerant of tumor necrosis factor (TNF) antagonists. 
EFC13752: An open-label, randomized, parallel group study assessing the immunogenicity and 
safety of sarilumab administered as monotherapy in patients with active rheumatoid arthritis. The 
study is completed. 
The primary objective was to evaluate the immunogenicity of sarilumab administered as 
monotherapy. 
 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of the study is to evaluate the long term safety of sarilumab in patients with 
RA.  
5.2 
SECONDARY 
The secondary objective of the study is to evaluate the long term efficacy of sarilumab in patients 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is a multicenter, multinational open label long term study, for patients with RA who 
participated and completed EFC11072, ACT11575, EFC10832, SFY13370, EFC13752 studies or 
for patients from 12 weeks onward with per protocol defined lack of efficacy from EFC10832. 
Patients, who were randomized in Part B of the study EFC11072 in a treatment arm subsequently 
not retained following pivotal dose selection, were also eligible for enrollment.  
Initially in LTS11210, patients received 150 mg of sarilumab SC weekly as the highest dose 
studied in EFC11072 Part A. The reduced dose (due to neutropenia, thrombocytopenia, or an 
increase in liver enzymes (ALT)), was 150 mg q2w.  Once the dose regimens were selected for 
the Phase 3 studies (150 mg q2w and 200 mg q2w), patients already ongoing in the study at the 
highest dose were switched to the new highest sarilumab dose 200 mg q2w, as soon as permitted 
by administrative process.  Patients previously assigned to the reduced dose of 150 mg q2w 
because of a safety issue continued to receive 150 mg q2w. 
6.2 
DURATION OF STUDY PARTICIPATION 
The IMP will be administered for 264 weeks from the first IMP administration in LTS11210. In 
addition the patients will continue to be treated beyond 264 weeks until sarilumab is commercially 
available in their country or until 2020 at the latest when the study will be closed. (In the UK the 
duration of treatment will be 264 weeks from the first study drug administration in LTS11210). 
The total maximum duration of study participation for a patient may be up to 523 weeks.  
• 1-week screening period if applicable  
• 516-week maximum treatment period in LTS11210 (for the earliest patients enrolled in 
LTS11210 in 2010 if sarilumab is not commercialized by 2020)  
• 6-week follow up period as required per protocol 
Further explanation is given below and in Section 12.1. 
Patients will either enter a 1-week screening period (patients from EFC11072 Part A or Part B1 
and ACT11575), or enrol directly into the treatment period (for patients from EFC11072 Part B2, 
EFC10832, SFY13370, or EFC13752 the EOT visit in the initial study corresponds to the 
randomization visit in the LTS11210 study).  
The duration of the treatment period in the study will be at least 264 weeks, or up to a maximum 
of 516 weeks (except in the UK where the duration of treatment will be 264 weeks).  
Patients will return for the safety follow-up visit 6 weeks after the EOT visit. In case of early 
treatment discontinuation, patients are required to complete the EOT visit and to return for the 
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6-week safety follow-up visit as well. In patients who complete sarilumab treatment per protocol 
in countries where sarilumab is commercially available the post treatment follow-up visit may be 
cancelled if the patient initiates treatment with commercial sarilumab during the post treatment 
follow-up period. However, in this case, a telephone contact must be established with the patient 
to capture all AEs occurring up to the 1st administration of commercial sarilumab. 
The study will be considered completed for a patient at the time he/she completes all the 
scheduled procedures as described in Section 12.1. 
6.3 
OPTIONAL PFS-S SUB-STUDY 
An optional 12-week sub-study aiming to evaluate the usability of pre-filled syringe with safety 
system (PFS-S) will be conducted in some countries. Patients enrolled in LTS11210 at selected 
sites in those countries may participate in the PFS-S sub-study from Week 24 of the main study 
after providing written informed consent for the sub-study. However, patients may continue to 
participate in the main trial without participating in the PFS-S sub-study if they wish. Full details 
of the PFS-S sub-study are presented in Appendix R. 
6.4 
STUDY COMMITTEES 
6.4.1 Data Monitoring Committee 
A Data Monitoring Committee (DMC) is in place for the sarilumab clinical study program. The 
sarilumab DMC monitors the safety of the patients participating in all ongoing sarilumab studies.  
The DMC is responsible for giving appropriate recommendations to the Sponsor on safety aspects 
during the conduct of the study, if needed.  In addition to the review of serious adverse events 
with fatal outcome and specific adverse events, the DMC has access to complementary safety 
parameters (eg, vital signs, laboratory test results etc.) and access to limited efficacy data.  The 
DMC responsibilities and the data review processes are fully described in the sarilumab DMC 
charter. 
Members of the DMC will be independent of those performing the study, being neither 
investigators nor employees of the Sponsor; and without conflict of interest regarding study 
outcome (whatever they are). 
6.4.2 Cardiovascular Adjudication Committee 
An independent Cardiovascular Adjudication Committee (CAC) has been established for the 
sarilumab clinical study program.  The role of the CAC is to apply uniform criteria for the 
evaluation of cardiovascular events (including retrospective events), and to adjudicate these 
events in a consistent and unbiased manner throughout the course of the study.  The goal of the 
CAC is to ensure that cardiovascular events reported by the site are judged uniformly, using the 
same criteria by a group of experts in cardiology and neurology, independent from Sanofi. The 
CAC will be blinded to treatment allocation.  The CAC responsibilities, detailed definitions of 
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cardiovascular events to be adjudicated and the adjudication processes are fully described in the 
CAC Charter and/or Manual of Operations.  
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7 
SELECTION OF PATIENTS 
7.1 
NUMBER OF PATIENTS PLANNED 
Approximately 2000 male and female patients with RA are planned to be included.  
7.2 
INCLUSION CRITERIA 
I 01. Patients with RA who were randomized:  
• 
in the study EFC11072 (a randomized, double-blind, placebo-controlled study in patients 
with active rheumatoid arthritis who are inadequate responders to MTX therapy) 
- 
and who have completed Part A (12 weeks) or Part B (52 weeks) of the study 
EFC11072. 
- 
or patients randomized in Part B of EFC11072 to a treatment arm subsequently not 
retained following pivotal dose selection. 
• 
in the study ACT11575 and completed the treatment period. 
• 
in the study EFC10832:  
- 
and completed the 24-week study treatment period. 
- 
or patients from 12 weeks onward with per protocol defined lack of efficacy 
• 
in the study SFY13370 and completed the treatment period. 
• 
in the study EFC13752 and completed the treatment period.  
I 02. Patients must give informed consent for participating in the study LTS11210 prior to any 
procedure related to the study.  
7.3 
EXCLUSION CRITERIA 
Exclusion criteria related to the mandatory background therapies 
E 01. Patients not willing to continue to take folic/folinic acid 5 mg weekly or greater (based on 
local recommendations) when using MTX. 
E 02. Deleted 
E 10. Patients rolling over from ACT11575, EFC11072, EFC10832, SFY13370 studies 
unwilling to continue the same background DMARD therapy as received in the initial 
study. Patients rolling over from EFC13752 study unwilling to continue sarilumab 
treatment without any background DMARD therapy. 
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E 12. Treatment with any DMARD other than those allowed per protocol (see Section 8.8) and 
limited to the maximum specified dosage. 
Exclusion criteria related to the Sanofi compound: 
E 03. Any patient who experienced an adverse event leading to permanent discontinuation from 
a prior study. 
E 04. Deleted 
E 05. Deleted 
E 06. Pregnant or breast-feeding women. 
E 07. Women of childbearing potential (WOCBP) not protected by highly-effective 
contraceptive method(s) of birth control (as defined in the informed consent form and/or in 
a local protocol addendum), and/or who are unwilling or unable to be tested for pregnancy.  
(For UK patients: Women of childbearing potential, unwilling to utilize adequate 
contraception methods or not become pregnant during the full course of the study. 
Adequate contraceptive measures include: 
- 
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. The use of barrier contraceptives 
should always be supplemented with the use of a spermicide. 
- 
Male sterilisation (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). 
- 
True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception].)  
E 08. Deleted 
E 09. Deleted  
E 11. Patients with an abnormality(ies) or adverse event(s) that per investigator judgment would   
adversely affect patient´s safety and/or participation of the patient in the study. 
E 13. Patients with temporary IMP discontinuation lasting > 31 days at the time of the planned 
first dose in the LTS11210 study. 
E 14.  Patients fulfilling the protocol-defined criteria for the permanent treatment discontinuation. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT 
• 
Pharmaceutical form: the pharmaceutical form of sarilumab has been modified since the 
initial version of the study protocol. Sarilumab, in vials (formulation C1F2), was 
dispensed to all patients enrolled into the study prior to the phase 3 dose selection 
decision. Thereafter, drug product in vials has been phased out of the study, and patients 
have been dispensed with drug product in prefilled syringes (pivotal formulation C2F3) 
once sufficient quantities were available and appropriate local approvals obtained. For 
completeness, all IMP formats used during the study are presented here: 
- 
Currently dispensed IMP for all patients:  
- 
Sarilumab in prefilled syringe (PFS): Glass syringes with a 27 gauge thin wall, 
1/2-inch staked needle, with FM30 needle tip cap (latex free) filled at 1.14 mL with 
C2F3 drug product at 131.6 mg/mL (150mg dose) or 175 mg/mL (200mg dose). 
PFS with FM30 needle tip is the only pharmaceutical form dispensed to patients 
from EFC10832, SFY13370, and EFC13752. 
- 
Sarilumab in prefilled syringe with safety system (PFS-S) with exactly the 
same formulation as the PFS with FM30 needle tip cap described above. The 
PFS-S is used for patients in the sub-study only. Refer to Appendix R for 
further details of the safety system. 
- 
Previously dispensed IMP: 
- 
Sarilumab in amber glass vials: filled to 2 mL with 75 mg/mL (150mg dose), or 
100 mg/mL (200mg dose) of C1F2 drug product 
- 
Sarilumab in PFS: Glass syringes as described above, but with FM27 rubber needle 
shield (needle cap may contain dry natural rubber latex)   
To ensure that the administration of the investigational product with PFS will minimally 
deliver the targeted doses of 150 mg and 200 mg, the PFS will contain an 8% average 
overfill.  
• Dose per administration 
Before the phase 3 pivotal dose regimens were selected: 
- 
150 mg administered weekly or every other week (reduced dose) 
After the phase 3 pivotal dose regimens were selected:  
- 
200 mg administered every other week or 150 mg administered every other week 
(reduced dose).  
• Route and method of administration:  Subcutaneously in abdomen, thigh or upper arm. 
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Each drug administration requires one single injection.  It is preferred that subcutaneous 
injection sites be rotated between the four quadrants of the abdomen (except the navel or 
waist area) or the thigh (front and side).  If needed, SC injection can be administered by a 
caregiver in the upper arm (lateral side). 
Subjects and/or their non-professional caregivers will be trained to prepare and administer 
study drug at the start of the double blind-treatment period of the previous study.  This 
training must be documented in the subject’s study file.  The study staff should review the 
subject’s self-administration technique at Visit 2 or V1/V2 (Week 0) for the LTS11210 
study.  For doses not given at the study site, diaries will be provided to record information 
pertaining to those injections.  If the subject is unable or unwilling to administer study 
drug, arrangements must be made for a qualified site personnel or a caregiver to 
administer study drug doses that are not scheduled to be given at the study site. 
The IMP administration should be taken strictly every 14 days as per protocol IMP 
administration schedule, however an IMP administration time window of ±3 days is 
permitted in exceptional circumstances (eg, the result of a repeat CBC test is not available, 
or an ongoing adverse event). For the subsequent IMP administration the initial IMP 
administration schedule should be followed again.  
Note: an interval of at least 11 days between 2 IMP doses must be maintained. 
8.2 
NON INVESTIGATIONAL PRODUCTS 
For patients rolling over from EFC11072, ACT11575, EFC10832, and SFY13370: 
All patients should continue to receive the non-biologic DMARD(s) background therapy that they 
were receiving in the initial study until the end of study treatment. However, at any time the 
DMARD(s) dose can be reduced, temporarily or permanently discontinued, or a patient may 
switch to alternate approved non-biologic DMARD for safety or tolerability reasons. If the new 
DMARD is initiated the dosing as well as safety monitoring should follow the applicable local 
labeling information. 
Each non-biologic DMARD will be recorded throughout the study on the e-CRF.  Any change 
should be recorded on the e-CRF.  DMARD(s) will not be dispensed or supplied by the Sponsor 
as an investigational product. 
All patients receiving MTX as their background DMARD will also receive folic/folinic acid 
(5 mg weekly or greater) according to local guidelines in the country where the study is 
conducted. 
For patients rolling over from EFC13752: 
Treatment with non-biologic DMARDs is not allowed. All patients should continue with 
sarilumab monotherapy until the end of study treatment. The IMP should be permanently 
discontinued if any DMARD is initiated.  
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8.3 
DELETED  
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
This is an open-label study and every patient will receive sarilumab. Treatment kit numbers will 
be allocated via interactive voice/web response system (IVRS/IWRS). Patients will keep the same 
identification number that they were allocated in the previous study. 
8.5 
PACKAGING AND LABELING 
The investigational products will be supplied in treatment kit boxes that are labeled in accordance 
with the local regulatory specifications and requirements and content information, dosing 
instructions and precautionary statement (“for clinical use only”). 
The number of treatment kits allocated to the patient will provide sufficient medication until the 
next clinic visit. An additional treatment kit, to provide medication to randomized patients in 
circumstances, e.g., a damaged kit, will be allocated by IVRS if a “replacement call” is made to 
the IVRS system. 
Each IMP unit will be labeled in accordance with the local regulatory requirement. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
All investigational drug supplies must be kept refrigerated in appropriate, secure area (for 
example, a locked cabinet or a locked room) under the responsibility of the Investigator or other 
authorized individual and must be stored separately from other medication and in the original 
carton as per specification mentioned on the label.  
8.7 
RESPONSIBILITIES 
The Investigator, the Hospital Pharmacist, or other personnel allowed to store and dispense 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 the applicable regulatory requirements. 
All IMP shall be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor.  Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor.  In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
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Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this Clinical Trial Protocol, or dispose of IMP in any other manner. 
8.7.1 Access to the randomization code during the study 
This section is not applicable for the study. 
However, in the case of a medically urgent situation, and if the Investigator (first contact person) 
cannot be reached, a competent medical professional can call a 24-hour emergency number 
provided by the Sponsor in order to get further information on the study or for medical questions. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient at the same time as any 
IMP(s). All medication taken during the study should be recorded on the corresponding pages of 
the e-CRF including any change in dose. 
8.8.1 Prohibited concomitant medication 
• Use of any biologic treatment for RA is not authorized during the study until 6 weeks 
following the EOT visit. If any of these treatments are used, the study treatment should be 
permanently discontinued. 
• Treatment with non-biologic DMARD(s) (such as cyclosporine, sulfasalazine, 
hydroxychloroquine, or cyclophosphamide) other than the DMARD(s) received in the 
initial study (ie, study immediately preceding LTS11210 enrollment) is not permitted until 
the end of treatment unless a change to an alternate approved non-biologic DMARD is 
made for safety or tolerability reasons. If the new DMARD is initiated the dosing as well 
as safety monitoring should follow local labeling information. For EFC13752 patients, the 
treatment with non-biologic DMARD(s) is not authorized until the end of the treatment. 
See Section 8.2 for additional details. 
• Treatment with tofacitinib or any other JAK inhibitor is not authorized during the course 
of the study. If any of these treatments are used, the patient should be discontinued. 
• Administration of any live (attenuated) vaccine is contraindicated (see list in Appendix K) 
until 3 months following the last study drug administration. 
• Treatment with any investigational medicinal product other than sarilumab is not 
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8.8.2 Permitted concomitant medication 
• Steroids 
- 
Oral corticosteroids are permitted to be taken at the time of study entry at the dose of 
≤ 10 mg prednisone or equivalent. 
- 
Intranasal or inhaled corticosteroids are authorized as needed throughout the study. 
- 
At any time the corticosteroid dose can be modified, temporarily or permanently 
discontinued, or a new steroid initiated (irrespective of the mode of administration), for 
any reason per investigator judgment including but not limited to worsening of RA, 
treatment of AEs or for the prevention of corticosteroid associated side effects.  
• Nonsteroidal anti-inflammatory drugs and analgesics: 
- 
Non-steroidal inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 inhibitors (COX-
2) are permitted as needed throughout the study. The dose used should be in 
accordance with the approved dose in the country in which the study is conducted.  
- 
Narcotic or non-narcotic analgesics (with no anti-inflammatory properties) for RA pain 
relief are permitted based on investigator judgment that there is insufficient RA pain 
relief with stable maintenance NSAIDs. As limited treatment for inter-current pain, all 
analgesics (with no anti-inflammatory properties) are allowed. These analgesics, 
including acetaminophen, should be avoided within 6 hours of efficacy assessments, 
including physical function and quality of life assessments. 
- 
Acetaminophen use should be limited to 4g/24h. Specific attention should be paid to 
co-administration of hepatotoxic drugs (see specific Section 10.2.4).   
• Cytochrome P450 enzyme substrates 
IL6 has been shown to reduce CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme 
expression in in-vitro studies. Therefore, when IL-6 is blocked using sarilumab IL-6 levels 
“normalize” and CYP450 enzymes may increase which could result in dose adjustment for 
drugs that are metabolized by CYP450 enzymes. As a precautionary measure, drugs which 
are metabolized via these cytochromes and with a narrow therapeutic index should be 
adjusted if needed: dose to be increased to maintain efficacy after initiation of sarilumab 
and to be decreased after sarilumab is stopped. Some examples of CYP450 substrates with 
a narrow therapeutic index, requiring monitoring of effect are warfarin or monitoring of 
drug concentration include cyclosporine, theophylline, digoxin, antiepileptics, such as 
carbamazepine (Carbatrol®, Tegretol®), divalproex (Depakote®), phenytoin (Dilantin®), 
or valproic acid (Depakene®); or antiarrhythmics, such as disopyramide (Norpace®), 
procainamide (Procan®, Pronestyl®), or quinidine (Quinidex®, Quin-Release Quin-G®). 
• Lipid lowering drugs: 
Lipid lowering drugs are permitted. Anti-IL-6 drugs, including sarilumab are known to 
increase serum cholesterol levels and this effect will be closely monitored during the 
study.  If, during the study, patients are found to have significant increase in cholesterol 
levels, then cholesterol lowering therapy per National Cholesterol Education program 
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(NCEP)Adult Treatment Panel (ATP)3 (NCEP/ATP3) or  local guidelines should be 
initiated or the dose of concomitant lipid lowering drug(s) adjusted.  A referral to a 
specialist should be considered when dyslipidemia is difficult to manage. 
8.9 
CONCOMITANT TREATMENT 
A concomitant treatment is any treatment received by the patient, at the same time as the IMP(s), 
other than medications. Treatments received during the study should be recorded on the 
corresponding pages of the patient’s e-CRF as appropriate. 
Joint replacement is permitted during the study. The IMP should be temporarily interrupted prior 
to surgery as per applicable guidelines and the IMP restarted as soon as proper wound healing is 
established.  
NOTE: The IMP can be temporarily discontinued for ≤59 days (3 IMP doses can be missed). If 
the re-initiation of the IMP occurs later than 38 days since the last IMP dose (2 IMP doses were 
already missed), the IMP has to be administered at the study site and the patient to be observed for 
30 minutes for any medical events. 
8.10 
TREATMENT ACCOUNTABILITY AND COMPLIANCE 
Measures taken to ensure and document treatment compliance and investigational medicinal 
product accountability include: 
• Proper recording of medication treatment pack number on appropriate e-CRF page for 
accounting purposes. 
• All medication treatment kits (containing vials, or prefilled syringes, whether empty or 
unused study medication) are returned by the patient at each visit.  
- 
As the used prefilled syringes cannot be safely returned to the study site after 
administration of IMP, the completed patient injection diary (returned to the site at 
each visit), returned treatment kit boxes and any unused prefilled syringes will be used 
for drug accountability purposes. 
• The study coordinator tracks treatment accountability/compliance, either by diary, or by 
counting the number of empty IMP containers (vials or prefilled syringes), 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 investigational 
medicinal product administration page by comparing them with the investigational 
medicinal product which has been retrieved and the patient treatment log form. 
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8.11 
RETURN AND/OR DESTRUCTION OF TREATMENTS 
All partially used or unused treatments will be retrieved by the investigator.  A detailed log of the 
returned IMP will be established with the Investigator (or the pharmacist) and countersigned by 
the Investigator and the Monitoring Team. 
Used or unused kits can be destroyed at site level upon approval of the study sponsor. 
 
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9 
ASSESSMENT OF INVESTIGATIONAL PRODUCT 
9.1 
ENDPOINTS 
9.1.1 Primary endpoint 
Incidence of adverse events: (see Section 10.1) 
9.1.2 Secondary endpoints 
The secondary endpoints will be: 
• The proportion of patients at week 12 and over time who achieve ACR20/ACR50/ACR70, 
DAS28 Remission, and EULAR Response. 
• DAS28-CRP over time 
• HAQ-DI results over time.   
• Van der Heijde modified total Sharp score over time and incidence of radiographic 
progression of the van der Heijde modified total sharp score for the subset of patients who 
previously completed the study EFC11072 Part B.  
• Each component of the ACR over time. 
• Health economic endpoints and Patient reported outcomes: patients will continue in 
evaluation of the health economic endpoints as per the initial study. 
9.1.2.1 ACR20/ACR50/ACR70 
Signs and symptoms are assessed with a composite rating scale of the ACR (American College of 
Rheumatology) that includes 7 variables: 
- 
Tender Joints Count (TJC) 
- 
Swollen Joints Count (SJC) 
- 
Levels of an acute phase reactant (CRP level) 
- 
Patient’s assessment of pain 
- 
Patient’s global assessment of disease activity 
- 
Physician’s global assessment of disease activity 
- 
Patient’s assessment of physical function 
The details of the ACR score are presented in Appendix B. 
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ACR20 is defined as the percentage of patients who achieve at least 20% improvement in both 
tender joint count and swollen joint count and, at least 20% improvement in at least 3 of the 5 
other assessments. 
ACR50 is defined as the percentage of patients who achieve at least 50% improvement in both 
tender joint count and swollen joint count and, at least 50% improvement in at least 3 of the 5 
other assessments. 
ACR70 is defined as the percentage of patients who achieve at least 70% improvement in both 
tender joint count and swollen joint count and, at least 70% improvement in at least 3 of the 5 
other assessments. 
ACR scores will only be assessed up to Week 264 at the time points as per study flowchart. 
9.1.2.2 DAS28-CRP  
Disease activity state will be measured and presented using the disease activity score (DAS28).  In 
this protocol, unless otherwise specified, DAS28 refers to DAS28-CRP.  DAS28 is a composite 
score that includes 4 variables: 
• 
Tender Joints Count (based on 28 joints - see Appendix B) 
• 
Swollen Joints Count (based on 28 joints - see Appendix B) 
• 
General health assessment (GH) by the patient assessed from the ACR RA core set 
questionnaire (patient global assessment) 
• 
Marker of inflammation assessed by the hs-CRP. 
It is a continuous measure allowing for measurement of absolute change in disease burden and 
percentage improvement.  It has been extensively validated for its use in clinical trials and 
accepted by Health Authorities.  The DAS28 can be calculated using the following formula: 
DAS28 = 0.56 x 
TJC
28
 + 0.28 x  
SJC
28
 + 0.36 x Log(CRP+1) + 0.014 x GH + 0.96 
The DAS28 provides a number indicating the current activity of the RA.  A DAS28 above 5.1 
means high disease activity, whereas a DAS28 below 3.2 indicates low disease activity and a 
DAS28 below 2.6 means disease remission.  
9.1.2.3 EULAR response 
Improvement in disease activity will also be assessed using the EULAR response criteria: 
• 
Good response = DAS28 improvement of >1.2 and a present DAS28 score ≤3.2 
• 
Moderate response = DAS28 improvement of >0.6 to ≤1.2 and a present DAS28 score 
≤5.1, or an improvement >1.2 and a present score >3.2 
• 
Nonresponse = DAS28 improvement of ≤0.6, or an improvement >0.6 to ≤1.2 and a 
present DAS28 score >5.1 
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9.1.2.4 Van der Heijde modified Total Sharp Score 
The van der Heijde modified Sharp method is a composite X-ray scoring system used to assess 
structural (joint) disease progression in RA (see Appendix C). The method evaluates both joint 
erosions (JE) and joint space narrowing (JSN) in bilateral hand and foot joints. 
The change from baseline in van der Heijde modified total Sharp score will be evaluated for 
patients who completed the EFC11072 Part B study in order to demonstrate maintenance of 
sarilumab effect on joints.  It will be assessed at week 48, 96, 144 and 192, or at the end of 
treatment for patients who prematurely discontinue from the study before Week 192. 
NOTE: the sponsor will not perform any medical evaluation on collected X-rays. They will be 
blindly assessed by independent graders and modified Van Der Heijde Total Sharp Score will be 
calculated per patient per visit. 
9.1.2.5 Physical Function 
Improvement in physical function is assessed by the change from baseline (original study) in 
HAQ-DI at week 48, 96, 144, 192, 240, 264, and EOT, if EOT is prior to Week 264.  It is based 
on the HAQ-DI assessment that is completed at each visit by the patient, as one of the ACR 
components. 
The HAQ-DI is composed of 8 categories as follows: dressing and grooming, arising, eating, 
walking, hygiene, reach, grip and activities, for which there are at least 2 questions by category. 
The patient will be asked to score how difficult he/she feels it is to perform such activities using a 
0 to 3 scoring (0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 
3=unable to do). If the patient is using assistance for any of these activities, scoring may be 
adjusted.  For each category, the highest score given for one of the question is attributed to the 
category.  The total score is the sum of all categories’ scores divided by the number of answered 
categories (at least 3 categories should be answered) (see Appendix J). 
9.1.2.6 ACR Components 
Each component of the ACR will be analysed as other secondary outcomes over time.  
All ACR components will be assessed up to Week 264.  
After Week 264, TJC and SJC (both based on 28 joints), patient´s global assessment of disease 
activity and hs-CRP will still be assessed to calculate DAS28. 
9.1.2.7 Health economic assessment and Patient reported outcomes (PROs)  
• Health economic assessments and PROs will be performed up to Week 264 as defined in 
the initial study and as specified in the study flowchart (See section 1.2). 
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• The Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-Fatigue) 
will be used to assess fatigue. The FACIT-Fatigue is a 13-item questionnaire rated 0 to 4 
originally developed to measure fatigue in patients with cancer and widely used in 
rheumatoid arthritis patients that demonstrates good consistency and sensitivity to change. 
The patient will be asked to answer 13 questions rated 0 to 4 (0 = not at all, 1 = a little bit, 
2 = some what, 3 = quite a bit, 4 = very much) (see Appendix F). The patient will be asked 
to fill in the questionnaire at different site visits (see flow chart, Section 1.2) 
• The Work Productivity and Activities Impairment (WPAI) will be assessed for patients 
coming from EFC11072 and ACT11575 only.  The WPAI was developed by Margaret 
Reilly for assessing productivity losses by measuring the effect of general health and 
symptom severity on work as well as usual activity productivity.  Specific-disease WPAI 
exists and can be adapted to different pathologies.  The RA WPAI (Appendix G): 
instrument consists of 6 questions that ask the subject the number of hours missed from 
work (ie, absenteeism) due to RA, the number of hours missed from work for anything 
other than RA, the number of hours totally worked, as well as how much the RA does 
affect the productivity at work or the ability to do daily activities over the past 7 days. The 
instrument can be self-, interview-, or telephone-administered and takes less than 5 
minutes to complete (~3 minutes). The 4 scores of the questionnaire are expressed as 
impairment percentages with higher numbers reflecting greater impairment and decreased 
productivity. The 4 scores are: 
1. Percent work time missed due to RA 
2. Percent impairment while working due to RA 
3. Percent overall work impairment due to RA 
4. Percent activity impairment due to RA 
• The WPAI has been tested in many disease states including migraine, arthritis, 
hypertension, diabetes, and depression and is adaptable to specific health problems such as 
RA. Inclusion of this measure in the study assesses the impact of sarilumab on a major 
component of subjects’ lives, which is their ability to perform daily activities and/or be 
able to work. The patient will be asked to fill in the questionnaire at different site visits 
(see flow chart, Section 1.2) 
• Assessment of joint replacement and joint procedures if any will be performed: total joint 
replacement (arthroplasty). 
• Sleep: Rheumatoid arthritis, like other chronic illness, is associated with sleep 
disturbances. Sleep disturbance is linked to pain, mood, and disease activity. The effect of 
sarilumab on pain will be assessed on a VAS scale (see Appendix H). The patient will be 
asked to fill in the questionnaire at different site visits (see flow chart, Section 1.2) 
• SF-36: The Short-Form 36 (SF-36) is a generic questionnaire measuring general health 
status (quality of life). It is one of the most frequently used and has been extensively 
validated in rheumatologic disease (see Appendix I ). The patient will be asked to fill in 
the questionnaire at different site visits (see flow chart, Section 1.2) 
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• The Rheumatoid Arthritis-Work Productivity Survey (WPS-RA): The WPS-RA is a 
validated questionnaire that evaluates productivity limitations within work and within 
home associated with RA over the previous month. 
It is interviewer-administered, is based on patient self-report.  It contains 8 items that 
include 3 work productivity related items and 5 home productivities related items 
(household activities) (see Section 27, Appendix Q) plus 1 item related to the employment 
status. 
Within work 
- 
Number of days of work missed 
- 
Number of days with productivity ≤ 50% at work 
- 
Arthritis interference with work productivity on a scale of 0 to 10 (0 = 'no 
interference' and 10 = 'complete interference') 
Within the home 
- 
Number of days of household work missed 
- 
Number of days with productivity ≤ 50% in household work 
- 
Number of days of family, social, or leisure activities missed 
- 
Number of days with outside help 
- 
Arthritis interference with household work productivity on a scale of 0 to 10 (0 = 
'no interference' and 10 = 'complete interference') 
9.2 
DELETED  
9.3 
PHARMACOKINETICS AND IMMUNOGENICITY 
Pharmacokinetics and immunogenicity assessment will be performed in all patients. 
9.3.1 Sampling time 
Serum samples will be collected for determination of functional sarilumab, anti-sarilumab 
antibody (also known as anti-drug antibody (ADA)) and IL-6 according to the Study Flow Chart 
(Section 1.2).  The date of collection should be recorded in the e-CRF. 
Serum concentrations of bound (serum sarilumab-sIL-6Rα complex) and functional sarilumab 
were intended to be analyzed in the study. After the completion of EFC11072 Part B study, the 
Sponsor made the decision to only analyze functional sarilumab concentrations. 
If a serious adverse event (SAE) occurs in a patient, serum samples should be collected for 
determination of sarilumab at or near the onset and completion of the occurrence of the event, if 
possible.  The exact date of sample collection and last dose must be recorded on the e-CRF. 
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9.3.2 Pharmacokinetic handling procedure 
Special procedures for collection, storage and shipping of serum will be described in separate 
operational manuals. 
An overview of sample handling procedures for pharmacokinetics (PK), anti-sarilumab antibody, 
and IL-6 is provided below: 
Table 1 - Summary of handling procedures for sarilumab, anti-sarilumab antibody, and IL-6 
 
 Sarilumab 
Anti-sarilumab antibody 
IL-6 
Blood Sample Volume 
6 mL 
6 mL 
2.5 mL 
Anticoagulant 
None 
None 
None 
Blood Handling 
Procedures 
See Operational Manual  
See Operational Manual  
See Operational 
Manual 
Serum Aliquot Split 
Two aliquots 
Two aliquots 
One aliquot 
Serum Storage 
Conditions 
< 6 month:  below  -70°C (preferred) / 
-20°C 
> 6 month: below  -70°C 
< 6 month:  below  -70°C (preferred) / 
-20ºC 
> 6 month: below  -70°C 
-20°C 
Serum Shipment 
Condition 
In dry ice 
In dry ice 
In dry ice 
 
 
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9.3.3 Bioanalytical method 
Serum samples will be assayed using validated methods as described below: 
Table 2 - Summary of bioanalytical methods for sarilumab and anti-sarilumab antibody 
Bioanalysis 
Sarilumab 
Anti-sarilumab antibody 
Matrix 
Serum 
Serum 
Analytical Technique 
ELISA 
Electrochemiluminescence 
Site of Bioanalysis 
Regeneron 
Regeneron 
 
 
In addition, IL-6 will be measured using validated assays. 
9.4 
SERUM AND RNA BIOMARKERS 
Please refer to the LTS11210 operations laboratory manual for a description of the collection, 
handling, storage, and shipment of the biomarker specimens.  
Potential studies may include examining markers related to IL-6 signaling, response to sarilumab, 
or related to the disease of RA. It is anticipated that the serum and RNA biomarker samples will 
be stored for up to 15 years (or as appropriate, according to applicable regulations) after 
completion of the final report of the main clinical trial. Storage after the end of the study will be at 
an accredited, dedicated long term biological sample storage facility which has established a strict 
and comprehensive security and confidentiality system. Samples will remain the property of the 
Sponsor and will be used only for the purposes described here, upon request by the Sponsor. 
9.4.1 Serum for future biomarker analysis 
A serum sample (5 ml) will be collected for future biomarker analysis at the EOT visit of the 
initial study, and at Week 2, Week 12, and Week 48 (except EFC13752 patients).  
9.4.2 RNA for future biomarker analysis 
Whole blood samples for ribonucleic acid (RNA) expression profiling (non-genetic analysis) will 
be collected at Week 0 (V2 or V1/V2), prior to treatment, and at Week 2/Visit 3 site visits only 
(except for SFY13370 and EFC13752 patients).  
If week 2/Visit 3 is scheduled as a “home visit”, the whole blood sample for RNA will not be 
collected. 
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10 
PATIENT SAFETY 
10.1 
SAFETY PARAMETERS ASSESSED IN THIS TRIAL 
• Adverse events: at every visit, the Investigator will ask the patient how he has felt since 
the last study visit. 
• Vital signs: 
- 
Vital signs including temperature, blood pressure, and heart rate will be collected prior 
to dosing per specifications on the study flow chart (see Section 1.2): 
- 
Body temperature will be collected using the same method for a given patient. Any 
fever:  body temperature ≥ 38°C should be recorded as an adverse event and the 
Investigator should perform all investigations necessary to rule out infection (see 
Section 10.2). 
- 
Blood pressure will be measured under standardized conditions, using the same well 
calibrated apparatus.  Both systolic and diastolic blood pressure should be recorded.  
Supine or sitting blood pressure should be checked after 2 minutes of rest.  Standing 
blood pressure is obtained 1 minute after the patient stands up.  The same arm should 
be used to measure blood pressure throughout the study. 
• Physical examination: A complete physical examination including a neurological 
examination will be performed as specified in the flowchart (see Section 1.2).  Any 
clinically significant abnormalities should be reported in the patient e-CRF as an adverse 
event.  Body Weight should be taken on a regular basis per specifications on the study 
flow chart (see Section 1.2) Body weight should be obtained with the patient wearing 
undergarments or very light clothing and no shoes, and with an empty bladder.  The same 
scale should be used throughout the study. 
• Tuberculosis assessment:  (see Section 1.2 and Section 10.2) 
• Electrocardiogram (ECG):  A standard 12-lead ECG will be performed as specified in 
the flowchart (see Section 1.2). Heart rate, QRS duration, PR interval, QT interval, ST 
deviation, T-wave morphology, U wave presence or absence will be determined using a 
centralized automatic and manual reading of all ECG. 
• Laboratory safety:  Blood will be taken before study drug dosing at the study site or at 
home by qualified personal. The following laboratory tests will be performed per 
specifications on the study flow chart (see Section 1.2): 
- 
Hematology 
Including: Hemoglobin, hematocrit, Red Blood Cell (RBC) morphology (if blood cell 
count is abnormal), WBC with differential, and platelet count 
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- 
Liver Function Test 
Including: Prothrombin Time (PT), albumin, Alanine Aminotransferase (ALT), 
Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), total bilirubin, 
conjugated bilirubin, unconjugated bilirubin. NOTE: after Week 264, PT will no 
longer be tested. 
− Lipids profile (patients need to be fasting) 
Including:  total cholesterol (TC), High Density Lipoprotein (HDL) cholesterol, Low 
Density Lipoprotein (LDL) cholesterol, triglycerides, Apolipoprotein A and 
Apolipoprotein B (Apolipoprotein A and B determination is not performed in 
SFY13370 study and results will not be available for the initial LTS11210 visit for 
SFY13370 patients). NOTE: after Week 264, only total cholesterol, HDL cholesterol, 
LDL cholesterol and triglycerides will be tested. 
- 
Clinical Chemistry (patients need to be fasting)  
Including: fasting glucose, total protein, calcium, sodium, potassium, Lactate 
Dehydrogenase (LDH), urea nitrogen and creatinine. Creatinine clearance will be 
calculated only at initial visit and during the study if clinical indicated. 
- 
For women of child-bearing potential: urine pregnancy testing will be performed as per 
study flow chart in Section 1.2. From V6, the site will dispense urine pregnancy kits to 
the patients who will perform the test at home on a monthly basis. The pregnancy test 
should be completed prior to any X-ray procedure. If any interim urine pregnancy test 
performed by the patient is positive, the patient should immediately report to the 
investigator for appropriate follow-up and pregnancy reporting as appropriate. 
- 
Urine analysis: including specific gravity, pH, glucose, blood, ketones, proteins, 
bilirubin, urobilinogen, nitrate, leukocytes will be performed per specifications on the 
study flow chart using a dipstick. If any parameter is abnormal, a urine sample should 
be sent to the central laboratory for testing. If positive for proteins, microscopic 
analysis will also be performed by central laboratory. NOTE: after Week 264, urine 
analysis will no longer be performed. 
- 
ANA/Anti-ds-DNA: testing will be done per specifications on the study flow chart (see 
Section 1.2).  
• Hepatitis B and C:  serology will be determined as clinically indicated (see Section 
10.2.4). 
• HIV: testing will be done anytime during the study when the patient has been at risk for 
HIV infection as per investigator judgment.   
Note: Local regulations or recommendations regarding regular eg, yearly HIV testing 
should be followed using a central or local laboratory facility.  
• 
Anti-sarilumab antibody: testing will performed per specifications on the study flow chart 
(see Section 1.2)   
Note that the laboratory values from the end of treatment in the study EFC11072, 
ACT11575, EFC10832, SFY13370, or EFC13752 studies will be the laboratory values for the 
initial visit of the LTS11210 study.  
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Specimens will be submitted for analysis as per the instructions of the central laboratory. 
10.2 
SAFETY INSTRUCTIONS 
10.2.1 Infections 
Biologics including TNF-α inhibitors and tocilizumab (another IL-6 receptor inhibitor similar to 
sarilumab) have been associated with an increased risk of infection, including black box warnings 
for serious infections leading to hospitalization or death. 
In the ongoing phase 3 program, serious infections including life threatening sepsis, have been 
reported, some notably associated with minor trauma. As a precautionary measure, investigators 
should carefully follow any signs of infection with particular care to identify potential infective 
complications in immune-suppressed individuals where superficial skin wounds or abrasions may 
lead to serious infections including necrotizing fasciitis and/or sepsis. 
Any infection should be reported by the Investigator as an adverse event and a corresponding 
e-CRF form should be filled in.  Treatment with antibiotics if any should be recorded with the 
route of administration. 
• Clinically significant infection: Section 10.5.4 defines clinically significant infections 
that require pre-specified monitoring and should be reported as adverse events of pre-
specified monitoring/adverse events of special interest (AEPM/AESIs) with immediate 
notification. In case of suspicion of clinically significant infection, a complete diagnosic 
work-up should be performed including but not limited to cultures for bacterial infections, 
fungi and/or mycobacteria, histopathological or cytological evaluation, antigen detection 
and serum antibody titers. The type of infection should be listed in the e-CRF form.  The 
patient should be referred to a specialist if needed for diagnosis and treatment.  In addition, 
the study Investigator should determine if the infection qualifies for serious adverse event 
reporting or not.  
• Note:  Systemic opportunistic infections should be reported as serious.  
- 
The IMP should be temporarily discontinued in case of infection requiring oral or 
parenteral treatment with antibacterial, antiviral and/or antifungal agents (See  
Section 11.1) or permanently discontinued in case of confirmed opportunistic 
infections including but not limited to TB. (See Section 11.2.1 and Appendix M). 
• 
Tuberculosis assessment:  Sarilumab is a biologic treatment that may induce 
immunosuppression, including the risk of reactivation of latent tuberculosis.  A special 
warning of the increased risk of tuberculosis is included in the labels of TNF antagonists 
and tocilizumab. 
As a precautionary measure, patients at risk for tuberculosis will be permanently 
discontinued from the study.  
A clinical examination and history will be performed at every visit to assess any signs and 
symptoms of tuberculosis or contact with a patient with active tuberculosis. 
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A QuantiFERON TB Gold test can be performed at any time during the course of the 
study in case of suspicion of tuberculosis.  A chest X-ray should be performed in all 
patients with suspected tuberculosis. 
In case of suspicion of TB, the Investigator should refer the patient to a specialist for a 
complete examination.  The study drug should be discontinued until TB is ruled out. 
Repeat chest radiographs should be performed as indicated by local treatment guidelines 
or practice for monitoring while on immunosuppressive/immunomodulatory therapy. If 
such guidelines are not available/ applicable, a chest X-rays should be performed when 
clinically indicated. 
10.2.2 Demyelinating / Neurological events 
Any demyelinating event or significant, unexplained neurological symptom should be considered 
as an adverse event with prespecified monitoring (see Section 10.5.4). Refer to Section 11.2 for 
demyelinating/neurological events requiring permanent treatment discontinuation. 
Rarely, biologics have been associated with Progressive Multifocal Leukoencephalopathy (PML).  
The investigator should check any signs that might be suggestive of a PML at every visit: such as, 
but not limited to, unusual weakness, loss of coordination, changes in vision, difficulty speaking 
and sometimes personality changes.  In case of suspicion of an event potentially related to a 
demyelinating event or significant, unexplained neurological symptom during the course of the 
study, the patient should be referred to a neurologist for a complete examination.   
10.2.3 Autoimmunity and Lupus-like syndrome 
Anti DNA antibodies: ANA (Antinuclear antibody) and Anti- double- stranded DNA (Anti- ds-
DNA) antibody will be performed to assess the effect of sarilumab to induce autoimmune 
disorders most specifically for Systemic Lupus Erythematosus (SLE).  Indeed, 
immunosuppressant agents such as TNF antagonists have been associated with induction of SLE 
and SLE like syndromes.  Anti-ds DNA antibody will be tested only if ANA is positive (≥1:160 
titer). 
The presence of either of these antibodies may be without clinical consequence or associated with 
a clinical syndrome.  Their significance will be determined on a by-patient basis. 
If a diagnosis of lupus-like syndrome is suspected, this should be reported as an AEPM/AESI (see 
Section 10.5.4). 
10.2.4 Liver Function 
Transient, generally mild, elevation of transaminases has been observed with sarilumab. See the 
Clinical Investigator’s Brochure (CIB). 
Moreover, the co-administration of MTX or NSAID may represent an additional risk factor for 
observing signs of hepatotoxicity which is reflected in the American College of Rheumatology 
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(ACR) guidelines (12). The investigator is recommended to monitor transaminases in any patient 
receiving MTX but without any defined threshold for transaminases to start reducing MTX 
dosage which is thus left to the investigator judgement. 
Please refer to Section 10.5.4 for LFT abnormalities to be reported as AEPM/AESI with or 
without immediate notification. 
The Sponsor relies on the Investigator´s judgement for adapting concomitant medication, 
including dose reduction of MTX dosage, in case of LFT abnormalities within the guidelines 
below. 
In the present protocol, in order to closely follow LFTs, assessment of ALT, AST, alkaline 
phosphatase, prothrombin time, albumin, total bilirubin, conjugated bilirubin and unconjugated 
bilirubin will be performed per specifications on the study flow chart (see Section 1.2). 
• 
The study drug should be permanently discontinued in case of confirmed ALT > 5 ULN or 
in case of confirmed ALT>3 ULN and concomitant total bilirubin >2 ULN (unless the 
patient has a documented Gilbert’s disease).  A complete serological and ultrasonography 
work-up should be conducted in case of ALT >5 ULN or ALT>3 ULN and concomitant 
bilirubin >2 ULN (see Appendix L). 
• 
If ALT ≥3 ULN and ≤5 ULN and bilirubin ≤2 ULN, administration of study drug must be 
temporarily interrupted, and the study Investigator should immediately contact the patient 
to arrange for repeat LFTs within 48 hours from the Investigator’s awareness of the 
abnormal LFT results: 
- 
IMP should be temporarily interrupted until the ALT is below <3 ULN then restarted 
at the dose of 150 mg q2w at the Investigator´s discretion. 
- 
LFTs should be repeated according to the provided guideline and at a minimum of 
every 7 days until conditions for resumption of IMP administration are met (see 
Appendix L).  
10.2.5 Neutrophils 
Refer to Section 10.5.4 criteria for reporting neutropenia as AEPM/AESI with or without 
immediate notification. 
For all patients, a CBC test must be performed a few days before or at Visit 3, but not earlier than 
the 12th day after the first dose of IMP administration (using either designated central lab or local 
laboratory facility), and results reviewed prior to the administration of the 2nd dose of study drug 
in order to confirm that the neutrophil count is not within the protocol-defined limits for 
temporary, or permanent discontinuation of study drug. 
For all subsequent visits, in order to prevent the administration of study drug in patients at risk for 
severe neutropenia, whenever the neutrophil count is ≥ 1000/mm3 but less than the lower limit of 
normal (LLN) based on designated central laboratory test specifications, the CBC test (with 
differential) must be repeated to confirm that the neutrophil count is not within the protocol-
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defined limits for temporary, or permanent discontinuation of study drug, before the next 
administration of study drug. The outlined procedures below will be followed: 
• 
Contact patient as soon as possible and schedule “repeat CBC blood test”; the repeat blood 
test can be arranged using the designated central lab or a local laboratory facility. 
• 
If the results of the “repeat CBC blood test” (either designated central lab or local 
laboratory facility results) confirm that the neutrophil count is ≥ 1000/mm3 (1.0 GI/L), the 
study drug may be administered. 
• 
If the results of the “repeat CBC blood test” (either designated central lab or local 
laboratory facility results) demonstrate that the neutrophil count is < 1000/mm3 (1.0 GI/L), 
the study drug must be temporarily or permanently discontinued, per protocol stopping 
rules defined below, and in Appendix L. 
• 
Note:  All per protocol-scheduled CBC tests must be performed using the designated 
central lab, even in circumstances when a local laboratory facility is also used to determine 
the neutrophil count before dosing. 
In case of a decrease in the neutrophil count to a level ≥ 500/mm3 and < 1000/mm3: 
• 
Study drug must be temporarily discontinued; the patient must be assessed for evidence of 
infection and CBC blood test repeated within 48 hours from the study Investigator’s 
awareness of neutrophil count ≥ 500/mm3 and <1000/mm3. 
• 
Discontinuation of study drug is maintained until the neutrophil count returns to ≥ 
1000/mm3 (Appendix L).  
• 
After the patient meets all requirements for resumption of study drug administration, 
including neutrophil count ≥ 1000/mm3, then study drug administration may resume at the 
dose of 150 mg q2w.  
In case of a decrease in neutrophil count < 500/mm3 or if neutrophil count < 1000/mm3 and signs 
of infection: 
• 
Study drug must be permanently discontinued. 
• 
The patient must be assessed for evidence of infection and CBC blood test repeated within 
48 hours from the study Investigator’s awareness of neutrophil count < 500/mm3, or 
< 1000/mm3 and signs of infection. 
• 
It is recommended to admit the patient to the hospital in case of neutrophil count 
< 1000/mm3 with suspicion of infection.  
• 
Neutrophil count <500/mm3 persisting for at least 5 days is to be reported as a serious 
adverse event. 
10.2.6 Platelets 
Refer to Section 10.5.4 criteria for reporting thrombocytopenia as AEPM/AESI with or without 
immediate notification. 
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For all patients, a CBC test must be performed a few days before or at Visit 3, but not earlier than 
the 12th day after the first dose of IMP administration (using either designated central lab or local 
laboratory facility), and results reviewed prior to the administration of the 2nd dose of study drug 
in order to confirm that the platelet count is not within the protocol-defined limits for temporary, 
or permanent discontinuation of study drug. 
For all subsequent visits, in order to prevent the administration of study drug in patients at risk for 
thrombocytopenia, whenever the platelet count is below the LLN based on designated central 
laboratory test specifications, the CBC test must be repeated to confirm that the platelet count is 
not within the protocol-defined limits for temporary, or permanent discontinuation of study drug, 
before the next administration of study drug. The outlined procedures below will be followed: 
- 
Contact patient as soon as possible and schedule “repeat CBC blood test”; the repeat 
blood test can be arranged using designated central lab or a local laboratory facility. 
- 
If the results of the “repeat CBC blood test” (either designated central lab or local 
laboratory facility results) confirm that the platelet count is ≥ 100,000/mm3 (100 GI/L), 
the study drug may be administered. 
- 
If the results of the “repeat CBC blood test” (either designated central lab or local 
laboratory facility results) demonstrate that the platelet count is below 100,000/mm3 
(100 GI/L), the study drug must be temporarily or permanently discontinued, per 
protocol stopping rules defined below, and in Appendix L. 
- 
Note:  All per protocol-scheduled CBC tests must be performed using designated 
central lab, even in circumstances when a local laboratory facility is also used to 
determine the platelet count before dosing. 
In case of a decrease in platelet count to a level ≥ 50,000/mm3 and < 100,000/mm3: 
- 
Study drug must be temporarily discontinued; the patient must be assessed for 
evidence of spontaneous bleeding, and CBC blood test repeated within 48 hours from 
the study Investigator’s awareness of platelet count ≥ 50,000/mm3 and < 100,000/mm3. 
- 
Discontinuation of study drug is maintained until the platelet count returns to 
≥100,000/mm3 (see Appendix L). 
- 
After the patient meets all requirements for resumption of study drug administration, 
including platelet count ≥100,000/mm3, then study drug administration may resume at 
the dose of 150 mg q2w.  
The study drug must be permanently discontinued if platelet count is <50,000/mm3 or if 
<100,000/mm3 with spontaneous bleeding (see Appendix L).   
10.2.7 Systemic Hypersensitivity reactions / Anaphylaxis 
Severe, systemic hypersensitivity reactions (in rare cases fatal anaphylaxis), have been reported to 
occur following exposure to biological drugs, including tocilizumab. Infrequent, mild to 
moderate, systemic hypersensitivity reactions have been observed with sarilumab.   
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Patient at study site visits should be monitored for 30 min after the injection.  Patients that self-
administer IMP should be aware of the clinical signs and symptoms of allergic reactions, and limit 
strenuous activity for 30 minutes after self-injection.  Any problem should be documented in the 
patient’s diary or medical notes.  In case of systemic hypersensitivity reaction, including 
anaphylaxis (see Appendix O for the clinical criteria for diagnosing anaphylaxis), the study drug 
should be permanently discontinued and the study Investigator should determine if the event 
qualifies for serious adverse event reporting (see Section 10.4 and Section 10.5.2).  If the clinical 
criteria for diagnosing anaphylaxis are met per Appendix O, then appropriate treatment should be 
administered immediately and the adverse event must be reported as an SAE and AEPM/AESI 
with immediate notification. 
10.2.8 Diverticulitis and Gastrointestinal perforation  
Gastrointestinal perforations have been reported as complications in patients with diverticulitis 
who have been treated with tocilizumab.   
Gastro-intestinal perforation is an AESI with immediate notification to be reported as SAE.  
Confirmed diverticulitis or gastrointestinal ulceration should be reported as AESI without 
immediate notification (see Section 10.5.4). 
The Investigator should pay particular attention to all gastrointestinal symptoms such as, but not 
limited to, abdominal pain, haemorrhage or unexplained change in bowel habits with fever to 
assure that the diagnosis is not missed and that the conditions are managed appropriately to avoid 
the complication of perforation.  If necessary, the patient should be referred to a specialist.   
Corticosteroid use or prior history of diverticulitis is known to increase the risk of gastrointestinal 
perforations. The Investigator should be aware of this potential risk and monitor any sign of 
diverticulitis. 
10.2.9 Acute renal failure 
See Appendix L.  Sarilumab is not known to be associated with a clinically significant effect on 
renal function. 
10.2.10 Management of dyslipidaemia, cardiovascular events, and deaths 
Patients treated with tocilizumab have been observed to have increased elevations of all lipid 
parameters, including LDL cholesterol.  A similar finding has been observed for sarilumab. The 
potential cardiovascular effect of the lipid elevations, including LDL levels in this population of 
RA patients treated with anti-IL-6 antagonists, is unknown.   
As rheumatoid arthritis is a known independent risk factor for cardiovascular events, 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 (ATP) III or applicable 
local guideline (http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf). 
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Specific cardiovascular events, as listed in Section 10.5.4, and all deaths will be reported as AESI 
with immediate notification and should always be reported as serious adverse events. These 
events will be subject to an adjudication process via the Cardiovascular Adjudication Committee 
described in Section 6.4.2.  
10.3 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
10.4 
DEFINITIONS OF ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE) 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
in a patient to whom a pharmaceutical product has been administered, and which does not 
necessarily have to have a causal relationship with this treatment. 
An Adverse Event of Special Interest also known as an Adverse Event of Pre-specified 
Monitoring (AEPM/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 rapid 
communication by the Investigator to the Sponsor may be appropriate. Such events may require 
further investigation in order to characterize and understand them. The AESI/AEPMs may be 
added or removed during a study by protocol amendment. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death or; 
• 
Is life-threatening or; 
Note:  The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. Requires inpatient hospitalization 
or prolongation of existing hospitalization or 
• 
Results in persistent or significant disability/incapacity or 
• 
Is a congenital anomaly/birth defect 
• 
Is a medically important event: 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention (ie, specific measures or corrective treatment) to prevent one of the other outcomes 
listed in the definition above. 
Note:  The following medical important events intend to serve as a guideline for determining 
which condition has to be considered as a medically important event.  It is not intended to be 
exhaustive: 
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• 
Intensive treatment in an emergency room or at home for: 
- 
allergic bronchospasm, 
- 
blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia…), 
- 
convulsions (seizures, epilepsy, epileptic fit, absence…). 
• 
Development of drug dependency or drug abuse. 
• 
ALT >3 ULN + total bilirubin >2 ULN or asymptomatic ALT increase >10 ULN. 
• 
Neutrophil count <500/mm3 lasting for at least 5 consecutive days 
• 
Suicide attempt or any event suggestive of suicidality. 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
• 
Bullous cutaneous eruptions. 
• 
Cancers diagnosed during the study or aggravated during the study. 
• 
Chronic neurodegenerative diseases, newly diagnosed or aggravated during the study. 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.5.1 Adverse Events 
All AEs regardless of seriousness or relationship to IMP/NIMP, spanning from the signature of 
the informed consent form, until the end of the study as defined by the protocol for that patient, 
are to be recorded on the corresponding page(s) or screen(s) included in the CRF. 
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 the 
NIMP (not assessed in EFC13752 patients). 
The Investigator should take appropriate measures to follow all AEs until clinical recovery is 
complete and laboratory results have returned to normal (or baseline), 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 Sponsor.  
• 
Patients who experience an ongoing SAE or an AESI with immediate notification, at the 
pre-specified study end-date, should be followed until resolution, stabilization, or death 
and related data will be collected.  
When treatment is prematurely discontinued, the patient’s observations will continue until the end 
of the study as defined by the protocol for that patient. 
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Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if they are medically 
relevant: symptomatic or requiring either corrective treatment or consultation or leading to 
discontinuation or modification of dosing and/or fulfilling a seriousness criterion and/or is defined 
as an AE with pre-specified monitoring (AEPM/AESI). 
10.5.2 Serious Adverse Events 
In the case of a serious adverse event the Investigator must immediately: 
• 
ENTER (within 24 hours of knowledge) the information related to the SAE in the 
appropriate screens of the e-CRF; the system will automatically send the notification to the 
Monitoring Team after approval of the Investigator within the e-CRF or after a standard 
delay. 
• 
SEND (preferably by fax or e-mail) the 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 source 
document provided to the Sponsor.  For laboratory results, include the laboratory normal 
ranges. 
• 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for Lab data, concomitant Medication, 
patient status.) should be sent (by fax or e-mail) to the Monitoring Team within 24 hours 
of knowledge.  In addition, any effort should be made to further document each Serious 
AE that is fatal or life threatening within the week (7 days) following initial notification. 
• 
A back-up plan is used (using paper flow) when the e-CRF system does not work. 
• 
In case of 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, this should be reported to the Monitoring team. 
10.5.3 Deleted  
10.5.4 Adverse events of special interest/Adverse events with pre-specified monitoring 
(AESI/AEPM) 
The needs for specific monitoring, documentation, and management of AEPM/AESIs are 
described in this section.   
The decision to report AEPM/AESI as a SAE is the same as for any adverse event; if the event 
meets any seriousness criteria as per the Investigator’s judgment, it should be reported as an SAE.  
If the AEPM (just as any other adverse event) does not meet seriousness criteria as per the 
Investigator’s judgment, it should be reported as a nonserious event.  Certain AEPM/AESI will 
require immediate notification to the Sponsor, even if not fulfilling seriousness criteria, while 
others will not. 
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For the following AEPM/AESI, the Sponsor will be informed immediately (i.e., within 24 hours 
of knowledge), even if not fulfilling a seriousness criterion, using the corresponding pages in the 
CRF (to be sent) or screens in the e-CRF, following the same process as described for the SAEs. 
• Clinically significant infections including:  
- 
Confirmed diagnosis of opportunistic infection based on the investigator’s assessment 
following appropriate diagnostic workups and consultations.  
Note: For reporting purposes, any infection from the list of potential opportunistic 
infections provided in Appendix M should be reported as AESI with immediate 
notification, even it is not considered to be an opportunistic infection based on the 
investigator’s assessment.     
- 
Tuberculosis or initiation of medication for suspected tuberculosis 
- 
Parasitic and fungal infections not considered opportunistic infections (Note: for 
fungal infections only systemic and/or extensive cutaneous cases) 
- 
Infection requiring prolonged medication (>14 days). These are infections which 
require treatment (continuous or intermittent) for > 14 days, with antibiotics, 
antifungals, or antivirals (exclude when medications are only administered topically). 
- 
Infections requiring any parenteral antibiotics, parenteral antifungals, or parenteral 
antiviral agents 
• Anaphylaxis (see Section 10.2.7) 
• Increased alanine aminotransferase (see Section 10.2.4 and Appendix L): ALT increase 
leading to permanent discontinuation 
• Neutropenia (see Section 10.2.5 and Appendix L): Grade 4 or any neutropenia leading to 
permanent discontinuation 
• Thrombocytopenia (see Section 10.2.6 and Appendix L) leading to permanent 
discontinuation 
• Lupus like syndrome 
• Demyelinating events (including suspicion of PML) or significant unexplained 
neurological symptoms meeting seriousness criteria 
• Gastrointestinal perforation 
• Specific cardiovascular events and deaths (see Section 10.2.10): 
- 
Myocardial infarction  
- 
Stroke 
- 
Hospitalization due to unstable angina 
- 
Hospitalization due to heart failure 
- 
Hospitalization due to transient ischemic attack 
- 
Deaths (cardiovascular and noncardiovascular) 
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• 
Pregnancy: 
- 
Pregnancy occurring in a female patient included in the clinical study (as well as 
pregnancy occurring in a female partner of a male patient included in the study with 
IMP/NIMP) will be recorded as a pre-specified AE with immediate notification in all 
cases.  It will be qualified as an SAE only if it fulfills the SAE criteria. 
- 
In the event of pregnancy in a female patient included in the trial, IMP should be 
discontinued. 
- 
The follow-up of the pregnancy in a female participant or in a female partner of a male 
participant will be mandatory until the outcome has been determined. 
• 
Symptomatic Overdose with IMP/NIMP: 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
dose of IMP during an interval of less than 11 days (NOTE: this definition was less 
than 6 days for patients on the initial weekly dosing regimen in the study). The 
circumstances (ie, accidental or intentional) should be clearly specified in the verbatim 
and symptoms, if any, entered on separate AE forms. 
- 
An overdose (accidental or intentional) with any NIMP (as defined in Section 8.2) is 
an event suspected by the Investigator or spontaneously notified by the patient and 
defined as at least twice of the intended dose within the intended therapeutic interval. 
The circumstances (ie, accidental or intentional) should be clearly specified in the 
verbatim and symptoms, if any, entered on separate adverse event forms. 
In addition, the following AESIs/AEPMs with immediate reporting must always be considered as 
medically important if not fulfilling any other seriousness criteria (see Section 10.4) and reported 
as serious adverse events.  
• 
Systemic opportunistic infections 
• 
Grade 4 neutropenia lasting for at least 5 days 
• 
Anaphylaxis fulfilling the criteria in Appendix O  
• 
Demyelinating events (including suspicion of PML), or significant, unexplained 
neurological symptoms meeting seriousness criteria  
• 
Gastrointestinal perforation 
• 
Myocardial infarction 
• 
Stroke 
• 
Hospitalization due to unstable angina 
• 
Hospitalization due to heart failure 
• 
Hospitalization due to transient ischemic attack 
• 
Deaths (cardiovascular and noncardiovascular) 
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For the following AEPM/AESI, the Sponsor will not require immediate notification; however if 
the event meets any seriousness criteria as per the Investigator’s judgment, it should be reported 
as a SAE. 
• 
Neutropenia grade 3 (<1000 and ≥500/mm3) without permanent treatment discontinuation 
(see Section 10.2.5) 
• 
Thrombocytopenia (<100 000/mm3) without permanent treatment discontinuation (see 
Section 10.2.6) 
• 
ALT elevation ≥3 x ULN without permanent treatment discontinuation (see 
Section 10.2.4) 
• 
Confirmed diverticulitis or gastrointestinal ulceration (see Section 10.2.8) 
• 
Significant unexplained neurological symptoms not meeting seriousness criteria (see 
Section 10.2.2) 
• 
Asymptomatic overdose (definition described above) with IMP/NIMP.  The circumstances 
(ie, accidental or intentional) and the lack of symptoms (ie, asymptomatic) should be 
clearly specified in the verbatim. 
 
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Table 3 - Summary of Adverse Event Reporting Instructions 
CASE REPORT FORM COMPLETION 
EVENT 
CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN THIS CATEGORY 
AE form 
Safety complementary 
form 
Other specific 
forms 
Adverse Event 
Routine 
Any AE that is not SAE or AEPM/AESI 
Any laboratory, vital sign, or ECG abnormality (non-SAE) other than those specifically listed 
in another section that is: symptomatic, requiring corrective treatment or consultation, leading 
to IMP discontinuation or dose modification 
Yes 
No 
No 
All Serious 
Adverse Events 
Expedited (within 
24 hours of 
knowledge) 
Any AE/AEPM/AESI meeting seriousness criterion per Section 10.4 
Yes 
Yes 
As needed for 
selected AESI 
Clinically significant infections including: 
Confirmed diagnosis of opportunistic infection based on the investigator’s assessment 
following appropriate diagnostic workups and consultations.  
Note: For reporting purposes, any infection from the list of potential opportunistic 
infections provided in Appendix M should be reported as AESI with immediate notification, 
even it is not considered to be an opportunistic infection based on the investigator’s 
assessment. 
Infection requiring prolonged medication (>14 days). These are infections which require 
treatment (continuous or intermittent) for > 14 days, with antibiotics, antifungals, or antivirals 
(exclude when medications are only administered topically). 
Infections requiring any parenteral antibiotics, parenteral antifungals, or parenteral antiviral 
agents  
Tuberculosis or initiation of medication for suspected tuberculosis  
Parasitic and fungal infections not considered opportunistic infections (Note: for fungal 
infections only systemic and/or extensive cutaneous cases) 
Yes 
Yes 
Yes  
ALT increase leading to permanent discontinuation 
Yes 
Yes 
Yes 
Grade 4 neutropenia or any neutropenia leading to permanent discontinuation 
Yes 
Yes 
No 
Thrombocytopenia leading to permanent discontinuation 
Yes 
Yes 
No 
AESI WITH 
immediate 
notification  
Expedited (within 
24 hours of 
knowledge) 
Lupus like syndrome 
Yes 
Yes 
No 
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CASE REPORT FORM COMPLETION 
EVENT 
CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN THIS CATEGORY 
AE form 
Safety complementary 
form 
Other specific 
forms 
Pregnancy of a female patient/or female partner of male patient 
Yes 
Yes 
Yesa 
Symptomatic overdose with IMP/NIMP 
Yes 
Yes 
No 
 
 
In addition, AESI WITH immediate notification to always be reported as serious: 
• 
Systemic opportunistic infection  
• 
Grade 4 neutropenia lasting for at least 5 days 
• 
Anaphylaxis (defined in Appendix O, report as SAE) 
• 
Gastrointestinal perforation 
• 
Demyelinating events (including suspicion of PML) or significant, unexplained 
neurological symptoms meeting seriousness criteria 
• 
Specific cardiovascular events and deaths: 
- 
Myocardial infarction 
- 
Stroke 
- 
Hospitalization due to unstable angina 
- 
Hospitalization due to heart failure 
- 
Hospitalization due to transient ischemic attack 
- 
Deaths (cardiovascular and noncardiovascular) 
 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
 
Yes 
No 
No 
Yes 
Yes 
Nob 
Neutropenia grade 3 (<1000 and ≥500 mm3) without permanent treatment discontinuation 
Yes 
No 
No 
Thrombocytopenia (<100,000/mm3) without permanent treatment discontinuation 
Yes 
No 
No 
ALT elevation ≥ 3 x ULN without permanent treatment discontinuation 
Yes 
No 
Yes 
Confirmed diverticulitis or gastrointestinal ulceration  
Yes 
No 
Yes 
Demyelinating events or significant, unexplained neurological symptoms not meeting 
seriousness criteria  
Yes 
No 
Yes 
AESI WITHOUT 
immediate 
notification (non-
SAE) 
Routine 
Asymptomatic overdose with IMP/NIMP 
Yes 
No 
No 
• 
Reminder: Safety Complementary Forms should be completed for all SAEs, AESIs with immediate notification, pregnancies, and symptomatic overdoses 
a This corresponds to “Drug exposure via parent data collection form” used by Global Pharmacovigilance and Epidemiology. 
b No specific form in CRF but a cardiovascular adjudication package needs to be submitted to the Cardiovascular adjudication committee. 
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10.6 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the IMP Suspected Unexpected Serious 
Adverse Reaction (SUSAR), to the Health Authorities, IECs/IRBs as appropriate and to the 
Investigators. 
In addition, the Sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to the IMPs to the Authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected: eg, arthralgia related to RA. 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered as unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report (CSR). 
 
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11 
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 if the stop can be made temporarily; permanent IMP discontinuation should be a last 
resort.  Any IMP discontinuation should be fully documented in the CRF.  In any case, the patient 
should remain in the study as long as possible. 
11.1 
TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
PRODUCT(S) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs eg, suspected malignancy or because of abnormal laboratory values.  
The following is a list of criteria for temporary discontinuation. This list is not exhaustive and 
IMP may be temporarily discontinued for additional reasons based on Investigator judgment: 
• Increase in ALT level ≥3 x ULN to ≤5 x ULN and bilirubin ≤2 x ULN (unless the patient 
has documented Gilbert’s disease). The IMP can be resumed at the dose of 150 mg q2w 
only after the ALT has returned to a value <3 ULN and all requirements for resumption of 
study drug administration are met (see Section 10.2.4 and Appendix L).  
• Decrease in neutrophil count to a level between 500/mm3 to <1000/mm3 without signs 
and symptoms of a potential infection. The IMP can be resumed at the dose of 150 mg 
q2w only after the neutrophils have returned to a value ≥1000/ mm3 and all requirements 
for resumption of study drug administration are met (see Section 10.2.5 and Appendix L). 
• Decrease in platelet count to between 50 000 cells/mm3 to < 100 000 cells/mm3 without 
spontaneous bleeding. The IMP can be resumed at the dose of 150 mg q2w only after the 
platelet count is ≥100 000/mm3 and all requirements for resumption of study drug 
administration are met (See Section 10.2.6 and Appendix L). 
• Infections requiring oral or parenteral treatment with antibacterial, antiviral and/or 
antifungal agents (See Section 10.2.1 for additional guidance) 
• Surgery requiring temporary treatment discontinuation of biologic DMARD as per 
applicable guidelines 
If the dose is reduced to 150 mg q2w the reduced dose will be maintained for the whole duration 
of the treatment period.  
The IMP can be temporarily discontinued for ≤59 days (3 IMP doses can be missed). 
Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring. 
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If the restart of the IMP occurs later than 38 days since the last IMP dose (2 IMP doses were 
already missed), the IMP has to be administered at the study site and the patient to be observed for 
30 minutes for any medical events. 
NOTE: in case of prolonged decreased neutrophil count to a level between 500/mm3 to 
<1000/mm3 without signs and symptoms of a potential infection and/or prolonged increased ALT 
level ≥3 x ULN to ≤5 x ULN detailed work-up should be performed before sarilumab is 
reinitiated to rule out other potential causes of neutropenia or ALT elevation. 
11.2 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
PRODUCT(S) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
11.2.1 List of criteria for definitive treatment discontinuation 
The patients may withdraw from treatment with 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 reasons for treatment discontinuation and this should be documented in the 
e-CRF. 
Study drug will be permanently discontinued in case of the following events: 
• 
Confirmed diagnosis of opportunistic infection based on the investigator’s assessment 
following diagnostic workups and expert consultations 
• 
Active tuberculosis: 
- 
the diagnosis can be made either on symptoms or on a chest radiograph suggestive of 
active TB.  Patients should be referred to appropriate medical specialists and whenever 
possible, culture confirmation of disease should be obtained and recorded in the 
e-CRF. 
• 
The patient is at risk through close contact with a person with active TB and the patient 
refuses to undergo TB evaluation. 
• 
Culture positive for non-tuberculosis mycobacteria 
• 
Symptoms of systemic hypersensitivity or anaphylactic reactions. 
• 
Severe neurologic disease such as demyelinating disease or PML. 
• 
Significant laboratory abnormalities:   
- 
ALT> 5xULN or ALT>3xULN with concomitant total bilirubin >2xULN (unless 
patient with documented Gilbert´s syndrome) 
- 
neutrophil count <500/mm3, or neutrophil count <1000/mm3 with evidence of infection  
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- 
platelet count <50 000/mm3, or platelet count <100 000/mm3 with evidence of 
bleeding (see Section 10.2). 
• 
Conversion to HIV positive status 
• 
Acute renal failure 
• 
Pregnancy in female participant. 
• 
Use of any biologic DMARDs other than IMP,  or use of any JAK inhibitor 
• 
For EFC13752 patients: use of any non-biologic DMARDs 
• 
Any adverse events, per investigator judgment, that may jeopardize the patient safety. 
11.2.2 Handling of patients after permanent treatment discontinuation 
Patients will be followed up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last: 
• If possible, and after the permanent discontinuation of treatment, the patients will be 
assessed using the procedures normally planned for the end of treatment visit and the 
follow up visit 6 weeks later. 
All permanent treatment discontinuation should be recorded by the Investigator in the appropriate 
pages when considered as confirmed.  
11.3 
PROCEDURE AND CONSEQUENCE FOR PATIENT WITHDRAWAL FROM STUDY  
The patients may withdraw from the study, before study completion if they decide to do so, at any 
time and irrespective of the reason: 
• 
If possible, the patients are assessed using the procedure normally planned for the end-of 
treatment visit and post treatment safety follow-up visit. 
For patients who fail to return to the site, the Investigator should make the best effort to re-contact 
the patient (eg, contacting patient’s family or private physician, review available registries or 
health care database), 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 enrolled again (treated) in the study.  Their 
inclusion and treatment number must not be re-used. 
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12 
STUDY PROCEDURES 
12.1 
VISIT SCHEDULE 
It is preferred that all study visits take place in the morning.  Some visits that include only 
scheduled blood sampling (V3, V5, V6.1) (Week 2, Week 6, and Week 10) can be scheduled as 
Home Visits or clinic visits. 
Patients will be considered as having completed their treatment per protocol and should complete 
the end of treatment visit (EOT): 
• 
At Week 264, if sarilumab has been commercialized in their country at that time. EOT 
visit should be performed instead of Week 264 visit and the assessments defined in the 
flowchart (Section 1.2.1, Section 1.2.2) should be completed. 
• 
At any visit after Week 264 once sarilumab is commercialized in their country (applicable 
for patients in the countries where commercial sarilumab is not available at the time the 
patients completed their Week 264). Some of the assessments are NOT required at EOT 
for these patients; please refer to the flowchart (Section 1.2.1, Section 1.2.2) for details.  
- 
When commercialization occurs in a given country, investigators in that country will 
be alerted by the Sponsor and they will inform their patients during the next scheduled 
study visit that their subsequent visit 12 weeks later will be the EOT visit. 
• 
At any visit after Week 264 at the time the study is closed in 2020 in countries where 
commercialization has still not occurred. Some of the assessments are NOT required at 
EOT for these patients; please refer to the flowchart (Section 1.2.1, Section 1.2.2) for 
details. 
- 
EOT visits for all patients remaining in the study at that time will occur at scheduled 
clinic visits over a 3-month period in order to stagger the completion of EOT visits 
across the study, and allow the completion of the 6-week follow up period for all 
patients prior to study closure. Investigators will be alerted by the Sponsor that the 
study closure is approaching and they will inform their patients during the next 
scheduled study visit that their subsequent visit 12 weeks later will be the EOT visit. 
• 
At Week 264, for patients in the UK no matter when the sarilumab is commercially 
available in the country. EOT visit should be performed instead of Week 264 visit and 
assessments defined in the flowchart (Section 1.2.1, Section 1.2.2) should be completed. 
If a patient is permanently and prematurely discontinued from treatment, all assessments planned 
at the end of treatment visit (EOT) should be performed.  Some assessments at EOT are not 
required if the EOT visit occurs after Week 264, as indicated in the flowchart. 
The safety follow-up visit should be performed six weeks from the end of treatment for all 
patients including those who discontinued before the planned end of treatment with the following 
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• 
In patients who complete sarilumab treatment per protocol in countries where sarilumab is 
commercially available the post treatment follow-up visit may be cancelled if the patient 
initiates treatment with commercial sarilumab during the post treatment follow-up period. 
However, in this case, a telephone contact must be established with the patient to capture 
all AEs occurring up to the 1st administration of commercial sarilumab.  
From Week 24 (Visit 8) onwards, some patients may participate in the PFS-S sub-study. No 
details of the sub-study assessments are described in this section. Please refer to the Appendix R 
for all information related to the sub-study assessments for these patients. 
12.1.1 Visit 1:  Screening Visit (D-7 to D-1) 
A Screening Visit will only be completed by patients enrolling in the LTS11210 study from 
ACT11575 or EFC11072 Part A and Part B Cohort 1. 
A specific written informed consent form (WICF) should be signed and dated to enter the 
LTS11210 prior to any screening assessment. 
The majority of the screening assessments and labs procedures for this study correspond to the 
last treatment visit in the study EFC11072 or ACT11575. 
The patient will be proposed to enter this study if eligible. If not eligible or unwilling to enter this 
long term study then he or she will have a follow-up visit 6 weeks after the completion of the 
study EFC11072 or ACT11575. 
The following items will then be checked and recorded: 
Assess eligibility by review of inclusion/exclusion criteria. 
• 
Prior and current medication dosage to confirm inclusion and exclusion criteria. 
• 
Previous medical and surgical history: record only new medical and surgical history that 
has occurred since the randomization visit in study EFC11072, or ACT11575 
• 
Record demographic information. 
• 
History of alcohol and illicit drug use and smoking history. 
• 
For patients entering LTS11210 from Part A of EFC11072 or ACT11575, complete SF-36 
questionnaire. 
The following will be obtained from the End of Treatment visit in the study EFC11072 or 
ACT11575: 
• 
Perform a physical examination. 
• 
Record vital signs including body temperature, blood pressure and Heart Rate. 
• 
Record body weight (kg). 
• 
(Fasting) blood for clinical laboratory determinations including hematology, clinical 
chemistry profile, LFTs and lipids.  
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• 
Obtain urine for urinalysis (dipstick) for:  specific gravity, pH, glucose, blood, ketones, 
proteins, bilirubin, urobilinogen, nitrate, leukocytes. If positive for proteins, microscopic 
analysis will be performed by central laboratory. 
• 
Obtain urine for pregnancy test if female of child bearing potential. 
• 
Obtain 12 – lead ECG 
• 
Perform tuberculosis assessments 
• 
Perform a complete joint examination to assess tender and swollen joints 
• 
Ask the patient to complete relevant questionnaires: HAQ, patient’s global assessment, 
patient’s pain questionnaire. 
• 
Ask the patient to complete a sleep questionnaire, the FACIT-Fatigue, WPAI, and for 
EFC11072 Part B patients, the SF-36.   
• 
Complete the physician global assessment. 
• 
Obtain blood sample for acute phase reactants:  hs-CRP. The investigator, patient and 
sponsor will be blind to the results of the hs-CRP at screening and at baseline. The 
investigator is advised not to do a local CRP testing unless needed for safety reasons. 
• 
Obtain blood sample for PK (sarilumab), Serum IL-6, and anti-sarilumab antibody. 
• 
Obtain serum sample for future biomarker tests 
• 
ANA (if ANA titer is >1:160 obtain Anti-ds DNA). 
• 
X-rays of hand and feet (applicable to patients who completed EFC11072 Part B  
In addition: 
• 
Schedule an appointment for Visit 2 (D1) Week 0. 
12.1.2 Baseline (D1) (WK0)  
12.1.2.1 Visit 2: Patients enrolling from ACT11575 or EFC11072 Part A or Part B Cohort 1 
The following assessments will be completed at Visit 2 by patients enrolling in the LTS11210 
study from ACT11575 or EFC11072 Part A and Part B Cohort 1 only. 
The Investigator will check the inclusion criteria. For those patients who are eligible the 
Investigator or designee will:  
• 
Enquire regarding AE/SAEs. 
• 
Complete assessment for TB: sign and symptom of TB or contact with any person with 
TB. 
• 
Record vital sign including body temperature, blood pressure, and HR. 
• 
Record body weight in Kg. 
• 
Reconfirm eligibility by review of Inclusion/Exclusion criteria with particular attention to: 
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• 
Exclusion criteria (see Section 7.3) and co-medication use. 
• 
Record all medication use with start date and dose in the patient’s CRF. 
• 
Perform a complete joint examination to assess tender and swollen joints. 
• 
Ask the patient to complete relevant questionnaires: HAQ, patient’s global assessment, 
patient’s pain questionnaire. 
• 
Complete the physician global assessment. 
• 
Obtain blood sample for acute phase reactant: hs-CRP. The investigator, patient and 
sponsor will be blind to the results of the hs-CRP at screening and at baseline. The 
Investigator is advised not to do a local CRP testing unless needed for safety reasons.  
• 
Obtain blood sample for rheumatoid factor (RF). 
• 
Obtain blood sample for haematology and LFTs. 
• 
Obtain whole blood sample for RNA. 
• 
Call IVRS and receive Medication Pack number assignment from IVRS. 
• 
Dispense the Investigational Product (4 weeks supply) to the patient and provide 
instructions on preparation and self-injection and dosing.  This training must be 
documented in the patients study file.  If the patient is unable or unwilling to administer 
study drug, arrangements must be made for qualified site personnel and/or caregiver to 
administer study drug at weekly intervals or specified dose interval by the doctor, 
including the doses that are not scheduled to be given at the study site. 
• 
The investigator should check the results of the LFTs and neutrophil count after every 
laboratory visit and take any necessary action to ensure patient safety, including, per 
protocol-specified rules for dose reduction, and permanent treatment discontinuation. 
• 
The study coordinator or designee will administer the subcutaneous injection of sarilumab 
comprising of the initial dose at the study office and will observe the patient for 
30 minutes for any medical events. 
• 
Patients will be provided with diaries to record medical events pertaining to injections 
performed at home (date, time, injection location; and local reaction if any). 
• 
Schedule an appointment for Visit 3 (D15±3D) Week 2. This visit can be done as Home 
Visit at the patient request; and scheduled an appointment for Visit 4 as well if Visit 3 is 
planned as a Home Visit. 
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12.1.2.2 Visit 1/Visit 2: Patients enrolling From EFC10832, SFY13370, EFC13752 and 
EFC11072 Part B Cohort 2 
The following assessments will be completed at Visit1/Visit 2 by patients enrolling in the 
LTS11210 study from EFC10832, SFY13370, EFC13752 or EFC11072 Part B Cohort 2. 
A specific written informed consent form (WICF) should be signed and dated to enter the 
LTS11210 prior to any assessment. 
The patient will be proposed to enter this study if eligible. If not eligible or unwilling to enter this 
long term study then he or she will have a follow-up visit 6 weeks after the completion of the 
study EFC11072, SFY13370, EFC10832, or EFC13752. 
The following V1/V2 assessments and lab procedures for this study will be obtained from 
the End of Treatment visit in the study EFC11072, SFY13370, EFC10832, or EFC13752. 
Results of these assessments (if available) should be reviewed prior to patient´s inclusion in 
the study as a part of eligibility assessment: 
• 
The Investigator or designee will enquire regarding AE/SAEs 
• 
Physical examination  
• 
Vital signs including body temperature, blood pressure and heart rate  
• 
Body weight (kg). 
• 
Clinical laboratory determinations including hematology, clinical chemistry profile, LFTs 
and lipids.  
• 
Results of urinalysis (dipstick) for:  specific gravity, pH, glucose, blood, ketones, proteins, 
bilirubin, urobilinogen, nitrate, leukocytes (to be included in eligibility assessment). If 
positive for proteins, results of microscopic analysis performed by central laboratory. 
• 
Results of pregnancy test if female of child bearing potential 
• 
12 – lead ECG  
• 
Tuberculosis assessments  
• 
Completed joint examination assessing tender and swollen joints 
• 
Completed relevant questionnaires: HAQ, patient’s global assessment, patient’s pain 
questionnaire, physician global assessment. 
• 
Completed health economic assessment questionnaires.   
• 
Laboratory results for acute phase reactants:  hs-CRP. The investigator, patient and 
sponsor will be blind to the results of the hs-CRP at Visit V1/V2. The investigator is 
advised not to do a local CRP testing unless needed for safety reasons. 
• 
Blood sample for PK (sarilumab), Serum IL-6 (for EFC11072 patients), and anti-
sarilumab antibody. 
• 
Serum sample for future biomarker tests (except EFC13752 patients) 
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• 
Laboratory results for rheumatoid factor (RF). 
• 
Laboratory results for ANA (if ANA titer is >1:160 obtain Anti-ds DNA). 
• 
X-rays of hand and feet (applicable to patients who completed EFC11072 Part B (Cohort 2 
and Cohort 1 selected dose arms). 
The following items will then be checked to assess eligibility and will be recorded in eCRF: 
• 
Prior and current medication dosage to confirm inclusion and exclusion criteria. 
• 
Previous medical and surgical history (NOTE: no record is needed in eCRF): record only 
new medical and surgical history that has occurred since the randomization visit in study 
EFC11072, SFY13370, EFC10832, or EFC13752. 
• 
Demographic information. 
• 
History of alcohol and illicit drug use and smoking history. 
If eligibility confirmed:  
• 
The Investigator or designee will call IVRS and receive Medication Pack number 
assignment from IVRS. 
• 
The Investigational Product (4 weeks supply) will be dispensed to the patient and 
instructions provided on preparation and self-injection and dosing.  This training must be 
documented in the patients study file.  If the patient is unable or unwilling to administer 
study drug, arrangements must be made for qualified site personnel and/or caregiver to 
administer study drug at weekly intervals or specified dose interval by the doctor, 
including the doses that are not scheduled to be given at the study site. 
• 
The study coordinator or designee will administer the subcutaneous injection of sarilumab 
comprising of the initial dose at the study office and will observe the patient for 
30 minutes for any medical events. 
• 
Whole blood sample for RNA expression (for EFC10832 and EFC11072 patients only) 
• 
Patients will be provided with diaries to record medical events pertaining to injections 
performed at home (date, time, injection location; and local reaction if any). 
• 
An appointment for Visit 3 (D15±3D) Week 2 will be scheduled. This visit can be done as 
Home Visit at the patient request; and schedule an appointment for Visit 4 as well if Visit 
3 is planned as a Home Visit. 
• 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as 
soon as received and take any necessary action to ensure patient safety, including per 
protocol-specified rules for dose reduction, and permanent treatment discontinuation. 
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12.1.3 Visit 3:  Home visit On-treatment/Week 2 (D15 ±3D) 
This visit can be performed at home.  
This visit will include: 
• 
Blood collection for laboratory determinations using the designated central laboratory: 
hematology and LFTs 
• 
NOTE: For all patients, a CBC test must be performed before or at Visit 3, but not earlier 
than the 12th day after the first dose of IMP administration (using either designated central 
laboratory or local laboratory facility) in order to confirm that the neutrophil and/or 
platelet count(s) are not within the protocol-defined limits for temporary, or permanent 
discontinuation of study drug. 
• 
For ACT11575, EFC10832 and EFC11072 patients: Collection of whole blood for RNA 
expression at site visit only; cancel RNA collection if home visit. 
• 
Collection of serum for future biomarker tests (except EFC13752 patients). 
• 
Inquiry regarding AE/SAEs 
• 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as 
soon as received and take any necessary action to ensure patient safety, including per 
protocol-specified rules for dose reduction, and permanent treatment discontinuation. 
12.1.4 Visit 4:  On-treatment/Week 4 (D29, ±3D) 
The Investigator or designee will: 
• 
Inquire regarding AE/SAEs. 
• 
Check compliance to the study drug and concomitant medication and record any changes 
in the patient’s CRF. 
• 
Record vital signs including body temperature, blood pressure and HR and weight. 
• 
Perform tuberculosis assessment.  In case of suspicion of tuberculosis, refer the patient to a 
TB specialist for complete examination and additional work-up (see specific instructions 
in Section 10.2.1). 
• 
Obtain (fasting) blood for complete clinical laboratory determinations including: 
hematology, and LFTs and lipids. 
• 
Before dosing obtain blood sample for PK (sarilumab), serum IL-6. 
• 
Obtain blood sample for acute phase reactant: hs-CRP. 
• 
Obtain urine for pregnancy test for female of childbearing potential. 
• 
Perform a complete joint examination to assess tender and swollen joints. 
• 
Ask the patient to complete relevant questionnaires: HAQ, patient’s global assessment, 
patient’s pain questionnaire. 
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• 
Complete the physician global assessment. 
• 
Dispense Investigational Product (4-week supply) and remind instructions on self-
injection and dosing. 
• 
The study coordinator or designee will administer the subcutaneous injection (if 14 ± 3 
days from the last administration), will observe the patient for 30 minutes. 
• 
Schedule appointment for Visit 5 (D43 ± 3D) either on site or as Home Visit and schedule 
an appointment for Visit 6 as well if Visit 5 is planned as a Home Visit. 
• 
Provide self-injection diary 
• 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as 
soon as received and take any necessary action to ensure patient safety, including per 
protocol-specified rules for dose reduction, and permanent treatment discontinuation. 
12.1.5  Visit 5, Home Visit: On-treatment/Week 6 (D43 ±3D) 
This visit can be performed at home.  
This visit will include: 
• 
Blood collection for laboratory determinations using the designated central laboratory: 
hematology and LFTs 
• 
Inquiry regarding AE/SAEs. 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as soon as 
received and take any necessary action to ensure patient safety, including per protocol-specified 
rules for dose reduction, and permanent treatment discontinuation. 
12.1.6 Visit 6, on-treatment/Week 8 (D57±3D) 
The Investigator will: 
• 
Check compliance to the study drug and concomitant medication and record any changes 
in the patient’s CRF. 
• 
Record vital signs including body temperature, blood pressure and HR and weight. 
• 
Tuberculosis assessment.  In case of suspicion of tuberculosis, refer the patient to a TB 
specialist for complete examination and additional work-up (see specific instructions in 
Section 10.2.1). 
• 
Inquire regarding AE/SAEs. 
• 
Obtain (fasting) blood for complete clinical laboratory determinations including: 
hematology, clinical chemistry profile, LFTs and lipids. 
• 
Obtain blood sample for acute phase reactant: hs-CRP. 
• 
Obtain urine for urinalysis (dipstick). 
• 
Obtain urine for pregnancy test for female of child bearing potential. 
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• 
Perform a complete joint examination to assess tender and swollen joints. 
• 
Ask the patient to complete relevant questionnaires: HAQ, patient’s global assessment, 
patient’s pain questionnaire. 
• 
Complete the physician global assessment. 
• 
Dispense Investigational Product (4-week supply) and remind instructions on self-
injection and dosing; and provide self-injection diary. 
• 
The study coordinator or designee will administer the subcutaneous injection (if 14±3 days 
from the last administration), and will observe the patient for 30 minutes. 
• 
Schedule appointment for Visit 6.1 (D71 ± 3D) either on site or as Home visit and 
schedule Visit 7 (D85 ±3D). 
• 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as 
soon as received and take any necessary action to ensure patient safety, including per 
protocol-specified rules for dose reduction, and permanent treatment discontinuation. 
12.1.7 Visit 6.1, Home Visit: On-treatment/Week 10 (D71 ±3D) 
This visit can be performed at home. 
This visit will include: 
• 
Blood collection for laboratory determinations using the designated central laboratory: 
hematology and LFTs 
• 
Inquire regarding AE/SAEs 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as soon as 
received and take any necessary action to ensure patient safety, including per protocol-specified 
rules for dose reduction, and permanent treatment discontinuation. 
12.1.8 Visit 7:  On-treatment/ Week 12 (D85±3D) 
The Investigator will: 
• Check compliance to the study drug and concomitant medication and record any changes 
in the patient’s CRF. 
• Record vital signs including body temperature, blood pressure and HR and body weight. 
• Tuberculosis assessment.  In case of suspicion of tuberculosis, refer the patient to a TB 
specialist for complete examination and additional work-up (see specific instructions in 
Section 10.2.1). 
• Inquire regarding AE/SAEs. 
• Obtain (fasting) blood for complete clinical laboratory determinations including: 
hematology, clinical chemistry profile, LFTs, lipids profile. 
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• 
Save an aliquot of serum (5 mL) for storage for future biomarkers (except for EFC13752 
patients). 
• 
Obtain blood sample for acute phase reactant:  hs-CRP. 
• 
Before dosing obtain blood sample for PK (sarilumab), serum IL-6, and anti-sarilumab 
antibody. 
• 
Obtain urine for urinalysis (dipstick).  
• 
Obtain urine sample for urine pregnancy test for female of child bearing potential. The 
patients should be instructed to do the urine pregnancy test at home on a monthly basis 
during the intervals in between on-treatment clinic visits for the duration of the treatment 
period. In case of a positive pregnancy test, the patient should be advised to stop the IMP 
and to contact immediately her study doctor. 
• 
Perform a complete joint examination to assess tender and swollen joints. 
• 
Ask the patient to complete relevant questionnaires: HAQ, patient’s global assessment, 
patient’s pain questionnaire. 
• 
Ask the patient (except for SFY13370 and EFC13752 patients) to complete health 
economic assessments as per initial study (See Section 1.2). 
• 
Complete the physician global assessment. 
• 
Dispense Investigational Product (12-week supply) and remind instructions on self-
injection and dosing; and provide self-injection diary. 
• 
The study coordinator or designee will administer the subcutaneous injection (if 14±3 days 
from last administration) and will observe the patient for 30 minutes. 
• 
Dispense urine pregnancy test kit for monthly urine pregnancy test (3 month supply). 
• 
Schedule appointment for Visit 8 (D169 ±3D). 
• 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as 
soon as received and take any necessary action to ensure patient safety, including per 
protocol-specified rules for dose reduction, and permanent treatment discontinuation. 
Patients will have on treatment visit every 12 weeks starting from Week 24 to Week 96 and then 
every 24 weeks until EOT. Each visit can be done within ± 3days. 
12.1.9 Visit 8 (Week 24) to Visit 14 (Week 96) and Visit 16 (Week 120), Visit 18 (Week 144), 
Visit 20 (Week 168), Visit 22 (Week 192), Visit 24 (Week 216), Visit 26 (Week 240), 
Visit 28 (Week 264): On treatment visits from Week 24 to Week 264  
This section refers to on-treatment visits with clinical assessments from week 24 up to the end of 
the initial 264-week period of the study (excluding the IMP dispensing visits). 
The Investigator will: 
• 
Check compliance to the study drug and concomitant medication and record any changes 
in the patient’s CRF. 
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• 
Record vital signs including body temperature, blood pressure, HR and body weight. 
• 
Physical examination will be done only at weeks: 48, 96, 144, 192, 240 and 264. 
• 
Tuberculosis assessment.  In case of suspicion of tuberculosis, refer the patient to a TB 
specialist for complete examination and additional work-up (see specific instructions in 
Section 10.2.1). 
• 
Inquire regarding AE/SAEs. 
• 
Obtain (fasting) blood for complete clinical laboratory determinations including: 
hematology, clinical chemistry profile, LFTs, lipids profile. 
• 
Save an aliquot of serum (5mL) for storage for future biomarkers at Week 48 (except 
EFC13752 patients). 
• 
Obtain blood sample for acute phase reactant:  hs-CRP. 
• 
Obtain blood sample for rheumatoid factor at week 48, 96, 144, 192, 240 and 264. 
• 
Before dosing obtain sample for serum IL-6 only at week 24, 36 and 48. 
• 
Before dosing, obtain serum sample for PK (sarilumab) and for anti-sarilumab antibody. 
• 
Obtain blood sample for ANA at Week 48, 96, 144, 192, 240 and 264 or sooner if 
clinically indicated. 
• 
Obtain urine for dipstick urinalysis. 
• 
Obtain urine sample for urine pregnancy test for female of child bearing potential. The 
patients should be instructed to do the urine pregnancy test at home on a monthly basis 
during the intervals in between on-treatment clinic visits for the duration of the treatment 
period. In case of a positive pregnancy test, the patient should be advised to stop the IMP 
and to contact immediately her study doctor.   
• 
X-Ray of the hands and feet (only for patients who completed EFC11072 Part B (Cohort 2 
and Cohort 1 selected dose arms)) at week 48, 96, 144, 192 (±14 days for each evaluation), 
and transfer images to the central readers. 
• 
ECG at week 48, 96, 144, 192, 240 and 264. 
• 
Perform a complete joint examination to assess tender and swollen joints. 
• 
Ask the patient to complete relevant questionnaires: HAQ, patient’s global assessment, 
patient’s pain questionnaire. 
• 
Ask the patient (except for SFY13370 and EFC13752 patients) to complete health 
economic assessments as per initial study (See Section 1.2). 
• 
Complete the physician global assessment. 
• 
Dispense Investigational Product (12-week supply) and remind instructions on self-
injection and dosing; and provide self-injection diary.   
• 
The study coordinator or designee will administer the subcutaneous injection (if 14±3 days 
from last administration) and will observe the patient for 30 minutes. 
• 
Dispense urine pregnancy test kits for monthly urine pregnancy test.  
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• 
Schedule appointment for next visit.  
• 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as 
soon as received and take any necessary action to ensure patient safety, including per 
protocol-specified rules for dose reduction, and permanent treatment discontinuation. 
12.1.10 Visit 15 (Week 108), Visit 17 (Week 132), Visit 19 (Week 156), Visit 21 (Week 180), 
Visit 23 (Week 204), Visit 25 (Week 228), Visit 27 (Week 252), Visit 29 (Week 276), 
Visit 31 (Week 300), Visit 33 (Week 324), Visit 35 (Week 348), Visit 37 (Week 372), 
Visit 39 (Week 396), Visit 41 (Week 420), Visit 43 (Week 444), Visit 45 (Week 468), 
Visit 47 (Week 492): IMP dispensing visits in between 24-week on-treatment visits 
(after Week 96) 
This section refers to the IMP dispensing visits that will occur every 24 weeks from week 108 to 
week 492, alternating with the visits at which clinical assessments are performed. 
After Week 96, at 12-week intervals in between the q 24-week on-treatment visits the Investigator 
will: 
• 
Check compliance to the study drug and concomitant medication and record any changes 
in the patient’s CRF. 
• 
Obtain blood sample for hematology and LFTs (applicable for Portugal and Sweden only; 
no PT required after Week 264). 
• 
Inquire regarding AE/SAEs. 
• 
Dispense Investigational Product (12-week supply) and remind instructions on 
self-injection and dosing; and provide self-injection diary. 
• 
Schedule appointment for next visit.  
12.1.11 Visit 30 (Week 288), Visit 32 (Week 312), Visit 34 (Week 336), Visit 36 (Week 360), 
Visit 38 (Week 384), Visit 40 (Week 408), Visit 42 (Week 432), Visit 44 (Week 456), 
Visit 46 (Week 480), Visit 48 (Week 504): On treatment visits from Week 288 to 
week 504 
This section refers to on-treatment visits with less complex clinical assessments, for patients who 
are continuing in the study after week 264 because sarilumab is not yet commercialized in their 
country. 
The Investigator will: 
• 
Check compliance to the study drug and concomitant medication and record any changes 
in the patient’s CRF. 
• 
Record vital signs including body temperature, blood pressure, HR and body weight. 
• 
Physical examination will be done only at weeks: 288, 336, 384, 432 and 480. 
• 
Tuberculosis assessment.  In case of suspicion of tuberculosis, refer the patient to a TB 
specialist for complete examination and additional work-up (see specific instructions in 
Section 10.2.1). 
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• 
Inquire regarding AE/SAEs. 
• 
Obtain (fasting) blood for complete clinical laboratory determinations including:  
- 
hematology 
- 
clinical chemistry profile  
- 
LFTs (no PT required)  
- 
lipids (only TC, HDL cholesterol, LDL cholesterol, triglycerides) will only be done  at 
weeks: 288, 336, 384, 432 and 480. 
• 
Obtain blood sample for acute phase reactant:  hs-CRP. 
• 
Before dosing, obtain serum sample for PK (sarilumab) and for anti-sarilumab antibody. 
• 
Obtain blood sample for ANA at week 288, 336, 384, 432 and 480, or sooner if clinically 
indicated. 
• 
Obtain urine sample for urine pregnancy test for female of child bearing potential. The 
patients should be instructed to do the urine pregnancy test at home on a monthly basis 
during the intervals in between on-treatment clinic visits for the duration of the treatment 
period. In case of a positive pregnancy test, the patient should be advised to stop the IMP 
and to contact immediately her study doctor.   
• 
Perform a complete joint examination to assess tender and swollen joints. Only the 28 
joints required for DAS28 calculation need to be evaluated (see Appendix B). 
• 
Ask the patient to complete patient’s global assessment. 
• 
Dispense Investigational Product (12-week supply) and remind instructions on 
self-injection and dosing; and provide self-injection diary.   
• 
The study coordinator or designee will administer the subcutaneous injection (if 14±3 days 
from last administration) and will observe the patient for 30 minutes. 
• 
Dispense urine pregnancy test kits for monthly urine pregnancy test.  
• 
Schedule appointment for next visit.  
• 
The Investigator should check the results of the LFTs, neutrophil and platelet counts as 
soon as received and take any necessary action to ensure patient safety, including per 
protocol-specified rules for dose reduction, and permanent treatment discontinuation. 
12.1.12 Visit 49: End of treatment (EOT) 
The investigator will: 
• 
Check compliance to the study drug and concomitant medication and record any changes 
in the patient’s CRF. 
• 
Record vital signs including body temperature, blood pressure, HR and body weight. 
• 
Perform physical examination 
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• 
Perform tuberculosis assessment.  In case of suspicion of tuberculosis, refer the patient to a 
TB specialist for complete examination and additional work-up (see specific instructions 
in Section 10.2.1). 
• 
Inquire regarding AE/SAEs. 
• 
Obtain blood sample for acute phase reactant:  hs-CRP. 
• 
Obtain serum sample for PK (sarilumab) and for anti-sarilumab antibody. 
• 
Obtain blood sample for ANA 
• 
Obtain urine sample for urine pregnancy test for female of child bearing potential. 
In addition: 
− If the EOT is prior to or including Week 264, the investigator will also: 
• 
Obtain (fasting) blood for complete clinical laboratory determinations including: 
- 
hematology 
- 
clinical chemistry profile 
- 
LFTs  
- 
lipids profile. 
• 
Obtain blood sample for rheumatoid factor. 
• 
Obtain urine for dipstick urinalysis. 
• 
Perform ECG. 
• 
Perform a complete joint examination to assess tender and swollen joints. 
• 
Ask the patient to complete relevant scales and questionnaires: patient’s global 
assessment, HAQ, patient’s pain questionnaire. 
• 
Complete the physician global assessment  
• 
Ask the patient (except for SFY13370 and EFC13752 patients) to complete health 
economic assessments as per initial study (See Section 1.2). 
• 
Arrange X-Ray of the hands and feet (only for patients who completed EFC11072 Part 
B (Cohort 2 and Cohort 1 selected dose arms)) when EOT is no later than the Week 
192 visit. 
− If the EOT is after Week 264, the investigator will also: 
• 
Obtain (fasting) blood for complete clinical laboratory determinations including: 
- 
hematology 
- 
clinical chemistry profile 
- 
LFTs (PT is not required) 
- 
lipids profile (only TC, HDL cholesterol, LDL cholesterol, triglycerides). 
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• 
Perform a complete joint examination to assess tender and swollen joints. Only the 28 
joints required for DAS28 calculation need to be evaluated (see Appendix B). 
• 
Ask the patient to complete patient’s global assessment. 
 
The investigator should schedule appointment for follow-up visit.  
The Investigator should check the results of the LFTs, neutrophil and platelet count as soon as 
received and take any necessary action to ensure patient safety. 
12.1.13 Visit 50: Post Treatment safety follow-up visit  
Patients that discontinued prematurely before the planned end of treatment, or who completed 
their treatment per protocol should have this visit performed 6 weeks from end of treatment visit 
with the following exception:  
− In patients who complete sarilumab treatment per protocol in countries where sarilumab is 
commercially available the post treatment follow-up visit may be cancelled if the patient 
initiates treatment with commercial sarilumab during the post treatment follow-up period. 
However, in this case, a telephone contact must be established with the patient to capture 
all AEs occurring up to the 1st administration of commercial sarilumab. 
The Investigator will: 
• 
Record vital signs including body temperature, blood pressure and HR and weight. 
• 
Perform tuberculosis assessment.  In case of suspicion of tuberculosis, refer the patient to a 
TB specialist for complete examination and additional work-up (see specific instructions 
in Section 10.2.1). 
• 
Inquire regarding AE/SAEs and concomitant medications. 
• 
Obtain urine for pregnancy test for female of child bearing potential. 
• 
Obtain serum sample for PK (sarilumab) and for anti-sarilumab antibody. 
12.2 
DEFINITION OF SOURCE DATA 
The source data will be the following: 
• 
Chest X-ray or signed documented X-ray and reports 
• 
Joints X-rays 
• 
HAQ-DI questionnaires 
• 
Patients assessments of pain 
• 
Patient’s global assessment of disease activity 
• 
Physician’s global assessment of disease activity 
• 
Tender/painful and swollen joint counts 
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• 
Patient diaries 
• 
Central and local lab reports 
• 
Completed FACIT-Fatigue 
• 
Health economics assessments and PROs 
• 
ECG tracings and reports 
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13 
STATISTICAL CONSIDERATIONS 
13.1 
DETERMINATION OF SAMPLE SIZE 
The number of patients to participate in this extension study will be approximately 2000.  
13.2 
ANALYSIS ENDPOINTS 
13.2.1 Demographic and baseline characteristics 
Baseline for this study is defined to be the baseline measurement from the previous (initial) study. 
13.2.1.1 Demographic and baseline characteristics 
Demographic characteristics 
The following demographic characteristics will be summarized: 
• 
Gender (male, female) 
• 
Race (Caucasian/White, Black, Asian/Oriental, other) 
• 
Ethnicity (Hispanic, Not Hispanic) 
• 
Region (Western countries, South America, Rest of the World) 
• 
Age (years) 
• 
Age group (<65, ≥65 to ≤75, ≥75 years) 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) 
• 
BMI group (<25, ≥25 and <30, ≥30 kg/m2). 
Disease characteristics at baseline 
The following baseline disease characteristics will be summarized: 
• 
Time since diagnosis of RA (Years) 
• 
Rheumatoid  factor (Positive: ≥1 IU/mL, negative: <1 IU/mL) 
• 
Anti CCP (positive, negative) 
• 
Prior biologic DMARD use for RA  
• 
Smoking history  
• 
Alcohol use  
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In addition, the summary of baseline values for clinical signs and symptoms and quality of life 
assessments will be presented in the summary tables for these data. 
13.2.1.2 Concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD). 
Concomitant medications are those patients used at any time during the study treatment period, 
from the first investigational product intake to the end of the follow-up period. 
13.2.2 Safety endpoints 
The safety variables include adverse events, clinical laboratory parameters, vital signs, and ECG.  
The primary safety analysis variables are adverse events. 
The same observation period (defined below) will be used for all safety observations. 
Observation period 
The observation of safety data will be as follows: 
• 
The treatment-emergent observation period is defined as the time from the first dose of 
sarilumab in this study LTS11210 up to last dose of sarilumab + 60 days. 
• 
The post-study period is defined as the time after the last dose of sarilumab + 60 days. 
13.2.2.1 Adverse events 
Adverse event observation period 
The adverse event observations are per the observation period defined above. 
13.2.2.2 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry 
and urinalysis).  Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. 
13.2.2.3 Vital signs 
Vital signs variables include: weight, systolic blood pressure, diastolic blood pressure, 
temperature, and heart rate. 
13.2.2.4 Electrocardiogram variables 
A standard 12-lead ECG will be performed and will be determined using centralized automatic 
and manual readings. 
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ECG parameters include heart rate, PR, QRS, QT as well as QTc (corrected according to 
Bazett/Fridericia formula). 
13.2.3 Efficacy endpoints 
The efficacy endpoints as defined in Section 9.1.2 will include: 
• 
ACR20 response over time up to Week 264 
• 
ACR50 and ACR70 response over time up to Week 264 
• 
DAS28 -CRP response over time 
• 
DAS28 remission over time 
• 
EULAR response over time 
• 
Change from baseline in the van der Heijde modified total Sharp score (for patients from 
Part B of EFC11072 with an end of treatment X-ray evaluation) at weeks 48, 96, 144, 192,  
or EOT, if EOT is prior to Week 192 
• 
Incidence of radiographic progression of the van der Heijde modified total sharp score at 
weeks 48, 96, 144, 192,  or EOT if EOT is prior to Week 192 
• 
Change from baseline in HAQ-DI over time up to Week 264 
• 
Change from baseline in ACR components up to Week 264.  After Week 264, TJC and 
SJC (both based on 28 joints), patient´s global assessment of disease activity and hs-CRP 
will still be assessed to calculate DAS28. 
13.2.4 Pharmacokinetic and immunogenicity variables 
Immunogenicity (anti sarilumab antibody) and pharmacokinetic blood samples (trough 
concentrations) will be collected according to the study flow chart (Section 1.2). Pharmacokinetic 
samples will also be collected at or near the onset and completion of the occurrence of a serious 
adverse event. 
13.2.5 Pharmacodynamic/genomics variables 
Serum concentrations of IL-6 will be assessed according to the study flow chart (Section 1.2). 
13.2.6 Health economic variables 
• Change from baseline in SF-36 version 2 scores (2 summary measures: physical 
component summary score and mental component summary score; 8 domains: physical 
function, role-physical, bodily pain, general health, vitality, social functioning, role-
emotional, and mental health) over time (for patients from EFC11072, ACT11575 and 
EFC10832 only) 
• Change from baseline in WPAI scores (percent work time missed, percent impairment 
while working, percent activity impairment, percent overall work impairment) (for patients 
from EFC11072 and ACT11575 only) 
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• Change from baseline in the FACIT-Fatigue score over time (for patients from EFC11072, 
ACT11575 and EFC10832 only) 
• Change from baseline in the sleep VAS scale over time (for patients from EFC11072 and 
ACT11575 only) 
•  Change from baseline in the WPS-RA scores (3 work productivity related items and 
5 home productivity related items over time) (for patients from EFC10832 only) 
Health economic variables will be assessed up to Week 264. 
13.3 
DISPOSITION OF PATIENTS 
The total number of patients for each of the following categories will be presented in the clinical 
study report: 
• All screened patients: all patients who have signed the informed consent 
• All patients entered in the LTS:  all patients who have signed the informed consent and are 
eligible to enter the study. 
• Safety population: defined as all patients entered in the LTS who have received at least 
1 dose of the study treatment in the LTS11210, 
• Patients who discontinued the treatment and reasons for treatment discontinuation. 
The percentage will be calculated using the total number of all patients entered in the LTS as the 
denominator. 
13.4 
ANALYSIS POPULATIONS 
The primary analysis population is the safety population which is defined as all patients who have 
received at least 1 dose of the study treatment in the LTS11210. 
All safety analyses and efficacy analyses will be performed based on the safety population. 
13.5 
STATISTICAL METHODS 
For patients from EFC11072, ACT11575, EFC10832 and SFY13370 with sarilumab + DMARD 
therapy in the initial and current studies, all analyses will be performed based on previous 
treatment prior to enrollment into LTS11210 (placebo, sarilumab 150mg q2w, sarilumab 200mg 
q2w, other sarilumab (non-selected) doses, and active control treatment) as well as overall in 
LTS11210, unless otherwise specified. Interim analyses may be performed based on overall 
sarilumab +DMARD therapy only. 
For patients from EFC13752 with sarilumab monotherapy in the initial and current studies, all 
analyses will be performed based on previous treatment prior to enrollment into LTS11210 
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(sarilumab 150mg q2w, sarilumab 200mg q2w) as well as overall in LTS11210, unless otherwise 
specified. Interim analyses may be performed based on overall sarilumab monotheraphy only. 
Data analysis results will be presented by sarilumab +DMARD therapy and sarilumab 
monotherapy in LTS11210 separately. All analyses will be performed in observed cases unless 
otherwise specified. 
13.5.1 Demographic and baseline characteristics 
Patient characteristics including demographics, medical history, and subject accountability will be 
summarized for the safety population.  The summaries will consist of descriptive statistics, eg, 
mean, standard deviation, median, minimum and maximum for quantitative values and counts and 
percentages for qualitative variables. 
13.5.2 Concomitant medications 
The concomitant medications will be presented based on the safety population.  Medications will 
be summarized according to the WHO-DD dictionary, considering the first digit of the Anatomic 
Category (ATC) class (anatomic category) and the first 3 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. 
13.5.3 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized based on 
the safety population. 
13.5.3.1 Extent of investigational product exposure 
Duration of exposure is defined as: 
For patients receiving weekly injections at the last injection 
[Date of last injection of the study med] – [Date of first injection of the study med] + 7 
For patients receiving biweekly injections at the last injection 
[Date of last injection of the study med] – [Date of first injection of the study med] + 14 
Temporary drug discontinuation will be ignored in the above calculation.  
Duration of exposure will be summarized by dose and overall using descriptive statistics such as 
mean, standard deviation, median, minimum and maximum. 
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The number and percentage of patients exposed of the investigational product will be presented by 
specific time periods for each treatment group.  The time periods of interest will be specified in 
the statistical analysis plan. 
13.5.3.2 Compliance 
Treatment compliance is defined as the actual amount of drug taken compared to the scheduled 
amount of treatment.  It is calculated according to the following formula: 
100 x total number of compliant injections administered / [nominal number of injections for the 
duration of exposure]. 
A given administration will be considered as noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance will be summarized using means, standard deviations, medians, minimums 
and maximums.  In addition, the percentage of patients with <80% treatment compliance will be 
summarized. 
13.5.4 Analyses of safety data 
The review of safety and tolerability will be performed based on the safety population, as defined 
in Section 13.4 .  The safety analyses will be presented based on the reported adverse events, 
clinical laboratory evaluations, vital signs, and 12-lead ECGs. 
The following definitions will be applied to laboratory parameters, vital signs and ECG. 
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs and ECG.   
• PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent period, taking into account all evaluations performed during the treatment-
emergent period, including nonscheduled or repeated evaluations. The number of all such 
patients will be the numerator for the treatment-emergent PCSA percentage. 
13.5.4.1 Adverse events 
Adverse events reported in this study will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) in effect at sanofi at the time of database lock. Treatment-emergent adverse 
events (TEAEs) are AEs that developed or worsened or became serious during the TEAE period. 
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Treatment-emergent adverse events 
The TEAE incidence will be presented by System organ class (SOC), High level group term 
(HLGT), High level term (HLT), and preferred term (PT) sorted in alphabetical order, the number 
(n) and percentage (%) of patients experiencing a TEAE will be presented. Multiple occurrences 
of the same event in the same patient will be counted only once in the tables. The denominator is 
based on the total number of patients in the safety population. In addition, the number of TEAEs 
(n) will be summarized. Multiple occurrences of the same event in the same patient will all be 
counted only once in the tables within a treatment group. The TEAE incidence rate adjusted for 
the total duration of exposure will be provided along with the exposure-adjusted number of 
TEAEs. 
Deaths 
The following deaths summary will be generated 
• TEAE leading to death (death as an outcome on the adverse event case report form page as 
reported by the Investigator) by primary SOC, HLGT, HLT, and PT showing the number 
(%) of patients sorted by internationally agreed order of SOC and alphabetic order of 
HLGT, HLT, and PT. 
Serious adverse events  
The number and percentage of patients with SAEs will be summarized by primary SOC, HLGT, 
HLT and PT. 
Adverse events leading to treatment discontinuation 
The number and percentage of patients with adverse events leading to permanent treatment 
discontinuation will be summarized by primary SOC, HLGT, HLT, and PT. 
Adverse events of special interest (AESI) 
AESIs will be flagged using search criteria. If available, a Standard MedDRA Query (SMQ) will 
be used to search (narrow search).  If no SMQ is available, then a Sponsor defined search criteria 
will be used. The number and percentage of patients with treatment emergent AESIs will be 
summarized by AESI category and PT. 
13.5.4.2 Liver Function Tests 
The liver function tests, namely, ALT, AST, alkaline phosphatase and total bilirubin are used to 
assess possible drug induced liver toxicity. The proportion of patients with PCSA values at any 
visit by baseline status will be displayed by treatment group for each parameter. The proportion of 
patients with PCSA values at any visit may be displayed by duration of exposure for each 
treatment group. 
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A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and Total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
The normalization (to ≤ ULN or return to baseline) of elevated liver function tests will be 
summarized by categories of elevation (3 x, 5 x, 10 x, 20 x ULN for ALT and AST, 1.5 x ULN 
for alkaline phosphatase, and 1.5 x and 2 x ULN for total bilirubin), with following categories of 
normalization: never normalized, normalized after IMP discontinuation. Note that a patient will be 
counted only under the maximum elevation category.  
The incidence of liver related adverse events will be summarized. The selection of PTs will be 
based on standardized MedDRA query (SMQ) Drug-related hepatic disorder – comprehensive 
search. 
13.5.4.3 Clinical laboratory evaluations 
Patients with PCSA for each laboratory test will be identified.  The incidence of PCSAs at any 
time during the TEAE period will be summarized by biological function and treatment received 
whatever the baseline level and/or according to the following original baseline status categories:  
1. normal/missing,  
2. abnormal according to PCSA criterion or criteria.  
Descriptive statistics will also be used to summarize baseline, raw value, and change from 
baseline at each visit.   
Shift tables showing changes with respect to the normal range between baseline and postbaseline 
will be provided. 
Listings will be provided with flags indicating the out of range values as well as the PCSA values. 
13.5.4.4 Vital signs 
Vital signs including weight, blood pressure (systolic and diastolic), and heart rate are measured 
throughout the study. Descriptive statistics will be provided for baseline, raw value, and change 
from baseline at each visit.   
The number and percentage of patients with at least 1 PCSA during the TEAE period will be 
summarized. 
13.5.4.5 Electrocardiogram 
12-lead ECG data will be collected throughout the study.  Descriptive statistics will be provided 
for baseline, absolute value, and change from baseline per visit. 
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The number and percentage of patients with at least 1 PCSA during the TEAE period will be 
summarized for each ECG parameter.  
13.5.5 Analyses of efficacy endpoints 
There will be no confirmatory analysis for the efficacy variables. All analysis will be done 
descriptively on the safety population by visit in observed case, as appropriate. 
For categorical variables, for example, percentage of patients who have maintained/reached 
ACR20 overtime, the number and percentage will be provided from all patients who have data 
available at that time point, and the 95% confidence intervals will be calculated if appropriate. 
For continuous variables, descriptive statistics such as the mean, standard deviation, median, 
minimum and maximum will be provided.  In addition, 95% confidence interval of the mean will 
be presented. This applies to the original values and change (or percent change) from baseline. 
Change from baseline in the van der Heijde modified total Sharp scores (mTSS) will be 
summarized for patients from EFC11072 Part B only.  Descriptive statistics, including the mean, 
standard deviation, median, minimum and maximum will be provided, along with 95% 
confidence intervals.  The actual values will be similarly summarized. 
Radiographic progression of the mTSS is defined as a change from baseline in the mTSS > 0. A 
change from baseline in the mTSS of less than or equal to zero is considered as no progression. 
The event of missing a change from baseline in the mTSS will be considered as progression. 
Summary of incidence of radiographic progression of mTSS will be provided. 
Additional sensitivity analyses may be performed if necessary. 
13.5.6 Analyses of pharmacokinetic and pharmacodynamic variables 
13.5.6.1 Pharmacokinetic descriptive analysis 
Serum concentrations of functional sarilumab will be summarized using standard descriptive 
statistics such as arithmetic and geometric means, standard deviation (SD), standard error of the 
mean (SEM), coefficient of variation (CV%), minimum, median, and maximum by dose and visit. 
Serum concentrations of bound (serum sarilumab-sIL-6Rα complex) and functional sarilumab 
were intended to be analyzed in the study. After the completion of EFC11072 Part B study, the 
Sponsor made the decision to only analyze functional sarilumab concentrations. Serum 
concentrations of bound sarilumab (serum sarilumab-sIL-6Rα complex) will not be summarized 
in this study. 
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13.5.6.2 Immunogenicity variables 
Anti-sarilumab antibody (ADA) assay results will be described categorically. The summary will 
be provided for patients with any positive ADA assay response during the TEAE period.  
Patients with any positive ADA assay response are defined as: 
• Patients with no positive assay response at baseline but with a positive assay response 
during the TEAE period or 
• Patients with a positive ADA assay response at baseline and also have at least a 4-fold 
increase in titer during the TEAE period. 
13.5.6.3 Pharmacodynamic descriptive analysis 
Serum concentrations of IL-6 will be summarized using arithmetic and geometric means, SD, 
SEM, CV%, minimum, median, and maximum by dose and visit. 
13.5.7 Analyses of quality of life/health economics variables 
Change from baseline in the SF36 version 2 scores (2 summary measures and 8 domains) will be 
summarized using raw value and change from baseline at each visit or study assessment (baseline, 
endpoint) by dose. 
Change from baseline in the 4 WPAI scores will be summarized using raw value and change from 
baseline at each visit or study assessment (baseline, endpoint) by dose. 
Change from baseline in the FACIT-Fatigue score and the sleep VAS will be summarized using 
raw value and change from baseline at each visit or study assessment (baseline, endpoint) by dose. 
Change from baseline in the 8 WPS-RA scores will be summarized using raw value and change 
from baseline at each visit or study assessment (baseline, endpoint) by dose (for the patients from 
EFC10832 only). 
13.6 
DATA HANDLING CONVENTIONS 
Missing dates will be handled using conservative approaches, and no imputation will be applied at 
the data level: 
• If the date of the last dose of investigational drug is missing, duration of exposure will be 
set to missing. 
• Handling of PCSAs: If a subject has a missing baseline value, he will be grouped in the 
category “normal /missing at baseline.”  For PCSA with 2 conditions, one based on a 
change from baseline value or a normal range and the other one on a threshold value, the 
first condition being missing, the PCSA will be based only on the second condition.  For 
PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold only if the normal range is missing.  For example, for eosinophils the PCSA is 
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>0.5 GIGA/L or > ULN if ULN ≥0.5 GIGA /L.  When the ULN is missing, the value 0.5 
should be used. 
13.7 
X-RAY DATA SUMMARY 
X-rays are performed in the subset of patients who previously completed EFC11072, Part B. 
X-ray data will be read in 3 campaigns in order to summarize: 
- 
2 year data up to Week 48 in LTS11210 
- 
3 year data up to Week 96 in LTS11210 
- 
5 year data up to Week 192 in LTS11210 
Each campaign will include screening/baseline EFC11072 X-ray data 
13.8 
INTERIM ANALYSIS  
This is an open-label study. Interim reports may be prepared for regulatory submissions or other 
purposes. However, no alpha adjustment is needed for the final CSR. 
 
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14 
ETHICAL AND REGULATORY STANDARDS 
14.1 
ETHICAL PRINCIPLES 
This Clinical Trial will be conducted in accordance with the principles laid down by the 18th 
World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the 
World Medical Assemblies, and the ICH guidelines for Good Clinical Practice (GCP). 
14.2 
LAWS AND REGULATIONS 
This Clinical Trial will be conducted in compliance with all international laws and regulations, 
and national laws and regulations of the country(ies) in which the Clinical Trial is performed, as 
well as any applicable guidelines. 
14.3 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the Patient of all 
pertinent aspects of the Clinical Trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC).  All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the Clinical Trial, the written Informed Consent Form should 
be signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion.  A copy of the 
signed and dated written Informed Consent Form will be provided to the patient. 
The Informed Consent Form 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. 
14.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this Clinical Trial 
Protocol to the appropriate Ethics Committee (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 Ethics Committee (IRB/IEC) composition. 
The Clinical Trial (study number, Clinical Trial Protocol title and version number), the documents 
reviewed (Clinical Trial Protocol, Informed Consent Form, Investigator’s Brochure, Investigator’s 
CV, etc.) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
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Investigational Product 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 Ethics Committee (IRB/IEC) before implementation, unless the change is 
necessary to eliminate an immediate hazard to the patients, in which case the IRB/IEC should be 
informed as soon as possible. It should also be informed of any event likely to affect the safety of 
patients or the continued conduct of the Clinical Trial, in particular any change in safety. All 
updates to the Investigator’s Brochure will be sent to the Ethics Committee (IRB/IEC). 
A progress report is sent to the Ethics Committee (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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15 
STUDY MONITORING 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator(s) undertake(s) to perform the Clinical Trial in accordance with this Clinical 
Trial Protocol, ICH guidelines for Good Clinical Practice and the applicable regulatory 
requirements. 
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 Case Report Form [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. 
15.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this Clinical Trial is responsible to Health Authorities for taking all reasonable 
steps to ensure the proper conduct of the Clinical Trial Protocol as regards ethics, Clinical Trial 
Protocol compliance, and integrity and validity of the data recorded on the Case Report Forms. 
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, Serious Adverse Event 
documentation and reporting, AESI documentation and reporting AE documentation, 
Investigational Product allocation, patient compliance with the Investigational Product regimen, 
Investigational Product accountability, concomitant therapy use and quality of data. 
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15.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH guidelines for Good Clinical Practice, the Monitoring Team must check the 
Case Report Form entries against the source documents, except for the pre-identified source data 
directly recorded in the Case Report Form.  The Informed Consent Form will include a statement 
by which the patient allows the Sponsor’s duly authorized personnel, the Ethics Committee 
(IRB/IEC), and the regulatory authorities to have direct access to original medical records which 
support the data on the Case Report Forms (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 rules). 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation.  
Should a correction be made, the corrected will be entered in the e-CRF 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 e-CRF. 
The computerized handling of the data by the Sponsor after receipt of the CRFs may generate 
additional requests (DRF) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be managed through the e-
CRF. 
15.5 
USE OF COMPUTERIZED SYSTEMS 
Computerized systems used during the different steps of the study are: 
• For data management activities: Oracle Clinical (RDC) 
• For statistical activities: SAS 
• For pharmacovigilance activities: AWARE 
• For monitoring activities: IMPACT 
• For medical writing activities: Domasys 
External data loading is planned for this clinical trial. 
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ADMINISTRATIVE RULES 
16.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-Investigator will be provided to the Sponsor prior to the beginning of 
the Clinical Trial. 
16.2 
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. 
It is recommended that the Investigator retain the study documents at least fifteen (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. 
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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, the CRFs, the Investigator's Brochure and the results obtained during the course of the 
Clinical Trial, is confidential, prior to the publication of results.  The Investigator and any person 
under his/her authority agrees to undertake to keep confidential and not to disclose the 
information to any third party without the prior written approval of the Sponsor. 
However, the submission of this Clinical Trial Protocol and other necessary documentation to the 
Ethics Committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-Investigators shall be bound by the same obligation as the Investigator.  The Investigator 
shall inform the Sub-Investigators of the confidential nature of the Clinical Trial. 
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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PROPERTY RIGHTS 
All information, documents and Investigational Product provided by the Sponsor or its designee 
are and remain the sole property of the Sponsor. 
The Investigator shall not 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. 
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DATA PROTECTION 
The patient's personal data and Investigator's personal data which may be included in the Sponsor 
database shall be treated in compliance with all applicable laws and regulations. 
When archiving or processing personal data pertaining to the Investigator and/or to the patients, 
the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
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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 
maintaining their own liability insurance policy.  An insurance certificate will be provided to the 
Ethics committees/IRB or Health Authorities in countries requiring this document. 
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SPONSOR AUDITS AND INSPECTIONS BY REGULATORY 
AGENCIES 
For the purpose of ensuring compliance with the Clinical Trial Protocol, Good Clinical Practice 
and applicable regulatory requirements, the Investigator should permit auditing by or on the 
behalf of the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that this 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. 
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PREMATURE DISCONTINUATION OF THE STUDY OR 
PREMATURE CLOSE-OUT OF A SITE 
22.1 
DECIDED BY THE SPONSOR IN THE FOLLOWING CASES: 
If the information on the product leads to doubt as to the benefit/risk ratio; 
If the Investigator has received from the Sponsor all Investigational Product, means and 
information necessary to perform the Clinical Trial and has not included any patient after a 
reasonable period of time mutually agreed upon; 
In the event of breach by the Investigator of a fundamental obligation under this agreement, 
including but not limited to breach of the Clinical Trial Protocol, breach of the applicable laws 
and regulations or breach of the ICH guidelines for Good Clinical Practice; 
If 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. 
22.2 
DECIDED BY THE INVESTIGATOR 
The Investigator must notify (30 days' prior notice) the Sponsor of his/her decision and give the 
reason in writing. 
In all cases (decided by the Sponsor or by the Investigator), the appropriate Ethics Committee(s) 
(IRB/IEC) and Health Authorities should be informed according to applicable regulatory 
requirements. 
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CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a Clinical Study Report and to provide a summary 
of study results to Investigator; 
When the data from all investigational sites have been fully analyzed by the Sponsor, the latter 
will communicate the results of the Clinical Trial to the Investigator(s). 
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PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the Study and/or 
results of the Study the Sponsor’s prior written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
The Study is being conducted at multiple sites; the Sponsor agrees that, consistent with scientific 
standards, first presentation or publication of the results of the Study shall be made only as part of 
a publication of the results obtained by all sites performing the Protocol.  However, if no 
multicenter publication has occurred 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, subject to the review procedure set forth herein.  The Investigator shall provide the 
Sponsor with a copy of any such presentation or publication derived from the Study for review 
and comment at least thirty (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 ninety (90) days, to allow for filing 
of a patent application or such other 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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CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this Clinical Trial Protocol. 
The Investigator should not implement any deviation from, or changes of the Clinical Trial 
Protocol without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to Clinical Trial Patients, or when the change(s) involves only logistical or 
administrative aspects of the trial.  Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this Clinical Trial Protocol. 
Any amendment to the Clinical Trial Protocol requires written approval/favorable opinion by the 
Ethics Committee (IRB/IEC) prior to its implementation, unless there are overriding safety 
reasons. 
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. 
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BIBLIOGRAPHIC REFERENCES 
1. 
Kremer JM, Rationale use of new and existing disease modifying agents in rheumatoid 
arthritis. Ann Intern Med. 2001;134:695-706 
2. 
Lipsky PE, van der Heijde D, St. Clair WE, et al. Infliximab and methotrexate in the 
treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with 
Concomitant Therapy Study Group. N Engl J Med 2000; 343:1594-602 
3. 
Strand V, Cohen S, Schiff M, et al. Leflunomide Rheumatoid Arthritis Investigators 
Group. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and 
methotrexate. Arch Intern Med. 1999 ;159(21):2542-50 
4. 
Keystone EC, Kavanaugh AF, Sharp JT, et al: Radiographic, clinical, and functional 
outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal 
antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: 
A randomized, placebo-controlled, 52-week trial.  Arthritis Rheum 2004;50:1400-11. 
5. 
Kremer JM, Genant HK, Moreland LW, et al: Effects of abatacept in patients with 
methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Intern Med 
2006;144:865-76. 
6. 
Cohen SB, Emery P, Greenwald MW, et al: Rituximab for rheumatoid arthritis refractory 
to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-
controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis 
Rheum 2006;54:2793-806. 
7. 
Klareskog L, van der Heijde D, de Jager JP. TEMPO (Trial of Etanercept and 
Methotrexate with Radiographic Patient Outcomes) Study Investigators, et al: Therapeutic effect 
of the combination of etanercept and methotrexate compared with each treatment alone in patients 
with rheumatoid arthritis: Double-blind randomised controlled trial. Lancet 2004;363:675-81. 
8. 
Van der Heijde D, Landewe R, Klareskog L, et al. Presentation and analysis of data on 
radiographic outcome in clinical trials: Experience from the TEMPO study. Arthritis Rheum 
2005;52:49-60 
9. 
Van der Heijde D, Klareskog L, Rodriguez-Valverde V. TEMPO Study Investigators, et 
al: Comparison of etanercept and methotrexate, alone and combined, in the treatment of 
rheumatoid arthritis: Two-year clinical and radiographic results from the TEMPO study, a double-
blind, randomized trial.  Arthritis Rheum 2006;54:1063-74 
10. 
Bongartz T, Sutton AJ, Sweeting MJ, et al: Anti-TNF antibody therapy in rheumatoid 
arthritis and the risk of serious infections and malignancies: Systematic review and meta-analysis 
of rare harmful effects in randomized controlled trials. JAMA 2006;295:2275-85 
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11. 
Robinson WH, Genovese MC, Moreland LW: Demyelinating and neurologic events 
reported in association with tumor necrosis factor alpha antagonism: By what mechanisms could 
tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple 
sclerosis? Arthritis Rheum 2001;44:1977-83. 
12. 
Saag KG, Teng GG, Patkar NM et al. American College of Rheumatology 2008 
Recommendations for the use of nonbiologic and biologic disease modifying antirheumatic drugs 
in rheumatoid arthritis. Arthritis Rheum 2008;59(6):762-84 
 
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APPENDICES 
 
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Appendix A 
ARA & ACR Criteria 
 
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Appendix B 
ACR Score 
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Appendix C 
Sharp Van Der Heijde Method 
 
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Appendix D 
Subject’s Global Assessment of Disease Activity  
 
 
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Appendix E 
Subject’s Assessment of Pain  
 
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Appendix G 
WPAI Questionnaire 
 
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Appendix H 
Sleep questionnaire (VAS)  
 
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Appendix I 
SF-36 Health Survey  
 
 
 
 
 
 
 
SF-36v2™ Health Survey © 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
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SF-36v2™ Health Survey © 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
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SF-36v2™ Health Survey © 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
 
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SF-36v2™ Health Survey © 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
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SF-36v2™ Health Survey © 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
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Appendix J 
HAQ-DI – Health Assessment Questionnaire 
HAQ © University of Stanford 1980, All rights reserved 
 
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Appendix K 
Prohibited Live (Attenuated) Vaccine List  
 
• Chickenpox (Varicella) 
• Intranasal influenza 
• Measles (Rubeola) 
• Measles-mumps-rubella (MMR) combination 
• Mumps 
• Oral polio (Sabin) 
• Oral typhoid 
• Rubella 
• Smallpox (Vaccinia) 
• Herpes zoster 
• Yellow fever 
• BCG 
 
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Appendix L 
General Guidance for the follow-up of laboratory abnormalities by 
sanofi-aventis  
 
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Appendix M 
List of potential opportunistic infections  
 
• Tuberculosis 
• Aspergillosis 
• Blastomyces dermatitiidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers) 
• Candidiasis – systemic or extensive mucocutaneous cases 
• Coccidioides immitis (endemic south-western US and Central and South America) 
• Paracoccidiodomycosis 
• Cryptococcus 
• Cytomegalovirus 
• Herpes Simplex (severe/disseminated) 
• Herpes Zoster 
• Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-
Ohio-Mississippi river basins) 
• Listeriosis 
• Infection with mycobacterium avium and other non-tuberculosis mycobacteria  
• Pneumocystis pneumonia (PCP) 
 
This list is indicative and not exhaustive. 
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Appendix N 
DELETED  
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Appendix O 
Clinical criteria for diagnosing anaphylaxis  
H.A. Sampson et al – J Allergy Clin Immunol, 2006; vol 117, n°2 : 391-7. 
 
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Appendix P 
DELETED  
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Appendix Q 
WPS-RA Questionnaire  
 
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Appendix R 
Abbreviated protocol of PFS-S sub-study  
 
 
TITLE: A multi-center open-label sub-study of SARIL-RA-EXTEND to explore the 
usability of the sarilumab pre-filled syringe with safety system (PFS-S)  in patients 
with active Rheumatoid Arthritis (RA) 
COMPOUND: SARILUMAB (SAR153191)   
STUDY NUMBER: LTS11210 
STUDY NAME: SARIL-RA-EXTEND SUB-STUDY 
This abbreviated protocol of sub-study includes only components additional to the 
main study 
Version 
Number: 
1  
EudraCT and/or IND 
Number(s) 
2010-019262-86 / 100,632 
Date: 
31-Aug-2015 
Total number of pages: 
22 
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1 
FLOW CHARTS 
 
1.1 
GRAPHICAL STUDY DESIGN 
 
Entry into 
sub-study 
Treatment Period (12 weeks) 
D85
D1 
Sarilumab PFS-S
 Either 150mg or 200mg  q2w  
Coinciding with any 
scheduled visit in the 
main study from Visit 
8 (Week 24) onwards 
End of 
sub-study
Coinciding with 
scheduled visit in the 
main study
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1.2 
STUDY FLOW CHART 
All assessments planned to be performed at the scheduled main study visit that coincides with the sub-study visit, are described in the main study 
flow charts. Below flowchart specifies only:  
• 
those actions that are additional to the scheduled main study visit in LTS11210 
• 
those actions that replace an action in the scheduled main study visit in LTS11210 (for example, study drug dispensing  of the PFS-S IMP 
format, instead of the main study IMP in PFS) 
 
 
Sub-study assessments  
VISIT 
V101 
V102  
DAY 
Week 
D1  
Wk0 
D85 (+/- 3 days) 
Wk12 
Eligibility 
X 
 
Written Informed Consent 
X 
 
IVRS call to start / end sub-study participation 
X 
X 
Training on use of the PFS-S 
X 
 
Dispense PFS-Sa 
X 
 
Dispense sub-study injection diaryb 
X 
 
Collect / review sub-study injection diaryb 
 
X 
PTC reporting 
 
X 
AE related to a PTC reportingc 
 
X 
Serum Sarilumab (PK)d 
X 
X 
ADAd 
X 
X 
a PFS-S dispensing will replace the scheduled IMP dispensing at the main study visit 
b Sub-Study Injection Diary dispensing and review will replace the dispensing and review of the main study Patient Diary in the scheduled main study visits 
c Refer to Section 10.4.1 for instruction of reporting AE related to PTC 
d If the sub-study visit coincides with a PK and ADA sampling  time point in the main study, no additional samples are required for the sub-study 
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2 
TABLE OF CONTENTS 
Not applicable. 
 
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3 
LIST OF ABBREVIATIONS 
Only abbreviations related to the sub-study are listed here 
 
AESI: Adverse Event of Special Interest 
ALP: Alkaline Phosphatase 
ALT: Alanine Aminotransferase 
AST: Aspartate Aminotransferase 
CV%: Coefficient of Variation 
ECG: Electrocardiogram 
FDD: failed drug deliveries 
HDL: High Density Lipoprotein  
IMP: investigational medicinal product 
PFS-S: pre-filled syringe with safety system 
PROs: Patient Reported Outcomes,  
PT: 
Preferred Term, Prothrombin Time 
PTC: product technical complaint 
PTF: product technical failure 
SD: 
Standard Deviation 
SEM: Standard Error of the Mean 
TB: 
Tuberculosis 
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4 
INTRODUCTION AND RATIONALE 
4.1 
 PRE-FILLED SYRINGE WITH SAFETY SYSTEM (PFS-S) 
Sarilumab has been delivered via prefilled syringes (PFS) in most of the Phase 3 studies.  
The pre-filled syringe with safety system (PFS-S) is a modified version of the prefilled syringe 
aimed at preventing needle stick injury by either the patient or by a caregiver (professional or 
non-professional) performing the administration. The “safety system” consists of a sharps injury 
prevention feature, which can be described as a sheath that automatically covers the needle once 
the injection is completed and thus prevents needle stick injury and re-use.  
Compared to PFS, PFS-S also includes: 
• 
a rigid needle shield that encloses the soft rubber needle shield covering the needle  
• 
a finger flange with an ergonomic design and a large piston rod 
The following figures show the unused and used PFS-S. At the end of the injection when the 
plunger rod has been pushed into the syringe as far as it will go, the needle safety shield is 
activated which can be seen as the syringe is pulled away from the skin. 
 
Unused syringe 
Used syringe with activated needle safety shield 
 
 
 
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4.2 
SUB-STUDY RATIONALE 
This sub-study is aimed to assess the usability of the PFS-S syringe when used by patients with 
moderate or severe RA, or their professional or non-professional healthcare providers in an 
unsupervised real-world situation.  To mimic the real-world practice, the sub-study was designed 
to incorporate into the LTS11210 study without additional visits compare to scheduled visits in 
the main study. 
The primary endpoint is the number of product technical failures (PTF), which is defined as any 
product technical complaint (PTC) that has a validated technical cause. A PTC is defined as any 
patient- or healthcare provider-reported complaint regarding the use of the PFS-S syringe and 
collected via the completion of the injection diary.  
In addition, the safety information of sarilumab 150 mg q2w PFS-S and 200 mg q2w PFS-S will 
be collected throughout the sub-study period and trough concentrations of sarilumab will be 
measured at entry into the sub-study and at the end of the 12-week sub-study period. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To assess the usability of the sarilumab pre-filled syringe with safety system (PFS-S) when 
administered to patients with active Rheumatoid Arthritis (RA) 
5.2 
SECONDARY 
To document the safety of sarilumab 150 mg q2w PFS-S and sarilumab 200 mg q2w PFS-S 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is a Phase 3, multicenter, worldwide, non-randomized, open-label, 1-arm, 12-week sub-study 
of the LTS11210/SARIL-RA-EXTEND study. The sub-study will only be performed in limited 
sites in selected countries.  
Patients at participating sites who have been enrolled in the main study (LTS11210) for at least 24 
weeks and are willing to participate in the sub-study will be enrolled in the sub-study. The entry 
into the sub-study (V101) will be at any scheduled visit in the main study from Visit 8 (Week 24) 
or after. Sarilumab 150 mg q2w PFS-S or sarilumab 200 mg q2w PFS-S will be used in the sub-
study to replace the sarilumab 150 mg q2w PFS or 200mg q2w PFS used in the main study. At the 
entry into the sub-study (V101), the patients will be trained how to use the PFS-S, and the sub-
study injection diary will be dispensed to replace the patient diary of the main study. All the 
procedures described in the sub-study are additional to the main study activities, unless specified 
to replace procedures in the main study. 
The person performing each sub-study injection will respond to 3 questions related to PFS-S use 
on the injection diary (See Section 9.1) after each PFS-S injection. A “no” response to any 
question will be defined as a PTC. For any PTC, the Investigator will complete a PTC form and 
will send this PTC form together with the PFS-S that triggered this PTC back to the Sponsor 
according to a predefined process (Section 12). The patients should be instructed to keep any PFS-
S associated with a PTC separately from other PFS-S, so it can be identified when returned to site 
at the end of sub-study. 
For patients receiving sarilumab 200 mg q2w PFS-S the dose can be reduced any time during the 
sub-study duration if the main protocol defined criteria for dose reduction are fulfilled. 
When the patients have completed the 12 weeks of the sub-study they will return to the clinic to 
complete Visit 102 in addition to the scheduled main study visit on that day. They will switch 
back to the main study and continue sarilumab PFS treatment.  
If the patient chooses to end the participation in the sub-study during the sub-study duration but to 
continue in the main study the Visit V102 should still be completed. 
If a patient discontinues Investigational Medicinal Product (IMP) permanently in LTS11210 
during the sub-study, he/she should complete all procedures planned for V102 in the sub-study as 
well as the end of treatment (EOT) and post treatment follow-up visits in the main study (see 
flowchart in main study Section 1.2). 
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6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
Each patient will participate in the sub-study for a period of 12 weeks from the first sub-study 
visit (V101) to the final sub-study visit (V102). At the time of V101, eligible patients will start 
receiving sarilumab 150 mg q2w PFS-S or sarilumab 200 mg q2w PFS-S for 12 weeks as 
replacement of original sarilumab PFS in the main study and on top of the background disease 
modifying anti-rheumatic drugs (DMARDs) therapy, if any. There is no post-treatment follow-up 
specific to the PFS-S sub-study, as all patients will switch back to the main study at V102.  
6.2.2 Determination of end of sub-study (all patients) 
The last on-treatment sub-study visit for patients who complete the sub-study will occur at Day 85 
(Visit 102). The sub-study will be considered completed when the last sub-study patient has 
completed V102. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
6.4 
STUDY COMMITTEES 
Please refer to the main study protocol. 
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7 
SELECTION OF PATIENTS 
Approximately 120 patients active in the main study (LTS11210) are planned to be enrolled at 
selected sites in countries participating in the sub-study. 
7.1 
INCLUSION CRITERIA 
I 01. Patients enrolled in the LTS11210 study who are receiving either sarilumab 200mg q2w 
PFS or sarilumab 150mg q2w PFS and who are able and willing to participate in this sub-
study 
I 02. Patients who have been enrolled in the main study for at least 24 weeks  
I 03. Patients must sign a sub-study written informed consent prior to any sub-study related 
procedure 
7.2 
EXCLUSION CRITERIA 
There are no additional exclusion criteria to those defined in LTS11210. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Investigational Medicinal Product  
Sarilumab, anti-IL-6R mAb (anti-interleukin 6 receptor monoclonal antibody) 
Pharmaceutical form  
1 mL long glass prefilled syringes with a needle safety shield (PFS-S) filled to a nominal injection 
volume of 1.14 mL with drug product at 131.6 mg/mL (150 mg) or 175 mg/mL (200 mg) 
Dose per administration 
• 
Single-use administration of sarilumab by PFS-S 
• 
Dose of either 150 mg or 200 mg q2w 
NOTE: Patients should continue to receive the same sarilumab dose as they have received in the 
main study, unless they fulfill main protocol defined criteria for dose reduction. 
Route and method of administration 
The route and administration method of sarilumab PFS-S used in the sub-study are same as 
sarilumab PFS used in the main study.  
 
Each sub-study injection will be performed by the patient, or their caregiver.  In exceptional 
circumstances (such as the 1st administration using PFS-S) the injection may be performed by the 
site staff. The patient or their caregiver will be trained on performing the injection with the PFS-S 
using a patient user instruction specific to the use of the PFS-S and a training PFS-S filled with 
sucrose together with an injection pad. This training must be documented in the patient’s study 
file. 
Duration of administration of PFS-S 
12 weeks (6 injections) 
 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
NIMP received in the sub-study corresponds to NIMP received in the main study. 
8.3 
BLINDING PROCEDURES 
Not applicable. This is an open-label study. 
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8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
This is a 1-arm open-label sub-study, no randomization will be performed for the study.  
At the sub-study entry (V101/D1), after the patient has given informed consent and the patient’s 
eligibility has been confirmed, the site staff will contact the IVRS/IWRS in order to enroll the 
patient into the sub-study and to allocate the sub-study treatment kits. Either sarilumab 150 mg 
q2w PFS-S or sarilumab 200 mg q2w PFS-S will be allocated to each patient. The allocated dose 
will be the same as in the main study except if conditions for dose reduction are met. 
The sub-study patients will continue to use the same patient number assigned during enrollment 
into the main study, which consists of 9 digits (3 digits indicating the country, 3 digits indicating 
the site and 3 digits indicating the patient) 
8.5 
PACKAGING AND LABELING 
The IMP (sarilumab in PFS-S) will be provided in a patient treatment kit box. The kit will be 
labeled in accordance with the local regulatory specifications and requirements, along with 
content information, dosing instructions, and precautionary statement (“for clinical use only”). A 
sub-study treatment kit has specific labeling that distinguishes syringes in a treatment kit. They 
are labeled “Dose 1” and “Dose 2”.  
Packaging is in accordance with the administration schedule. The number of treatment kits 
allocated to the patient will provide sufficient medication until the next clinic visit. Additional 
treatment kits, to provide medication to patients under circumstances, such as a damaged kit, will 
be allocated by IVRS/IWRS when a “replacement treatment call“ is made to IVRS/IWRS.  
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
The storage conditions and shelf life of sarilumab PFS-S used in the sub-study are the same as 
sarilumab PFS used in the main study. 
8.7 
RESPONSIBILITIES 
Site personnel responsibilities in the sub-study are the same as in the main study. 
8.7.1 Treatment accountability and compliance 
The completed injection diary should be returned by the patient at the end of the sub-study 
(V102/D85). 
All PFS-S medication treatment kits (with all used or unused PFS-S) must be returned by the 
patient at the end of the sub-study (V102/D85). 
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The study coordinator will track treatment accountability/compliance of PFS-S by comparing the 
information recorded in the patient diary with the number of returned treatment boxes and 
used/unused PFS-S and fill in the appropriate page of the patient treatment log. 
The monitor in charge of the study will then check the data entered on the e-CRF IMP 
administration page by comparing them with the IMP that has been retrieved and the patient 
treatment log. 
8.7.2 Return and/or destruction of treatments 
All used and unused PFS-S will be collected by the study site at V102/D85. All used PFS-Ss for 
which a PTC was reported will be returned to the Sponsor. 
At selected sites, used PFS-S which functioned normally with no PTC will be returned to the 
Sponsor as well. 
Used PFS-S with complaints regarding labeling, packaging or a cosmetic defect of the PFS-S, will 
not be further investigated as a part of the sub-study. 
A detailed treatment log of the returned PFS-S returned to the sponsor will be established with the 
Investigator (or the pharmacist) and countersigned by the Investigator and the monitoring team. 
8.8 
CONCOMITANT MEDICATION 
Prohibited and permitted concomitant medication is defined in the main study protocol. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
The primary endpoint is the number of validated PFS-S-associated PTFs. A PTF is defined as any 
PTC related to the use of the PFS-S which has a validated technical cause. A PTC is defined as 
any patient- or healthcare provider-reported complaint regarding the use of the PFS-S syringe and 
collected via the completion of the injection diary.  
The injection diary will include specific questions about PTCs. The person performing each sub-
study injection will record the answers to these questions in the diary each time he/she performs 
an injection with a PFS-S. 
The questions include: 
1. Were you able to remove the cap? 
a) Yes 
b) No 
i 
If no, please describe / explain:  
2. Was the needle safety system activated?  
a) Yes 
b) No 
i 
If no, please describe / explain:  
3. Did the safety system entirely cover the needle? 
a) Yes 
b) No 
i 
If no, please describe / explain:  
At Visit 102, the Investigator will review the diary, confirm with the patient whether there were 
any problems associated with the use of PFS-S either during drug administration or otherwise, and 
record the responses in the e-CRF.   
If the answer is “no” to any of the questions stated in the diary, the patients will be asked to 
provide further details of the complaint and a PTC form will be completed by the investigator. 
The PTC form and the PFS-S associated with PTC will be sent to the Sponsor following the 
process defined in Section 12. The sponsor will validate or invalidate the occurrence of a PTF. If 
the PTF is ruled out the event is considered as a failed drug delivery (FDD) and is defined as 
patient’s failure to administer the full dose at a given attempt. 
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In addition, another question will be asked in the diary to confirm whether the person who 
performed the injection was trained: 
4. Was the person who performed the injection the person who was trained by the site 
staff? 
a) Yes 
b) No 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Device related endpoints 
• 
Number of PFS-S-associated product technical complaints (PTCs).  
• 
Number and percentage of patients with PTFs 
• 
Number and percentage of patients with PTCs 
• 
Number and percentage of patients with FDDs 
9.2.2 Safety endpoints  
• 
Adverse events related to PTCs 
Note: adverse events, laboratory values, vital signs, and electrocardiograms (ECG), assessed as 
part of the main LTS11210 study will not be described for the sub-study. If any adverse event 
reported during the sub-study is considered linked to a PTC by the investigator the potential link 
with the PTC should be specified in AE/SAE verbatim. If any laboratory or ECG abnormality or 
vital signs finding reported during the sub-study is considered clinically significant and linked to a 
PTC by the investigator an adverse event needs to be reported and the potential link with the PTC 
should be specified in AE/SAE verbatim. In addition a PTC of the PFS-S must be reported to the 
sponsor on a PTC form. 
9.2.3 EXPLORATORY ENDPOINT OF pk 
• Sarilumab Ctrough at Day 1 and Day 85 
9.2.4 PHARMACOKINETICS AND IMMUNOGENICITY 
9.2.4.1 Sampling time 
Pre-dose serum samples will be collected for determination of serum concentration of sarilumab 
and ADA at Visit V101 (D1) and at Visit V102 (D85). See study flow chart (Section 1.2). 
Serum trough concentrations of functional sarilumab will be evaluated in patients on stable dose 
of sarilumab at V101 (D1) before using the PFS-S and at Visit V102 (D85) after 12 weeks 
administration of sarilumab using the PFS-S in the sub-study. Patients are considered to be on 
stable dose of sarilumab at V101 (D1) if they received the same dose of sarilumab without 
treatment interruption for at least 24 weeks in LTS11210 prior to V101.   
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9.2.4.2 Sample handling procedure 
Sample handling procedures and bioanalytical method are same as in main study. 
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Page 164 
10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
All the procedures performed in the sub-study are in addition to those planned in the main study 
unless sub-study procedures replace the main study procedures. 
10.1.1 Visit 101: Entry of sub-study / Day 1 
A sub-study specific written informed consent form must be signed by the patient prior to any 
sub-study procedure being performed. 
The following items will be checked and recorded by the Investigator or designee: 
• 
Assess eligibility by review of inclusion criteria. 
• 
Before sarilumab administration, obtain blood sample for PK (serum sarilumab) and anti-
sarilumab antibodies assessment. If the sub-study visit coincides with a PK and ADA 
sampling time point in the main study, no samples are required to be obtained for the sub-
study. 
• 
Access IVRS/IWRS to enroll patient into the sub-study and to allocate sub-study IMP. 
NOTE: this replaces the scheduled resupply IVRS/IWRS transaction for the main 
scheduled study visit. 
• 
Dispense sarilumab PFS-S. 
• 
Dispense sub-study injection diary, provide instructions for use, and remind the patient to 
complete the diary after each injection and to bring the completed diary back to the site at 
next visit. 
• 
Provide training on injection using a patient user instruction specific to the use of the 
PFS-S and a PFS-S prefilled with sucrose together with a pad. Allow the patient or the 
caregiver to inject into the training pad under observation, provide feedback on technique. 
This training must be documented in the patient’s study file. 
• 
The first dose of IMP will be administered by the patient or caregiver or study 
doctor/nurse at the study site and an appropriate record will be made in the source data by 
the person who performed the injection using the injection diary. 
10.1.2 Visit 102: End of sub-study / Day 85 
• 
Check compliance to the IMP and collect PFS-S medication kits and syringes (used and 
unused). 
• 
Collect injection diary and review for content and completeness. 
• 
Report diary feedback on each injection into the e-CRF. 
• 
Collect and assess any PTC using the injection diary. The Investigator will ask the patient 
whether there were any problems associated with the PFS-S – either during drug 
administration or otherwise and will obtain more details as appropriate.  
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• 
Inquire about and record any adverse events/SAEs related to PTC. 
• 
Prior to the IMP administration (sarilumab in PFS), obtain blood sample for sub-study PK 
(serum sarilumab) and anti-sarilumab antibodies assessment. If the sub-study visit 
coincides with a PK and ADA sampling time point in the main study, no samples are 
required to be obtained for the sub-study. 
• 
Access IVRS/IWRS to register the end of sub-study and to obtain the next scheduled IMP 
(sarilumab in PFS) if the patient returns to the main study. 
10.2 
DEFINITION OF SOURCE DATA 
Besides source data defined in the main study, the injection diary in sub-study is also considered 
as source data. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION DURING THE SUB-STUDY AND OF PATIENT STUDY 
DISCONTINUATION 
Please refer to the main study as regards handling of patients at the time of temporary or 
permanent treatment discontinuation. 
If the patient chooses to end the participation in the sub-study but to continue in the main study 
they should complete the Visit V102. 
If a patient discontinues the Investigational Medicinal Product (IMP) permanently in LTS11210 
during the sub-study, he/she should complete all procedures planned for V102 in the sub-study as 
well as the end of treatment (EOT) and post treatment follow-up visits in the main study (see 
flowchart in main study Section 1.2). 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Instructions for reporting PTC and adverse events related to PTC 
PTCs may or may not be associated with an adverse event. Any PTC of the PFS-S, whether or not 
associated with an adverse event, must be reported to the sponsor on a PTC form. 
If a PTC is suspected of being associated with the occurrence of an adverse event, the Investigator 
must document the adverse event on an adverse event page in the e-CRF, in addition to 
completing the PTC form. The potential link of the adverse event with the PTC must be specified 
in AE verbatim. 
If a PTC is suspected of being associated with the occurrence of an SAE, the SAE must be 
reported in accordance with the SAE reporting procedures and the Investigator must specify the 
potential link with the PTC in SAE verbatim.  
Please refer to the related section in the main study for general safety instructions. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size of this sub-study is based on empirical consideration. No formal sample size 
calculation is performed but an estimate of 120 patients included in this sub-study with up to 
6 injections per patient will provide approximately 680 injections to evaluate PTF during the 
12 weeks of the study assuming 5% of drop-out rate.  
11.2 
DISPOSITION OF PATIENTS 
Enrolled patients are defined as any patient who met the inclusion criteria and none of the 
exclusion criteria, and signed the informed consent. 
11.3 
ANALYSIS POPULATIONS 
The safety population will consist of all enrolled patients who receive at least 1 dose or part of a 
dose of IMP administered via PFS-S during this sub-study. 
Safety analyses will be performed on the safety population.  Patient data will be analyzed 
according to the treatment actually received (200mg q2w PFS-S, 150mg q2w PFS-S, dose 
reduction). 
The PK population will consist of all enrolled patients who receive at least 1 dose of the IMP and 
at least one non-missing serum concentration value. 
11.4 
STATISTICAL METHODS 
The phrase ‘treatment group’ used throughout this section refers to the following device/dose 
groups (200mg q2w PFS-S, 150mg q2w PFS-S, 200mg q2w PFS-S to 150mg q2w PFS-S).  The 
baseline value is defined as original baseline in initial studies. 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
The duration of IMP exposure is defined as: last dose date – first dose date at D1 + 14 days 
(regardless of unplanned intermittent discontinuations).  The duration of exposure to the IMP will 
be summarized for each treatment group by using descriptive statistics such as mean, SD, median, 
minimum, and maximum. 
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Treatment compliance to the IMP is defined as the actual number of doses received compared to 
the scheduled number of doses during the treatment period.  It is calculated according to the 
following formula: 
100 x total number of doses administered  
nominal number of doses for the duration of exposure 
A given administration will be considered noncompliant if the patient does not take the planned 
dose as required by the protocol.  No imputation will be made for patients with missing or 
incomplete data. 
Treatment compliance during the treatment period will be summarized descriptively (N, mean, 
standard deviation, median, minimum, and maximum).  The percentage of patients with 
compliance <80% will be summarized. 
11.4.2 Analyses of endpoints 
11.4.2.1 Analysis of primary endpoint(s) 
Data will be described for the 12 weeks of this sub-study using the safety population. The primary 
analysis variable is the number of validated PFS-S-associated PTFs during the sub-study. The 
primary analysis will be performed using descriptive statistics. 
11.4.2.2 Analyses of secondary and exploratory endpoints 
Descriptive statistics will be used for continuous variables; discrete variables will be described 
using counts and proportions. Data will be presented by treatment dose group.  
Serum concentrations of functional sarilumab will be summarized using standard descriptive 
statistics such as arithmetic and geometric means, standard deviation (SD), standard error of the 
mean (SEM), coefficient of variation (CV%), minimum, median, and maximum by visit  
For PK parameters Ctrough, estimates and 90% CIs for the ratio of geometric means (Day 85 versus 
Day 1) will be provided using a linear fixed effects model on the log-transformed data. Serum 
trough concentrations of functional sarilumab will be evaluated in patients on stable dose of 
sarilumab at V101 (D1) before using the PFS-S. Patients are considered to be on stable dose of 
sarilumab at V101 (D1) if they receive the same dose of sarilumab without treatment interruption 
for at least 24 weeks in LTS11210 prior to V101. Patients changing dose during the 12 week 
sub-study will be excluded from the Ctrough analyses. 
11.4.2.3 Multiplicity considerations 
Not applicable 
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11.5 
INTERIM ANALYSIS 
No interim analysis is planned. 
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12 
HANDLING PROCESS FOR PRODUCT TECHNICAL COMPLAINT 
REPORTING 
 
 
 
To complete the diary with each 
injection and to identify and 
keep the PFS-S associated with 
product technical complaint 
(PTC)
To bring to the next site visit the 
PFS-S associated with the PTC 
together with the diary 
Identified PFS-S 
shipped for technical 
evaluation 
Technical evaluation 
Completion of eCRF and 
complaint form page
PTF
FDD 
or
Patient’s 
responsibility 
Investigator’s 
responsibility 
Sponsor’s 
responsibility 
 
 
 
PFS-S = pre-filled syringe with safety system; PTC= product technical 
complaint; PTF = product technical failure; FDD = failed drug delivery  
(electronic 
 
 
 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy 
HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LTS11210 Amended Protocol 9

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 5.0 (27-JUL-2015) 
Page 1
STATISTICAL ANALYSIS PLAN 
A multi-center, uncontrolled extension study evaluating efficacy and safety of 
sarilumab in patients with active Rheumatoid Arthritis (RA) 
SAR153191-LTS11210 
STATISTICIAN: 
 
DATE OF ISSUE: 22-Dec-2015 
Total number of pages: 
104 
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NCT01146652


Statistical Analysis Plan  
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Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN....................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................9 
1.2.1 
Primary objectives............................................................................................................................9 
1.2.2 
Secondary objectives .......................................................................................................................9 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................9 
1.4 
STUDY PLAN.................................................................................................................................10 
1.4.1 
Graphical Study Design for Patients in ACT11575 and EFC11072 Part A or Part B Cohort 1......10 
1.4.2 
Graphical Study Design for Patients in EFC11072 Part B Cohort 2, EFC10832, SFY13370, 
and EFC13752 ...............................................................................................................................11 
1.4.3 
Study Flowchart..............................................................................................................................12 
1.4.3.1 
Study Flow Chart for Patients Enrolling From ACT11575 and EFC11072 Part A or Part B 
Cohort 1..........................................................................................................................................12 
1.4.3.2 
Study Flow Chart for Patients Enrolling From EFC10832, EFC11072 Part B Cohort 2, 
SFY13370, and EFC13752 ............................................................................................................18 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................23 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN......................24 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................25 
2.1 
ANALYSIS ENDPOINTS................................................................................................................25 
2.1.1 
Demographic and baseline characteristics ....................................................................................25 
2.1.2 
Prior or concomitant medications...................................................................................................26 
2.1.3 
Safety endpoints.............................................................................................................................27 
2.1.3.1 
Adverse events variables ...............................................................................................................27 
2.1.3.2 
Deaths............................................................................................................................................29 
2.1.3.3 
Laboratory safety variables ............................................................................................................29 
2.1.3.4 
Vital signs variables........................................................................................................................30 
2.1.3.5 
Electrocardiogram variables...........................................................................................................30 
2.1.4 
Efficacy endpoints ..........................................................................................................................30 
2.1.5 
Pharmacokinetic and immunogenicity variables ............................................................................37 
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2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................37 
2.1.7 
Quality-of-life endpoints..................................................................................................................37 
2.1.8 
Health economic endpoints............................................................................................................38 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................40 
2.2.1 
Randomization and drug dispensing irregularities .........................................................................41 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................41 
2.3.1 
Safety populations..........................................................................................................................42 
2.3.2 
Efficacy population .........................................................................................................................42 
2.3.3 
Pharmacokinetics and immunogenicity population ........................................................................42 
2.4 
STATISTICAL METHODS .............................................................................................................42 
2.4.1 
Demographics and baseline characteristics ..................................................................................42 
2.4.2 
Prior or concomitant medications...................................................................................................43 
2.4.3 
Extent of investigational medicinal product exposure and compliance..........................................43 
2.4.3.1 
Extent of investigational medicinal product exposure ....................................................................44 
2.4.3.2 
Compliance ....................................................................................................................................44 
2.4.4 
Analyses of safety data ..................................................................................................................45 
2.4.4.1 
Analyses of adverse events ...........................................................................................................46 
2.4.4.2 
Deaths............................................................................................................................................48 
2.4.4.3 
Analyses of laboratory variables ....................................................................................................49 
2.4.4.4 
Analyses of vital sign variables ......................................................................................................50 
2.4.4.5 
Analyses of ECG variables.............................................................................................................51 
2.4.5 
Analyses of efficacy endpoints.......................................................................................................51 
2.4.5.1 
Multiplicity issues............................................................................................................................52 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................52 
2.4.7 
Analyses of quality of life/health economics variables ...................................................................53 
2.4.8 
Analysis of immunogenicity variables.............................................................................................53 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................55 
2.5.1 
General conventions ......................................................................................................................55 
2.5.2 
Data handling conventions for efficacy variables ...........................................................................57 
2.5.3 
Missing data ...................................................................................................................................58 
2.5.4 
Windows for time points.................................................................................................................59 
2.5.5 
Unscheduled visits .........................................................................................................................62 
2.5.6 
Pooling of centers for statistical analyses ......................................................................................62 
2.5.7 
Statistical technical issues .............................................................................................................62 
3 
INTERIM ANALYSIS .....................................................................................................................63 
4 
DATABASE LOCK ........................................................................................................................64 
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5 
SOFTWARE DOCUMENTATION..................................................................................................65 
6 
REFERENCES...............................................................................................................................66 
7 
LIST OF APPENDICES .................................................................................................................67 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA..........68 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES.........................................................................75 
APPENDIX C 
SUMMARY OF MISSING DATA IMPUTATION RULES FOR EFFICACY 
VARIABLES ...................................................................................................................................76 
APPENDIX D 
X-RAY MISSING DATA IMPUTATION PROCESS .............................................................79 
APPENDIX E 
SF-36 V2 SCORING ............................................................................................................82 
APPENDIX F 
FACIT-FATIGUE SCORING GUIDELINES (VERSION 4)...................................................84 
APPENDIX G 
WPAI SCORING .................................................................................................................85 
APPENDIX H 
WPS-RA QUESTIONNAIRE ...............................................................................................86 
APPENDIX I 
SAS CODE FOR SF-36 SCORING.......................................................................................88 
APPENDIX J 
CLASSIFICATION OF EVENTS REVIEWED BY THE COMMITTEE .................................95 
APPENDIX K 
ANALYSIS PLAN OF THE PFS-S STUDY ..........................................................................97 
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Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
AE(s) 
adverse event(s) 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
ANA 
ANC 
alanine aminotransferase 
antinuclear antibody 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Class 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CAC 
Cardiovascular adjudication committee 
CCP 
cyclic citrullinated peptides 
CI 
Confidence interval 
CLcr 
creatinine clearance 
CPK 
creatine phosphokinase 
CRP 
C-reactive protein 
CRF 
case report form 
CSR 
clinical study report 
CV 
coefficient of variation 
CV event 
cardiovascular event 
DAS28 
Disease Activity Score 28 
DBP 
diastolic blood pressure 
DILI 
drug induced liver injury 
DMARD 
disease modifying antirheumatic drug 
DNA 
deoxyribonucleic acid 
ds-DNA 
double-stranded DNA 
ECG 
electrocardiogram 
EULAR 
European League Against Rheumatism 
HAQ-DI 
Health Assessment Questionnaire-Disability Index 
HbA1c 
hemoglobin A1C 
HDL 
high density lipoprotein 
HLGT 
high level group term 
HLT 
high level term 
HR 
heart rate 
hs-CRP 
high sensitivity C-reactive protein 
IL6-R 
interleukin 6 receptor 
IMP 
investigational medicinal product 
ITT 
intent to treat 
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IVRS 
Interactive Voice Response Systems 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LLN 
lower limit normal 
LLT 
MACE 
lower level term 
major adverse cardiovascular event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTX 
Methotrexate 
PCSA 
potentially clinically significant abnormalities 
PFS-S 
pre-filled syringe with safety system 
PK 
pharmacokinetic 
PT 
preferred term 
PTC 
product technical complaint 
PTF 
product technical failure 
q2w 
bi-weekly (every-other-week) 
RA 
rheumatoid arthritis 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SF-36 V2 
Short Form 36 Version 2 
SJC 
swollen joint count 
SMQ 
standardized MedDRA query 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
TJC 
TNF 
tender joint count 
tumor necrosis factor 
ULN 
upper limit normal 
VAS 
Visual Analogue Scale 
WBC 
white blood cell 
WHO-DD 
World Health Organization – Drug Dictionary 
WPAI 
Work Productivity and Activity Impairment 
 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
This document is the statistical analysis plan (SAP) for the final clinical study report (CSR) and 
guidance for interim analysis reports during the study. 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a multicenter, multinational open label long term study, for patients with RA who 
participated and completed EFC11072, ACT11575, EFC10832, SFY13370, and EFC13752 or for 
patients from 12 weeks onward with per protocol defined lack of efficacy from EFC10832. 
Patients, who were randomized in Part B of EFC11072 in a treatment arm subsequently not 
retained following pivotal dose selection, were also eligible for enrollment.  
The 5 previous studies are described briefly below: 
EFC11072:  A randomized, double-blind, placebo-controlled, multi-centre, two-part, dose 
ranging (Part A) and confirmatory (Part B) study with an operationally seamless design, 
evaluating efficacy and safety of sarilumab added to methotrexate (MTX) in patients with active 
rheumatoid arthritis who are inadequate responders to MTX therapy. The study was completed. In 
the dose ranging part of the study (Part A), 5 doses (100 mg weekly [qw], 150 mg qw, 100 mg 
every other week [q2w], 150 mg q2w, and 200 mg q2w) and placebo were tested in combination 
with methotrexate (MTX).  The confirmatory (Phase 3) portion (Part B) which initially had the 
same 6 arms (Cohort 1) and then after Phase 3 dose selection (150 mg q2w and 200 mg q2w) had 
3 arms (Cohort 2: placebo, 150 mg q2w, 200 mg q2w ) for 52-week treatment. In EFC11072 Part 
B, beginning at Week 16, patients with lack of efficacy (defined as less than 20% improvement 
from baseline on 2 consecutive visits in either TJC or SJC, or with any other clear lack of efficacy 
based on Investigator judgment) might have started OL rescue therapy with sarilumab 150 mg qw 
(150 mg qw prior to Phase 3 dose selection; 200 mg q2w after Phase 3 dose selection) in this 
study. These patients were also eligible to enter LTS11210 study if completed the treatment 
period. There were 1283 patients who rolled over to LTS11210. 
ACT11575:  A randomized, double-blind, parallel-group, placebo- and active 
calibrator-controlled study assessing the clinical benefit of sarilumab on top of MTX in patients 
with active RA who have failed previous TNF-α antagonists was terminated by the Sponsor due to 
administrative reasons with only 16 patients enrolled.  There were 7 patients who rolled over to 
LTS11210.  
EFC10832:  A randomized, double-blind, parallel-group, placebo-controlled study assessing the 
efficacy and safety of sarilumab added to DMARD therapy in patients with active rheumatoid 
arthritis (RA) who are inadequate responders or intolerant to tumor necrosis factor-alpha (TNF-α) 
antagonists. Patients are randomized into 3 arms (placebo, 150 mg q2w, 200 mg q2w) with 
24-week treatment. There were 456 patients who rolled over to LTS11210. 
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SFY13370:  A randomized, double-blind, double-dummy study assessing the safety and 
tolerability of sarilumab and tocilizumab in patients with rheumatoid arthritis who are inadequate 
responders to or intolerant of TNF antagonists. Patients are randomized into 3 arms (Tocilizumab 
IV 4/8 mg/k q4w, 150 mg q2w, 200 mg q2w) with 24-week treatment. There were 168 patients 
who rolled over to LTS11210. 
EFC13752:  An Open-label, Randomized, Parallel Group Study Assessing the Immunogenicity 
and Safety of Sarilumab Administered as Monotherapy in Patients with Active Rheumatoid 
Arthritis. Patients are randomized into 2 arms (150 mg q2w, 200 mg q2w) with 24-week 
treatment. There were 111 patients who rolled over to LTS11210. 
Patients may have been exposed with sarilumab for 12 weeks if they were initially randomized in 
EFC11072 Part A or ACT11575; between 2 and 52 weeks, if initially randomized in EFC11072 
Part B; between 12 and 24 weeks, if initially randomized in EFC10832; or for 24 weeks, if 
initially randomized in SFY13370 and EFC13752. 
Initially in LTS11210, patients received 150 mg of sarilumab SC weekly as the highest dose 
studied in EFC11072 Part A. The reduced dose (due to neutropenia, thrombocytopenia, or an 
increase in liver enzymes [ALT]), was 150 mg q2w.  Once the dose regimens were selected for the 
Phase 3 studies (150 mg q2w and 200 mg q2w), patients already ongoing in the study at the 
highest dose were switched to the new highest sarilumab dose 200 mg q2w, as soon as permitted 
by administrative process.  Patients previously assigned to the reduced dose of 150 mg q2w due to 
safety issue continued to receive 150 mg q2w.   
The duration of the treatment period in the study will be at least 264 weeks, or up to a maximum 
of 516 weeks (except in the UK where the duration of treatment will be 264 weeks) descripted in 
Protocol Amendment 9. However, some patients may complete this study with 260 week 
treatment duration per Protocol Amendment 8 before the approval of Protocol Amendment 9 in 
their countries. The total maximum duration of study participation for a patient may be up to 523 
weeks.  
• 
1-week screening period if applicable  
• 
516-week maximum treatment period in LTS11210 (for the earliest patients enrolled in 
LTS11210 in 2010 if sarilumab is not commercialized by 2020) 
• 
6-week follow up period as required per protocol 
Patients will either enter a 1-week screening period after the EOT visit (Visit 1 in LTS11210) in 
initial studies (for patients from EFC11072 Part A or Part B1 and ACT11575), or enrol directly 
into the treatment period (for patients from EFC11072 Part B2, EFC10832, SFY13370, or 
EFC13752, the EOT visit in the initial study corresponds to the randomization visit, Visit 1/2 in 
LTS11210). 
At Visit 2 or Visit 1/2 (Week 0) after confirmation of eligibility, patients will be administered the 
first open-label dose of sarilumab at the investigational site and will be observed for 30 minutes 
for any medical events. At dosing time points occurring outside site visits, sarilumab can be 
injected by the patients, or by trained caregivers. 
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Patients will return for the safety follow-up visit 6 weeks after the EOT visit (V49). In case of 
early treatment discontinuation, patients are required to complete the EOT visit (V49) and to 
return for the 6-week safety follow-up visit (Visit 50) as well.  
The study will be considered completed for a patient at the time he/she completes all the 
scheduled procedures. 
An optional 12-week sub-study aiming to evaluate the usability of pre-filled syringe with safety 
system (PFS-S) will be conducted in some countries. Patients enrolled in LTS11210 at selected 
sites in those countries may participate in the PFS-S sub-study from Week 24 of the main study 
after providing written informed consent for the sub-study. However, patients may continue to 
participate in the main trial without participating in the PFS-S sub-study if they wish. Full details 
of the PFS-S sub-study are presented in Appendix K. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of the study is to evaluate the long term safety of sarilumab in patients with 
RA. 
1.2.2 Secondary objectives 
The secondary objective of the study is to evaluate the long term efficacy of sarilumab in patients 
with RA. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The number of patients to participate in this extension study is approximately 2000 from previous 
studies as follows: 
• EFC11072: 243 patients from Part A, 1040 patients from Part B 
• ACT11575: 7 patients 
• SFY13370: 168 patients 
• EFC10832:  454 patients 
• EFC13752: 111 patient
(electronic 
 
 
 
6.0)


Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 10 
 
1.4 
STUDY PLAN 
1.4.1 Graphical Study Design for Patients in ACT11575 and EFC11072 Part A or Part B Cohort 1 
 
 
Last treatment visit of 
ACT11575 and EFC11072 
Part A or Part B Cohort 1 
Initial LTS11210 visit
Screening 
period
Treatment Period
D-7
D1 
SAR153191 (200 mg q2w)
Duration of the study treatment will be at least 264 
weeks from the first study drug administration in 
LTS11210, or until sarilumab is commercially available 
in the patient’s country whichever later, but no later than 
2020 when the study will be closed. 
  
The dose regimen will change 
at the time of the dose 
selection for phase 3 if 
patients have been included 
before.
SAR153191 (150 mg qw)
Wk 264 
Year 2020
(electronic 
 
 
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Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 11 
1.4.2 Graphical Study Design for Patients in EFC11072 Part B Cohort 2, EFC10832, SFY13370, and EFC13752 
 
Treatment Period
D1
SAR153191 (200 mg q2w)
Duration of the study treatment will be at least 264 weeks 
from the first study drug administration in LTS11210, or 
until sarilumab is commercially available in the patient’s 
country whichever later, but no later than 2020 when the 
study will be closed. 
  
Wk 264 
Year 2020
Last treatment visit of  
EFC11072 Part B Cohort 2, 
EFC10832, SFY13370, or 
EFC13752 
Initial LTS11210 visit 
In the UK the duration of treatment will be 264 weeks 
from the first study drug administration in LTS11210. 
(electronic 
 
 
6.0)


Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 12 
1.4.3 Study Flowchart 
1.4.3.1 Study Flow Chart for Patients Enrolling From ACT11575 and EFC11072 Part A or Part B Cohort 1 
 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 15
 
 
Wk 2 
Day 
29 
 
 
Wk 4
Day 43
 
 
Wk 6 
Day 
57 
 
 
Wk 8
Day 71
 
 
Wk 10 
D85 
 
 
Wk 12
Wk 24-96 
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 
204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 312, 
…, 504a 
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days) 
V 4
(±3 
days)
HV 5c
(±3 
days) 
V 6
(±3 
days)
HV 6.1c
(±3 
days) 
V 7
(±3 
days)
V 8 to V 14
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days)
V49 (±3 
days) 
V50(±3 days) 
Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Previous 
medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking, alcohol, 
and illicit drug use 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
(electronic 
 
 
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Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 13 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 15
 
 
Wk 2 
Day 
29 
 
 
Wk 4
Day 43
 
 
Wk 6 
Day 
57 
 
 
Wk 8
Day 71
 
 
Wk 10 
D85 
 
 
Wk 12
Wk 24-96 
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 
204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 312, 
…, 504a 
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days) 
V 4
(±3 
days)
HV 5c
(±3 
days) 
V 6
(±3 
days)
HV 6.1c
(±3 
days) 
V 7
(±3 
days)
V 8 to V 14
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days)
V49 (±3 
days) 
V50(±3 days) 
Detail history for 
tuberculosis (TB) 
and opportunistic 
infection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination
e 
Xd 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Confirm eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
dispensingb  
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Study drug 
complianceb 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature, heart 
rate, blood 
pressure 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Weight in Kg 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
(electronic 
 
 
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Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 14 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 15
 
 
Wk 2 
Day 
29 
 
 
Wk 4
Day 43
 
 
Wk 6 
Day 
57 
 
 
Wk 8
Day 71
 
 
Wk 10 
D85 
 
 
Wk 12
Wk 24-96 
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 
204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 312, 
…, 504a 
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days) 
V 4
(±3 
days)
HV 5c
(±3 
days) 
V 6
(±3 
days)
HV 6.1c
(±3 
days) 
V 7
(±3 
days)
V 8 to V 14
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days)
V49 (±3 
days) 
V50(±3 days) 
Efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACR disease core 
seth 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X-ray (hand, feet)g  
Xd 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Health Economic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 
Xd 
 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
WPAI  
Xd 
 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
FACIT-Fatigue, 
Sleep 
questionnaire 
Xd 
 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis 
assessments 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
AE/SAE recording 
(if any) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High sensitive- C- 
Reactive protein 
(hs-CRP) 
Xd 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
(electronic 
 
 
6.0)


Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 15 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 15
 
 
Wk 2 
Day 
29 
 
 
Wk 4
Day 43
 
 
Wk 6 
Day 
57 
 
 
Wk 8
Day 71
 
 
Wk 10 
D85 
 
 
Wk 12
Wk 24-96 
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 
204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 312, 
…, 504a 
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days) 
V 4
(±3 
days)
HV 5c
(±3 
days) 
V 6
(±3 
days)
HV 6.1c
(±3 
days) 
V 7
(±3 
days)
V 8 to V 14
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days)
V49 (±3 
days) 
V50(±3 days) 
Hematology: CBC 
and differentiali 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Liver Function 
Tests (LFTs)j  
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Lipids (fasting)k  
Xd 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
Clinical  chemistry 
(fasting)l  
Xd 
 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
ANA/Anti-ds-DNAm 
Xd 
 
 
 
 
 
 
 
X  
 
X  
X 
X 
 
Dipstick urinalysis n 
Xd 
 
 
 
 
X 
 
X 
X 
 
X 
 
Xf 
 
Urine pregnancy 
test (for women of 
childbearing 
potential)o 
Xd 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Dispense urine 
pregnancy kitso 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
 
12-lead 
electrocardiogramp 
Xd 
 
 
 
 
 
 
 
X 
 
X 
 
Xf 
 
Other analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rheumatoid factorq 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Xf 
 
Serum IL-6v 
Xd 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
Pharmacokineticsr  
Xd 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
(electronic 
 
 
6.0)


Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 16 
Evaluation 
Screening 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY 
 
 
Week 
Day -7 to 
D-1 
 
Day 1 
 
 
Wk0 
Day 15
 
 
Wk 2 
Day 
29 
 
 
Wk 4
Day 43
 
 
Wk 6 
Day 
57 
 
 
Wk 8
Day 71
 
 
Wk 10 
D85 
 
 
Wk 12
Wk 24-96 
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 108- 492 
IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 
204, 
228…492a 
Wk120 – 
264 
 (every 24 
weeks) 
 
Wk120, 
144, 168, 
192, 216, 
240, 264a
Wk288 – 504
 (every 24 
weeks) 
 
Wk 288, 312, 
…, 504a 
EOT visita 
 
6 weeks after 
end of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V 1 
D-7 to D-1 
V 2 
HV 3c
(± 3 
days) 
V 4
(±3 
days)
HV 5c
(±3 
days) 
V 6
(±3 
days)
HV 6.1c
(±3 
days) 
V 7
(±3 
days)
V 8 to V 14
(±3 days) 
V15, V17, 
V19, V21, 
V23, 
V25…V47(±3 
days) 
V16, V18, 
V20, V22, 
V24, V26 
V28(±3 
days) 
V30, V32, 
V34, V36, 
V38, …,  
48(±3 days)
V49 (±3 
days) 
V50(±3 days) 
Anti-sarilumab 
antibody 
Xd 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
Serum sample to 
be stored  for future 
biomarkerss 
Xd 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
Expression RNAt 
 
Xd 
X 
 
 
 
 
 
 
 
 
 
 
 
a EOT visit and follow up visit 6 weeks later should be completed for all patients at the end of treatment (in patients who complete sarilumab treatment per protocol in countries where sarilumab is commercially 
available the post treatment follow-up visit may be cancelled if the patient initiates treatment with commercial sarilumab during the post treatment follow-up period; however, in this case, a telephone contact must 
be established with the patient to capture all AEs occurring up to the 1st administration of commercial sarilumab). EOT visit may occur when the patients complete 264 weeks of sarilumab treatment from the 
LTS11210, or at any visit thereafter when sarilumab is commercialized in their country, but no later than 2020 when the study will be closed. In case of permanent discontinuation of treatment, the patients will be 
assessed using the procedures normally planned for the EOT visit and the 6 week follow up visit 6 weeks later.  
b From Week 24, patients at limited sites in selected countries may participate in PFS-S sub-study. If the patient enters the sub-study, then the sub-study IMP will be dispensed instead of the main study IMP at the 
entry into sub-study and IMP compliance with sub-study IMP will be reviewed at the end of sub-study. Full details of the sub-study are provided in Appendix R  
c HV: Visit can be home visit or clinic visit to draw and collect the blood sample only for hematology and LFTs using the designated central laboratory.  
d Last treatment visit from the study EFC11072 or ACT11575. Please note that the SF-36 must be completed at the screening visit of the LTS11210 study for patients rolling over from EFC11072 Part A and 
ACT11575 studies.  Please note that the RNA sample must be collected at V2 of the LTS11210 study for patients rolling over from EFC11072. 
e Physical examination to be done at Week 48, 96, 144, 192, 240, 264, 288, 336, 384, 432, 480 and EOT visit.  
f 
Assessment is NOT required when EOT visit is after Week 264. 
g X-ray of hand and feet (only for patients who completed Part B of the study EFC11072 (not performed for Part A patients, or patients from Part B non-selected dose arms) will be done at Weeks 48, 96, 144, 192 
(±14 days for each assessment), and EOT; No X-ray evaluation will be performed after Week 192 including EOT if EOT is after Week 192. Required x-ray must be done after confirmation of negative urine 
pregnancy test in women of child bearing potential. 
(electronic 
 
 
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Statistical Analysis Plan  
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SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 17 
h After Week 264, only DAS28 components of ACR core set will be assessed (TJC & SJC for 28 joints, patient´s global assessment of disease activity). 
i 
Hematology:  Hemoglobin, hematocrit, red blood cell (RBC) morphology (if blood cell count is abnormal), white blood cell (WBC) with differential, platelets count. For all patients, a CBC test must be performed 
before or at Visit 3 (using either designated central lab or a local laboratory facility), but not earlier than the 12th day after the first dose of IMP administration in order to confirm that the neutrophil count and platelet 
count are not within the protocol-defined limits for temporary or permanent discontinuation of study drug. 
j 
Liver Function Tests (LFTs): Prothrombin Time (PT), Albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated 
bilirubin. PT is NOT required at any visit after Week 264. 
k Lipids (fasting): Total cholesterol (TC), High-Density Lipoprotein (HDL) cholesterol, Low-Density Lipoprotein (LDL) cholesterol, triglycerides, Apolipoprotein A, and Apolipoprotein B. After Week 264, lipids (excluding 
Apolipoprotein A, and Apolipoprotein B ) will only be assessed at Weeks 288, 336, 384, 432, 480 (including EOT if EOT is after Week 264)  
l 
Clinical chemistry (fasting): fasting glucose, total proteins, calcium, sodium, potassium, Lactate Dehydrogenase, (LDH), urea nitrogen and creatinine. Creatinine clearance will be calculated during the study if 
clinical indicated.  
m ANA titer will be done at screening, at Week 48, 96, 144, 192, 240, 264, 288, 336, 384, 432, 480 and EOT visit or sooner if clinical indicated (Anti-ds-DNA only if ANA titer is >1:160) 
n Dipstick urinalysis for:  specific gravity, pH, glucose, blood, ketones, proteins, bilirubin, urobilinogen, nitrite, leukocytes. If any parameter is abnormal, a urinalysis sample should be sent to central laboratory for 
testing. If positive for proteins, microscopic analysis will be performed by central laboratory. 
o After Visit 7 (Week 12) between study visits the patient will have a urine pregnancy test at home on a monthly basis.  Patients will be given sufficient urine pregnancy kits to take home at each successive visit for 
monthly testing up until the final treatment visit. When the testing coincides with a clinical visit as indicated in the flow chart, the results should be reported in the eCRF. No pregnancy test kits will be dispensed at 
EOT.  
p ECG to be done at Weeks 48, 96, 144, 192, 240, 264 or EOT; No ECG will be done after Week 264 including EOT if EOT is after Week 264. 
q Rheumatoid factor only at baseline Visit 2 (Week 0) and at Weeks 48, 96, 144, 192, 240, 264 or EOT. No Rheumatoid factor will be assessed after Week 264 including EOT if EOT is after Week 264. 
r 
If throughout the study a serious adverse event (SAE) occurs in a patient, blood samples should be collected for sarilumab at or near the onset and completion of the occurrence of the event, if possible.  The exact 
date of sample collection and last dose must be recorded on the e-CRF.  
s Serum sample for biomarkers to be collected at screening (ie, the last treatment visit from the EFC11072 or ACT11575), Week 2, Week 12, and Week 48. 
t 
Blood sample for RNA to be collected at Week 0 (baseline, prior to administration of study drug) and Week 2 (at site visit only; cancel RNA collection if home visit). 
u Deleted. 
v Samples for IL-6 to be collected at Screening (ie the last treatment visit from EFC11072 or ACT11575) and at V4 (Week 4), V7 (Week 12), V8 (Week 24), V9 (Week 36), and V10 (Week 48).  
(electronic 
 
 
6.0)


Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 18 
1.4.3.2 Study Flow Chart for Patients Enrolling From EFC10832, EFC11072 Part B Cohort 2, SFY13370, and EFC13752 
 
Evaluation 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY and/or WEEK 
 
 
 
Day 1 
 
 
WK0 
Day 15
 
 
Wk 2 
Day 29 
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71 
 
 
Wk 10 
D85 
 
 
Wk 12 
Wk 24-96  
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 
108-492IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228… 492a 
Wk120 – 
264 
(every 24 
weeks) 
 
 
Wk120, 144, 
168, 192, 
216, 240, 
264a 
Wk288 – 
504 
(every 24 
weeks) 
 
 
Wk288, 
312,…, 
504a  
EOT visita 
 
 
6 weeks 
after end 
of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V1/V 2 
HV 3c
(± 3 
days) 
V 4 
(±3 days)
HV 5c
(±3 
days) 
V 6 
(±3 
days) 
HV 6.1c
(±3 days)
V 7 
(±3 days) 
V 8 to V14
(±3 days) 
V15, V17, 
V19, V21, 
V23, V25… 
V47 (±3 days)
V16, V18, 
V20, V22, 
V24, V26, 
V28 (±3 
days) 
V30, V32, 
V34, V36, 
V38, … , 
V48 (±3 
days) 
V49 (±3 
days) 
V50(±3 
days) 
Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Previous medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking, alcohol, and illicit 
drug use history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Detail history for tuberculosis 
(TB) and opportunistic 
infection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
Xd 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Confirm eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensingb  
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
(electronic 
 
 
6.0)


Statistical Analysis Plan  
22-Dec-2015 
SAR153191-LTS11210 - sarilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 19 
Evaluation 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY and/or WEEK 
 
 
 
Day 1 
 
 
WK0 
Day 15
 
 
Wk 2 
Day 29 
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71 
 
 
Wk 10 
D85 
 
 
Wk 12 
Wk 24-96  
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 
108-492IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228… 492a 
Wk120 – 
264 
(every 24 
weeks) 
 
 
Wk120, 144, 
168, 192, 
216, 240, 
264a 
Wk288 – 
504 
(every 24 
weeks) 
 
 
Wk288, 
312,…, 
504a  
EOT visita 
 
 
6 weeks 
after end 
of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V1/V 2 
HV 3c
(± 3 
days) 
V 4 
(±3 days)
HV 5c
(±3 
days) 
V 6 
(±3 
days) 
HV 6.1c
(±3 days)
V 7 
(±3 days) 
V 8 to V14
(±3 days) 
V15, V17, 
V19, V21, 
V23, V25… 
V47 (±3 days)
V16, V18, 
V20, V22, 
V24, V26, 
V28 (±3 
days) 
V30, V32, 
V34, V36, 
V38, … , 
V48 (±3 
days) 
V49 (±3 
days) 
V50(±3 
days) 
Study drug complianceb 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature, heart rate, 
blood pressure 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Weight in Kg 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
ACR disease core seth 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X-ray (hand, feet)g  
Xd 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Health Economic 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 (EFC11072, 
EFC10832) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
WPAI (EFC11072) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
FACIT-Fatigue (EFC11072, 
EFC10832) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
Sleep questionnaire 
(EFC11072) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
WPS-RA (EFC10832) 
Xd 
 
 
 
 
 
X 
X 
 
X 
 
Xf 
 
(electronic 
 
 
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Page 20 
Evaluation 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY and/or WEEK 
 
 
 
Day 1 
 
 
WK0 
Day 15
 
 
Wk 2 
Day 29 
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71 
 
 
Wk 10 
D85 
 
 
Wk 12 
Wk 24-96  
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 
108-492IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228… 492a 
Wk120 – 
264 
(every 24 
weeks) 
 
 
Wk120, 144, 
168, 192, 
216, 240, 
264a 
Wk288 – 
504 
(every 24 
weeks) 
 
 
Wk288, 
312,…, 
504a  
EOT visita 
 
 
6 weeks 
after end 
of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V1/V 2 
HV 3c
(± 3 
days) 
V 4 
(±3 days)
HV 5c
(±3 
days) 
V 6 
(±3 
days) 
HV 6.1c
(±3 days)
V 7 
(±3 days) 
V 8 to V14
(±3 days) 
V15, V17, 
V19, V21, 
V23, V25… 
V47 (±3 days)
V16, V18, 
V20, V22, 
V24, V26, 
V28 (±3 
days) 
V30, V32, 
V34, V36, 
V38, … , 
V48 (±3 
days) 
V49 (±3 
days) 
V50(±3 
days) 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis assessments 
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
AE/SAE recording (if any) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
High sensitive- C- Reactive 
protein (hs-CRP)  
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
Hematology: CBC and 
differentiali  
Xd 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Liver Function Tests (LFTs)j  
Xd 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Lipids (fasting)k  
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
Clinical  chemistry (fasting)l  
Xd 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
ANA/Anti-ds-DNA n 
Xd 
 
 
 
 
 
 
X  
 
X 
X 
X 
 
Dipstick urinalysiso 
Xd 
 
 
 
X 
 
X 
X 
 
X 
 
Xf 
 
Urine pregnancy test (for 
women of childbearing 
potential)p  
Xd 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Dispense urine pregnancy 
kitsp 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
 
(electronic 
 
 
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Page 21 
Evaluation 
Open Label Treatment 
Post 
Treatment 
follow-up 
DAY and/or WEEK 
 
 
 
Day 1 
 
 
WK0 
Day 15
 
 
Wk 2 
Day 29 
 
 
Wk 4 
Day 43
 
 
Wk 6 
Day 57
 
 
Wk 8 
Day 71 
 
 
Wk 10 
D85 
 
 
Wk 12 
Wk 24-96  
(every 12  
wks)  
Wk 24, 36, 
48, 60, 72, 
84, 96 
 
Wk 
108-492IMP 
dispensing 
visits  
(every 24 
weeks) 
Wk108, 132, 
156, 180, 204, 
228… 492a 
Wk120 – 
264 
(every 24 
weeks) 
 
 
Wk120, 144, 
168, 192, 
216, 240, 
264a 
Wk288 – 
504 
(every 24 
weeks) 
 
 
Wk288, 
312,…, 
504a  
EOT visita 
 
 
6 weeks 
after end 
of 
treatmenta 
Post 
treatment  
follow-up 
Visit no. 
V1/V 2 
HV 3c
(± 3 
days) 
V 4 
(±3 days)
HV 5c
(±3 
days) 
V 6 
(±3 
days) 
HV 6.1c
(±3 days)
V 7 
(±3 days) 
V 8 to V14
(±3 days) 
V15, V17, 
V19, V21, 
V23, V25… 
V47 (±3 days)
V16, V18, 
V20, V22, 
V24, V26, 
V28 (±3 
days) 
V30, V32, 
V34, V36, 
V38, … , 
V48 (±3 
days) 
V49 (±3 
days) 
V50(±3 
days) 
12-lead electrocardiogramq 
Xd 
 
 
 
 
 
 
X 
 
X 
 
Xf 
 
Other analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rheumatoid factorr 
Xd 
 
 
 
 
 
 
X 
 
X 
 
Xf 
 
Serum IL-6w 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
Pharmacokineticss 
Xd 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
Anti-sarilumab antibody 
Xd 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
Serum sample to be stored  
for future biomarkerst 
Xd 
X 
 
 
 
 
X 
X 
 
 
 
 
 
Expression RNAu 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
a EOT visit and follow up visit 6 weeks later should be completed for all patients at the end of treatment (in patients who complete sarilumab treatment per protocol in countries where sarilumab is commercially 
available the post treatment follow-up visit may be cancelled if the patient initiates treatment with commercial sarilumab during the post treatment follow-up period; however, in this case, a telephone contact must 
be established with the patient to capture all AEs occurring up to the 1st administration of commercial sarilumab). EOT visit may occur when the patients complete 264 weeks of sarilumab treatment from 
LTS11210, or any visit thereafter when sarilumab is commercialized in their country, but no later than 2020 when the study will be closed. (In UK, the duration of treatment will be 264 weeks from the first study 
drug administration in LTS11210).  In case of permanent discontinuation of treatment, the patients will be assessed using the procedures normally planned for the EOT visit and the 6 week follow up visit 6 weeks 
later.  
b From Week 24, patients at limited sites in selected countries may participate in PFS-S sub-study. If the patient enters the sub-study, then the sub-study IMP will be dispensed instead of the main study IMP at the 
entry into sub-study and IMP compliance with sub-study IMP will be reviewed at the end of sub-study. Full details of the sub-study are provided in Appendix R  
c HV: Visit can be home visit or clinic visit to draw and collect the blood sample only for hematology and LFTs using the designated central laboratory.  
d Last treatment visit from the study EFC11072, EFC10832, SFY13370, or EFC13752.   
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e Physical examination to be done at Week 48, 96, 144, 192, 240, 264, 288, 336, 384, 432, 480 and EOT visit 
f 
The assessment is NOT required when EOT visit is after Week 264. 
g X-ray of hands and feet (only for patients who completed Part B of the study EFC11072 will be done at Weeks 48, 96, 144, 192 (±14 days for each assessment), and EOT; No X-ray evaluation will be performed 
after Week 192 including EOT if EOT is after Week 192. Required x-ray must be done after confirmation of negative urine pregnancy test in women of child bearing potential. 
h After Week 264, only DAS28 components of ACR core set will be assessed (TJC & SJC for 28 joints, patient´s global assessment of disease activity). 
i 
Hematology:  Hemoglobin, hematocrit, red blood cell (RBC) morphology (if blood cell count is abnormal), white blood cell (WBC) with differential, platelets count. For all patients, a CBC test must be performed 
before or at Visit 3 (using either designated central or a local laboratory facility) but not earlier than the 12th day after the first dose of IMP administration in order to confirm that the neutrophil count and platelet 
count are not within the protocol-defined limits for temporary or permanent discontinuation of study drug. 
j 
Liver Function Tests (LFTs): Prothrombin Time (PT), Albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated 
bilirubin. PT is NOT required at any visit after Week 264. 
k Lipids (fasting): Total cholesterol (TC), High-Density Lipoprotein (HDL) cholesterol, Low-Density Lipoprotein (LDL) cholesterol, triglycerides, Apolipoprotein A, and Apolipoprotein B. After Week 264, lipids 
(excluding Apolipoprotein A, and Apolipoprotein B ) will only be assessed at Weeks 288, 336, 384, 432, 480 (including EOT if EOT is after Week 264) 
l 
Clinical chemistry (fasting): fasting glucose, total proteins, calcium, sodium, potassium, Lactate Dehydrogenase, (LDH), urea nitrogen and creatinine.  Creatinine clearance will be calculated during the study if 
clinical indicated.  
m Deleted. 
n ANA titer will be done at V1/V2 ( ie the last treatment visit from the initial study),  at Week 48, 96,  144, 192, 240, 264, 288, 336, 384, 432, 480 and EOT visit , or sooner if clinical indicated (Anti-ds-DNA only if 
ANA titer is >1:160) 
o Dipstick urinalysis for:  specific gravity, pH, glucose, blood, ketones, proteins, bilirubin, urobilinogen, nitrite, leukocytes. If any parameter is abnormal, a urinalysis sample should be sent to central laboratory for 
testing. If positive for proteins, microscopic analysis will be performed by central laboratory.  
p After Visit 7 (Week 12) between study visits the patient will have a urine pregnancy test at home on a monthly basis.  Patients will be given sufficient urine pregnancy kits to take home at each successive visit for 
monthly testing up until the final treatment visit. When the testing coincides with a clinical visit as indicated in the flow chart, the results should be reported in the e-CRF. No pregnancy test kits will be dispensed 
at EOT. 
q ECG to be done at Weeks 48, 96, 144, 192, 240, 264 or EOT; No ECG will be done after Week 264 including EOT if EOT is after Week 264  
r 
Rheumatoid factor only at Weeks 48, 96, 144, 192, 240, 264 or EOT; No Rheumatoid factor will be assessed after Week 264 including EOT if EOT is after Week 264 
s If throughout the study a serious adverse event (SAE) occurs in a patient, blood samples should be collected for sarilumab at or near the onset and completion of the occurrence of the event, if possible.  The 
exact date of sample collection and last dose must be recorded on the eCRF.  
t 
Serum sample for biomarkers to be collected for all patients except EFC13752: at V1/V2 (ie, the last treatment visit from the initial study), as well as Week 2, Week 12, and Week 48. 
u Blood sample for RNA except for SFY13370 and EFC13752 patients: to be collected at V1/V2 (Week 0) (baseline prior to administration of study drug) and V3 (Week 2) at site visit only (cancel RNA collection if 
home visit).  
v Deleted 
w Samples for IL-6 to be collected at V1/V2 for EFC11072 patients only (ie the last treatment visit) and for all patients at V4 (Week 4), V7 (Week 12), V8 (Week 24), V9 (Week 36), and V10 (Week 48). 
 
(electronic 
 
 
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Page 23 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled).   
A few modifications are made in the statistical section in the following amendments.  
Amendment 1 
The following cut-offs for age group and BMI group defined in the protocol: 
• 
Age group (<45, ≥45 and < 65, ≥65 years old) 
• 
BMI group (< 25, ≥25 kg/m2) 
were changed in Protocol Amendment 1to: 
• 
Age group (< 65, ≥65 and <75, ≥75 years old) 
• 
BMI group (<25, ≥25 and <30, ≥30 kg/m2) 
Amendment 3 
• 
Updated the description of the study endpoints and statistical methodology for clarification 
purposes. The intent of the statistical analysis plan established in the original protocol is 
not changed. 
• 
Incorporate the Rheumatoid Arthritis-Work Productivity Survey (WPS-RA) into the 
protocol for patients that completed the EFC10832 study. The WPS-RA is added into the 
LTS11210 study because the WPS-RA was included in the EFC10832  
• 
Added  x-ray data summary  
Amendment 8 
• 
Added: Data analysis results for patients who roll over from EFC13752 will be presented 
separately as sarilumab is administered as monotherapy in the EFC13752 and these 
patients will continue to be on sarilumab monotherapy in LTS11210  
• 
Updated analysis treatment groups: The safety analyses will be presented by original actual 
treatment groups in the respective previous studies (placebo, 150 mg q2w, 200 mg q2w, 
other sarilumab, and active control treatment groups) as well as overall in LTS11210, 
based on the reported adverse events, clinical laboratory evaluations, vital signs, and 
12-lead ECGs  
• 
Updated analysis treatment groups: The efficacy analyses will be done descriptively on the 
safety population by the originally randomized treatment groups as assigned in the 
respective previous studies (placebo, 150 mg q2w, 200 mg q2w, other sarilumab, and 
active control treatment groups) as well as overall and by visit in observed case, as 
appropriate  
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Page 24 
• 
Add: Radiographic progression of the mTSS is defined as a change from baseline in the 
mTSS >0. A change from baseline in the mTSS of less than or equal to zero is considered 
as no progression. The event of missing a change from baseline in the mTSS will be 
considered as progression. Summary of incidence of radiographic progression of mTSS 
will be provided  
• 
Deleted X-ray assessment at Week 192 as the time point is very close to EOT visit. X-rays 
performed at EOT will serve as source to provide X-ray data after 5 years of treatment with 
sarilumab.  
• 
Changed Section 13.8 title “Database Lock” as “Interim Analysis” with sentence 
modification. 
Amendment 9 
• 
Adjust timepoints up to Week 264 for efficacy endpoints (except DAS28 and EULAR) and 
health economic variables 
• 
The timepoints are up to Week 516 for DAS28 and EULAR endpoints 
• 
Updated analysis treatment groups for patients from EFC11072, ACT11575, EFC10832 
and SFY13370 with sarilumab + DMARD therapy in the initial and current studies , and 
for patients from EFC13752 with sarilumab monotherapy in the initial and current studies,  
per previous SAP version 2 
• 
Clearly state serum concentrations of bound Sarilumab are not analyzed per sponsor’s 
decision after EFC11072 study 
• 
Clearly state 3 campaigns of x-ray data (2 year data up to Week 48, 3 year data up to 
Week 96, and 5 year data up to Week 192 in LTS11210)  
• 
Add the PFS-S sub-study (see Protocol  Amendment 9 Appendix R) 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
The statistical analysis plan (SAP) Versions 1 and 2 were based on the original protocol dated 
16 Febr2010, and Protocol Amendments 1-8, respectively. The current SAP is modified per 
Protocol Amendment 9 with the modification mentioned in Section 1.5 
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Page 25 
2 
STATISTICAL AND ANALYTICAL PROCEDURES 
Below are general rules for the analysis procedure. 
For patients from EFC11072, ACT11575, EFC10832 and SFY13370 with sarilumab + DMARD 
therapy in the initial and current studies, all analyses will be performed based on previous 
treatment prior to enrollment into LTS11210 (placebo, sarilumab 150 mg q2w, sarilumab 200 mg 
q2w, other sarilumab (non-selected) doses, and active control treatment) as well as overall in 
LTS11210, unless otherwise specified. Interim analyses may be performed based on overall 
sarilumab +DMARD therapy only. 
For patients from EFC13752 with sarilumab monotherapy in the initial and current studies, all 
analyses will be performed based on previous treatment prior to enrollment into LTS11210 
(sarilumab 150 mg q2w, sarilumab 200 mg q2w) as well as overall in LTS11210, unless otherwise 
specified. Interim analyses may be performed based on overall sarilumab monotheraphy only. 
Data analysis results will be presented by sarilumab +DMARD therapy and sarilumab 
monotherapy in LTS11210 separately. All analyses will be performed in observed cases unless 
otherwise specified. 
Data analyses for the PFS-S sub-study will be described in Appendix K. 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
For patients who roll over to LTS11210, new demographic data are collected in LTS11210, but 
some baseline characteristic information (such as height, time since diagnosis of RA, rheumatoid  
factor and prior biologic use) is not collected in LTS11210. This missed information will be 
captured from the previous study databases.   
All baseline safety and efficacy parameters (apart from the ones listed below) are presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.4 and 
Section 2.4.5). 
Demographic characteristics 
The following demographic characteristics will be summarized: 
• 
Gender (Male, Female)  
• 
Race (Caucasian/white, Black, Asian/Oriental, other) 
• 
Ethnicity (Hispanic, Not Hispanic) 
• 
Region (Region1:Western countries, Region2:South America, Region3:Rest of the World) 
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• 
Age (years) 
• 
Age group (< 65, ≥65 and <75, ≥75 years) 
• 
Weight (kg) 
• 
Height (cm) 
• 
Body mass index (BMI, kg/m2) 
• 
BMI group (<25, ≥25 and < 30, ≥30 kg/m2). 
Medical or surgical history 
The medical and surgical history data were collected in the previous studies.  
This information will be coded to a “Lower Level Term (LLT)”, “Preferred Term (PT)”, “High 
Level Term (HLT)”, “High Level Group Term (HLGT)”, and associated primary “System Organ 
Class (SOC)” using the version of MedDRA currently in effect at sanofi at the time of database 
lock. 
Disease characteristics at baseline   
The following baseline disease characteristics will be summarized: 
• 
Time since diagnosis of RA (years) 
• 
Rheumatoid  factor (Positive: ≥1 IU/mL, negative: <1 IU/mL) 
• 
Prior biologic DMARD use for RA  
• 
Smoking history 
• 
Alcohol use  
In addition, the summary of baseline values for clinical signs and symptoms and quality of life 
assessments will be presented in the summary tables for these data. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5.  
2.1.2 Prior or concomitant medications  
All medications taken at any time during LTS11210 period, from the enrollment to the end of the 
follow-up period, including those ongoing at study start, are to be reported in the CRF pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using version currently in effect at sanofi at the time of database lock.  
Concomitant medications are any treatments received by the patient concomitantly to the/any IMP, 
from the first IMP intake in LTS11210 to the end of the follow-up period. 
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Prior medications are those the patient used prior to first IMP intake in LTS11210. Prior 
medications can be discontinued before first dosing or can be ongoing during treatment phase. The 
data before enrollment were reported in the previous study reports. However the data from 
enrollment up to the time of first IMP intake will be reported in LTS11210 database. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Safety endpoints 
The primary endpoint is the incidence of adverse events.  The safety analysis will be based on the 
reported adverse events (AEs) and other safety information, such as clinical laboratory data, vital 
signs and ECG. 
Observation period  
The observation period will be divided into 4 epochs: 
• 
The SCREENING epoch is defined as beginning with the last visit in the previous studies 
to the first dose of IMP in LTS11210  
• 
The TREATMENT epoch is defined as the time from first dose of IMP in LTS11210 to 
last dose of IMP + 13 days (6 days for patients receiving weekly injections only ) 
• 
The FOLLOW-UP epoch is defined as the time from the end of TREATMENT epoch to 
last dose of IMP + 60 days 
• 
The POST-STUDY epoch is defined as the time after the last dose of IMP + 60 days  
The rational of having “last dose of IMP + 60 days” as the end of follow-up epoch is to capture the 
events observed within an approximately 5 half-lives of the last IMP. The treatment-emergent AE 
(TEAE) period will include both TREATMENT and FOLLOW-UP epochs.  
Please note: Not all the patients will have all 4 epochs. For example, if a patient died on the 7th 
day after the last dose of IMP, his/her TREATMENT epoch will be from the first dose of IMP to 
his/her death date and will have no FOLLOW-UP or POST-STUDY epoch; if a patient had his 
last visit (i.e. follow-up visit 29) on the 50th day after the last dose of IMP and have no AE 
reported after this date, his/her FOLLOW-UP epoch will be ended on last dose of IMP+50 days 
and will have no POST-STUDY epoch. 
2.1.3.1 Adverse events variables 
Adverse event observation period  
• 
Pre-treatment AEs are AEs that developed or worsened or became serious from the signed 
informed consent date up to first dose of IMP in LTS11210. The ongoing AEs from 
previous studies filled out on AE switch CRF pages are also considered as pre-treatment 
AEs 
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• 
TEAEs are AEs that developed or worsened or became serious during the TEAE period 
• 
Post-study AEs are AEs that developed or worsened or became serious during the 
post-study period 
All AEs (including SAEs and AESIs and ongoing AEs from previous studies filled out on AE 
switch CRF pages) will be coded to a “Lowest Level Term (LLT)”, “Preferred Term (PT)”, “High 
Level term (HLT)”, “High Group Level Term (HLGT)” and associated primary “System Organ 
Class (SOC)” using the version of MedDRA currently in effect at sanofi at the time of database 
lock. 
The occurrence of AEs (including SAEs and AESIs and ongoing AEs from previous studies filled 
out on AE switch CRF pages) will be recorded from the time of signed informed consent until the 
end of the study.  
Adverse event of special interest (AESI)  
AESIs will be flagged in the database using search criteria.  All AEs captured on the general AE 
form, the ALT increase form, the suspected infection event form, the diverticulitis or 
gastrointestinal ulceration form, or the neurological event form will be searched.  The list of the 
AESIs with the search criteria are provided below: 
Table 1 - AESI and search criteria 
AESI flag 
Searcha criteria 
Leukopenia 
SMQ: Haematopoietic leukopenia 
Thrombocytopenia 
SMQ: Haematopoietic thrombocytopenia 
Infections (Opportunistic infections, 
Tuberculosis) 
Primary SOC: Infections and infestations (CRF checkbox:  Opportunistic 
infections; HLT Tuberculosis infections) 
Hepatic disorders 
SMQ : Drug-related hepatic disorders – comprehensive search 
Diverticulitis/potential GI perforationsb 
SMQ: Gastrointestinal perforation and HLT: Diverticulum inflammations 
GI ulcerations 
SMQ: Gastrointestinal ulceration 
Elevation in lipids 
SMQ: Dyslipidemias 
Anaphylaxis 
SMQ: Anaphylactic reaction 
Hypersensitivity 
SMQ Hypersensitivity 
Injection site reactions 
HLT Injection site reactions 
Malignancy 
SMQ: Malignant or unspecified tumours 
Excluding non-melanoma skin cancer:  SMQ Malignant or unspecified tumours 
excluding HLT of Skin neoplasms malignant and unspecified (excl melanoma) 
Lupus-like syndrome 
SMQ: Systemic lupus erythematosus 
Demyelinating disorders 
SMQ: Demyelination 
Pregnancyc 
CRF checkbox: Pregnancy 
Overdosec 
CRF checkbox:  Symptomatic overdose 
a All SMQs are narrow search 
b These events will be further reviewed to identify cases of GI perforations 
c Standard AESI applies to all Sanofi studies 
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Cardiovascular Adjudication Committee  
All deaths and potential CV events reported by the investigator, identified by pre-specified search 
criteria described in the Cardiovascular Adjudication Committee (CAC) charter will be 
prospectively adjudicated in a blinded manner by the CAC.  The committee will adjudicate 
qualifying events according to the CAC Charter.   
The CV adjudication committee will adjudicate each event as: a CV event, a non-CV event or not 
evaluable (Appendix J provides further categorization of CV event, non-CV event). 
Two composite Major Adverse Cardiac Events (MACE) endpoints are defined as: 
• 
MACE (primary): CV Death, MI, Stroke, Hospitalization for unstable angina (UA) or 
Hospitalization for Transient Ischemic Attack (TIA). 
• 
MACE (narrow): CV Death, MI, or Stroke. 
2.1.3.2 Deaths 
The deaths observation period are per the observation periods defined above:  
• 
Death on-treatment: deaths occurring during the treatment period  
• 
Death during follow-up: deaths occurring during the follow-up period 
• 
Death post-study:  deaths occurring during the post-study period 
2.1.3.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry and 
urinalysis. Clinical laboratory values will be converted to standard international units; 
international units will be used in all listings and tables. In addition, the lipids parameters will also 
be summarized in US units.  
Blood samples for clinical laboratories will be taken at Visits 1-49 and/or early termination unless 
otherwise specified. The laboratory parameters will be classified as follows:  
• 
Hematology  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, platelet 
count, RBC, RBC morphology (if RBC count is abnormal), and prothrombin time. 
- 
White blood cells: WBC, WBC differential (neutrophils/ANC, lymphocytes, 
monocytes, basophils, eosinophils) 
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• 
Clinical chemistry  
- 
Metabolism: total cholesterol, HDL, LDL, ratio of HDL versus LDL (HDL:LDL), 
triglycerides tests; glucose and total protein in fasting condition; HbA1c; 
Apolipoprotein A and B (determination is not performed in SFY13370 and results will 
not be available for the initial LTS11210 visit for SFY13370 patients); and acute phase 
reactants: hs-CRP. 
- 
Electrolytes: sodium, potassium, chloride, calcium, and bicarbonate. 
- 
Renal function: creatinine, CLcr, BUN, uric acid. 
- 
Liver function: ALT/SGPT, AST/SGOT, ALP, albumin, total bilirubin, conjugated 
and unconjugated bilirubin, and LDH. 
- 
Antibody: anti-CCP antibodies, RF, ANA/anti-ds DNA. 
- 
Pregnancy test : Serum β-hCG for all female patients. 
Urine samples will be collected as follows (when urine dipstick is abnormal at site): 
• 
Urinalysis - quantitative analyses: pH, specific gravity, ketone, proteins, blood, glucose, 
bilirubin, urobilinogen, nitrate and leukocytes.  
Technical formulas are described in Section 2.5.1. 
2.1.3.4 Vital signs variables 
Vital Signs include: Heart Rate (HR), Systolic and Diastolic Blood Pressure (SBP and DBP) 
according to position (standing and supine), as well as orthostatic changes in blood pressure 
(standing – supine). It also includes weight and temperature. 
2.1.3.5 Electrocardiogram variables 
A standard 12-lead ECG will be performed and will be determined using centralized automatic 
and manual readings.  
ECG parameters include Heart Rate, PR, QRS, QT as well as corrected QTc (according to 
Bazett/Fridericia), ST deviation, T-wave morphology, and U wave presence or absence. 
2.1.4 Efficacy endpoints 
Efficacy is a secondary endpoint of this study.  The efficacy variables will include: 
• 
ACR20 response over time up to Week 264 
• 
ACR50 and ACR70 response over time up to Week 264 
• 
Change from baseline in ACR components up to Week 264 
• 
DAS28 –CRP response over time 
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• 
DAS28 remission over time 
• 
EULAR response over time 
• 
Change from baseline in the van der Heijde modified total Sharp score (for patients from  
EFC11072  Part B Cohort 2 and Cohort 1 selected dose arms with an end of treatment 
X-ray evaluation) at Weeks 48, 96, 144 and  192  or EOT if EOT is prior to Week 192 
• 
Incidence of radiographic progression of the van der Heijde modified total sharp score at 
Weeks 48, 96, 144, and 192  or EOT if EOT is prior to Week 192 
• 
Change from baseline in HAQ-DI over time up to Week 264. 
Note that TJC and SJC (both based on 28 joints), patient’s global assessment of disease activity 
and hs-CRP will still be assessed after Week 264 to calculate DAS28. 
As mentioned before, the baseline value for efficacy parameters is the original baseline from the 
previous study databases for patients who rolled over to LTS11210.  
A) ACR20 response over time 
To be classified as an ACR20 Responder, a patient must achieve 20% improvement in the 
Tender joint count (68 joints) and the Swollen joint count (66 joints), as well as 20% 
improvement in at least 3 of the following 5 assessments: 
• 
Levels of an acute phase reactant (CRP level) 
• 
Patient’s assessment of pain based on the 0 – 100mm Visual Analogue Scale (VAS) 
• 
Patient’s global assessment of disease activity based on the VAS 
• 
Physician’s global assessment of disease activity based on the VAS 
• 
Patient’s assessment of physical function based on the HAQ_DI 
The 7 ACR components assessing the signs and symptoms of RA are measured as follows  
a) Tender Joint Count (TJC) 
A total of 68 joints will be assessed for tenderness. The 68 joints to be examined for 
tenderness are: temporomandibular (n=2), sternoclavicular (n=2), acromioclavicular (n=2), 
shoulder (n=2), elbow (n=2), wrist (n=2), metacarpophalageal (n=10), interphalangeal of 
thumb (n=2), distal interphalangeal (n=8), proximal interphalangeal (n=8), hip (n=2), knee 
(n=2), ankle mortise (n=2), ankle tarsus (n=2), metatarsophalangeal (n=10),interphalangeal of 
great toe (n=2), and proximal/distal interphalangeal of the toes (n=8).  
A formal count of the joints will be performed by a trained independent assessor. Joint 
tenderness is defined as pain induced by the pressure of the joints, exerted by the assessor’s 
thumb and index finger. The assessor will classify each joint as painful yes/no and swollen 
yes/no. A score of 0/1 will be given to each tender joint with 0 representing no pain and 1 
representing pain. The tender joint count ranges from 0 to 68 where 0 is considered the best 
and 68 the worst.  
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b) Swollen Joint Count (SJC) 
The 66 joints to be examined for swelling are the same as those examined for tenderness, 
except the hip joints are not included.  
A formal count of the joints will be performed by a trained independent assessor. The assessor 
will classify each joint as swollen yes/no. A score of 0/1 will be given to each swollen joint 
with 0 representing no swollen and 1 representing a swollen joint. The swollen joint count 
ranges from 0 to 66 where 0 is considered the best and 66 the worst. 
c) Physician’s Global Assessments of Disease Activity 
Physician’s global assessments of the patient’s current disease activity will be accessed on an 
anchored 100 mm horizontal VAS where 0 is considered the best disease activity (no disease 
activity) and 100 the worst (most disease activity). 
d) Patient’s Global Assessments of Disease Activity 
Patient’s global assessments of their current disease activity will be rated on an anchored 
100 mm horizontal VAS where 0 is considered the best disease activity (no disease activity) 
and 100 the worst (most disease activity). 
e) Patient’s Assessment of Pain 
Patients will be requested to indicate their pain intensity due to their RA using a 100 mm 
horizontal VAS where 0 is considered “No pain” and 100 “the worst pain you can imagine”. 
f) Patient’s Assessment of Physical function – Health Assessment Questionnaire Disease 
Index (HAQ-DI) 
The HAQ-DI is a standardized questionnaire developed for use in RA. The HAQ-DI, with the 
past week as the time frame, focuses on whether the respondent “is able to…” do the activity 
and covers 8  categories in 20 items: dressing and grooming, arising, eating, walking, hygiene, 
reach, grip and activities, for which there are at least 2 questions by category. The 4  responses 
for the HAQ-DI questions are graded as follows: without any difficulty = 0; with some 
difficulty = 1; with much difficulty = 2; and unable to do = 3. To calculate the Standard 
HAQ-DI Score (With Aids/Devices), there are 3 steps   
1. Sum the 8 category scores by using the highest sub-category score from each category. 
- 
For example, in the category ARISING there are 3 sub-category items. A patient who 
responds with a 1, 2, and 0, respectively, results in category score of 2. 
2. Adjust for use of aids/devices and/or help from another person when indicated. 
- 
Adjust the score for a category by increasing a 0 or a 1 to a 2. 
- 
If a patient's highest score for that sub-category is a 2 it remains a 2, and if a 2, it 
remains a 2. 
- 
The data entered at field “Other specify” will not be used for score adjustment. 
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3. Divide the summed category scores by the number of categories answered (must be a 
minimum of 6) to obtain a HAQ-DI score of 0-3 (3=worst functioning). 
A HAQ-DI score cannot be calculated validly when there are scores for less than 6 of the 8 
categories. HAQ-DI scoring ranges between 0 and 3. A high HAQ-DI score has been found to 
be a strong predictor of morbidity and mortality in RA.  
g) The level of an acute phase reactant measured by CRP 
High sensitivity CRP will be assessed centrally. Since CRP levels are directly correlated with 
Interleukin 6 receptor (IL6-R) activity, it is expected that active dose regimens will have a 
dramatic lowering effect on CRP levels. 
The ACR components are further described in  
Table 2 - ACR components 
ACR component 
Range 
Direction 
TJC 
0-68 
Lower is better 
SJC 
0-66 
Lower is better 
Pain VAS 
0-100 
Lower is better 
Patient global VAS 
0-100 
Lower is better 
Physician global VAS 
0-100 
Lower is better 
HAQ-DI 
0-3 
Lower is better 
CRP ( mg/dL)  
>0 
Lower is better 
TJC: Total Joint Counts, SJC: Swollen Joint Counts, VAS: Visual Analog Scale 
 
B) ACR50 response over time 
ACR50 is defined as the percentage of patients who achieve at least 50% improvement in both 
tender joint count and swollen joint count, and at least 50% improvement in at least 3 of the 5 
remaining ACR components.  
C) ACR70 response over time 
ACR70 is defined as the percentage of patients who achieve at least 70% improvement in both 
tender joint count and swollen joint count, and at least 70% improvement in at least 3 of the 5 
remaining ACR components.  
D) Change in ACR components over time 
The change in each ACR component will be calculated from baseline of the previous studies. 
E) DAS28-CRP  over time 
DAS28-CRP is a composite score that includes 4 variables: 
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• 
Tender joints count (based on 28 joints: shoulder (n=2), elbow (n=2), wrist (n=2), 
metacarpophalageal (n=10), interphalangeal of thumb (n=2), proximal interphalangeal 
(n=8), knee (n=2)) 
• 
Swollen joints count (based on 28 joints: shoulder (n=2), elbow (n=2), wrist (n=2), 
metacarpophalageal (n=10), interphalangeal of thumb (n=2), proximal interphalangeal 
(n=8), knee (n=2)) 
• 
General health (GH) or patient’s global assessment of disease activity based on VAS (mm) 
assessed from the ACR questionnaire 
• 
Marker of inflammation here assessed by the hs-CRP ( mg/L). 
It is a continuous measure allowing for measurement of absolute change in disease burden and 
percentage improvement. It has been extensively validated for its use in clinical trials and accepted 
by health authorities. Using this data, the DAS28 can be calculated using the following formula: 
DAS28-CRP  = 0.56 x 
TJC
28
 + 0.28 x 
SJC
28
 + 0.36 x Log(CRP+1) + 0.014 x GH + 0.96, 
Where 28TJC and 28SJC are the tender and swollen joint counts from 28 joints and GH is the 
patient’s global assessment of disease activity and CRP is in mg/L.  
DAS28-CRP provides a number on a scale from 0 to 10 indicating the current activity of the RA. 
DAS28 –CRP will be considered as missing if one of the components is missing. 
F) DAS28 remission over time 
DAS28 Remission is the event of having a DAS28-CRP score <2.6. 
G) European League Against Rheumatism (EULAR) response over time 
The European League Against Rheumatism (EULAR) response criteria combine the DAS28 score 
at the time of evaluation with the change in DAS28 score between 2 time points. The EULAR 
response criteria are defined as: 
• 
Good response = The event of having an improvement of >1.2 and a present DAS28-CRP 
score ≤3.2. 
• 
Moderate response = The event of having either an improvement of >0.6 to ≤1.2 and a 
present DAS28-CRP score ≤5.1, OR, having an improvement of >1.2 and a present 
DAS28-CRP score >3.2. 
• 
No response = The event of having either an improvement of ≤0.6, OR, having an 
improvement of >0.6 to ≤1.2 and a present DAS28-CRP score >5.1. 
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Table 3 - EULAR response categories 
Change from baseline in DAS28-CRP  score 
DAS28-CRP  score 
< -1.2 
< -0.6 to ≥ -1.2 
≥ -0.6 
≤ 3.2 
Good response 
Moderate response 
No response 
> 3.2 to ≤ 5.1 
Moderate response 
Moderate response 
No response 
> 5.1 
Moderate response 
No response 
No response 
H) Change in van der Heijde modified total Sharp score over time 
X-ray data will be collected for patients from EFC11072 Part B Cohort 2 and Cohort 1 selected 
dose arms only. The degree of joint damage will be assessed using the van der Heijde modified 
total Sharp score (mTSS). This methodology quantifies the extent of bone erosions for 44 joints 
and joint space narrowing for 42 joints, with higher scores representing greater damage. The van 
der Heijde mTSS at a time point is the sum of the scores from both the erosion score and the joint 
space narrowing score, for a maximum score of 448. 
Erosion score 
The joint erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints of 
the feet. Each joint is scored, according to the surface area involved, from 0 to 5 for hand joints 
and 0 to 10 for the joints of the foot. The maximum erosion score (5 for the hand and 10 for the 
foot) indicates extensive loss of bone from more than one half of the articulating bone. A score of 
0 in either the hand or foot indicates no erosion. The maximum erosion score is 280 (160 in the 
hands and 120 in the feet) for a time point. 
Joint space narrowing score 
The joint space narrowing (JSN) score summarizes the severity of JSN in 30 joints of the hands 
and 12 joints of the feet. Assessment of JSN for each hand (15 joints per hand) and foot (6 joints 
per foot), including subluxation, is scored from 0 to 4, with 0 indicating no/normal JSN and 4 
indicating complete loss of joint space, bony ankylosis or luxation. Thus, the maximum JSN score 
is 168 at a time point. 
X-ray data reading 
Campaign 1 
X-rays read in Campaign 1 will include baseline and EOT (or last available visit) from EFC11072, 
Week 48 and any unscheduled visits between Week 0 and Week 48 in LTS11210. Two primary 
readers and an adjudicator will perform reading of data up to Week 48 in LTS11210 (see details in 
Appendix D). The X-rays at baseline and Year 1 (EOT or last available visit in EFC11072) will be 
reread. 
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The linear extrapolation method will be used to impute missing modified total Sharp score, 
erosion score, or joint space narrowing score at Week 48 in LTS11210 from Campaign 1 data for 
patients who have EOT (or last available data) in EFC11072 and any unscheduled visit data 
between Week 0 and Week 48 in LTS11210. In the linear extrapolation method, for example, the 
missing modified total Sharp score at Week 48 is imputed according to the following formula: 
Week 48 modified total Sharp score = EOT score in EFC11072 + 336*(modified total Sharp 
score of the last measurement in LTS11210 – EOT score in EFC11072)/(date of last measurement 
in LTS11210 – date of EOT visit in EFC11072).  
Campaign 2 
X-rays in Campaign 2 will include baseline from EFC11072, Weeks 48 and 96, and any 
unscheduled visits between Week 48 and Week 96 in LTS11210. The linear extrapolation method 
will be used to impute missing the modified total Sharp score, erosion score, or joint space 
narrowing score at Week 96. Similarly, the missing modified total Sharp scores at Week 96 are 
imputed by the linear extrapolation method according to the following formula: 
Week 96 modified total Sharp score = Week 48 score + 336*(modified total Sharp score of the 
last measurement – Week 48 score)/(date of last measurement – date of Week 48 measurement),  
Campaign 3 
X-rays in Campaign 3 will include baseline from EFC11072, Weeks 96, 144 and 192 (or EOT), 
and any unscheduled visits between Week 96 and Week 192 (or EOT) in LTS11210. The linear 
extrapolation method will be used to impute missing the modified total Sharp score, erosion score, 
or joint space narrowing score at Weeks 144 and 192 in LTS11210 based on Campaign 3 data. 
Similarly, the missing modified total Sharp scores at Week 144 and Week 192 in LTS11210 are 
imputed by the linear extrapolation method according to the following formula: 
Week 144 modified total Sharp score = Week 96 score+ 336*(modified total Sharp score of the 
last measurement – Week 96 score)/(date of last measurement – date of Week 96 measurement),  
Week 192 modified total Sharp score = Week 96 score + 672*(modified total Sharp score of the 
last measurement – Week 96 score)/(date of last measurement – date of Week 96 measurement),  
Where EOT visit for X-ray in LTS11210 will be prior to  Week 192 if a patient discontinues the 
study prior to Week 192. 
I) Incidence of radiographic progression of the van der Heijde modified total Sharp 
score over time 
Note that missing modified total Sharp scores are imputed by the linear extrapolation method. And 
then a change from the baseline in the modified total SHARP score will be calculated.  A change 
from the baseline in the modified total SHARP scores of ≤ 0 is considered as no progression.  
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J) Change from baseline in HAQ-DI 
The HAQ-DI is composed of 8 categories as follows: dressing and grooming, arising, eating, 
walking, hygiene, reach, grip and activities, for which there are at least 2 questions by category. 
The patient will be asked to score how difficult he/she feels it is to perform such activities using a 
0 to 3 scoring (0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 
3=unable to do). If the patient is using assistance for any of these activities, scoring may be 
adjusted. For each category, the highest score given for one of the question is attributed to the 
category. The total score is the sum of all categories’ scores divided by the number of answered 
categories (at least 3 categories should be answered). 
2.1.5 Pharmacokinetic and immunogenicity variables 
Immunogenicity (anti-sarilumab antibody) and pharmacokinetic blood samples (trough 
concentrations) will be collected according to the study flow chart. Pharmacokinetic samples will 
also be collected at or near the onset and completion of the occurrence of a serious adverse event. 
Note that there are some missing data after Week 48 since pharmacokinetic evaluation were added 
after Week 48 per Protocol Amendment 8 and by that time some patients already reach more than 
48 weeks of treatment. 
At each sample time the result of the ADA assay will be categorized as either positive or negative, 
and in the case of a positive result will be further characterized as either neutralizing or 
non-neutralizing. 
2.1.6 Pharmacodynamic/genomics endpoints 
Serum concentrations of IL-6 will be assessed according to the study flow chart. 
2.1.7 Quality-of-life endpoints 
SF-36 V2 (for patients from EFC11072, ACT11575 and EFC10832 only) 
The SF-36 version 2 is a multi-purpose, short-form health survey with 36 questions.  It yields 
scores for 8 domains (Physical Functioning, Role-Physical, Bodily pain, General health, Vitality, 
Social Functioning, Role-Emotional, and Mental Health, each scale is scored from 0 to 100 where 
higher scores indicate better health and well-being), as well as 2 summary measures of physical 
and mental health: the Physical Component Summary and Mental Component Summary (1). 
The scoring process is summarized below: 
1. Enter item response data 
2. Recode item response values 
3. Determine health domain scale raw scores.  
4. Transform health domain scale raw scores to 0-100 scores. 
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5. Transform health domain scale 0-100 to norm-based scores 
6. Score physical and mental component summary measures 
The following table shows the construction and summary measures of the SF-36 scales: 
Table 4 - SF-36 V2 measurement model 
Summary measures 
Scales 
Items 
Physical Component  
Physical Functioning (PF) 
3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j 
Summary (PCS)* 
Role-Physical (RP) 
4a, 4b, 4c, 4d 
 
Bodily Pain (BP) 
7, 8 
 
General Health (GH) 
1, 11a, 11b, 11c, 11d 
Mental Component 
Vitality (VT) 
9a, 9e, 9g, 9i 
Summary (MCS)* 
Social Functioning (SF) 
6, 10 
 
Role-Emotional (RE) 
5a, 5b, 5c 
 
Mental Health (MH) 
9b, 9c, 9d, 9f, 9h 
MCS and PCS derived from the eight scales 
The score of each of the 36 items is collected in CRF.  Appendix I provides the SAS code to 
calculate the 8 scales, the 2 summary measure scores and standardized summary scores. 
The PCS and MCS summary measure scores will be computed if at least 50% of the component 
scales are available. The scale scores will be computed if at least 50% of items are available 
within the corresponding scale. The missing items will be imputed by the mean of available items. 
Change from baseline in SF-36 scores (physical component summary score and mental component 
summary score as well as the eight domains) will be analyzed. 
2.1.8 Health economic endpoints 
WPAI (for patients from EFC11072 and ACT11575 only) 
Work Productivity and Activity Impairment (WPAI) will be assessed. WPAI outcomes are 
expressed as impairment percentages, with higher numbers indicating greater impairment and less 
productivity, ie., worse outcomes, as follows:  
• 
Q1 = currently employed 
• 
Q2 = hours missed due to specified problem (RA) 
• 
Q3 = hours missed other reasons 
• 
Q4 = hours actually worked 
• 
Q5 = degree problem affected productivity while working 
• 
Q6 = degree problem affected regular activities Scores  
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Scores will be expressed in percentages. 
• 
Percent work time missed due to problem (RA): 100*Q2/(Q2+Q4) 
• 
Percent impairment while working due to problem: 10*Q5 
• 
Percent activity impairment due to problem: 10*Q6 
• 
Percent overall work impairment due to problem (RA):  
100*Q2/(Q2+Q4)+100*[(1-Q2/(Q2+Q4))*(Q5/10)] 
When deriving the 4 WPAI scores, missing data will be handled using the following rules. 
• 
Percent work time missed due to problem (RA): The score will be missing if either Q2 or 
Q4 is missing. 
• 
Percent impairment while working due to problem: The score will be missing if Q5 is 
missing. 
• 
Percent activity impairment due to problems: The score will be missing if Q6 is missing. 
Percent overall work impairment due to problem (RA): The score will be missing if either 
percent work time missed due to problem (RA) is missing or percent impairment while 
working due to problem is missing. 
FACIT-Fatigue (for patients from EFC11072, ACT11575 and EFC10832 only) 
The Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-Fatigue) will be 
used to assess fatigue. The FACIT-Fatigue is a 13-item questionnaire rated 0 to 4 originally 
developed to measure fatigue in patients with cancer and is widely used in RA patients to 
demonstrate good consistency and sensitivity to change. The patient will be asked to answer 13 
questions rated 0 to 4 (0=not at all, 1=a little bit, 2=some what, 3=quite a bit, 4=very much). The 
fatigue scale has 13 items, with 52 as the highest possible score. A higher score in the fatigue scale 
corresponds to a lower level of fatigue and indicates better Quality of Life. 
To calculate the FACIT-fatigue score, the response scores on negatively phrased questions are 
reversed and then the 13 item responses are added. Eleven items with responses have their scores 
reversed (item score = 4 – response, if the response is not missing), and two items (items 7-8) 
have their responses unchanged (Appendix F). All items are added so that higher scores 
correspond to less fatigue. In cases where individual questions are skipped, scores are prorated 
using the average of other answers in the scale.  
FACIT-Fatigue = 13*[sum(reversed items)+sum(items 7-8)]/number of answered items 
Sleep questionnaire (for patients from EFC11072 and ACT11575 only) 
RA like other chronic illness is associated with sleep disturbances. Sleep disturbances is linked to 
pain, mood and disease activity. The effect of sarilumab on pain will be assessed on a sleep 
questionnaire VAS scale ranges from 0 (sleep is not a problem) to 100 (sleep is a major problem). 
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WPS-RA (for patients from EFC10832 only) 
The rheumatoid arthritis-work productivity survey (WPS-RA) is a validated questionnaire that 
evaluates productivity limitations within work and within home associated with RA over the 
previous month. The questionnaire is interviewer-administered and is based on patient self-report. 
It contains 9 questions addressing employment status (1 item), productivity at work (3 items) and 
within and outside the home (5 items) (Appendix H). 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations for LTS11210 only, unless otherwise specified. 
• 
All screened patients are defined as those patients who signed the informed consent. 
• 
All enrolled patients are defined as all patients with signed informed consent who met the 
eligibility criteria to enter into LTS11210.   
• 
The Safety population consists of all enrolled patients who received at least one dose of the 
LTS11210 study medication. 
For patient study status, the total number of patients for each one of the following categories will 
be presented using a summary table: 
• 
All screened patients (informed consent signed) 
• 
Screen failure patients and reasons for screen failure (not eligible per eligible CRF page) 
• 
Non-enrolled but treated patients 
• 
All enrolled patients by previous studies  
• 
Enrolled but not treated patients 
• 
Enrolled and treated patients 
• 
Patients who had dose reductions 
• 
Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
• 
Status at last study contact 
For all categories of patients (except for the screened and non-enrolled categories), percentages 
will be calculated using the total of all enrolled patients as the denominator.  Reasons and time to 
treatment discontinuation will be supplied in tables giving numbers and percentages.  This 
summary will be further sub-grouped by region and by prior biological use. 
A patient is considered as lost to follow-up at the end of the study if he/she is not assessed at the 
last protocol planned visit. 
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All major or critical deviations potentially impacting analyses, drug dispensing irregularities and 
other major or critical deviations will be summarized in tables giving numbers and percentages of 
deviations. 
The analysis populations for safety, efficacy and PK will be summarized in a table by patient 
counts on the enrolled patients. 
• 
Safety population (for safety and efficacy analyses), 
• 
PK population. 
 
2.2.1 Randomization and drug dispensing irregularities 
There is no randomization procedure in LTS11210. Drug dispensing irregularities occur 
whenever: 
• 
A patient is dispensed an IMP kit not allocated by the IVRS, such as, a) a patient at any 
time in  the study is dispensed a different treatment kit than as assigned (which may or may 
not contain the correct assigned IMP), or b) a non-screened patient is treated with study 
medication reserved for enrolled patients. 
Drug dispensing irregularities will be monitored throughout the study and reviewed on an ongoing 
basis.  
All drug dispensing irregularities will be documented.  If the number of irregularities is large 
enough to make a tabular summary useful, the irregularities will be categorized and summarized 
among all patients (number and percentages). 
Drug dispensing irregularities to be prospectively identified include but are not limited to:  
Table 5 - Drug Allocation Irregularities 
Drug Allocation Irregularities 
   Kit dispensation without IVRS transaction 
   Erroneous kit dispensation 
   Kit not available 
   Subject switched to another site 
 
2.3 
ANALYSIS POPULATIONS 
The primary analysis population is the safety population.  All safety analyses and efficacy analyses 
will be performed based on the safety population.  
The patients who enroll into LTS11210 study but are not treated will be reported separately, and 
these patients will not be in the safety population for this study. 
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2.3.1 Safety populations 
Safety population is defined as all enrolled patients who have received at least one dose of the 
study treatment in LTS11210.   
All analyses will be performed on the safety population based on previous treatment prior to 
enrollment into LTS11210. This will allow for assessment of any differences between treatment 
groups based on previous treatment. 
2.3.2 Efficacy population 
The efficacy analysis population is the same as safety population. 
Efficacy analyses will be performed on the safety population based on previous treatment prior to 
enrollment into LTS11210.  This will allow for assessment of the efficacy improvement if it is 
related to the different original treatments. Note that X-ray data will be collected for patients from 
EFC11072 Part B Cohort 2 and Cohort 1 selected dose arms only.  
2.3.3 Pharmacokinetics and immunogenicity population 
The PK population will consist of all patients in the safety population with at least one post-dose 
non-missing plasma concentration value. The ADA population will consist of all patients in the 
safety population with at least one post-dose, evaluable ADA sample. Patients will be analyzed 
according to the treatment actually received. 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Only patients enrolled and treated in LTS11210 will be summarized on demographic and baseline 
characteristic data.  
Continuous data will be summarized using number of available data, mean, SD, median, 
minimum, and maximum. Categorical and ordinal data will be summarized using number and 
percentage of patients. 
Parameters described in Section 2.1.1 will be summarized based on the safety population using 
descriptive statistics.  
Medical and surgical history will be summarized on the safety population by system organ class 
(SOC) and preferred term (PT) sorted by internationally agreed order of SOC and by the 
decreasing frequency of PT within SOC. 
No specific description of the safety/efficacy parameters will be provided at baseline. If relevant, 
the baseline values will be described along with each safety/efficacy analysis. 
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2.4.2 Prior or concomitant medications  
Prior medications are those the patients used prior to first IMP intake in LTS11210. The data 
before enrollment were collected and reported in the previous studies. However the data from 
enrollment up to the time of first IMP intake will be reported in LTS11210 database.  
Prior and concomitant medications in LTS11210 will be presented based on the enrolled 
population.  
Medications will be summarized by treatment received 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 times for the same 
medication. In addition, the summaries for concomitant DMARDs (MTX, non-MTX DMARDs), 
folic acid, NSAIDs, corticosteroids, and lipid modifying agents will also be provided. 
The tables for 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 (respectively therapeutic categories), alphabetical order will be used. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be presented on the safety population. In 
addition, the extent of IMP exposure will also be assessed and summarized by actual treatment 
received (150 mg qw, 200 mg q2w, 150 mg q2w) in LTS11210. 
Dose reduction 
Per study design, patients can reduce dose due to safety consideration. These patients who were 
switched to a lower dose regimen (ie. 150 mg q2w) due to safety consideration, not administration 
errors, will be listed and/or summarized separately. There are 3 type cases of dose reduction: 
initial 150 mg qw reduced to 150 mg q2w, initial 200 mg q2w reduced to 150 mg q2w, initial 
150 mg qw switched to 200 mg q2w (per Protocol Amendment 3) then reduced to 150 mg q2w. 
The reasons for dose reduction are collected and the summary will be provided accordingly. In 
addition, time to first dose reduction will be analyzed using Kaplan-Meier method for each type of 
dose reduction by previous treatment prior to enrollment into LTS11210. The maximal grade of 
neutropenia and maximal grade of ALT elevation after dose reduction will be summarized for 
each type of dose reduction by dose reduction reason. Treatment discontinuation after dose 
reduction, such as discontinuation reason and time from dose reduction date to treatment 
discontinuation date, will also be analyzed by summary and Kaplan-Meier plot. Detailed analyses 
will be performed in the integrated summary of safety (ISS) and the final CSR. 
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2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure and actual dose 
information. 
Extend of IMP exposure 
Due to a global switch to the pivotal dose or a dose reduction to a lower pivotal dose if it applies, 
each patient may receive multiple doses. Hence the duration of IMP exposure will be calculated 
under ‘sarilumab’ treatment regardless what doses the patient received during LTS11210.   
For patients receiving weekly injections at the time of last injection, duration of IMP exposure is 
defined as:  [Date of last injection of the study medication in LTS11210] – [Date of first injection 
of the study medication in LTS11210] + 7 day, regardless of unplanned intermittent 
discontinuations (see Section 2.5.3 for calculation in case of missing or incomplete data).  
For patients receiving biweekly injections at the time of last injection, duration of IMP exposure is 
defined as:  [Date of last injection of the study medication in LTS11210] – [Date of first injection 
of the study medication in LTS11210] + 14 day, regardless of unplanned intermittent 
discontinuations (see Section 2.5.3 for calculation in case of missing or incomplete data).  
Duration of each dose 
Period for each treatment dose received is calculated as the days from the starting (injection) date 
of that dose regimen to one day before the starting date of the following dose regimen or to the 
end (injection) date of the same dose + 14 days (7 days for patients receiving weekly injections 
only) if that is the last dose regimen in the study. Duration of IMP exposure will be summarized 
descriptively as a quantitative variable (number, Mean, SD, Median, Minimum, and Maximum). 
In addition, duration of treatment exposure will also be summarized categorically by counts and 
percentages for each of the following categories and cumulatively according to these categories: 
≤4 weeks, >4 and ≤12 weeks, >12 and ≤24 weeks, > 24 and ≤48 weeks, > 48 and ≤72 weeks, 
>72 and ≤96 weeks, and at 24-week intervals through the end of the study. 
 Additionally, the cumulative duration of treatment exposure, defined as the sum of patients’ 
duration of treatment exposure and expressed in patient years, will be provided. 
2.4.3.2 Compliance 
A given administration will be considered as 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. 
Percentage of compliance for a patient will be defined as the number of administrations 
(injections) the patient was compliant divided by the total number of administrations (injections) 
the patient was planned to take during the treatment epoch (ie, from the 1st to the last 
administration). 
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Treatment compliance percentages will be summarized descriptively as quantitative variables 
(Number, Mean, SD, Median, Min, and Max). The percentage of patients whose compliance is 
<80% will be summarized. In addition, patients with the wrong dose or an overdose will be 
summarized. 
Cases of overdose (administering 2 or more sarilumab doses in less than 11 calendar days) will be 
listed as such.  More generally, dosing irregularities are listed in Section 2.2.1. 
2.4.4 Analyses of safety data 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
The baseline value for safety parameters is the original baseline from the previous studies. 
• 
The value at Week 0 is the last non˜ missing measurement in data collected at scheduled 
visits: visit1, visit2 and/or visit1/2 in LTS11210 or EOT visit of previous studies prior to 
first IMP in LTS11210 study design. 
• 
The Potentially Clinically Significant Abnormality (PCSA) values are defined as abnormal 
values considered medically important by the sponsor according to predefined 
criteria/thresholds based on literature review and defined by the sponsor for clinical 
laboratory tests, vital signs and ECG (PCSA version in BTD-009536 version 3, see 
Appendix A). 
• 
PCSA criteria will determine which patients had at least one PCSA during the TEAE 
period, taking into account all evaluations performed during the TEAE period, including 
non-scheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.   
• 
The treatment emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the TEAE period by 
treatment received on the safety population. 
• 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment received.  Summaries will include the endpoint value. The endpoint 
value is commonly defined as the value collected at the same day/time of the last dose of 
investigational product. If this value is missing, this endpoint value will be the closest one 
prior to the last dose intake. 
• 
The analysis of the safety variables will be essentially descriptive and no systematic testing 
is planned.  
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2.4.4.1 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on TEAEs. Pre-treatment and post-study AEs 
will be described separately. 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, or TEAE. The algorithm for 
imputing date/time of onset will be conservative and will classify an AE as a treatment emergent 
unless there is definitive information to determine it is pre-treatment. Details on classification of 
AEs with missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will present by system-organ-class (SOC), High level group term 
(HLGT), High level term (HLT) and preferred term (PT) sorted in alphabetical order by treatment 
received and overall, the number (n) and percentage (%) of patients experiencing an AE.  Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
dose group.  Overall counts will also be provided, counting each patient once and also counting 
the total number of events.  The denominator for computation of percentages is the safety 
population within the treatment group. 
The incidence and number of events per 100 patient-years (number of events adjusted for the total 
duration of exposure) will be provided for all the TEAE summaries.  In addition, the number of 
patients with event(s) per 100 patient-years (number of patients adjusted for the exposure up to the 
first event or up to the end of the duration of exposure for patients with no event) will also be 
provided for serious TEAEs and for each type of adverse event of special interest (AESI).  
Sorting within tables should ensure same presentation.  For that purpose, the table of all TEAEs 
presented by SOC and PT sorted by internationally agreed order of SOC and decreasing frequency 
of PT within SOC will define the presentation order for all other tables unless otherwise specified.  
Sorting will be based on results for overall sarilumab group. 
Listings will be provided for all pre-treatment AEs, all TEAEs, all SAEs, all CV events undergone 
adjudication, and TEAEs leading to treatment discontinuation with flags indicating on-treatment 
status 
Analysis of all TEAE(s) 
The following TEAE summaries will be generated for the safety population. 
• 
Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE 
- 
Serious TEAE  
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
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• 
All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least one TEAE sorted by SOC internationally agreed order. The other level (HLGT, 
HLT, and PT) will be presented in an alphabetic order. 
• 
All TEAEs by primary SOC and PT, showing number (%) of patients with at least one 
TEAE, sorted by SOC internationally agreed order and decreasing incidence of PTs within 
SOC.  
• 
All TEAEs by relationship, presented by primary SOC, HLGT, HLT and PT, showing 
number (%) of patients with at least one TEAE, sorted by SOC internationally agreed 
order. The other level (HLGT, HLT, PT) will be presented in an alphabetic order. 
• 
All TEAEs by maximal severity, presented by primary SOC and PT, showing number (%) 
of patients with at least one TEAE by severity (i.e., mild, moderate, or severe), sorted by 
sorting order defined above.  
Analysis of all treatment emergent SAE(s) 
• 
All treatment emergent SAEs by primary SOC, HLGT, HLT and PT, showing number (%) 
of patients with at least one serious TEAE, sorted by SOC internationally agreed order. 
The other level (HLGT, HLT, PT) will be presented in an alphabetic order. 
• 
All treatment emergent SAEs by primary SOC and PT, showing number (%) of patients 
with at least one TEAE, sorted by SOC internationally agreed order and decreasing 
incidence of PTs within SOC 
• 
A separate listing of non-treatment emergent SAEs occurred in previous studies which are 
ongoing from the previous studies into LTS11210 study will be provided.  
Analysis of all TEAE(s) leading to treatment discontinuation 
• 
All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT and PT, 
showing number (%) of patients sorted by SOC internationally agreed order. The other 
level (HLGT, HLT, PT) will be presented in an alphabetic order. The table summary will 
be presented only if the number of patients concerned is greater than 3. 
• 
All TEAEs leading to treatment discontinuation, by primary SOC and PT, showing number 
(%) of patients with at least one TEAE, sorted by SOC internationally agreed order and 
decreasing incidence of PTs within SOC 
• 
A separate listing of AEs (occurred in previous studies) leading to treatment 
discontinuation in LTS11210, which are ongoing from the previous studies into LTS11210 
study, will be provided.  
Analysis of adverse events of special interest (AESI) 
Summaries of AESI defined by the search criteria: 
• 
All treatment emergent AESIs, by AESI category and PT, showing number (%) of patients, 
sorted by decreasing incidence of PT within each AESI category. 
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• 
Within each treatment emergent AESI category, at a minimum the data display will 
include: 
- 
Overview summary 
- 
Treatment duration summary 
- 
Incidence by patient and by event 
- 
Serious TEAEs  
- 
TEAEs leading to treatment discontinuation 
- 
TEAEs leading to death 
- 
Possibly related TEAEs 
The number at risk and the number with events will be provided by visit and treatment group 
Analysis of adjudicated CV events  
The following CV event summaries will be generated for the safety population: 
• 
MACE (primary) and MACE (narrow), showing number (%) of patients with at least one 
adjudicated treatment-emergent CV event and number of such events per 100 patient-years 
(number of events adjusted for the total duration of exposure). 
• 
All adjudicated treatment-emergent CV events by CV events categories, showing number 
(%) of patients with at least one adjudicated treatment-emergent CV event and number of 
events per 100 patient-years, sorted by alphabetical order.  
• 
All events undergone adjudication, all events adjudicated as non-CV event, and all events 
that are not evaluable, showing number (%) of events (patients). 
Summary describing the investigator-reported treatment-emergent SAE and the associated CAC 
adjudication classification will be provided. 
2.4.4.2 Deaths 
The incidence of death and number of death per 100 patient-years (number of death adjusted for 
the total duration of exposure) will be generated on the safety population. The following deaths 
summaries will be generated on the safety population. 
• 
Number (%) of patients who died by study period (on-treatment, during follow-up or 
post-study) 
• 
TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT.  
Listings will be provided for all deaths with flags indicating on-treatment, during follow-up or 
post-study status. 
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2.4.4.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each visit or study assessment (baseline, each post baseline time point, and 
endpoint) by treatment received.  This section will be organized by biological function as specified 
in Section 2.1.3.3. 
The incidence of PCSAs (list provided in Appendix C) at any time during the TEAE period will 
be summarized by biological function and treatment received whatever the baseline level and/or 
according to the following original baseline status categories:  
• 
Normal/Missing 
• 
Abnormal according to PCSA criterion or criteria 
The incidence of abnormal laboratory values at any time during the TEAE period will be 
summarized in shift tables by biological function and treatment group whatever the baseline level 
and/or according to the following original baseline status categories:  
• 
Normal/Missing 
• 
Abnormal high according to the normal range 
• 
Abnormal low according to the normal range 
In addition, for all laboratory parameters, the mean change from baseline at each scheduled visit 
during the double-blind treatment period will be plotted by treatment groups.  
Time to onset of the first G3 or G4 neutropenia (absolute neutrophil count <1.0 Giga/L) in 
LTS11210, and time to onset of the first platelet count <100 Giga/L in LTS11210 will be analyzed 
using Kaplan-Meier estimates, using the midpoint of the time interval between the first assessment 
showing the elevation and the previous assessment, presented by previous treatment prior to 
enrollment into LTS11210. Further analyses will be in the report of integrated summary of safety.  
Listings will be provided with flags indicating the out-of-range values as well as the PCSA values. 
Neutrophils 
The incidence of neutropenia by maximal grade (lowest neutrophils value reported) during the 
TEAE period will be summarized. The 4 grades are defined as below: 
• 
Grade 1: ≥1.5 Giga/L-LLN 
• 
Grade 2: ≥1.0 Giga/L-1.5 Giga/L 
• 
Grade 3: ≥0.5 Giga/L-1.0 Giga/L 
• 
Grade 4: <0.5 Giga/L 
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For patients with Grade 3 or 4 neutropenia, a listing with the individual neutropenia counts, WBC, 
platelet counts, lymphocytes and hemoglobin at each visit (including unscheduled visits for 
re-test) will be provided. In addition, the neutropenia counts at each scheduled visit during the 
study will be plotted by previous treatment prior to enrollment into LTS11210. In addition, 
summaries will include the following data:  discontinuation, restart dosing, dosing delay, number 
of episodes, and normalization (to >LLN or return to baseline if baseline is <LLN). The labs 
measured during the post-study period will be considered in the analysis of normalization. 
Summaries of neutropenia by maximal grade at dose regimens (150 mg qw, 150 mg q2w, 200 mg 
q2w) may be provided. 
Liver function tests 
The liver function tests, namely AST, ALT, alkaline phosphatase and total bilirubin are used to 
assess possible drug induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by treatment group for each parameter. The 
proportion of patients with PCSA values at any post baseline visit may be displayed by duration of 
exposure for each treatment group.  
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and Total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3xULN for ALT and a 
horizontal line corresponding to 2xULN for total bilirubin. 
The normalization (to <1 ULN) or return to baseline (in case of baseline is >ULN) of elevated 
liver function tests will be summarized by categories of elevation (>3 ULN, >5 ULN, >10 ULN, 
>20 ULN for ALT and AST; >1.5 ULN for ALP; and >1.5 ULN and >2 ULN for total bilirubin), 
with following categories of normalization: 1) normalized on-treatment; 2) normalized after last 
dose; 3) last value not normal. The laboratory values measured during the post-study period will 
be considered in the analysis of normalization. Note that a patient will be counted only under the 
maximum elevation category. 
2.4.4.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables (vital signs values and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each post baseline time point, and 
endpoint) by treatment group.  
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group whatever the baseline level and/or according to the following baseline status categories:  
• 
Normal/Missing 
• 
Abnormal according to PCSA criterion or criteria 
Listings will be provided with flags indicating the PCSA values. 
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2.4.4.5 Analyses of ECG variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all ECG variables (ECG values and changes from baseline) will be calculated for 
each visit or study assessment (baseline, each post baseline time point, and endpoint) by treatment 
group.   
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
received whatever the baseline level and/or according to the following baseline status categories:  
• 
Normal/Missing 
• 
Abnormal according to PCSA criterion or criteria 
Listings will be provided with flags indicating the PCSA values. 
2.4.5 Analyses of efficacy endpoints 
There will be no confirmatory analysis for the efficacy variables. All analysis will be done 
descriptively on the safety population by visit in observed case, as appropriate.  In addition to the 
by-visit analysis, efficacy assessments summarized on a yearly basis will be provided. 
The baseline value for efficacy parameters is the original baseline from the previous studies. The 
value at Week 0 is the last non˜mi ssing measurement in data collected at scheduled visits: visit1, 
visit2, and/or visit1/2 in LTS11210 or EOT visit of previous studies prior to first IMP in 
LTS11210 study. 
For categorical variables, for example, percentage of patients who have maintained/reached 
ACR20 overtime, the number and percentage will be provided from all patients who have data 
available at that time point, and the 95% confidence intervals (CI) will be calculated if 
appropriate. 
For continuous variables, descriptive statistics such as the mean, standard deviation, median, 
minimum and maximum will be provided.  In addition, 95% confidence interval of the mean will 
be presented.  This applies to the original values and change (or percent change) from baseline.   
The 2-year (EFC11072 52 weeks + LTS11210 48 weeks) X-ray data  from Campaign 1 will be 
described using the van der Heijde modified total Sharp score for the subset of patients who 
previously completed study EFC11072, Part B when the 2-year X-ray data are available for all 
these patients. The modified total Sharp score and the change from baseline in the modified total 
sharp score will be described using mean, standard deviation, median, minimum and maximum, 
along with 95% confidence intervals. There is no formal treatment comparison and no alpha 
adjustment will be made (further analyses will be in the report of integrated summary of efficacy). 
In addition, the incidence of radiographic progression will be summarized using descriptive 
statistics. 
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The above analyses will also be performed for X-ray data from Campaign 2 and Campaign 3 
respectively once X-ray data are available. 
2.4.5.1 Multiplicity issues 
Not applicable.  
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
The baseline value for PK and PD variables is the original baseline from the previous studies. The 
value at Week 0 is the last non˜mi ssing measurement in data collected at scheduled visits: visit1, 
visit2, and/or visit1/2 in LTS11210 or EOT visit of previous studies prior to first IMP in 
LTS11210 study design. 
No PK values at baseline and Week 0 for patients with placebo treatment in EFC10832 and 
patients with active control (Tocilizumab) treatment in SFY13370. No ADA sample values at 
baseline and Week 0 for patients with active control (Tocilizumab) treatment in SFY13370. 
Pharmacokinetic variables 
All the PK analyses will be performed using the PK population. 
Serum samples will be analyzed for functional SAR153191 concentrations using validated 
enzyme-linked immunosorbent assay (ELISA) methods with a targeted lower limit of quantitation 
(LLQ) of 0.294 mg/L (REGN88-AV-07026-SA-01V1) or 0.3125 mg/L 
(REGN88-AV-13131-VA-01V1).  Serum concentrations of functional sarilumab will be 
summarized using arithmetic and geometric means, standard deviation (SD), standard error of the 
mean (SEM), coefficient of variation (CV%), minimum, median and maximum by actual dose and 
visit.  Concentrations below LLOQ were replaced by LLOQ/2.  
After the completion of EFC11072 (Mobility) Part B study, the Sponsor made the decision to 
discontinue measurement of bound sarilumab concentration from ongoing studies globally. Serum 
concentrations of bound sarilumab (serum sarilumab-sIL-6Rα complex) will not be summarized in 
this study. 
Pharmacodynamics variables 
Serum concentrations of IL-6 will be summarized using descriptive statistics (including number, 
arithmetic and geometric means, standard deviation, standard error of the mean (SEM), coefficient 
of variation (CV%), minimum, median and maximum) by actual dose received at each visit. 
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2.4.7 Analyses of quality of life/health economics variables 
The summary statistics will be provided for the 8 dimensions of SF-36 and the 2 summary 
measures of physical and mental health (raw value and change from baseline) at each visit or study 
assessment (baseline, endpoint) by treatment group.  Summary statistics will also be produced for 
WPAI questionnaires, FACIT-Fatigue, WPS-RA and the sleep questionnaire scales. 
2.4.8 Analysis of immunogenicity variables 
The baseline value for ADA is the original baseline from the previous studies. The value at 
Week 0 is the last non˜missing  measurement in data collected at scheduled visits: visit1, visit2, 
or visit1/2 in LTS11210 or EOT visit of previous studies prior to first IMP in LTS11210 study 
design. 
ADA population will consist of all patients in the safety population with at least one post-dose 
evaluable ADA sample (positive, negative) in LTS11210.  Patients will be analyzed according to 
the treatment actually received in LTS11210. 
Definitions  
ADA positive patient is defined as patient with at least 1 treatment-emergent or treatment-boosted 
ADA positive sample during the TEAE period, where: 
• 
Treatment-emergent ADA positive patient is defined as a patient with non-positive assay 
(meaning negative or missing) response at baseline but with a positive assay response 
during the TEAE period. 
• 
Treatment-boosted ADA positive patient is defined as a patient with a positive ADA assay 
response at baseline and with at least a 4-fold increase in titer during the TEAE period. 
ADA negative patient is defined as patient without a treatment-emergent or treatment-boosted 
ADA positive sample during the TEAE period.  
ADA prevalence and titer 
The following summary will be provided based on ADA population: 
• 
Number (%) of patients with an ADA positive sample at baseline 
- 
Number (%) of neutralizing antibody 
- 
Number (%) of non-neutralizing antibody 
- 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) 
of the titer for the baseline ADA positive patients 
• 
Number (%) of patients with an ADA negative sample at baseline 
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ADA incidence and titer 
The following summary will be provided based on ADA population during TEAE period: 
• 
Number (%) of ADA-negative patients 
• 
Number (%) of ADA-positive patients 
- 
Number (%) of patients with neutralizing antibody 
- 
Number (%) of patients with non-neutralizing antibody 
• 
Number (%) of treatment-emergent ADA-positive patients. 
- 
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) 
of the peak post-baseline titer for treatment-emergent ADA-positive patients 
- 
Number (%) of patients with neutralizing antibody 
- 
Number (%) of patients with non-neutralizing antibody 
• 
Number (%) of treatment-boosted ADA positive patients.  
- 
Number (%) of patients with neutralizing antibody 
- 
Number (%) of patients with non-neutralizing antibody   
A plot of the log titers over time will be provided by treatment group. At each time point, a box 
plot representing the titer range, Q1, median (Q2), Q3 (excluding outliers) and outliers of the 
positive ADA samples will be provided. The number of ADA positive samples, the number of 
total subjects evaluable for immunogenicity and the proportion of ADA positive subjects at that 
time point will be also be provided along with the box plot.    
ADA and clinical safety 
The safety assessment will focus on the following events: 
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
• 
Injection-site reactions (HLT: Injection site reactions) 
• 
TEAEs leading to permanent treatment discontinuations 
Number (%) of patients with these events will be summarized by ADA patient classifications 
(positive or negative) and  previous treatment prior to enrollment into LTS11210 . The 
relationship between the timing and the titer of the positive ADA and events will also be explored 
as necessary.  
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ADA and clinical efficacy 
The following efficacy endpoints will be analyzed by ADA patient classifications (positive or 
negative; persistent, non-persistent; neutralizing, non-neutralizing):   
• 
ACR20/50 response by visit 
• 
Number (%) of patients with lack of efficacy or loss of efficacy  
- 
Lack of efficacy is defined as permanent treatment discontinuation due to lack of 
efficacy. 
- 
Loss of efficacy is defined as permanent treatment discontinuation due to lack of 
efficacy after achieving an ACR50 or EULAR Good response (at least one visit). 
ADA and PK 
By visit descriptive summary of serum concentration of sarilumab will be provided by ADA 
patient classifications (positive or negative) for each actual sarilumab dose (150 mg qw, 150 mg 
q2w, or 200 mg q2w). 
Scatter plot of serum concentration versus visit will also be provided by ADA classifications 
(positive or negative) and each actual sarilumab dose (150 mg qw, 150 mg q2w, or 200 mg q2w). 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computations of parameters. 
Demographic formulas 
Age is calculated as follows: 
Age = (informed consent date – birth date)/365.25 
BMI is calculated as follows: 
BMI = Weight in kg/(height2 in meters) 
Renal function formulas 
Creatinine clearance (CLcr) value will be derived using the equation of Cockroft and Gault: 
CLcr (ml/min) = (140 - age) * weight (kg) * (1 - 0.15*sex (0-M, 1-F)) /(0.814*creatinine (µmol/l)) 
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CLcr will be calculated using weight assessed at the same visit that creatinine was assessed and 
age at the lab sampling date. Age is calculated as follows: 
Age = (laboratory sampling date – birth date)/365.25 
Number of TEAE per 100 patient years 
The number of TEAE per 100 patient years is defined as the total number of TEAEs divided by 
the total exposure (expressed under the unit of 100 patient years) of the corresponding treatment 
group. Specifically, it is calculated as follows for each treatment group: 
Number of TEAE/100 patient years = (Total number of TEAEs) / total treatment duration (Unit: 
100 patient years) 
The total treatment duration is defined as [(end of TEAE period) – (date of first IMP) + 1], where 
the end of TEAE period is defined as minimum [(the last IMP + 60 days), (last contact date), 
(death date)], where the last contact date is defined as maximum [last complete AE start date, last 
visit date, last subject vital status date]. 
The number of PCSA per 100 patient years for the laboratory values, vital signs and ECGs will be 
defined similarly.  
Number of patients with special event per 100 patient-years 
The number of patients with at least one specific event per 100 patient-years will be calculated as 
the number of patients having a specific event in question divided by the total person-year among 
patients at risk of an initial occurrence of the specific event in question. In particular, it is 
computed as follows: 
∑
×
it
n
100
 
Where n is the number of patients with the specific events; ti is patient exposure time in 
person-year unit. For each of the specific events of interest, the exposure time for patients who 
have experienced the specific events will be defined as the time to first specific event in question, 
whereas the exposure time for those who have not had this specific event will be total duration of 
exposure as defined above. Please note, the time to first PCSA will be calculated using the 
midpoint of the time interval between the first assessment showing the PCSA and the previous 
assessment. 
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2.5.2 Data handling conventions for efficacy variables 
The missing data handling rules are summarized in a table in Appendix C. 
ACR20/ACR50/ACR70 
In the primary method of missing data handling, the data collected after treatment discontinuation 
will be set to missing. No imputation of missing post-baseline values will be performed. 
Responder status will be determined if possible. With these rules patients will automatically 
become non-responders for all time points beyond the time point they discontinue study treatment. 
Patients with insufficient data (ie, TJC, SJC, and at least 3 of the remaining 5 ACR components) 
at baseline and a time point will be non-responders in ACR20/ACR50/ACR70 at that time point. 
ACR components - TJC/SJC 
When calculating the TJC and SJC, with individual missing joint scores (the ‘”replaced or fused” 
joints are not taken into consideration for the swelling or tenderness) imputed as the mean of the 
scored joints, the TJC/SJC after imputation are as follows: 
TJC/SJC = sum (scored tender/swollen joints)*(number of joints in the full joint set / number of 
scored tender/swollen joints) 
The number of joints in the full joint set is defined as (68 – number of replaced or fused joints) for 
tenderness; (66 – number of replaced of fused joints) for swollenness; and the scored joints refer 
to those with an answer (0 – no pain, 1- pain). 
ACR components - HAQ-DI 
The highest score for any component question in a category determines the category score. If the 
patient is using assistance for any of these activities, scoring may be adjusted. The total score is 
the sum of all category scores divided by the number of answered categories. At least 6 categories 
should be answered in order to have a total score. 
DAS28-CRP 
When calculating DAS28-CRP, the following rules will be applied in order: 
• 
When calculating the 28TJC and 28SJC, with individual missing joint scores (the 
“replaced or fused” joints are not taken into consideration for the swelling or tenderness) 
imputed as the mean of the scored joints, the tender/swollen joint counts after imputation 
are as follows: 
28TJC/28SJC = sum (scored tender/swollen joints)*(number of joints in the full joint 
set / number of scored tender/swollen joints) 
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The number of joints in the full joint set is defined as (28 – number of replaced or fused joints) 
and the scored joints refer to those with an answer (0 – no pain, 1- pain). 
• 
No imputation will be performed. 
• 
If any of the 4 variables: 28TJC, 28SJC, GH (patient global), CRP is missing, then 
DAS28-CRP will be set to missing. 
SF-36 
The score of each of the 36 items is collected on the CRF.  Appendix I provides the SAS code to 
calculate the 8 scales, the 2 summary measure scores and standardized summary scores. 
The PCS and MCS summary measure scores will be computed if at least 50% of the component 
scales are available.  The scale scores will be computed if at least 50% of the items are available 
and valid within the corresponding scale.  The missing items will be imputed by the mean of 
available items. 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data is 
presented. 
Handling of computation of treatment duration if investigational drug end of treatment date is 
missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the dosing CRF page. If this date is missing, the exposure duration 
should be kept as missing.  
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing, so it cannot be determined whether it was taken prior or 
concomitantly, it will be considered as a prior and concomitant medication. 
Handling of AEs with missing or partial date/time of onset 
Missing or partial missing AE onset dates and times will be imputed so that if the partial AE onset 
date/time information does not indicate that the AE started prior to treatment or after the TEAE 
period, the AE will be classified as treatment-emergent. No imputation of AE end dates/times will 
be performed.  These data imputations are for categorization purpose only and will not be used in 
listings. No imputation is planned for date/time of AE resolution. 
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Handling of AE when date and time of first investigational drug date is missing 
When the date and time of the first investigational drug is missing all adverse events that occurred 
after or on the day of enrolled should be considered as treatment-emergent adverse events. The 
exposure duration should be kept as missing. 
Handling of missing relationship to investigational product of AEs 
If the assessment of the relationship to investigational product is missing, then the relationship to 
investigational product has to be assumed and the AE considered as such in the frequency tables 
of possibly related AEs, but no imputation should be done at the data level. 
Handling of missing severity of AEs 
If the severity is missing for one of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences a “missing” category will be added in summary table. 
Handling of PCSA  
If a patient has a missing baseline, that patient will be grouped in the category  “normal /missing at 
baseline”. 
For PCSA with two conditions, one based on a change from baseline value or a normal range and 
the other one on a threshold value, the first condition being missing, the PCSA will be based only 
on the second condition. 
For PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range are missing; e.g., for eosinophils the PCSA is > 0.5 Giga/L or >ULN 
if ULN ≥ 0.5 Giga/L. When ULN is missing the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized nor be taken into 
account in the computation of PCSA values. 
2.5.4 Windows for time points 
For efficacy parameters (except X-ray), a discontinuation visit (EOT, Visit 49) will be mapped to 
the scheduled visit for the analyses. If a discontinuation visit happens at a regular visit, then the 
visit number will be reassigned as the regular visit number where an assessment is planned. If a 
discontinuation visit happens between 2 regular visits, then the visit number will be reassigned to 
the next visit number where an assessment is planned. For example, if a discontinuation visit 
happens between Visits 9 and 10, then the visit number will be reassigned as 10. Similarly, the 
EOT visit (Visit 49) for patients who complete the study with 260-week treatment duration per 
Protocol Amendment 8, will be mapped to the Visit 28. 
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For X-ray data, the linear extrapolation method for the modified total Sharp score, the erosion 
score, and the joint space narrowing score will use true date to extrapolate missing values at 
Weeks 48, 96, 144, and 192 with no visit remapping. 
All efficacy analyses will be performed by the nominal visit number and no visit window will be 
defined. 
For safety assessments, the reference date for the derivation of relative days of events or findings 
will be the date of first drug intake as documented in the study drug administration page of the 
eCRF.  Selected safety variables will be summarized using the visit window defined in Table 6 for 
the by-visit descriptive analysis. Note that only the laboratory measurements performed at the 
central laboratory will be used for the by-visit descriptive analysis. All available values obtained 
between two visits including unscheduled measurements will be assigned to the appropriate visit 
window.  The following rule will be applied when mapping the measurements to the visit: 
1. When a patient has more than one measurement on the same laboratory parameter (or vital 
sign or ECG) on the same date, then the one with the later/largest sample ID will be used. 
2. For the same laboratory parameter (vital sign or ECG), if a patient has more than one 
measurement at different dates within the same visit window, the scheduled measurement 
that is closest to the target date will be used. If there is no scheduled measurement within 
the visit window, the unscheduled measurement that is closest to the target date will be 
used.  
3. When a patient has more than one measurement on the same laboratory parameter with the 
same distance from the target date, select the one with the latest date. 
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Table 6 - Study window (in days) for safety variables in LTS11210 
Week (Visit) 
Tar
get 
day 
Blood 
hematolo
gy 
Blood 
liver 
function 
Blood 
chemistrya 
/Urinalysis 
Vital signs 
ECGs 
PK/ADA/
Serum 
IL-6b 
sample 
ANA/Anti
-ds-DNA/
Rheumat
oid 
factorc 
Baselined (-1) 
 
  
 
 
 
 
 
0e (1,2 or 1/2) 
1 
 
 
 
 
 
 
2 (3) 
15 
2-21  
 
 
 
 
 
4 (4) 
29 
22-35 
 
2-42 
 
2-56 
 
6 (5) 
43 
36-49 
 
 
 
 
 
8 (6) 
57 
50-63 
2-70 
43-70 
 
 
 
10 (6.1) 
71 
64-77 
 
 
 
 
 
12 (7) 
85 
78-126  
71-126 
71-126 
 
57-126 
 
24 (8) 
169 
127-210 
127-210 
127-210 
 
127-210 
 
36 (9) 
253 
211-294  
211-294  
211-294  
 
211-294  
 
48 (10) 
337 
295-378 
295-378 
295-378 
2-504 
295-378 
2-504 
60 (11) 
421 
379-462 
379-462 
379-462 
 
379-462 
 
72 (12) 
505 
463-546 
463-546 
463-546 
 
463-546 
 
84 (13) 
589 
547-630 
547-630 
547-630 
 
547-630 
 
96 (14) 
673 
631-756 
631-756 
631-756 
505-840 
631-756 
505-840 
120 (16) 
841 
757-924 
757-924 
757-924 
 
757-924 
 
144 (18) 
1009 
925-1092 
925-1092 
925-1092 
841-1176 
925-1092 
841-1176 
168 (20) 
1177 
1093-1260 
1093-1260 
1093-1260 
 
1093-1260 
 
192 (22) 
1345 
1261-1428 
1261-1428 
1261-1428 
1177-1512 
1261-1428 
1177-1512 
216 (24) 
1513 
1429-1596 
1429-1596 
1429-1596 
 
1429-1596 
 
240 (26) 
1681 
1597-1764 
1597-1764 
1597-1764 
1513-1764 
1597-1764 
1513-1764 
264 (28) 
1849 
1765-1932 
1765-1932 
1765-1932 
≥1765 
1765-1932 
1765-1932 
288 (30) 
2017 
1933-2100 
1933-2100 
1933-2100 
 
1933-2100 
1933-2184 
312 (32) 
2185 
2101-2268 
2101-2268 
2101-2268 
 
2101-2268 
 
336 (34) 
2353 
2269-2436 
2269-2436 
2269-2436 
 
2269-2436 
2185-2520 
360 (36) 
2521 
2437-2604 
2437-2604 
2437-2604 
 
2437-2604 
 
384 (38) 
2689 
2605-2772 
2605-2772 
2605-2772 
 
2605-2772 
2521-2856 
408 (40) 
2857 
2773-2940 
2773-2940 
2773-2940 
 
2773-2940 
 
432 (42) 
3025 
2941-3108 
2941-3108 
2941-3108 
 
2941-3108 
2857-3192 
456 (44) 
3193 
3109-3276 
3109-3276 
3109-3276 
 
3109-3276 
 
480 (46) 
3361 
3277-3444 
3277-3444 
3277-3444 
 
3277-3444 
3193-3486 
504 (48) 
3529 
3445-3570 
3445-3570 
3445-3570 
 
3445-3570 
 
516 (49) 
3613 
≥3571 
≥3571 
≥3571 
 
≥3571 
≥3487 
a Lipids profile (metabolism) was also performed at Weeks 4 and 8 (Week 4: 2-42 days, Week 8: 43-70 days) 
b Serum IL-6 sample is collected at Weeks 0, 4, 12, 24, 36, and 48 only; ADA at Week 12 (2-126 days) due to no ADA at Week 4.  
c Anti-ds-DNA only if ANA titer is >1:160; Rheumatoid factor only at Week 0, 48, 96, 144, 192, 240, and 264 (or EOT). 
d Baseline from previous studies 
e The value at Week 0 is defined as the last non-missing value in the measurements collected at Visits 1, 2 and/or 1/2,  and/or EOT 
visit in previous studies. 
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For PK, ADA and Vital signs, the follow-up (ie, 6-week post-treatment) measurement will be 
defined based on the sample collected at the follow-up Visit 50. 
2.5.5 Unscheduled visits 
In any efficacy analyses or summaries, unscheduled visit measurements of CRP will be included 
for computation of the baseline, but not other visits. 
Laboratory, vital sign and ECG data from scheduled and unscheduled visits will be used in PCSA 
analysis no matter if the data are from the central laboratory or local laboratories.  For the by-visit 
summary on the laboratory parameters, only the measurements performed at the central laboratory 
will be used.  
Unscheduled visit measurements of vital signs and ECG will be included in the by-visit 
summaries using the visit window defined in Section 2.5.4. 
2.5.6 Pooling of centers for statistical analyses 
Countries are pooled by region: Western countries, South American and Rest of the world. These 
lists may be updated as the study is ongoing. Countries may be added and non-active countries 
will be removed. Countries will not be switched from region to region. 
• 
Region 1 (Western countries): Austria , Australia , Belgium , Canada , Czech Republic,   
Finland, Germany, Greece, Hungary, Italy, Israel, The Netherlands, New Zealand , 
Norway, Portugal, Spain, Sweden, United Kingdom, USA 
• 
Region 2 (South American): Argentina , Brazil, Chile, Colombia, Ecuador, Guatemala, 
Mexico, Peru 
• 
Region 3 (Rest of the world): Belarus , China, Egypt, Estonia, India , Lithuania, Malaysia , 
Philippines , Poland, Romania, Russia, South Africa, South Korea, Ukraine, Taiwan, 
Thailand, Turkey 
2.5.7 Statistical technical issues 
None. 
 
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3 
INTERIM ANALYSIS 
This is an open-label study. Interim reports may be prepared for regulatory submissions or other 
purposes. However, no alpha adjustment is needed for the final CSR. 
Interim reports for BLA submissions (FDA, EU MAA, etc) 
In general, the analyses for these reports will be performed in the overall sarilumab group, and not 
according to previous treatment prior to enrollment into LTS11210 due to ongoing imbalanced 
enrollment from previous studies, different previous treatment duration and rescue sarilumab in 
EFC11072, except the disposition tables and some special safety analyses such as neutropenia.  
Only selected efficacy and safety analyses will be determined and performed for the interim 
reports. PK and ADA analyses will be performed on certain cut-off data in each interim report 
since not all time points are reached by patients or by study design.  The analysis of patient 
reported outcomes may not be performed. However, the full analyses described in this SAP will be 
performed in the final CSR. 
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4 
DATABASE LOCK 
At the time of the initial sarilumab marketing authorization application for the treatment of RA, an 
interim database (soft) lock will be performed. Additional database snapshots may be performed 
prior to subsequent marketing authorization applications in major markets, eg. the EU. The final 
database lock is planned to occur 4 weeks after last patient last visit. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS Version 9.2 or higher. 
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6 
REFERENCES 
1. 
Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: A 
User’s Manual. Boston, MA: The Health Institute, 1994. 
 
 
 
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7 
LIST OF APPENDICES 
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria  
Appendix B: 
Summary of statistical analyses 
Appendix C: 
Summary of missing data imputation rules for efficacy variables 
Appendix D: 
X-Ray missing data imputation process 
Appendix E: 
SF-36 V2 Scoring 
Appendix F: 
FACIT-Fatigue scoring guidelines (Version 4) 
Appendix G: 
WPAI scoring 
Appendix H: 
WPS-RA Questionnaire 
Appendix I: 
SAS code for SF-36 scoring 
Appendix J: 
Classification of events reviewed by the CV adjudication committee 
Appendix K: 
Analysis Plan of the PFS-S Study 
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Appendix A 
Potentially clinically significant abnormalities (PCSA) criteria  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From QSD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– 
Version 3 –21-MAY-2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Additional analysis*: 
>1 – 1.5 ULN 
>1.5 – 3 ULN 
>3 - 5 ULN 
>5 – 8 ULN 
> 8 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Additional analysis*: 
>1 – 1.5 ULN 
>1.5 – 3 ULN 
>3 - 5 ULN 
>5 – 8 ULN 
> 8 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative  
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From QSD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– 
Version 3 –21-MAY-2014) 
Parameter 
PCSA 
Comments 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
 
Additional analysis*: 
>1.5 ULN 
>2 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
PCSA to be retrieved manually 
Unconjugated bilirubin 
Additional analysis*: 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, whatever 
the interval between measurement. 
CPK** 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Creatinine 
≥150 µmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on the 
Cokcroft-Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on dosing 
and labeling 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From QSD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– 
Version 3 –21-MAY-2014) 
Parameter 
PCSA 
Comments 
eGFR** (mL/min/1.73m2) 
(Estimate of GFR based 
on an MDRD equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on dosing 
and labeling 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 µmol/L 
<120 µmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
≥6.2 mmol/L* 
Threshold for therapeutic intervention. 
LDL 
≥4.1 mmol/L* 
≥4.9 mmol/L 
 
Triglycerides 
≥4.6 mmol/L 
≥5.6 mmol/L* 
Threshold for therapeutic intervention. 
Lipasemia** 
≥3 ULN 
 
Amylasemia** 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
(electronic 
 
 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From QSD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– 
Version 3 –21-MAY-2014) 
Parameter 
PCSA 
Comments 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
<0.5 Giga/L* 
≥0.5 Giga/L - LLN* 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
<1.0 Giga/L* 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th 
Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with 
that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
< 50 Giga/L* 
≥ 50 - 100 Giga/L* 
≥700 Giga/L 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
(electronic 
 
 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From QSD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– 
Version 3 –21-MAY-2014) 
Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
(electronic 
 
 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From QSD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– 
Version 3 –21-MAY-2014) 
Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A 
(2012), and Cardiac Safety Research 
Consortium White Paper on PR and QRS 
(Nada et al. Am Heart J. 2013; 165(4) : 
489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
>450 ms 
>480 ms 
>500 ms 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and ∆QTc>60 ms are the 2 PCSA 
categories to be identified in individual 
subjects/patients listings. 
 
(electronic 
 
 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From QSD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– 
Version 3 –21-MAY-2014) 
Parameter 
PCSA 
Comments 
*: Project specific request 
**: Not applicable for sarilumab project. 
 
 
(electronic 
 
 
 
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Appendix B 
 Summary of statistical analyses 
 
 
Analysis 
 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Population 
Primary Analysis 
Method 
Analysis 
Analysis 
Analyses 
Efficacy 
 
 
 
 
 
 
ACR20, ACR50, ACR70 
Safety 
Response rate at all visits 
Descriptive statistics 
No 
No 
No 
DAS28-CRP 
Safety 
Change from baseline at all visits 
Descriptive statistics 
No 
No 
No 
DAS28 remission 
Safety 
Remission rate at all visits 
Descriptive statistics 
No 
No 
No 
EULAR response 
Safety 
Response rate at all visits 
Descriptive statistics 
No 
No 
No 
Each of the seven individual 
ACR components 
Safety 
Change from baseline at all visits 
Descriptive statistics 
No 
No 
No 
Van der Heijde modified 
total Sharp score (for 
patients from EFC11072 
Part B) 
Safety 
Change from baseline at all visits 
Descriptive statistics 
No 
No 
No 
Incidence of radiographic 
progression (for patients 
from EFC11072 Part B) 
Safety 
Rate of radiographic progression at all 
visits 
Descriptive statistics 
No 
No 
No 
HAQ-DI 
Safety 
Change from baseline at all visits 
Descriptive statistics 
No 
No 
No 
Safety  
 
 
 
 
 
 
Adverse Events 
Safety 
Follow safety guidelines 
Descriptive statistics 
Exposure adjusted 
No 
No 
Lab, vital signs, ECGs 
Safety 
Follow safety guidelines 
Descriptive statistics 
No 
No 
No 
 
  
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Appendix C 
 Summary of missing data imputation rules for efficacy variables  
 
Endpoints 
Approach 
Missing data imputation rules 
ACR20, ACR50, 
ACR70 
Primary 
Missing tender/swollen joints: When calculating the TJC and SJC, with individual missing joint scores (the ‘replaced or fused’ joints are not taken into 
consideration for the swelling or tenderness) imputed as the mean of the scored joints, the TJC/SJC after imputation are as follows: 
TJC/SJC = sum (scored tender/swollen joints)*(number of joints in the full joint set / number of scored tender/swollen joints) 
The number of joints in the full joint set is defined as (68 – number of replaced or fused joints) for tenderness; (66 – number of replaced of fused joints) 
for swollenness; and the scored joints refer to those with an answer (0 – no pain, 1- pain). 
Missing questions/categories for HAQ-DI: The highest score for any component question in a category determines the category score. If the 
patient is using assistance for any of these activities, scoring may be adjusted. The total score is the sum of all categories’ scores divided by the 
number of answered categories. At least six categories should be answered in order to have a total score. 
Missing items within a measurement:   No imputation of missing post-baseline values will be performed. Responder status will be determined if 
possible.  
Visit level: 
 
Patients who discontinue treatment due to lack of efficacy will be considered as non-responders for all time points beyond the time they 
discontinue.  
 
Patients with insufficient data (ie, TJC, SJC, and at least three of the remaining five ACR components) at baseline and a time point will 
be considered as non-responders at that time point. 
HAQ-DI 
Primary 
Missing questions/categories for HAQ-DI: The highest score for any component question in a category determines the category score. If the 
patient is using assistance for any of these activities, scoring may be adjusted. The total score is the sum of all categories’ scores divided by the 
number of answered categories. At least six categories should be answered in order to have a total score. 
Visit level: No imputation will be performed. 
(electronic 
 
 
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Endpoints 
Approach 
Missing data imputation rules 
Seven individual 
ACR components 
Primary 
Missing tender/swollen joints: When calculating the TJC and SJC, with individual missing joint scores (the ‘replaced or fused’ joints are not taken into 
consideration for the swelling or tenderness) imputed as the mean of the scored joints, the TJC/SJC after imputation are as follows: 
TJC/SJC = sum (scored tender/swollen joints)*(number of joints in the full joint set / number of scored tender/swollen joints) 
The number of joints in the full joint set is defined as (68 – number of replaced or fused joints for tenderness); (66 – number of replaced of fused 
joints) for swollenness; and the scored joints refer to those with an answer (0 – no pain, 1- pain). 
Missing questions/categories for HAQ-DI: The highest score for any component question in a category determines the category score. If the 
patient is using assistance for any of these activities, scoring may be adjusted. The total score is the sum of all categories’ scores divided by the 
number of answered categories. At least six categories should be answered in order to have a total score. 
Visit level: No imputation of missing post-baseline values will be performed.  
Modified total sharp 
score, erosion, joint 
space narrowing 
Primary 
Missing joint scores within a segment: Same approach as described in Appendix D. 
Visit level:  The linear extrapolation method will be used to impute missing the modified total Sharp score, erosion score, or joint space narrowing 
score at Weeks 48, 96, 144 and 192. 
Radiographic 
progression of 
modified total sharp 
score, erosion, joint 
space narrowing 
Primary 
Missing joint scores within a segment: Same approach as described in Appendix D. 
Visit level:  The linear extrapolation method will be used to impute missing modified total Sharp score, erosion score, or joint space narrowing 
score at Weeks 48, 96, 144 and 192. 
 
The event of missing a change from baseline in the modified total Sharp score at a time pint will be considered as progression. 
 
The event of missing a change from baseline in the erosion score at a time pint will be considered as progression. 
 
The event of missing a change from baseline in the joint space narrowing score at a time pint will be considered as progression. 
DAS28-CRP 
Primary 
Missing tender/swollen joints: When calculating the 28TJC and 28SJC, with individual missing joint scores (the ‘replaced or fused’ joints are not taken 
into consideration for the swelling or tenderness) imputed as the mean of the scored joints, the tender/swollen joint counts after imputation are as 
follows: 
28TJC/28SJC = sum (scored tender/swollen joints)*(number of joints in the full joint set / number of scored tender/swollen joints) 
The number of joints in the full joint set is defined as (28 – number of replaced or fused joints) and the scored joints refer to those with an answer (0 – no 
pain, 1- pain).   
Missing items within a measurement:. No imputation will be performed.  
Visit level:  
• 
Patients with any of the four terms missing (28TJC, 28SJC, GH and CRP) will have a missing DAS28-CRP  score at that time point. 
DAS28 remission 
Primary 
DAS28  remission will be defined using the DAS28 –CRP scores as described above.  
EULAR response 
Primary 
EULAR response will be defined using the DAS28-CRP scores as described above.  
(electronic 
 
 
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Endpoints 
Approach 
Missing data imputation rules 
SF-36 components 
and domains, 
FACIT-Fatigue, 
Sleep VAS 
Primary 
 No imputation will be performed. 
WPS-RA , Four 
WPAI scores 
Primary 
 No imputation will be performed. 
 
 
(electronic 
 
 
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Appendix D 
  X-Ray missing data imputation process 
Details of the radiographic score derivation process conducted by BioClinica, Inc. are described in 
the supplementary document entitled “X-Ray Score Derivations Process for Determination of 
Adjudication in Rheumatoid Arthritis Clinical Trials”. 
Handling of missing joint data 
The handling of missing joint data and the logistics for being able to calculate mTSS change score 
are given below and outlined in the attached document: 
• 
The first step is to determine the adequacy of the joints in each segment. In case of missing 
or inadequate (eg. confirmed surgery, technical reasons) scores for a joint at one particular 
time point, it will first be determined whether these missing joint scores qualify for 
imputation. On a per joint basis, eligibility for imputation depends on the number of 
missing or inadequate joints in a segment in relation to the number of adequate joints in 
that segment. If the number of adequate joints is below the adequacy threshold, imputation 
of change scores will not be done (see below). 
Table 7 - Adequacy threshold for the 8 segments 
Measure 
Segment 
Number of Joints n (L + R) 
Minimum number of joints 
scored 
Erosion 
PIP 
8 
5 
 
MCP 
12 
7 
 
Wrist Images 
12 
7 
 
Foot Images 
12 
7 
Joint Space Narrowing 
PIP 
8 
5 
 
MCP 
10 
6 
 
Wrist Images 
12 
7 
 
Foot Images 
12 
7 
PIP: proximal interphalangeal, MCP: metatarsophalangeal. 
If, for example, 4 joints of the PIP segment (erosion) are missing or inadequate and 4 joints are 
adequate, that segment will be set to missing for that time point, implying that this segment cannot 
be imputed. 
Change from baseline (change score) will be calculated for each joint, in each of the 8 segments, 
at each time point. For adequate segments with individual missing joint scores (missing due to 
definite surgery/joint replacement or radiographically inadequate), the mean change from baseline 
for the adequately scored joints within the corresponding segment (ie., left and right sides 
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together) will be calculated, and that mean change score will be used to impute the missing change 
score for the joints with missing joint score. 
• 
The next step in the algorithm is to determine the adequacy of the time points per reader 
per patient. 
- 
Baseline time point: All 8 segments must be adequate at the baseline time point for the 
baseline time point to be considered adequate. 
- 
Follow-up time point: At least 5 segments must be adequate at a following-up time 
point for the time point to be considered adequate. Note that these 5 adequate segments 
can be composed of only hand segments if the foot segment is inadequate. 
For adequate follow-up time points that have less than 4 inadequate segments, the missing joint 
change score within inadequate segment will be calculated by using the mean of the total mean 
change from baseline of adequate segments to impute the change score of every joint with a 
missing value within the inadequate segments. 
• 
The third step is to determine the adequacy of the reads per patient. 
- 
If both readers consistently score X-rays of all time points as adequate or inadequate, 
then both reads are considered adequate.  
- 
If both readers score baseline as inadequate, then the patient will not proceed to 
adjudication even if a follow-up time point is scored by one reader as adequate and the 
other reader as inadequate. 
- 
If one reader scores a time point as inadequate while the second reader scores the same 
time point as adequate, then the reads are considered inadequate and the patient will 
proceed to adjudication (all time points). 
Adjudication 
A patient will be selected for adjudication based on the following criteria: 
• 
Technical adequacy: One reader scores inadequate segments within a time point while the 
second reader scores adequate segments within the same time point, then the patient will 
proceed to adjudication (all time points). 
• 
Total change score: The total change score for a time point is the sum of all individual 
joint change scores (erosion and JSN) from the 8 segments within the time point. If the 
difference between the two readers’ change scores is > ±10 at a follow-up time point, this 
patient will be adjudicated (all time points). 
At each time point, the mean (rounded to 1 decimal place) of the two primary readers’ total 
change score will be calculated, and that mean will be the total change score in mTSS for each 
corresponding time point. The mTSS will be back calculated as the total change score + baseline. 
In cases of adjudication, the following rules will be applied: 
(electronic 
 
 
 
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• 
In adjudication cases where the differences between the two primary readers’ change score 
is > ±10, the mean of the adjudicator and the primary reader with a closer total change 
score will be calculated, and that will be the total change score of the mTSS.  
• 
In adjudication cases of technical inadequacy in one primary reader, the mean of the other 
primary reader and the adjudicator will be calculated, and that will be the total change 
score of the mTSS.  
Handling of missing mTSS data:  
The imputation methods for missing radiographic data in randomized clinical trials in rheumatoid 
arthritis are compared in Huang et al.’s article “Missing radiographic data handling in randomized 
clinical trials in rheumatoid arthritis” as in the supplementary document which will appear in the 
Journal of Biopharmaceutical Statistics. 
(electronic 
 
 
 
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Appendix E 
  SF-36 V2 Scoring 
General Scoring information 
Items and scales are scored in 3 steps 
• 
Step 1. Item recoding, for then 10 items that require recoding 
• 
Step 2. Computing scale scores by summing across items in the same scale (raw scale 
scores) 
• 
Step 3. Transforming raw scale scores to a 0-100 scale (transformed scale) 
Item recoding 
• 
All 36 items should be checked for out-of-range values prior to assigning the final item 
value. All out-of-range values should be recoded as missing data. 
• 
The following tables show the recoding of response choice 
How to treat missing data 
A scale score is calculated if a respondent answered at least half of the items in a multi-item scale 
(or half plus one in the case of scales with an odd number of items). 
The recommended algorithm substitutes a person-specific estimate for any missing item when the 
respondent answered at least 50 percent of the items in a scale. A psychometrically sound estimate 
is the average score, across completed items in the same scale, for that respondent. For example, if 
a respondent leaves one item in the 5-item mental Health scale blank, substitute the respondent’s 
average score (across the 4 completed mental health items) for that one item. When estimating the 
respondent’s average score, use the respondent’s final item values. 
Computing raw scale scores 
After item recoding, including handling of missing data, a raw score is computed for each scale. 
This score is a simple algebraic sum of responses for all items in that scale. 
If the respondent answered at least 50%of the items in a multi-items scale, the score can be 
calculated. If the respondent did not answer at least 50% of the items, the score for that scale 
should be set to missing. 
Transformation of the scale scores 
The next step involves transforming each raw score to a 0 to 100 scale using the following 
formula: 
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Transformed scale = [(actual raw score – lowest possible raw score) / possible raw score range] x 
100 
This transformation converts the lowest and highest possible scores to zero and 100, respectively. 
Table 8 - SF-36 V2 raw scores of eight domains 
Scale 
Lowest and highest possible raw scores 
Possible raw score range 
Physical Functioning 
10,30 
20 
Role-Physical 
4,20 
16 
Bodily pain 
2,12 
10 
General health 
5,25 
20 
Vitality 
4,20 
16 
Social Functioning 
2,10 
8 
Role-Emotional 
3,15 
12 
Mental Health 
5,25 
20 
 
 
 
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Appendix F 
  FACIT-Fatigue scoring guidelines (Version 4) 
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Appendix G 
  WPAI scoring 
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Appendix H 
  WPS-RA Questionnaire 
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(electronic 
 
 
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Appendix I 
 SAS code for SF-36 scoring 
 
******************************************************************** 
*  PROGRAM: SF36 V2                                                * 
*  PURPOSE: SAS SCORING PROGRAM FOR THE SF-36 VERSION2             * 
*                                                                  * 
*******************************************************************; 
 
*****************************************************************; 
***               STEP 1: INPUT DATA                          ***; 
*****************************************************************; 
 
DATA SF36DATA; 
INFILE IN; 
INPUT ID $ 1-3 
      @ 5 (GH1 HT PF01-PF10 RP1-RP4 RE1-RE3 SF1 
      BP1-BP2 VT1 MH1 MH2 MH3 VT2 MH4 VT3 MH5 
      VT4 SF2 GH2 GH3 GH4 GH5) (1.); 
RUN; 
 
 
*****************************************************************; 
***               STEP 2: SF-36 SCALE CONSTRUCTION            ***; 
*****************************************************************; 
 
 
****************************************************************** 
*  USING THE SAS DATASET CREATED IN PART 1, CHANGE OUT-OF-RANGE 
*  VALUES TO MISSING FOR EACH ITEM.  RECODE AND RECALIBRATE ITEMS 
*  AS NEEDED.  AN 'R' PREFIX MEANS THE VARIABLE IS RECODED. 
*****************************************************************; 
 
DATA SF36SCAL; 
  SET SF36DATA; 
 
 
****************************************************************** 
*  THE SF-36 PHYSICAL FUNCTIONING INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM 
*  VALUE, THE BETTER THE PHYSICAL HEALTH. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE PHYSICAL FUNCTIONING. 
******************************************************************; 
 
ARRAY PFI(10) PF01-PF10; 
 
DO I = 1 TO 10; 
   IF PFI(I) < 1 OR PFI(I) > 3 THEN PFI(I) = .; 
END; 
 
PFNUM = N(OF PF01-PF10); 
PFMEAN = MEAN(OF PF01-PF10); 
 
DO I = 1 TO 10; 
  IF PFI(I)= . THEN PFI(I) = PFMEAN; 
END; 
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IF PFNUM GE 5 THEN RAWPF = SUM(OF PF01-PF10); 
PF = ((RAWPF - 10)/(30-10)) * 100; 
 
LABEL  PF = 'SF-36 PHYSICAL FUNCTIONING (0-100)' 
       RAWPF = 'RAW SF-36 PHYSICAL FUNCTIONING'; 
 
 
****************************************************************** 
*  THE SF-36 ROLE-PHYSICAL INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM VALUE, 
*  THE BETTER THE ROLE-PHYSICAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE ROLE-PHYSICAL. 
*****************************************************************; 
 
ARRAY RPA(4) RP1-RP4; 
 
DO I = 1 TO 4; 
   IF RPA(I) < 1 OR RPA(I) > 5 THEN RPA(I) = .; 
END; 
 
ROLPNUM = N(OF RP1-RP4); 
ROLPMEAN = MEAN(OF RP1-RP4); 
 
DO I = 1 TO 4; 
   IF RPA(I) = . THEN RPA(I) = ROLPMEAN; 
END; 
 
IF ROLPNUM GE 2 THEN RAWRP = SUM(OF RP1-RP4); 
RP = ((RAWRP - 4)/(20-4)) * 100; 
LABEL  RP = 'SF-36 ROLE-PHYSICAL (0-100)' 
       RAWRP = 'RAW SF-36 ROLE-PHYSICAL'; 
 
 
***************************************************************** 
*  THE SF-36 PAIN ITEMS. 
*  ITEM RECODING DEPENDS ON WHETHER BOTH PAIN1 AND PAIN2 
*  ARE ANSWERED OR WHETHER ONE OF THE ITEMS HAS MISSING DATA. 
*  AFTER RECODING, ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER 
*  THE SCORE, THE LESS PAIN (OR THE MORE FREEDOM FROM PAIN). 
* 
*   THIS SCALE IS POSITIVELY SCORED.  THE HIGHER THE 
*   SCORE THE LESS PAIN OR THE MORE FREEDOM FROM PAIN. 
*****************************************************************; 
 
IF BP1 < 1 OR BP1 > 6 THEN BP1 = .; 
IF BP2 < 1 OR BP2 > 5 THEN BP2 = .; 
 
*  RECODES IF NEITHER BP1 OR BP2 HAS A MISSING VALUE; 
 
IF BP1 NE . AND BP2 NE . THEN DO; 
 
   IF BP1 = 1 THEN RBP1 = 6; 
   IF BP1 = 2 THEN RBP1 = 5.4; 
   IF BP1 = 3 THEN RBP1 = 4.2; 
   IF BP1 = 4 THEN RBP1 = 3.1; 
   IF BP1 = 5 THEN RBP1 = 2.2; 
   IF BP1 = 6 THEN RBP1 = 1; 
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Property of the Sanofi Group - strictly confidential 
Page 90 
 
 
   IF BP2 = 1  AND BP1 = 1 THEN RBP2 = 6; 
   IF BP2 = 1  AND 2 LE BP1 LE 6 THEN RBP2 = 5; 
   IF BP2 = 2  AND 1 LE BP1 LE 6 THEN RBP2  = 4; 
   IF BP2 = 3  AND 1 LE BP1 LE 6 THEN RBP2  = 3; 
   IF BP2 = 4  AND 1 LE BP1 LE 6 THEN RBP2  = 2; 
   IF BP2 = 5  AND 1 LE BP1 LE 6 THEN RBP2  = 1; 
 
END; 
 
*  RECODES IF BP1 IS NOT MISSING AND BP2 IS MISSING; 
 
IF BP1 NE . AND BP2 = . THEN DO; 
   IF BP1 = 1 THEN RBP1 = 6; 
   IF BP1 = 2 THEN RBP1 = 5.4; 
   IF BP1 = 3 THEN RBP1 = 4.2; 
   IF BP1 = 4 THEN RBP1 = 3.1; 
   IF BP1 = 5 THEN RBP1 = 2.2; 
   IF BP1 = 6 THEN RBP1 = 1; 
   RBP2 = RBP1; 
 
END; 
 
*  RECODES IF BP1 IS MISSING AND BP2 IS NOT MISSING; 
 
IF BP1 = . AND BP2 NE . THEN DO; 
 
   IF BP2 = 1 THEN RBP2 = 6; 
   IF BP2 = 2 THEN RBP2 = 4.75; 
   IF BP2 = 3 THEN RBP2 = 3.5; 
   IF BP2 = 4 THEN RBP2 = 2.25; 
   IF BP2 = 5 THEN RBP2 = 1; 
   RBP1 = RBP2; 
 
END; 
 
BPNUM = N(BP1,BP2); 
 
IF BPNUM GE 1 THEN RAWBP = SUM(RBP1,RBP2); 
BP = ((RAWBP - 2)/(12-2)) * 100; 
 
LABEL  BP = 'SF-36 PAIN INDEX (0-100)' 
       RAWBP = 'RAW SF-36 PAIN INDEX'; 
 
 
****************************************************************** 
*  THE SF-36 GENERAL HEALTH PERCEPTIONS INDEX. 
*  REVERSE TWO ITEMS AND RECALIBRATE ONE ITEM.  AFTER RECODING 
*  AND RECALIBRATION, ALL ITEMS ARE POSITIVELY SCORED --  THE 
*  HIGHER THE SCORE, THE BETTER THE PERCEIVED GENERAL HEALTH. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE HEALTH PERCEPTIONS. 
*****************************************************************; 
 
ARRAY GHP(5) GH1-GH5; 
 
DO I= 1 TO 5; 
  IF GHP(I) < 1 OR GHP(I) > 5 THEN GHP(I) = .; 
END; 
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IF GH1 = 1 THEN RGH1 =   5; 
IF GH1 = 2 THEN RGH1 = 4.4; 
IF GH1 = 3 THEN RGH1 = 3.4; 
IF GH1 = 4 THEN RGH1 =   2; 
IF GH1 = 5 THEN RGH1 =   1; 
 
RGH3 = 6 - GH3; 
RGH5 = 6 - GH5; 
 
GHNUM = N(GH1,GH2,GH3,GH4,GH5); 
GHMEAN = MEAN(RGH1,GH2,RGH3,GH4,RGH5); 
 
ARRAY RGH(5) RGH1 GH2 RGH3 GH4 RGH5; 
 
DO I= 1 TO 5; 
  IF RGH(I) = . THEN RGH(I) = GHMEAN; 
END; 
 
IF GHNUM GE 3  THEN RAWGH = SUM(RGH1,GH2,RGH3,GH4,RGH5); 
GH = ((RAWGH - 5)/(25-5)) * 100; 
 
LABEL  GH = 'SF-36 GENERAL HEALTH PERCEPTIONS (0-100)' 
       RAWGH = 'RAW SF-36 GENERAL HEALTH PERCEPTIONS'; 
 
 
***************************************************************** 
*  THE SF-36 VITALITY ITEMS. 
*  REVERSE TWO ITEMS.  AFTER ITEM REVERSAL, ALL ITEMS ARE 
*  POSITIVELY SCORED -- THE HIGHER THE SCORE, THE LESS THE FATIGUE 
*  AND THE GREATER THE ENERGY. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE GREATER THE VITALITY. 
****************************************************************; 
 
ARRAY VI(4) VT1-VT4; 
 
DO I = 1 TO 4; 
  IF VI(I) < 1 OR VI(I) > 5 THEN VI(I) =.; 
END; 
 
RVT1 = 6-VT1; 
RVT2 = 6-VT2; 
 
VITNUM = N(VT1,VT2,VT3,VT4); 
VITMEAN = MEAN(RVT1,RVT2,VT3,VT4); 
 
ARRAY RVI(4) RVT1 RVT2 VT3 VT4; 
 
DO I = 1 TO 4; 
  IF RVI(I) = . THEN RVI(I) = VITMEAN; 
END; 
 
IF VITNUM GE 2 THEN RAWVT= SUM(RVT1,RVT2,VT3,VT4); 
VT = ((RAWVT-4)/(20-4)) * 100; 
 
LABEL  VT = 'SF-36 VITALITY (0-100)' 
       RAWVT = 'RAW SF-36 VITALITY'; 
 
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Page 92 
 
 
**************************************************************** 
*  THE SF-36 SOCIAL FUNCTIONING INDEX. 
*  REVERSE ONE ITEM SO THAT BOTH ITEMS ARE POSITIVELY SCORED -- 
*  THE HIGHER THE SCORE, THE BETTER THE SOCIAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE SOCIAL FUNCTIONING. 
*****************************************************************; 
 
ARRAY SOC(2) SF1-SF2; 
 
DO I = 1 TO 2; 
   IF SOC(I) < 1 OR SOC(I) > 5 THEN SOC(I) = .; 
END; 
 
RSF1 = 6 - SF1; 
SFNUM = N(SF1,SF2); 
SFMEAN = MEAN(RSF1,SF2); 
 
ARRAY RSF(2) RSF1 SF2; 
 
DO I = 1 TO 2; 
  IF RSF(I) = . THEN RSF(I) = SFMEAN; 
END; 
 
IF SFNUM GE 1 THEN RAWSF = SUM(RSF1,SF2); 
SF = ((RAWSF - 2)/(10-2)) * 100; 
 
LABEL  SF = 'SF-36 SOCIAL FUNCTIONING (0-100)' 
       RAWSF = 'RAW SF-36 SOCIAL FUNCTIONING'; 
 
 
****************************************************************** 
*  THE SF-36 ROLE-EMOTIONAL INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM VALUE, 
*  THE BETTER THE ROLE-EMOTIONAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE, THE BETTER THE ROLE-EMOTIONAL. 
*****************************************************************; 
 
ARRAY RM(3) RE1-RE3; 
 
DO I = 1 TO 3; 
   IF RM(I) < 1 OR RM(I) > 5 THEN RM(I) = .; 
END; 
 
ROLMNUM = N(OF RE1-RE3); 
ROLMMEAN = MEAN(OF RE1-RE3); 
 
DO I = 1 TO 3; 
   IF RM(I) = . THEN RM(I) = ROLMMEAN; 
END; 
 
IF ROLMNUM GE 2 THEN RAWRE = SUM(OF RE1-RE3); 
RE = ((RAWRE - 3)/(15-3)) * 100; 
 
LABEL  RE = 'SF-36 ROLE-EMOTIONAL (0-100)' 
       RAWRE = 'RAW SF-36 ROLE-EMOTIONAL'; 
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***************************************************************** 
*  THE SF-36 MENTAL HEALTH INDEX. 
*  REVERSE TWO ITEMS.  AFTER ITEM REVERSAL, ALL ITEMS ARE 
*  POSITIVELY SCORED -- THE HIGHER THE SCORE, THE BETTER THE 
*  MENTAL HEALTH. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE MENTAL HEALTH. 
****************************************************************; 
 
ARRAY MHI(5) MH1-MH5; 
 
DO I = 1 TO 5; 
   IF MHI(I) < 1 OR MHI(I) > 5 THEN MHI(I)=.; 
END; 
 
RMH3 = 6-MH3; 
RMH5 = 6-MH5; 
 
MHNUM=N(MH1,MH2,MH3,MH4,MH5); 
MHMEAN=MEAN(MH1,MH2,RMH3,MH4,RMH5); 
 
ARRAY RMH(5) MH1 MH2 RMH3 MH4 RMH5; 
 
DO I = 1 TO 5; 
   IF RMH(I) = . THEN RMH(I) = MHMEAN; 
END; 
 
IF MHNUM GE 3 THEN RAWMH = SUM(MH1,MH2,RMH3,MH4,RMH5); 
MH = ((RAWMH-5)/(25-5)) * 100; 
 
LABEL  MH = 'SF-36 MENTAL HEALTH INDEX (0-100)' 
       RAWMH = 'RAW SF-36 MENTAL HEALTH INDEX'; 
 
 
***************************************************************** 
*  THE SF-36 HEALTH TRANSITION ITEM. 
*  THIS ITEM SHOULD BE ANALYZED AS CATEGORICAL DATA, 
*  PENDING FURTHER RESEARCH. 
****************************************************************; 
 
IF HT < 1 OR HT > 5 THEN HT = .; 
 
LABEL  HT='RAW SF-36 HEALTH TRANSITION ITEM'; 
RUN; 
 
 
*****************************************************************; 
***               STEP 3: SF-36 SCALE CONSTRUCTION            ***; 
*****************************************************************; 
 
 
 
DATA SF36INDX; 
  SET SF36SCAL; 
 
  
*******************************************************************; 
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*  purpose: create physical and mental health index scores 
*           standardized but not normalized 
*           and standard deviations calculated with vardef=wdf 
*******************************************************************; 
 
         
/********************************************************************/ 
/* NORM-BASED SCORING OF SF-36, STANDARD RECALL (4 WEEKS)           */ 
/* USING  WEIGHTED MEANS AND SD'S FROM 1998 GENERAL US POPULATION   */ 
/* FROM COMBINED SAMPLES                                            */ 
/********************************************************************/ 
 
********************************************************** 
**********************1998 US NORMS*********************** 
**********************************************************; 
 
*CREATING SF-36 STANDARDIZED SCORES (0-1 
00 Means/SD's from 1998 General Population)*; 
 
pf_z=(pf-83.29094)/23.75883; 
rp_z=(rp-82.50964)/25.52028; 
bp_z=(bp-71.32527)/23.66224; 
gh_z=(gh-70.84570)/20.97821; 
vt_z=(vt-58.31411)/20.01923; 
sf_z=(sf-84.30250)/22.91921; 
re_z=(re-87.39733)/21.43778; 
mh_z=(mh-74.98685)/17.75604; 
 
 
**************************************************************; 
*     COMPUTE SAMPLE RAW FACTOR SCORES                       *; 
*     Z SCORES ARE FROM ABOVE                                *; 
*     SCORING COEFFICIENTS ARE FROM U.S. GENERAL POPULATION  *; 
*     FACTOR ANALYTIC SAMPLE N=2393: HAVE ALL EIGHT SCALES   *; 
**********************************************************; 
 
praw=(pf_z * .42402)+(rp_z * .35119)+(bp_z * .31754)+(sf_z * -.00753)+ 
     (mh_z * -.22069)+(re_z * -.19206)+(vt_z * .02877)+(gh_z * .24954); 
 
mraw=(pf_z * -.22999)+(rp_z * -.12329)+(bp_z * -.09731)+(sf_z * .26876)+ 
     (mh_z * .48581)+(re_z * .43407)+(vt_z * .23534)+(gh_z * -.01571); 
 
 
*COMPUTE AGGREGATE STANDARDIZED SUMMARY SCORES*; 
 
PCS = (praw*10) + 50; 
MCS = (mraw*10) + 50; 
 
label PCS='STANDARDIZED PHYSICAL COMPONENT SCALE-00' 
      MCS='STANDARDIZED MENTAL COMPONENT SCALE-00'; 
 
 
run;  
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Appendix J 
 Classification of Events Reviewed by the Committee 
 
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Appendix K 
  Analysis Plan of the PFS-S Study 
This appendix is the statistical analysis plan for the PFS-S sub-study.   
Pre-filled syringe with safety system (PFS-S) 
Sarilumab has been delivered via prefilled syringes (PFS) in most of the Phase 3 studies.  
The pre-filled syringe with safety system (PFS-S) is a modified version of the prefilled syringe 
aimed at preventing needle stick injury by either the patient or by a caregiver (professional or 
non-professional) performing the administration. The “safety system” consists of a sharps injury 
prevention feature, which can be described as a sheath that automatically covers the needle once 
the injection is completed and thus prevents needle stick injury and re-use.  
Compared to PFS, PFS-S also includes: 
• 
a rigid needle shield that encloses the soft rubber needle shield covering the needle  
• 
a finger flange with an ergonomic design and a large piston rod 
The following figures show the unused and used PFS-S. At the end of the injection when the 
plunger rod has been pushed into the syringe as far as it will go, the needle safety shield is 
activated which can be seen as the syringe is pulled away from the skin. 
 
Unused syringe 
Used syringe with activated needle safety shield 
 
 
 
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Study design 
This is a Phase 3, multicenter, worldwide, non-randomized, open-label, 1-arm, 12-week sub-study 
of the LTS11210/SARIL-RA-EXTEND study. The sub-study will only be performed in limited 
sites in selected countries.  
Patients at participating sites who have been enrolled in the main study (LTS11210) for at least 24 
weeks and are willing to participate in the sub-study will be enrolled in the sub-study. The entry 
into the sub-study (V101) will be at any scheduled visit in the main study from Visit 8 (Week 24) 
or after. Sarilumab 150 mg q2w PFS-S or sarilumab 200 mg q2w PFS-S will be used in the 
sub-study to replace the sarilumab 150 mg q2w PFS or 200 mg q2w PFS used in the main study. 
At the entry into the sub-study (V101), the patients/persons performing injections will be trained 
how to use the PFS-S, and the sub-study injection diary will be dispensed to replace the patient 
diary of the main study. All the procedures described in the sub-study are additional to the main 
study activities, unless specified to replace procedures in the main study. 
The patient/person performing each sub-study injection will respond to 3 questions related to 
PFS-S use on the injection diary after each PFS-S injection. A “no” response to any of these 3 
questions will be defined as a product technical complaint (PTC). For any PTC, the Investigator 
will complete a PTC form and will send this PTC form together with the PFS-S that triggered this 
PTC back to the Sponsor according to a predefined process. The patients should be instructed to 
keep any PFS-S associated with a PTC separately from other PFS-S, so it can be identified when 
returned to site at the end of sub-study. The sponsor will validate or invalidate the occurrence of a 
product technical failure (PTF), which is defined as a PTC that has a validated technical cause. 
For patients receiving sarilumab 200 mg q2w PFS-S the dose can be reduced to 150 mg q2w 
PFS-S at any time during the sub-study duration if the defined criteria specified in the main 
protocol for dose reduction are fulfilled.  
When the patients have completed the 12 weeks of the sub-study they will return to the clinic to 
complete Visit 102 (V102) in addition to the scheduled main study visit on that day. They will 
switch back to the main study and continue sarilumab treatment through PFS.  
If the patient chooses to end the participation in the sub-study during the sub-study duration but to 
continue in the main study with IMP administration via PFS, the V102 should still be completed 
and the patient should switch back to take IMP administration through PFS on and after V102 per 
the patient’s IMP administration schedule. 
If a patient discontinues Investigational Medicinal Product (IMP) permanently in LTS11210 
during the sub-study, he/she should complete all procedures planned for V102 in the sub-study as 
well as the end of treatment (EOT) and post treatment follow-up visits in the main study (see 
flowchart in main study). 
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Study objective 
Primary 
To assess the usability of the sarilumab pre-filled syringe with safety system (PFS-S) when 
administered to patients with active Rheumatoid Arthritis (RA) 
Secondary 
To document the safety of sarilumab 200 mg q2w PFS-S and sarilumab 150 mg q2w PFS-S. 
 
Determination of sample size 
The sample size of this sub-study is based on empirical consideration. No formal sample size 
calculation is performed but an estimate of 120 patients included in this sub-study with up to 
6 injections per patient will provide approximately 680 injections to evaluate PTF during the 
12 weeks of the study assuming 5% drop-out rate.  
Study plan 
 
 
 
 
 
 
 
 
 
All assessments planned to be performed at the scheduled main study visit that coincides with the 
sub-study visit, are described in the main study flow charts. Below flowchart specifies only:  
• 
those actions that are additional to the scheduled main study visit in LTS11210 
• 
those actions that replace an action in the scheduled main study visit in LTS11210 (for 
example, study drug dispensing  of the PFS-S IMP format, instead of the main study IMP 
in PFS) 
Entry 
into 
sub-stud
y 
Treatment Period (12 weeks)
D85
D
1 
Sarilumab PFS-S
 Either 150 mg or 200 mg  q2w 
Coinciding with 
any scheduled 
visit in the main 
study from Visit 8 
(Week 24) 
onwards 
End of 
sub-stud
Coinciding with 
scheduled visit in 
the main study
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Sub-study assessments  
VISIT 
V101 
V102  
DAY 
Week 
D1  
Wk0 
D85 (+/- 3 days) 
Wk12 
Eligibility 
X 
 
Written Informed Consent 
X 
 
IVRS call to start / end sub-study 
participation 
X 
X 
Training on use of the PFS-S 
X 
 
Dispense PFS-Sa 
X 
 
Dispense sub-study injection 
diaryb 
X 
 
Collect / review sub-study injection 
diaryb 
 
X 
PTC reporting 
 
X 
AE related to a PTC reportingc 
 
X 
Serum Sarilumab (PK)d 
X 
X 
ADAd 
X 
X 
a PFS-S dispensing will replace the scheduled IMP dispensing at the main study visit 
b Sub-Study Injection Diary dispensing and review will replace the dispensing and review of the main study Patient Diary in the scheduled main 
study visits 
c Refer to Section 10.4.1 in Protocol Amendment 9 for instruction of reporting AE related to PTC 
d If the sub-study visit coincides with a PK and ADA sampling  time point in the main study, no additional samples are required for the 
sub-study.  
 
Each patient will participate in the sub-study for a period of 12 weeks from the first sub-study visit 
(V101) to the final sub-study visit (V102). At the time of V101, eligible patients will start 
receiving sarilumab 200 mg q2w PFS-S or sarilumab 150 mg q2w PFS-S, if they reduced the dose 
in the main study per protocol, for 12 weeks as replacement of original sarilumab PFS in the main 
study in addition to background disease modifying anti-rheumatic drugs (DMARDs) therapy, if 
any. There is no post-treatment follow-up specific to the PFS-S sub-study, as all patients except 
patients who discontinue IMP permanently in LTS11210 during the sub-study will switch back to 
the main study at V102. For patients who discontinues IMP permanently in LTS11210 during the 
sub-study, they should complete all procedures planned for V102 in the sub-study as well as the 
end of treatment (EOT) and post treatment follow-up visits in the main study The last 
on-treatment sub-study visit for patients who complete the sub-study will occur at Day 85 (Visit 
102). The sub-study will be considered completed when the last sub-study patient has completed 
V102. 
Statistical analysis procedures and method 
The phrase ‘treatment group’ used throughout this appendix refers to the following device/dose 
groups (PFS-S sarilumab 200 mg q2w, PFS-S sarilumab 150 mg q2w, PFS-S sarilumab 200 mg 
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q2w to 150 mg q2w ).  The baseline value is defined as the original baseline in initial/previous 
studies before LTS11210, as in the main study. 
 
Disposition of patients 
Below describes patient disposition for both patient study status and the patient analysis 
populations for the sub-study only, unless otherwise specified. 
• 
All screened patients are defined as those patients who signed the informed consent for the 
sub-study. 
• 
All enrolled patients are defined as all patients with signed informed consent who met the 
eligibility criteria to enter into the sub-study.   
• 
The Safety population consists of all enrolled patients who received at least one dose of the 
IMP administered via PFS-S during this sub-study. 
• 
The PK population consists of all enrolled patients on stable dose of sarilumab (receiving 
the same dose of sarilumab without treatment interruption) at least 24 weeks prior to V101 
until V102 who receive at least 1 dose of the IMP and at least one non-missing serum 
concentration value during this sub-study. 
For patient study status, the total number of patients for each one of the following categories will 
be presented using a summary table: 
• 
All screened patients (informed consent signed) 
• 
Screen failure patients and reasons for screen failure (not eligible per eligible CRF page) 
• 
Non-enrolled but treated patients 
• 
Enrolled but not treated patients 
• 
Enrolled and treated patients 
• 
Patients who had stable dose at least 24 weeks prior V101 
• 
Patients who had dose reductions during the duration of the sub-study 
• 
Patients who discontinued the sub-study treatment by main reason for discontinuation 
¾ 
Patients who discontinued the sub-study treatment but continues in the main study 
¾ 
Patients who permanently discontinued the study treatment during participation in the 
sub-study  
• 
Status for  returning to the main study (Yes/No) 
For all categories of patients (except for the screened and non-enrolled categories), percentages 
will be calculated using the total of all enrolled patients as the denominator.  Reasons and time to 
treatment discontinuation will be supplied in tables giving numbers and percentages.   
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Demographics and baseline characteristics  
Demographics and baseline characteristics will be presented for the enrolled patients in this 
sub-study. 
Extent of investigational product exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by actual 
treatment received within the safety population. 
The duration of IMP exposure is defined as: last dose date – first dose date at D1 + 14 days 
(regardless of unplanned intermittent discontinuations).   
Treatment compliance to the IMP is defined as the actual number of doses received compared to 
the scheduled number of doses during the treatment period.  Treatment compliance during the 
treatment period in the sub-study will be summarized descriptively. 
Efficacy (Device) analysis 
Data will be described for the 12 weeks of this sub-study using the safety population. The efficacy 
analyses will be performed using descriptive statistics and presented by treatment group. 
 
Primary endpoint 
The primary endpoint is the number of validated PFS-S-associated PTFs.  
The injection diary will include specific questions about PTCs. The person performing each 
sub-study injection will record the answers to these questions in the diary each time he/she 
performs an injection with a PFS-S. 
The questions include: 
1. Were you able to remove the cap? 
• Yes 
• No 
 
  If no, please describe / explain:  
2. Was the needle safety system activated?  
• 
Yes 
• 
No 
                If no, please describe / explain:  
3. Did the safety system entirely cover the needle? 
• 
Yes 
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• 
No 
                 If no, please describe / explain:  
At Week 12 (Visit 102), the Investigator will review the diary, confirm with the patient whether 
there are any problems associated with the use of PFS-S and record the responses in the e-CRF.   
If the answer is “no” to any of the questions stated in the diary, the patients will be asked to 
provide further details of the complaint and a PTC form will be completed by the investigator. The 
PTC form and the PFS-S associated with PTC will be sent to the Sponsor following the 
pre-defined process. The sponsor will validate or invalidate the occurrence of a PTF. If the PTF is 
ruled out, the event is considered as a failed drug delivery (FDD) that is defined as patient’s 
failure to administer the full dose at a given attempt. 
In addition, another question will be asked in the diary to confirm whether the person who 
performed the injection was trained: 
4. Was the person who performed the injection the person who was trained by the site staff? 
• 
Yes 
• 
No 
Secondary endpoints 
• 
Number of  PTCs  
• 
Number and percentage of patients with PTFs 
• 
Number and percentage of patients with PTCs 
• 
Number and percentage of patients with FDDs 
Safety analysis  
Adverse events related to PTC per investigator’s judgment will be summarized by treatment group 
during the sub-study. If an adverse event reported during the sub-study is considered linked to a 
PTC by the investigator the potential link with the PTC should be specified in AE/SAE verbatim. 
If a laboratory or ECG abnormality or vital signs finding reported during the sub-study is 
considered clinically significant and linked to a PTC by the investigator an adverse event needs to 
be reported and the potential link with the PTC should be specified in AE/SAE verbatim.  
Injection site reaction adverse events will be summarized during the sub-study period (that is, 
those events with start date from the date of first dose of the sub-study to the date of last sub-study 
dose+14 days, but no later than one day before the date of next non-sub study dose). The specific 
summaries to be performed are described for the main study. 
Other adverse events, such as needle stick, skin irritation, etc, occurring during the sub-study 
period will be reviewed manually to evaluate if the events are related to the device. For the events 
related to the device but not PTC, a summary table will be provided or event description will be 
provided in details if only a few events reported. 
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Note:  The safety analyses for the sub-study will be limited to the AEs noted above.  Overall AEs, 
laboratory values, vital signs, and electrocardiograms (ECG) that occurs for patients participating 
in the sub-study will be described with the main LTS11210 study results.    
 PK analysis 
Serum concentrations of functional sarilumab will be summarized using standard descriptive 
statistics by visit.  
For PK parameters Ctrough, estimates and 90% CIs for the ratio of geometric means (Day 85 versus 
Day 1) will be provided using a linear fixed effects model on the log-transformed data. Serum 
trough concentrations of functional sarilumab will be evaluated in patients on stable dose of 
sarilumab at V101 (D1) before using the PFS-S. Patients are considered to be on stable dose of 
sarilumab at V101 (D1) if they receive the same dose of sarilumab without treatment interruption 
for at least 24 weeks in LTS11210 prior to V101. Patients changing dose during the 12 week 
sub-study will be excluded from the Ctrough analyses 
Interim analysis 
No interim analysis is planned for this sub-study. 
 
(electronic 
 
 
 
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LTS11210 16.1.9 Statistical Analysis Plan