Clinical trial NCT03600818
Conditions: Polymyalgia Rheumatica
Sponsor: Sanofi
Start date: 2018-10-09; Completion date: 2021-05-19
Enrollment: 118 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate the efficacy of KEVZARA (sarilumab) in participants with polymyalgia rheumatica (PMR) as assessed by the proportion of participants with sustained remission for sarilumab with a shorter corticosteroid (CS) tapering regimen as compared to placebo with a longer CS tapering regimen.

Secondary Objectives:

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

Detailed description:
Study duration per participant was approximative 62 weeks including up to a 4-week screening period, 52-week treatment period and 6-week follow-up period.

Arms: arm 1: Participants received sarilumab-matching placebo as subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone/prednisone-matching placebo tapering oral daily doses for 52 weeks. arm 2: Participants received sarilumab 200 milligrams (mg) as SC injection q2w up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 14 weeks and prednisone-matching placebo from Week 14 up to Week 52.
Interventions: intervention 1: Sarilumab SAR153191 (REGN88) intervention 2: Sarilumab-matching placebo intervention 3: Prednisone intervention 4: Prednisone-matching placebo intervention 5: Prednisone
Intervention descriptions: intervention 1: Pharmaceutical form:solution for injection Route of administration: subcutaneous intervention 2: Pharmaceutical form:solution for injection Route of administration: subcutaneous intervention 3: Pharmaceutical form:over-encapsulated tablets Route of administration: oral administration intervention 4: Pharmaceutical form:over-encapsulated tablets Route of administration: oral administration intervention 5: Pharmaceutical form:tablets Route of administration: oral administration

Protocol documents:
Prot_000.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
 
According to template: QSD-002579 VERSION N°16.0 (31-JUL-2017) 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL 02  
 
COMPOUND: Kevzara®/Sarilumab (SAR153191)  
 A randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of sarilumab in patients with polymyalgia rheumatica  
STUDY NUMBER: EFC15160 
 
Version Number: 
1  
EudraCT 
2017-002989-42 
IND Number(s) 
100632 
WHO universal trial number: 
Clinical trial.gov registration number: 
U1111-1201-0777 
NTC03600818 
Date: 
19-Apr-2021  
Total number of pages: 
138 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 02 
All 
Date: 19-Apr-2021, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01  
All 
Date: 19-Sep-2018, version 1 (electronic 1.0) 
Clinical Trial Protocol 
  
Date: 08-Feb-2018, version 1 (electronic 2.0) 
 
Amended protocol 02 (19 April 2021) 
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT  
The overall rationale for the changes implemented in the protocol amendment is the inability to 
recruit due to COVID-19 resulting in premature termination of enrollment.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover 
 
 
Section CLINICAL TRIAL SUMMARY-STUDY 
POPULATION- Total expected number of 
patients 
Clinical trial.gov registration number 
"NTC03600818" added 
 
Change in total expected number of 
patients 
 
 
 
 
As a result of the inability to recruit due 
to the COVID19 pandemic, the study 
was terminated prematurely resulting in 
a change in the total expected number 
of patients.  
Section CLINICAL TRIAL SUMMARY-
STATISTICAL CONSIDERATIONS-Sample 
size determination 
Change in statistical significance 
level from 0.01 to 0.05 and updated 
power 
Due to the change in total expected 
number of patients, the statistical 
significance level has been changed and 
power calculations revised. 
Section CLINICAL TRIAL SUMMARY-
STATISTICAL CONSIDERATIONS-Primary 
analysis 
Change significant level for analysis 
of primary efficacy endpoint from 
0.01 to 0.05 
Due to the change in total expected 
number of patients, the statistical 
significance level has been changed. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5 DISCUSSION OF STUDY 
DESIGN AND CHOICE OF CONTROL 
GROUPS 
Change in total expected number of 
patients  
As a result of the inability to recruit due 
to the COVID19 pandemic, the study 
was terminated prematurely resulting in 
a change in the total expected number 
of patients. 
Section 11.1 Determination of sample size 
Updated sample size and power 
calculations 
Revised power calculations associated 
with the change in total expected sample 
size from 280 to 118, and the change in 
statistical significance level from 0.01 to 
0.05. 
Section 11.4.2.1 Analysis of primary efficacy 
endpoint(s) 
Change significant level for analysis 
of primary efficacy endpoint from 
0.01 to 0.05  
Due to the change in total expected 
number of patients, the statistical 
significance level has been changed. 
Section 11.4.2.2 Analysis of secondary 
efficacy endpoints 
Revised 99% CI to 95% CI 
Associated with the change in significant 
level from 0.01 to 0.05. 
Section 11.4.2.3 Multiplicity considerations 
Change significant level for analysis 
of secondary efficacy endpoints 
 from 0.01 to 0.05 
Due to the change in total expected 
number of patients, the statistical 
significance level has been changed. 
Section 11.4.5 Analysis of patient reported 
outcomes 
Revised 99% CI to 95% CI 
Associated with the change in significant 
level from 0.01 to 0.05. 
Section 17 Appendices 
Addition of Appendix N: Protocol 
amendment history 
 
 
 
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: Sarilumab 
STUDY No.: EFC15160 
TITLE 
A randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of sarilumab in patients with polymyalgia 
rheumatica (PMR). 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
Phase 3 
STUDY OBJECTIVE(S) 
 
Primary objective: 
• 
To evaluate the efficacy of KEVZARA® (sarilumab) in 
patients with PMR as assessed by the proportion of 
subjects with sustained remission at Week 52 for 
sarilumab with a 14 weeks corticosteroid (CS) tapering 
regimen as compared to placebo with a 52 weeks CS 
tapering regimen. 
Secondary objective(s): 
• 
To demonstrate the efficacy of sarilumab (with 14-week 
taper of CS) compared to placebo (with 52-weeks taper of 
CS) in patients with PMR with regard to: 
- 
Clinical responses (such as components of sustained 
remission, disease remission rates, time to first 
disease flare) over time. 
- 
Cumulative corticosteroid (including prednisone) 
exposure. 
• 
To assess the safety (including immunogenicity) and 
tolerability of sarilumab in patients with PMR. 
• 
To measure sarilumab concentrations from serum of 
patients with PMR. 
• 
To assess the effect of sarilumab in reducing 
glucocorticoid toxicity as measured by the composite 
glucocorticoid toxicity index (GTI) questionnaire. 
Other objectives: 
• 
To assess the effect of sarilumab on physician assessment 
of disease activity as measured by a visual analogue scale 
(MD-VAS). 
• 
To assess the effect of sarilumab on a variety of PRO 
concepts, including fatigue (as measured by FACIT-fatigue 
scale), health status (as measured by EQ-5D-3L and 
SF-36v2), physical function (as measured by HAQ-DI), 
pain (as measured via HAQ-DI by a visual analogue scale 
[VAS]) and patient assessment of disease activity (as 
measured via HAQ-DI by a VAS). 
• 
To assess the impact of ESR/CRP levels on remission 
status. 
• 
To characterize the disease activity of PMR patients while 
on steroid taper or sarilumab treatment in a subset of 
patients using comprehensive approaches to evaluate 
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circulating immune cell types. 
• 
To characterize the disease activity of PMR patients while 
on steroid taper or sarilumab treatment by evaluating 
circulating proteins, genetics and gene expression in 
patients who consent for this optional part of the study.  
STUDY DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled 
52-week study with a 6-week post-treatment follow-up phase, 
evaluating the efficacy and safety of sarilumab in patients with PMR.  
There are 2 parallel treatment groups with sarilumab 200 mg or 
placebo plus protocol defined CS tapering regimens of varying 
durations (as described below). 
Patients with active PMR will be randomized to the following 2 arms 
in a ratio of 1:1. 
• 
Group 1: Sarilumab 200 mg once every 2 weeks (q2w) 
with a 14 week taper of CS. 
• 
Group 2: Sarilumab matching placebo q2w with a 52 week 
taper of CS. 
All patients will receive sarilumab 200 mg or placebo for 52 weeks. 
Upon randomization at baseline, patients will start the protocol 
defined taper of prednisone of either 14 weeks duration or 52 weeks 
duration. All patients will receive prednisone 15 mg/day during the 
initial 2 weeks of the taper. 
During the initial 12 weeks of prednisone taper, treatment for one 
flare before Week 12 is permitted if it can be successfully treated 
with a low dose (≤5 mg/day) prednisone add-on taper regimen 
(completed prior to Week 12) and provided that all other sustained 
remission parameters are met. 
For the management of predefined neutropenia, thrombocytopenia 
and alanine aminotransferase increases, study drug 
(sarilumab/matching placebo) must be temporarily withheld and a 
request to reduced dosage to sarilumab 150 mg q2w (for patients 
randomized to the 200 mg q2w arm only)/matching placebo may be 
made in a blinded manner through IRT system which will implement 
the request appropriately based upon the patient’s treatment 
assignment, based on investigator judgment. 
Patients, who experience a flare or persistent disease activity and 
cannot follow the per protocol CS taper during the 52-week 
treatment period or the permitted prednisone add-on treatment prior 
to Week 12, will continue in the study with a CS rescue regimen as 
determined by the Investigator (as long as it does not pose a safety 
risk or contraindication with concomitant sarilumab administration) 
while double-blind injections of sarilumab or matching placebo will 
continue for the full 52 week treatment period. 
All patients who prematurely and permanently discontinue study 
medication will be asked to return to the site for study assessments 
as per protocol until end of study evaluation. 
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STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
• 
Diagnosis of PMR according to the European League 
against Rheumatism/American College of Rheumatology 
(EULAR/ACR) classification criteria as follows (must 
satisfy all criteria): 
- 
Age ≥50 years at time of diagnosis. 
- 
Bilateral shoulder pain. 
- 
Elevated acute phase reactants CRP >10 mg/L 
and/or ESR >30 mm/hour. 
AND one of the following: 
- 
A score ≥4 at the time of diagnosis based on the 
following (without ultrasound): 
- Duration of morning stiffness >45 minutes: 2 points 
- Hip pain or limited range of motion: 1 point. 
- Seronegative for rheumatoid factor (RF) and 
anti-cyclic citrullinated peptide (anti-CCP): 2 points. 
- Absence of other joint involvement: 1 point. 
                   OR 
- 
A score ≥5 at the time of diagnosis based on the 
following (with ultrasound): 
- 
Duration of morning stiffness >45 minutes: 2 points. 
- 
Hip pain or limited range of motion: 1 point. 
- 
Seronegative for RF and anti-CCP: 2 points. 
- 
Absence of other joint involvement: 1 point. 
- 
At least one shoulder with subdeltoid bursitis and/or 
biceps tenosynovitis and/or glenohumeral synovitis 
(either Posterior or axillary) and at least one hip with 
synovitis and/or trochanteric bursitis: 1 point. 
(confirmed with ultrasound) 
- 
Both shoulders with subdeltoid bursitis, biceps 
tenosynovitis or glenohumeral synovitis: 1 point. 
(confirmed with ultrasound)   
• 
Patients must be on prednisone of at least 7.5 mg/day (or 
equivalent) and not exceeding 20 mg/day at screening and 
during the screening period. 
• 
Patient is willing and able to take prednisone of 15 mg/day 
at randomization. 
• 
Patients must have a history of being treated for at least 
8 weeks with prednisone (≥10 mg/day or equivalent). 
• 
Patient must have had at least one episode of unequivocal 
PMR flare while attempting to taper prednisone at a dose 
that is ≥7.5 mg/day (or equivalent) within the past 
12 Weeks prior to screening: 
- 
Unequivocal symptoms of PMR flare include shoulder 
and/or hip girdle pain associated with inflammatory 
stiffness. 
• 
Patients must have ESR ≥30 mm/hr and/or CRP ≥10 mg/L 
associated with PMR disease activity within 12 weeks prior 
to screening. 
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Exclusion criteria: 
• 
Diagnosis of giant cell arteritis (GCA) (eg, persistent or 
recurrent localized headache, temporal artery or scalp 
tenderness, jaw claudication, extremity claudication, blurry 
or loss of vision, symptoms of stroke). 
• 
Concurrent diagnosis of active fibromyalgia. 
• 
Concurrent rheumatoid arthritis or other inflammatory 
arthritis or other connective tissue diseases, such as but 
not limited to systemic lupus erythematosus, systemic 
sclerosis, vasculitis, myositis, mixed connective tissue 
disease, and ankylosing spondylitis. 
• 
Concurrent diagnosis of rhabdomyolysis or neuropathic 
muscular diseases. 
• 
Inadequately treated hypothyroidism. 
• 
Organ transplant recipient. 
• 
Therapeutic failure including inadequate response or 
intolerance, or contraindication, to biological IL-6 
antagonist. 
• 
Any prior (within the defined washout period below) or 
concurrent use of immunosuppressive therapies but not 
limited to any of the following: 
- 
Janus kinase (JAK) inhibitor within 4 weeks of 
baseline. 
- 
Alkylating agents including cyclophosphamide within 
6 months of baseline. 
- 
Cell-depletion agents (eg, anti CD20) without 
evidence of recovery of B cells to baseline level. 
- 
Tumor necrosis factor (TNF) inhibitors within 
2-8 weeks (etanercept within 2 weeks, infliximab, 
certolizumab, golimumab, or adalimumab within 
8 weeks), or after at least 5 half-lives have elapsed, 
whichever is longer. 
- 
Abatacept within 8 weeks of baseline. 
- 
Anakinra within 1 week of baseline. 
- 
Cyclosporine (CsA), azathioprine (AZA) or 
mycophenolate mofetil (MMF) or leflunomide within 
4 weeks of baseline. 
• 
Unstable methotrexate (MTX) dose and/or MTX dose 
>15 mg/week within 3 months of baseline  
• 
Concurrent use of systemic CS for conditions other than 
PMR. 
• 
Evidence of serious, uncontrolled concomitant disease 
(eg, cardiovascular, respiratory, hepatic, renal, endocrine 
etc.). 
Total expected number of patients 
Approximately 280 revised to 118  
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STUDY TREATMENT(s) 
 
Investigational medicinal product 
Sarilumab 
Formulation: 
Single-use prefilled glass syringes of sarilumab 200 mg, sarilumab 
150 mg or matching placebo for sarilumab. 
Route(s) of administration: 
Subcutaneous (SC) route, in abdomen or thigh, or upper arm. 
Dose regimen: 
Sarilumab 200 mg, sarilumab 150 mg or matching placebo is to be 
administered q2w. 
 
 
Investigational medicinal product 
Prednisone and matching placebo will be used in the study for 
standardized prednisone-taper regimen for treatment of PMR.  
Formulation: 
Phase I: 5 mg over-encapsulated tablets, Phase 2: over-
encapsulated matching placebo tablets 
Route(s) of administration: 
Oral administration 
Dose regimen: 
For the purpose of this study, there will be 2 standardized CS-taper 
regimens: 
• 
14 weeks - initial 2 weeks of 15mg/day dose followed by 
12 weeks of gradual decrease in dose (sarilumab 
treatment arm). 
• 
52 weeks - initial 2 weeks of 15mg/day dose followed by 
50 weeks of gradual decrease in dose (sarilumab matching 
placebo treatment arm). 
Blinding of CS treatment: 
• 
Prednisone and matching placebo will be used to maintain 
blinding of the taper regimen. 
 
 
Investigational medicinal product 
Add-on Prednisone 
Formulation: 
Add on ≤5 mg regimen: Commercial 1 mg tablets 
Route(s) of administration: 
Oral administration 
Dose regimen: 
As determined by the investigator but up to maximum dose of 
5mg/day 
 
 
Non-Investigational medicinal product 
Rescue corticosteroids 
Formulation: 
Commercial tablets 
Route(s) of administration: 
Oral administration 
Dose regimen: 
As determined by the investigator 
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ENDPOINT(S) 
 
Primary endpoint: 
Proportion of patients achieving sustained remission at Week 52. 
Sustained remission at Week 52 is defined by having met all of the 
following parameters: 
• 
Achievement of disease remission no later than Week 12, 
AND 
• 
Absence of disease flare from Week 12 through Week 52, 
AND 
• 
Sustained reduction of CRP (to <10 mg/L, with an absence 
of successive elevations to ≥10 mg/L) from Week 12 
through Week 52, AND 
• 
Successful adherence to the prednisone taper from 
Week 12 through Week 52. 
Disease remission is defined as resolution of signs and symptoms 
of PMR, and normalization of CRP (<10 mg/L). 
Note: A single CRP elevation (≥10 mg/L) is not considered absence 
of remission unless CRP remains elevated (≥10 mg/L) at 2 
consecutive study visits. 
Flare is defined as recurrence of signs and symptoms attributable to 
active PMR requiring an increase in CS dose, or elevation of ESR 
attributable to active PMR plus an increase in CS dose. Increase in 
CS dose is defined as: 
• 
Any dose increase during the protocol defined steroid 
taper.  
• 
Re-initiation of prednisone therapy after the protocol 
defined taper has been completed. 
Note: During the initial 12 weeks of prednisone taper, 
treatment for one flare before Week 12 is permitted if it can 
be successfully treated with a ≤5 mg/day prednisone  
add-on taper regimen (completed prior to Week 12) and 
provided that all other sustained remission parameters are 
met. 
Secondary endpoint(s): 
Efficacy: 
• 
Summary of the components of sustained remission at 
Week 52. 
• 
Total cumulative prednisone dose (or equivalent) over  
52 weeks. 
• 
Time to first PMR flare 
• 
Changes from baseline in GTI (and components) 
Safety: 
• 
Adverse events (AEs), laboratory values (including 
antidrug antibody [ADA], vital signs. 
Pharmacokinetic 
• 
Serum concentrations of sarilumab. 
Other efficacy endpoint(s): 
• 
Change from baseline in the Physician global assessment 
of disease activity- visual analog scale (MD-VAS). 
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• 
Patient Reported Outcome (changes from baseline for the 
following): 
- 
Functional assessment of chronic illness therapy 
fatigue scale (FACIT-fatigue) – total score. 
- 
EuroQol 5 dimension questionnaire; 3-level version 
(EQ-5D-3L) – index score and visual analogue scale 
score.  
- 
Short-form 36-item questionnaire (SF-36v2) –domain 
scores, and physical and mental component summary 
scores 
- 
Health Assessment Questionnaire Disability Index 
(HAQ-DI) – total score, pain score, patient global 
impression score 
Pharmacodynamic 
• 
Changes in ESR and CRP over time. 
• 
Changes in IL-6 level and soluble IL-6 receptor. 
• 
Changes in markers of inflammation and disease activity 
over time as assessed in circulating immune cell types, 
circulating proteins and gene expression changes. 
ASSESSMENT SCHEDULE 
The study will consist of the following visits: 
• 
Visit 1 (D-28-D-1): Screening 
• 
Visit 2 (D1): Baseline, randomization, first study drug 
administration. 
• 
Visit 3 to 11 (Week 2-Week 40): on treatment (during 
double-blind phase). 
• 
Visit 12 (Week 52): End of Treatment (EOT) visit (last 
SC IMP administration at Week 50 and last oral IMP 
administration day before Visit 12). 
• 
Visit 13 (Week 58): End of Study (EOS) visit. 
At screening and baseline visits, a physical examination to assess 
disease activity and general health will be performed. Patients will be 
assessed for active or latent tuberculosis (TB) at baseline and during 
the study.  
For an overview of the laboratory tests see the study flow chart 
below, which includes hematology, chemistry, lipids, glucose, insulin, 
antinuclear antibodies (ANA), glycosylated hemoglobin A1c (HbA1c), 
urinalysis, human immunodeficiency virus (HIV), Hepatitis B and C, 
serum and plasma for biomarkers and a 12-lead electrocardiogram 
(ECG). A serum pregnancy test for women of child bearing potential 
(WOCBP) will be obtained at screening as well. Future Use Sample 
(serum and plasma) used for future analysis (eg, circulating proteins) 
will be collected from each consenting patient using a separate 
informed consent form (optional).  Blood samples (DNA and RNA for 
sequencing or gene expression [RNA only]) will be collected from 
each consenting patient using a separate informed consent form 
(optional). 
Safety assessments are done at each study visit and include AEs, 
serious adverse events (SAEs) and adverse events of special 
interest (AESIs) including but not limited to neutropenia, 
thrombocytopenia, elevations in hepatic enzymes leading to 
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permanent discontinuation and TB, and potential opportunistic 
infections. 
A dual assessor approach will be required in order to maintain the 
blind during the double-blind treatment period with sarilumab, 
prednisone and matching placebos.  The Efficacy Assessor should 
be a rheumatologist or other skilled PMR assessor and may be the 
principal investigator who will be responsible for completing the 
overall evaluation and management of PMR disease activity. The 
Safety Assessor should be a physician who will be responsible for 
assessing and managing any safety concerns related to the patient 
during the course of the study including reviewing the patient’s 
laboratory data and assessing/reporting/managing any AEs. The 
Safety Assessor cannot be the Efficacy Assessor. 
Patients and Investigators must respect the visit schedule per study 
flow chart. If a visit date is changed, the next visit should take place 
according to the original schedule. 
Blood samples in a subset of patients will be collected to evaluate 
circulating immune cell phenotypes. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: There are no prior controlled 
study data to establish the placebo remission rate in PMR. The 
sample size of 59 per group provides at least 85% and 95% power to 
detect 25% and 30% treatment difference respectively, assuming 5% 
to 15% placebo response rate, and using a significance level of 0.05. 
Analysis population: The primary efficacy analysis population 
will be the intent-to-treat (ITT) population, which consists of all 
randomized patients. All patients will be analyzed according to the 
treatment to which they are randomized. 
The safety population will include all randomized patients who have 
received at least one dose or part of a dose of the study medication. 
All patients will be analyzed according to the treatment they have 
actually received. 
Primary analysis: The proportion of patients in sustained 
remission at Week 52 will be analyzed using 2-sided Fisher's exact 
test. A significance level of 0.05 will be used. 
Analysis of secondary endpoints: Other binary endpoints 
will be analyzed using the same approach as the primary analysis. 
Total cumulative prednisone (or equivalent) dose will be analyzed by 
Wilcoxon rank-sum test. Time to event analysis will use Kaplan-
Meier estimates and a log rank test. 
DURATION OF STUDY PERIOD (per 
patient)  
Total duration of study per patient is expected to be approximately 
62 weeks: 
• 
Up to 4 week screening 
• 
52 weeks treatment (double-blind phase) 
• 
6 weeks post-treatment follow-up 
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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN  
 
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1.2 
STUDY FLOW CHART  
 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
 
V11 
V12  
(EOT) 
V13 
(EOS) 
DAY 
D-28 to 
D-1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85  
(±3) 
D113 
(±3) 
D141 
(±3) 
D169 
(±3) 
D225 
(±3) 
D281 
(±3) 
D365    
(±3) 
D407 
(±3) 
WEEK 
 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 32 
Week 40 
Week 52 
Week 58 
Eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriat 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound central readingv 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical/smoking-alcohol 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Family cardiovascular history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
Targeted physical examinationa 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Confirm eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Call IRT 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial treatment kit assignment (IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IMP administrationb 
 
Xw 
X 
X 
X 
X 
X 
X 
Xs 
Xs 
Xs 
 
 
Concomitant medication review 
Xu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
 
V11 
V12  
(EOT) 
V13 
(EOS) 
DAY 
D-28 to 
D-1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85  
(±3) 
D113 
(±3) 
D141 
(±3) 
D169 
(±3) 
D225 
(±3) 
D281 
(±3) 
D365    
(±3) 
D407 
(±3) 
WEEK 
 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 32 
Week 40 
Week 52 
Week 58 
Dispense patient diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance/review patient diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature, heart rate, blood 
pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
PMR clinical assessments       
(including disease flare) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician global assessment         
(MD-VAS)  
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Patient reported outcomesc 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Glucocorticoid toxicity index (excl. bone 
density assessment) 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Bone density assessmentd 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE recording 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QuantiFERON® 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyf 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
 
V11 
V12  
(EOT) 
V13 
(EOS) 
DAY 
D-28 to 
D-1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85  
(±3) 
D113 
(±3) 
D141 
(±3) 
D169 
(±3) 
D225 
(±3) 
D281 
(±3) 
D365    
(±3) 
D407 
(±3) 
WEEK 
 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 32 
Week 40 
Week 52 
Week 58 
Chemistryg 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
ANAh 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Fasting lipidsi and fasting 
glucose/insulinj 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
HbA1c 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
CRPk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESRk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysisl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Virologym 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testn 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum sarilumabj 
 
X 
X 
X 
 
X 
X 
Xr 
 
 
X 
X 
Antibodies to sarilumab/ADAj 
 
X 
 
 X 
  
 
 X 
  
 
X 
X 
Genotyping and biomarkersj 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers-IL-6 and sIL-6R 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Immune Cell Phenotyping (Whole 
Blood)o 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
Future Use Samples (Serum and 
Plasma)lp - Optional 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
 
V11 
V12  
(EOT) 
V13 
(EOS) 
DAY 
D-28 to 
D-1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85  
(±3) 
D113 
(±3) 
D141 
(±3) 
D169 
(±3) 
D225 
(±3) 
D281 
(±3) 
D365    
(±3) 
D407 
(±3) 
WEEK 
 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 32 
Week 40 
Week 52 
Week 58 
DNAq- Optional 
 
X 
 
 
 
 
 
 
 
 
 
 
 
RNAq- Optional 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
AE = Adverse event; D = Day; DNA = Deoxyribonucleic acid; ECG = Electrocardiogram; EOT = End of treatment; EOS = End of study; EQ-5D = EuroQol; ESR = erythrocyte sedimentation rate; EUL = elevate upper 
limb; FACIT-Fatigue = Functional assessment of chronic illness therapy fatigue scale; GCA = Giant cell arteritis; GTI = Glucocorticoid toxicity index; HbA1c = Hemoglobin A1c; HBsAg = Hepatitis B surface antigen; 
HBcore Ab = Hepatitis B core antibodies; HCV = Hepatitis C virus; CRP = C-reactive protein; IL = Interleukin; IMP = Investigational medicinal product; IRT = Interactive voice response system; MD-VAS = Physician 
global assessment of disease activity- visual analog scale; Pain VAS = Pain visual analog scale; Pt-VAS = Patient global assessment of disease activity– visual analog scale; RNA = Ribonucleic acid; SAE = Serious 
adverse event; SF-36v2 = Short form 36v2; V = Visit; Wk = Week. 
a Targeted physical examination: head, eyes, ears, neck and throat, skin, respiratory, cardiovascular, neurologic, lymphatic examinations and abdominal examination. 
b Last administration of sarilumab is at Week 50. Patients will be monitored for at least 30 minutes or up to 2 hours as per country specific requirements after each dose of SC IMP for any signs or symptoms of a 
hypersensitivity reaction.  
c Patient Reported Outcomes include EQ-5D-3L, FACIT-Fatigue, SF-36v2, HAQ-DI 
d Bone Mineral Density assessment will be performed at the baseline (Visit 2) and Week 52 (Visit 12) using a DXA scan. The scan can be performed within ± 14 days of Visit 2 and within -14 days of Visit 12 and 
needs to include the lumbosacral and femoral neck regions.  However, the baseline visit DXA scan is not required if there is one available within 12 weeks of baseline. 
e Chest X-ray is required during the screening period if no chest imaging (X-ray, CT, MRI) is available within the previous 12 weeks of V1 that clearly documents the exclusion of TB or if it does not follow the local 
guidelines and requirements for active screening of TB.  In countries for which a specific approval procedure for the x-ray is required by a different committee than the local EC/IRB, a chest MRI between V1 and 
V2 can be performed. 
f 
Hematology (blood should be drawn before drug administration): Hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential, platelet count, 
absolute neutrophil count (ANC). 
g Chemistry(blood should be drawn before drug administration): Sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine and creatinine clearance, calcium, phosphate, total protein, albumin, 
alanine aminotransferase (ALT) (SGPT), aspartate aminotransferase (AST) (SGOT), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated bilirubin, lactate dehydrogenase (LDH), uric acid 
h Anti-nuclear antibody (ANA) will be collected at Visit 2 and EOT visits only. 
i 
Lipids (blood should be drawn before drug administration): Triglycerides (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol. Fasting is defined as having no 
food or liquid intake (except water/ice) for six hours or more. 
j 
Blood should be drawn before drug administration. Fasting is defined as having no food or liquid intake (except water/ice) for six hours or more. 
k CRP and ESR results will be blinded to both Investigator and Sponsor (except screening and baseline). ESR kits will be provided by the central laboratory while the test will be performed locally at the site; results 
will be blinded to Investigator and staff directly involved in management of study patient except the safety assessor. 
l 
Urinalysis dipstick: specific gravity, pH, glucose, blood, protein, nitrites, leukocytes, ketones, urobilinogen and bilirubin (by dipstick) at screening visit only. If any parameter on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for testing. If positive for proteins, microscopic analysis is performed by central laboratory. 
m Human immunodeficiency virus antibodies - if required locally, the locally provided consent for the required HIV screening test will be collected; Hepatitis B: Hep B surface antigen, total Hep B core antibody, Hep B 
surface antibody, and Hep B viral DNA (if necessary); Hepatitis C: HCV-antibody.  
n In women of child-bearing potential. 
o Immune Cell Phenotyping (Whole Blood): Approximately 40 patients from each of the two treatment arms will be selected for this whole blood draw and immune cell phenotyping analysis.   
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p A separate Future Use Samples Informed Consent has to be obtained before any sampling.  Both serum and plasma will be drawn and the samples will be used for future analysis (eg, circulating proteins). 
q A separate Pharmacogenetic Research Informed Consent for collecting and sequencing DNA and RNA samples has to be obtained before any sampling. One DNA (at baseline or any treatment or follow up visit) 
and RNA sample for sequencing sampling time point at baseline and pre-dose (V3) are needed. 
r 
Additional sample is to be drawn 4-7 days after Week 24 dosing. 
s Since the visit interval exceeds 4 weeks, interim shipments of IMP to patients home may be performed using direct to patient (DTP) shipping in order to provide the patient with only 4 weeks IMP at a time in order 
to minimize compliance errors. 
t 
If the ultrasound is employed in the diagnosis of PMR, then the ultrasound images need to be submitted to the central reader for confirmation that they fulfill the ultrasound part of the diagnostic criteria for PMR. 
u For patients who are on >15mg/day (but not exceeding 20mg/day) of prednisone at screening and during the screening period, the Investigator should judiciously taper the prednisone down to 15mg/day prior to 
randomization in order to prevent a disease flare upon entering the study at 15mg/day of prednisone. 
v If ultrasound is being used as a diagnostic tool of PMR, the image needs to be submitted to the central reader for confirmation of eligibility. 
w IMP training. Prior to the first dose of IMP, provide instructions on preparation and self-injection of the pre-filled syringes and the use of the weekly blister packs of prednisone. Document this training in the patients 
study file. Note: If the patient is unable or unwilling to perform the subcutaneous injections themselves, arrangements must be made for qualified site personnel and/or caregiver to administer study drug every 
2 weeks for doses that are not scheduled to be given at the study site. 
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2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 2 
1 
FLOW CHARTS ............................................................................................................................. 13 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 13 
1.2 
STUDY FLOW CHART .................................................................................................................. 14 
2 
TABLE OF CONTENTS ................................................................................................................ 19 
2.1 
LIST OF TABLES ........................................................................................................................... 25 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 26 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 27 
5 
STUDY OBJECTIVES ................................................................................................................... 29 
5.1 
PRIMARY ....................................................................................................................................... 29 
5.2 
SECONDARY ................................................................................................................................ 29 
5.3 
OTHER ........................................................................................................................................... 29 
6 
STUDY DESIGN ............................................................................................................................ 30 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 30 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 31 
6.2.1 
Duration of study participation for each patient ............................................................................. 31 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 31 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 31 
6.4 
STUDY COMMITTEES .................................................................................................................. 32 
6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS ............................. 32 
7 
SELECTION OF PATIENTS .......................................................................................................... 33 
7.1 
INCLUSION CRITERIA .................................................................................................................. 33 
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7.2 
EXCLUSION CRITERIA ................................................................................................................ 34 
7.2.1 
Exclusion criteria related to disease .............................................................................................. 34 
7.2.2 
Exclusion criteria related to study methodology ............................................................................ 34 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound ...................................... 36 
8 
STUDY TREATMENTS ................................................................................................................. 39 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 39 
8.1.1 
Sarilumab or matching placebo: .................................................................................................... 39 
8.1.2 
Prednisone or matching placebo: .................................................................................................. 41 
8.1.3 
Add on prednisone taper in the case of flare within initial 12 weeks ............................................. 42 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 42 
8.3 
BLINDING PROCEDURES ............................................................................................................ 43 
8.3.1 
Methods of blinding ........................................................................................................................ 43 
8.3.1.1 
Blinding of IMP: .............................................................................................................................. 43 
8.3.2 
Randomization code breaking during the study ............................................................................. 44 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 44 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING ............................. 45 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 45 
8.7 
RESPONSIBILITIES ...................................................................................................................... 46 
8.7.1 
Treatment accountability and compliance...................................................................................... 46 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 47 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 47 
8.8.1 
Steroids .......................................................................................................................................... 47 
8.8.2 
Nonsteroidal anti-inflammatory drugs and analgesics ................................................................... 48 
8.8.3 
Treatment for dyslipidemia ............................................................................................................. 48 
8.8.4 
Glucocorticoid-Induced Osteopenia/Osteoporosis Prevention and Treatment.............................. 48 
8.8.5 
CYP Substrates .............................................................................................................................. 48 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 50 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 50 
9.1.1 
Primary efficacy endpoint ............................................................................................................... 50 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 51 
9.2.1 
Secondary efficacy endpoints ........................................................................................................ 51 
9.2.1.1 
Components of sustained remission composite measure at Week 52 .......................................... 51 
9.2.1.2 
Total cumulative corticosteroid (including prednisone) dose over 52 weeks................................. 51 
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9.2.1.3 
Time to first PMR flare ................................................................................................................... 52 
9.2.1.4 
Composite glucocorticoid toxicity index and components ............................................................. 52 
9.2.2 
Safety endpoints ............................................................................................................................ 52 
9.2.2.1 
Adverse events .............................................................................................................................. 52 
9.2.2.2 
Laboratory safety variables ............................................................................................................ 53 
9.2.2.3 
Chest x-ray ..................................................................................................................................... 53 
9.2.2.4 
Vital signs ....................................................................................................................................... 54 
9.2.2.5 
Physical examination ..................................................................................................................... 54 
9.2.2.6 
Electrocardiogram variables .......................................................................................................... 54 
9.3 
OTHER EFFICACY ENDPOINTS .................................................................................................. 55 
9.3.1 
Clinical Outcome Assessments ..................................................................................................... 55 
9.3.1.1 
Patient-Reported Outcomes .......................................................................................................... 55 
9.3.1.2 
Clinician-reported Outcomes ......................................................................................................... 56 
9.4 
PHARMACODYNAMIC .................................................................................................................. 56 
9.4.1 
Pharmacodynamic variables .......................................................................................................... 56 
9.5 
PHARMACOKINETICS AND ANTI-DRUG ANTIBODIES ............................................................. 57 
9.5.1 
Sampling time ................................................................................................................................ 57 
9.5.2 
Sample handling procedure ........................................................................................................... 57 
9.5.3 
Bioanalytical method ...................................................................................................................... 57 
9.5.4 
Pharmacokinetics parameters ....................................................................................................... 58 
9.6 
PHARMACOGENETIC ASSESSMENT ......................................................................................... 58 
9.6.1 
Optional stored DNA and RNA samples ........................................................................................ 58 
9.7 
FUTURE USE OF SAMPLES ........................................................................................................ 59 
9.8 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 59 
10 
STUDY PROCEDURES ................................................................................................................ 60 
10.1 
INDEPENDENT EFFICACY AND SAFETY ASSESSORS ........................................................... 60 
10.2 
VISIT SCHEDULE .......................................................................................................................... 61 
10.2.1 
Visit 1: Screening from Day -28 to Day -1 ..................................................................................... 61 
10.2.2 
Double blind period (52 weeks) ..................................................................................................... 62 
10.2.2.1 Visit 2/Baseline visit (Day 1, Week 0) ............................................................................................ 62 
10.2.2.2 Visit 3 (Day 15±3 Week 2) ............................................................................................................. 64 
10.2.2.3 Visit 4-11 (Day 29±3 Week 4 to Day 281±3, Week 40) ................................................................. 64 
10.2.2.4 Visit 12/End of treatment (Day 365±3 Week 52) ........................................................................... 66 
10.2.3 
Post-treatment follow-up period (6 weeks) .................................................................................... 67 
10.2.3.1 Visit 13/End of study (Day 407±3, Week 58) ................................................................................. 67 
10.3 
DEFINITION OF SOURCE DATA .................................................................................................. 67 
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10.4 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 68 
10.4.1 
Temporary treatment discontinuation with investigational medicinal product (sarilumab or 
matching placebo) .......................................................................................................................... 68 
10.4.2 
Permanent treatment discontinuation with investigational medicinal product(s) ........................... 69 
10.4.3 
List of criteria for permanent treatment discontinuation ................................................................. 69 
10.4.4 
Handling of patients after permanent treatment discontinuation ................................................... 70 
10.4.5 
Procedure and consequence for patient withdrawal from study .................................................... 71 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 71 
10.5.1 
Definitions of adverse events ......................................................................................................... 71 
10.5.1.1 Adverse event ................................................................................................................................ 71 
10.5.1.2 Serious adverse event ................................................................................................................... 71 
10.5.1.3 Adverse event of special interest ................................................................................................... 72 
10.5.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities ....................................................................................................................................... 74 
10.5.3 
General guidelines for reporting adverse events ........................................................................... 74 
10.5.4 
Instructions for reporting serious adverse events .......................................................................... 74 
10.5.5 
Guidelines for reporting adverse events of special interest ........................................................... 75 
10.5.6 
Guidelines for management of specific laboratory abnormalities .................................................. 75 
10.5.7 
Guidelines for reporting product complaints (IMP) ........................................................................ 75 
10.6 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 76 
10.7 
SAFETY MONITORING ................................................................................................................. 76 
10.8 
SAFETY INSTRUCTIONS ............................................................................................................. 77 
10.8.1 
Infections ........................................................................................................................................ 77 
10.8.2 
Liver function tests ......................................................................................................................... 78 
10.8.3 
Neutrophils ..................................................................................................................................... 79 
10.8.4 
Platelets ......................................................................................................................................... 79 
10.8.5 
Systemic hypersensitivity reactions/anaphylaxis ........................................................................... 80 
10.8.6 
Diverticulitis and gastrointestinal perforation ................................................................................. 80 
10.8.7 
Management of dyslipidemia ......................................................................................................... 80 
10.8.8 
Acute renal failure .......................................................................................................................... 81 
10.9 
ADVERSE EVENTS MONITORING .............................................................................................. 81 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 82 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 82 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 82 
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11.3 
ANALYSIS POPULATIONS ........................................................................................................... 83 
11.3.1 
Efficacy populations ....................................................................................................................... 83 
11.3.1.1 Intent–to-treat /modified intent-to-treat population ......................................................................... 83 
11.3.2 
Safety population ........................................................................................................................... 83 
11.3.3 
Pharmacokinetic analysis population ............................................................................................. 83 
11.4 
STATISTICAL METHODS ............................................................................................................. 83 
11.4.1 
Extent of study treatment exposure and compliance ..................................................................... 84 
11.4.1.1 Extent of investigational medicinal product exposure .................................................................... 84 
11.4.1.2 Compliance .................................................................................................................................... 84 
11.4.2 
Analyses of efficacy endpoints ....................................................................................................... 84 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................ 84 
11.4.2.2 Analyses of secondary efficacy endpoints ..................................................................................... 85 
11.4.2.3 Multiplicity considerations .............................................................................................................. 85 
11.4.3 
Analyses of safety data .................................................................................................................. 85 
11.4.3.1 Analysis of adverse event data ...................................................................................................... 86 
11.4.3.2 Analysis of laboratory data ............................................................................................................. 86 
11.4.3.3 Analysis of vital signs data ............................................................................................................. 88 
11.4.3.4 Analysis of immunogenicity data .................................................................................................... 88 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 88 
11.4.5 
Analyses of patient reported outcomes.......................................................................................... 89 
11.5 
INTERIM ANALYSIS ...................................................................................................................... 89 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 90 
12.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 90 
12.2 
INFORMED CONSENT ................................................................................................................. 90 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE ................................................................................................................... 91 
13 
STUDY MONITORING................................................................................................................... 92 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 92 
13.2 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 92 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 92 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST ...................................................................................................................................... 93 
13.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 93 
14 
ADDITIONAL REQUIREMENTS ................................................................................................... 94 
14.1 
CURRICULUM VITAE.................................................................................................................... 94 
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14.2 
RECORD RETENTION IN STUDY SITES .................................................................................... 94 
14.3 
CONFIDENTIALITY ....................................................................................................................... 94 
14.4 
PROPERTY RIGHTS ..................................................................................................................... 95 
14.5 
DATA PROTECTION ..................................................................................................................... 95 
14.6 
INSURANCE COMPENSATION .................................................................................................... 96 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................. 96 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................................ 96 
14.8.1 
By the Sponsor ............................................................................................................................... 96 
14.8.2 
By the Investigator ......................................................................................................................... 97 
14.9 
CLINICAL TRIAL RESULTS .......................................................................................................... 97 
14.10 
PUBLICATIONS AND COMMUNICATIONS ................................................................................. 97 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS .......................................................................... 99 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 100 
17 
APPENDICES .............................................................................................................................. 103 
APPENDIX A 
STANDARDIZED CORTICOSTEROID-TAPER REGIMEN DURING DOUBLE-
BLIND STUDY TREATMENT PERIOD ....................................................................................... 104 
APPENDIX B 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 106 
APPENDIX C 
COMPOSITE GLUCOCORTICOID TOXICITY INDEX ..................................................... 109 
APPENDIX D 
SPECIFIC LIST FOR GLUCOCORTICOID TOXICITY INDEX ......................................... 115 
APPENDIX E 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 117 
APPENDIX F 
LIST OF OPPORTUNISTIC INFECTIONS ........................................................................ 120 
APPENDIX G  
DEFINITION OF ANAPHYLAXIS ..................................................................................... 121 
APPENDIX H 
FACIT- FATIGUE (PAPER VERSION)* ............................................................................ 122 
APPENDIX I 
EUROQOL QUESTIONNAIRE (EQ-5D-3L) (PAPER VERSION)* ..................................... 123 
APPENDIX J 
SF-36V2 (PAPER VERSION)* ........................................................................................... 126 
APPENDIX K 
HAQ-DI – HEALTH ASSESSMENT QUESTIONNAIRE (PAPER VERSION)* ................. 132 
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APPENDIX L 
PHYSICIAN’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY (PAPER 
VERSION)* .................................................................................................................................. 135 
APPENDIX M 
BIOMARKER OBJECTIVES ............................................................................................. 136 
APPENDIX N 
PROTOCOL AMENDMENT HISTORY ............................................................................. 138 
 
2.1 
LIST OF TABLES  
Table 1 - Summary of investigational medicinal products ............................................................................. 39 
Table 2 - Summary of bioanalytical methods for functional sarilumab and anti- sarilumab antibody ........... 58 
Table 3 - Power calculations based on total sample size of 118 randomized patients ................................. 82 
 
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3 
LIST OF ABBREVIATIONS  
 
ADA: 
antidrug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ANC: 
absolute neutrophil count 
CRP: 
C-reactive protein 
CS: 
Corticosteroids 
CYP: 
Cytochrome P450 
DMARDs: 
disease modifying anti-rheumatic drugs 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EOT: 
end of treatment 
hs-CRP: 
high-sensitivity C-reactive protein 
IEC: 
independent ethics committee 
IL-6: 
Interleukin 6 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRB/IEC: 
institutional review board/independent ethics committee 
IRT: 
interactive response technology 
LDL: 
low-density lipoprotein 
LFT: 
liver function test 
PCSA: 
potentially clinically significant abnormality  
PFS: 
prefilled syringe 
PMR: 
Polymyalgia Rheumatica 
q2w: 
once in every 2 weeks 
RA: 
Rheumatoid Arthritis 
SAE: 
serious adverse events 
SC: 
subcutaneous 
SD: 
standard deviation 
SF-36v2: 
short form 36v2 
 
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4 
INTRODUCTION AND RATIONALE  
Polymyalgia Rheumatica (PMR) is a chronic, inflammatory disease of unknown etiology 
characterized by pain and morning stiffness of the shoulder, neck and pelvic girdle, and is 
frequently associated with low-grade fever, fatigue, malaise, and weight loss. The debilitating 
effect of the disease can significantly affect the quality of life of PMR patients. It typically affects 
individuals older than 50 years, with prevalence varying by age and population (1). In 2008, the 
number of PMR cases in the US was estimated to be 711,000 (2). The prevalence is higher in 
women than in men and increases dramatically with age. Based on the only population-based 
study of PMR in the US, a study in Olmsted County, Minnesota, the prevalence ranged from  
21 per 100,000 among persons ages 50–54 years to 4,070 per 100,000 among those age ≥90 years 
(2). In Europe, higher rates have been noted in Northern European compared with Southern 
European populations. In patients who are ≥50 years of age, annual incidence rates of 50/100,000 
were noted in Sweden and 68/100,000 in Denmark compared to 13/100,000 in Italy and  
14-19/100,000 in Spain (1). 
Although the cause is unknown, both genetic and the environmental factors are thought to be 
involved. Research suggests that inflammation of the joints and the bursae around these joints 
leads to the symptoms of pain and stiffness associated with PMR. Although there are no definitive 
tests, there are guidelines to help in the clinical diagnosis of PMR (3). 
Although PMR is typically treated with low doses of corticosteroids (CS), there is a subset of 
patients who are steroid- dependent or are unable to taper off prednisone or equivalent below 
10 mg/day without relapse of symptoms and are therefore at risk of complications of long-term 
steroid therapy. In the 2015 American College of Rheumatology/European League against 
Rheumatism (ACR/EULAR) guidelines, the recommended minimum effective starting dose is 
within the range of 12.5-25 mg of prednisone (or equivalent) daily (4). Mean treatment duration is 
approximately 2 to 3 years. CS with a slow taper will reduce symptoms rapidly for most patients. 
However, nearly half of the patients with PMR treated with CS do not respond adequately based 
on laboratory and clinical markers of disease activity in one report (3) (2010). In another report, 
among patients with baseline prednisone doses >10 mg/day, only 30% had remission at 1 year (5). 
Therefore, there exists an unmet medical need in this patient population to spare the toxicities 
related to chronic CS exposure. 
Interleukin 6 (IL-6) plays a key role in the inflammatory responses of PMR (6). Circulating levels 
of IL-6 are significantly elevated in PMR patients compared to healthy controls. IL-6 signaling 
leads to the production of acute phase reactants, such as C-reactive protein (CRP) and fibrinogen, 
which are decreased by anti-IL6R (Interleukin-6 receptor) therapy (7, 8). Persistently elevated 
CRP levels are observed in PMR patients at relapse (9, 10, 11) and (12). 
While not recommended in guidelines for clinical treatment of PMR patients (3) other unproven 
treatment options, including biologic disease modifying anti-rheumatic drugs (DMARDs), are 
sometimes used in patients who cannot undergo a slow taper of CS (13). Several biologic anti-
inflammatory therapies have been evaluated in Phase 2 clinical trials without success, including 
secukinumab and canakinumab (14). Evaluation of IL-6R antagonists in Phase 2 clinical trials 
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suggests blockade of IL-6 signaling may be an effective therapeutic approach for management of 
PMR (15, 16). These data show that the therapeutic options for patients who cannot tolerate a long 
course of CS or who are dependent on CS are limited and suggest that IL-6 blockade may provide 
a treatment option in these patients. 
Sarilumab, a fully human immunoglobulin G1 (IgG1) monoclonal antibody, targets IL-6R and 
inhibits IL-6 signaling. In this study, PMR patients will be treated with sarilumab with CS in order 
to evaluate the efficacy and safety of sarilumab in patients with PMR. 
The efficacy and safety of sarilumab have been evaluated in the phase 2 and phase 3 studies of the 
rheumatoid arthritis (RA) clinical development program across different segments of the RA 
populations, patients with sarilumab treatment showed clinically relevant and significant 
improvements compared with placebo or active comparator either in combination with 
methotrexate or as monotherapy, respectively. Based on the safety profile of sarilumab available 
to date and other biological DMARDs, important identified risks include serious infections, 
neutropenia, and hypersensitivity reactions; important potential risks to be considered with 
sarilumab administration, consistent with this class of therapy, include laboratory abnormalities 
and the potential clinical consequences, such as thrombocytopenia and the risk of bleeding, 
clinically evident hepatic injury with elevated hepatic transaminases, and lipid abnormalities and 
increased risk of MACE. Other potential important risks include increased risk of malignancy and 
gastrointestinal perforation. 
In addition to clinical development for RA, sarilumab has also been studied in patients with 
ankylosing spondylitis and non-infectious uveitis. Overall, the safety observations from these 
studies were consistent with what has been observed in patients with RA. 
The primary dose of sarilumab for this study/indication (ie, 200 mg subcutaneously [SC]) once 
every 2 weeks [q2w]) is selected based largely on the aggregate data from the sarilumab 
rheumatoid arthritis (RA) clinical development program. 
Both 200 mg q2w and 150 mg q2w doses have demonstrated robust clinical efficacy responses in 
the Phase 3 RA clinical development program, and suppression of biological markers of disease 
and inflammation similar to those found in PMR patients. While the higher dose has a generally 
more favorable efficacy response, both doses have acceptable safety profiles (see Investigator 
Brochure for additional details). Therefore, the dose of sarilumab 200 mg q2w is more likely to 
provide beneficial effects for patients with PMR and is selected for further evaluation in this 
study. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
To evaluate the efficacy of KEVZARA® (sarilumab) in patients with PMR as assessed by 
proportion of patients with sustained remission at Week 52 for sarilumab with a 14-week CS 
tapering regimen as compared to placebo with a 52 week CS tapering regimen. 
5.2 
SECONDARY  
• To demonstrate the efficacy of sarilumab (with 14-week taper of CS) compared to placebo 
(with 52-week taper of CS) in patients with PMR with regards to: 
- 
Clinical responses (such as components of sustained remission, disease remission 
rates, time to first disease flare) over time. 
- 
Cumulative corticosteroid (including prednisone) exposure. 
• To assess the safety (including immunogenicity) and tolerability of sarilumab in patients 
with PMR. 
• To measure sarilumab concentrations from serum of patients with PMR. 
• To assess the effect of sarilumab on reducing glucocorticoid toxicity as measured by the 
composite glucocorticoid toxicity index (GTI) questionnaire. 
5.3 
OTHER  
• To assess the effect of sarilumab on physician assessment of disease activity as measured 
by a visual analogue scale (MD-VAS) 
• To assess the effect of sarilumab on a variety of PRO concepts, including fatigue (as 
measured by FACIT-fatigue scale), health status (as measured by EQ-5D-3L and  
SF-36v2), physical function (as measured by HAQ-DI, pain (as measured via HAQ-DI by 
a visual analogue scale [VAS]) and patient assessment of disease activity (as measured via 
HAQ-DI by a VAS). 
• To assess the impact of ESR/CRP levels on remission status. 
• To characterize the disease activity of PMR patients while on steroid taper or sarilumab 
treatment in a subset of patients using comprehensive approaches to evaluate circulating 
immune cell types. 
• To characterize the disease activity of PMR patients while on steroid taper or sarilumab 
treatment by evaluating circulating proteins, genetics and gene expression in patients who 
consent for this optional part of the study. 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This is a multicenter, randomized, double-blind, placebo-controlled 52-week, Phase 3 study, 
evaluating the efficacy and safety of sarilumab in patients with active PMR. 
Patients with active PMR who meet the entry criteria will be randomized to the following 
2 parallel treatment groups with sarilumab 200 mg or placebo plus protocol-defined CS tapering 
regimens of either 14 or 52 weeks (as described below and in Section 9.3.1) in a 1:1 ratio. 
• Group 1: Sarilumab 200 mg q2w with a 14 weeks taper of CS 
• Group 2: Sarilumab matching placebo q2w with a 52 weeks taper of CS 
All patients will receive sarilumab 200 mg or placebo for 52-weeks. 
All patients will receive prednisone treatment (CS taper) with different regimen depending on the 
assigned group (see Appendix A). Prior to randomization and initiation of study treatment, 
corticosteroid therapy should be optimized to minimize the risk of serious adverse events 
associated with tapering of corticosteroids. The initial dose of prednisone for both groups will be 
15 mg/day for the first 2 weeks after randomization and then prednisone and/or prednisone 
matched placebo will be given to patients in order to ensure the double blind CS tapering regimen 
as defined below. 
• Group 1: From Week 2 to Week 13, patients will receive gradually decreasing dose levels 
of prednisone (prednisone or combination of prednisone and placebo to prednisone (see 
Appendix A). From Week 14 onwards, patients without flare will receive prednisone 
matching placebo. 
• Group 2: From Week 2 to Week 51, patients will receive gradually decreasing dose levels 
of prednisone (prednisone or combination of prednisone and placebo to prednisone 
(see Appendix A). 
At each site visit, the patients’ disease will be assessed to determine whether the patient can 
adhere to the protocol defined prednisone taper schedule. 
During the initial 12 weeks of prednisone taper, treatment for one flare is permitted if it can be 
successfully treated with a low dose (≤5 mg/day) prednisone add-on taper regimen (completed 
prior to Week 12) and provided that all other sustained remission parameters are met. 
For the management of predefined laboratory abnormalities, such as neutropenia, 
thrombocytopenia, and liver enzymes (Refer to Section 10.5.6 and Appendix E), study 
investigators may decide to temporarily hold the study drug (sarilumab or matching placebo) 
and/or permanently reduce the dose of sarilumab to 150 mg q2w or matching placebo in a 
continuous blinded manner. A request to reduce dosage will be made in a blinded manner through 
the IRT system which will implement the request appropriately based on the patient's treatment 
assignment. 
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For patients who experience a disease flare and are in need of rescue therapy (such as CS) as per 
investigator judgment, during the course of the study, they may continue administration of 
sarilumab or matching placebo in a double-blinded fashion for the full duration of the 52-week 
treatment period only if corticosteroids are used as rescue therapy (See Section 8.8 for details). 
Treatment with non-biological immunosuppressive drugs (such as alkylating agents, 
hydroxychloroquine, CsA, MMF, AZA, etc) is not permitted during the course of the study, 
unless used for the purpose of rescue therapy. 
During the course of study, for patients in need of rescue therapy as per investigator judgment, 
corticosteroids should be the agent of first choice. Patients may continue SC administration of 
sarilumab or matching placebo only if CS is used as rescue therapy. If the patients remain 
symptomatic despite CS rescue therapy, then other treatment options including non-biological 
immunosuppressive drugs may be used (patient must have symptomatic PMR disease) and the 
patient must be discontinued from the study treatment and considered a non-responder. 
If the patient or investigator decides to prematurely and permanently discontinue the 
administration of blinded sarilumab injections and blinded CS tapering regimen, then please refer 
to Section 10.4.4 for subsequent procedures. 
6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation for each patient  
Total duration of study participation for each patient is up to 62 weeks 
• An up to 4 weeks screening period 
• 52-week treatment period 
• A 6-week post treatment follow up period 
6.2.2 Determination of end of clinical trial (all patients)  
The last patient last visit will occur when the last patient completed the 52-week double blind 
treatment period and the follow up period of 6 weeks (Visit 13/EOS). The end of the clinical trial 
is defined as the last patient’s last visit. 
6.3 
INTERIM ANALYSIS  
No interim analysis is planned 
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6.4 
STUDY COMMITTEES  
Central review and certification of diagnostic ultrasounds 
If ultrasound is used to diagnose PMR and determine patient eligibility, the ultrasound images 
will be centrally reviewed by an expert rheumatologist (from a group of expert rheumatologists) 
specialized in the performance and interpretation of diagnostic ultrasounds of the shoulders and 
hips in order to confirm the diagnosis. Additionally, the same group of expert rheumatologists will 
also serve to help certify the sites who wish to have the option of using ultrasound in the diagnosis 
of PMR for their patients. 
6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS  
EFC15160 has been designed as a 52-week, double-blind, placebo-controlled, randomized, study 
to evaluate the efficacy and safety of sarilumab in patients with active PMR. The 52-week study 
treatment duration reflects the usual duration of therapy required to ensure sustained remission for 
patients with PMR (hence, the primary endpoint of sustained remission is at Week 52). The 
treatment arms are as follows: 
• Group 1: Sarilumab 200 mg q2w with a 14-week taper of CS 
• Group 2: Sarilumab matching placebo q2w with 52-week taper of CS  
Approximately 280 patients who satisfy the eligibility criteria will be enrolled and randomized 
into 2 parallel arms to receive either sarilumab 200 mg q2w with 14-weeks prednisone taper 
(Group 1) or sarilumab matching placebo with 52-weeks prednisone taper (Group 2) in the ratio 
of 1:1. As a result of the inability to recruit due to the COVID19 pandemic, the patient number 
has been revised to 118. 
The ability to taper off of CS rapidly in 14 weeks (as opposed to the usual tapering regimen of a 
year or more) after initiating therapy while maintaining disease remission with continuing 
sarilumab alone would represent an important clinically meaningful benefit over usual care. 
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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
I 01. Signed written informed consent. 
I 02. Diagnosis of PMR according to the European League against Rheumatism/American 
College of Rheumatology (EULAR/ACR) classification criteria as follows (must satisfy all 
criteria): 
a) Age ≥50 years at time of diagnosis. 
b) Bilateral shoulder pain. 
c) Elevated acute phase reactants (CRP >10 mg/L and/or ESR >30 mm/hr). 
AND one of the following: 
1. A score ≥4 at the time of diagnosis based on the following (without ultrasound): 
- 
Duration of morning stiffness >45 minutes: 2 points. 
- 
Hip pain or limited range of motion: 1 point. 
- 
Seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide 
(anti-CCP): 2 points. 
- 
Absence of other joint involvement: 1 point. 
OR 
2. A score ≥5 at the time of diagnosis based on the following (with ultrasound): 
- 
Duration of morning stiffness >45 minutes: 2 points. 
- 
Hip pain or limited range of motion: 1 point. 
- 
Seronegative for RF and anti-CCP: 2 points. 
- 
Absence of other joint involvement: 1 point. 
- 
At least one shoulder with subdeltoid bursitis and/or biceps tenosynovitis and/or 
glenohumeral synovitis (either Posterior or axillary) and at least one hip with synovitis 
and/or trochanteric bursitis: 1 point. (confirmed with ultrasound) 
- 
Both shoulders with subdeltoid bursitis, biceps tenosynovitis or glenohumeral 
synovitis: 1 point. (confirmed with ultrasound) 
Note: Sites that will consider inclusion of patients in the study using ultrasound as part 
of screening and diagnostic process for relevant disease status confirmation should 
only employ this method following completion of certification by the sponsor (details 
of the ultrasound certification process are found in the manual). 
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I 03. Patient must be on prednisone of at least 7.5 mg/day (or equivalent) and not exceeding 20 
mg/day at screening and during the screening period. 
I 04. Patient is willing and able to receive prednisone of 15 mg/day at randomization. 
I 05. Patient must have a history of being treated for at least 8 weeks with prednisone 
≥10 mg/day or equivalent. 
I 06. Patient must have had at least one episode of unequivocal PMR flare while attempting to 
taper prednisone at a dose that is ≥7.5 mg/day (or equivalent) within the past 12weeks 
prior to screening: 
• Unequivocal symptoms of PMR flare defined as shoulder and/or hip girdle pain associated 
with inflammatory stiffness. 
I 07. Patient must have ESR ≥30 mm/hr or CRP ≥10 mg/L associated with PMR disease activity 
within 12 weeks prior to screening. 
7.2 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following subsections:  
7.2.1 Exclusion criteria related to disease  
E 01. Diagnosis of Giant Cell Arteritis (GCA) (eg, persistent or recurrent localized headache, 
temporal artery or scalp tenderness, jaw claudication, extremity claudication, blurry or loss 
of vision, symptoms of stroke). 
E 02. Concurrent rheumatoid arthritis or other inflammatory arthritis or other connective tissue 
diseases, such as but not limited to systemic lupus erythematosus, systemic sclerosis, 
vasculitis, myositis, mixed connective tissue disease, ankylosing spondylitis. 
E 03. Concurrent diagnosis of rhabdomyolysis or neuropathic muscular diseases. 
E 04. Concurrent diagnosis of active fibromyalgia. 
E 05. Inadequately treated hypothyroidism. 
E 06. Organ transplant recipient 
7.2.2 Exclusion criteria related to study methodology  
E 07. Any prior (within the defined periods below) or concurrent use of immunosuppressive 
therapies including but not limited to the following: 
• Janus kinase (JAK) inhibitor (eg, tofacitinib) within 4 weeks of baseline.  
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• Cell-depletion agents (eg, anti CD20) without evidence of recovery of B cells to baseline 
level.  
• Anakinra within 1 week of baseline. 
• Abatacept within 8 weeks of baseline. 
• Tumor necrosis factor (TNF) inhibitors within 2-8 weeks (etanercept within 2 weeks, 
infliximab, certolizumab, golimumab, or adalimumab within 8 weeks), or after at least 5 
half-lives have elapsed, whichever is longer. 
• Alkylating agents including cyclophosphamide (CYC) within 6 months of baseline. 
• Cyclosporine (CsA), azathioprine (AZA) or mycophenolate mofetil (MMF) or leflunomide 
within 4 weeks of baseline. 
E 08. Therapeutic failure, including inadequate response or intolerance, or contraindication, to 
biological IL-6 antagonist (prior IL-6 antagonist treatment that was terminated for reasons 
unrelated to therapeutic failure at least 3 months before baseline is not exclusionary). 
E 09. Unstable methotrexate (MTX) dose and/or MTX dose >15 mg/week within 3 months of 
baseline. 
E 10. Concurrent use of systemic CS for conditions other than PMR. 
E 11. Participation in any clinical research study that evaluated an investigational drug or 
therapy within 5 half-lives or 60 days of the Screening Visit, whichever is longer. 
E 12. History of alcohol or drug abuse within 5 years prior to the screening visit. 
E 13. Patient who withdraws consent during the screening period (following signing of the 
informed consent form). 
E 14. Unable or unwilling to complete the patient-reported outcome (PRO) questionnaires. 
E 15. Patient who meets any of the following conditions/situations: 
• Patients with short life expectancy. 
• Conditions/concomitant diseases making patients non-evaluable for the efficacy endpoints 
(eg, patients with chronic pain). 
• Patient is the INVESTIGATOR or any Subinvestigator, Research Assistant, Pharmacist, 
Study Coordinator, other staff or relative thereof, directly involved in the conduct of the 
study, or, as applicable to employee of site/Investigator or Sponsor. 
• Uncooperative, or any condition, that could make the patient potentially noncompliant to 
the study procedures, etc, and individuals who are institutionalized due to regulatory or 
legal order. 
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7.2.3 Exclusion criteria related to the current knowledge of Sanofi compound  
E 16. Pregnant or breastfeeding woman. 
E 17. Woman of childbearing potential (WOCBP) not protected by highly-effective 
contraceptive method(s) of birth control (as defined in Appendix B), and/or who are 
unwilling or unable to be tested for pregnancy. 
E 18. Exclusion related to Tuberculosis (TB): 
• Active TB or a history of incompletely treated TB regardless of screening Quantiferon 
result 
• Quantiferon positive patients (no active disease) are excluded from the study unless the 
following conditions are met: 
- 
Patients with a history of prior documented completed chemoprophylaxis for latent 
tuberculosis infection (eg, acceptable treatments include 9 months of isoniazid 300 mg 
oral daily or equivalent proven regimen per local guidelines) or treatment of active 
tuberculosis infection (TBI) who has obtained consultation with a specialist to rule out 
active TBI or the need to receive further treatment. 
- 
Patients with no prior history of chemoprophylaxis for latent TBI or treatment for 
active TBI but have obtained consultation with a specialist to initiate an appropriate 
regimen of chemoprophylaxis, based on local epidemiology and applicable guidelines 
and have demonstrated compliance and tolerated treatment for ≥1 month. 
- 
Consultation with and prior approval from sponsor are required in either of the 
aforementioned scenarios. 
• Clinically significant abnormality consistent with prior/active TB infection based upon 
chest radiograph with at least posterior-anterior view (See Section 10.8.1). Additional 
lateral view is recommended but not required. 
• Suspected extra-pulmonary TB infection regardless of screening Quantiferon result. 
• Patients at high risk of contracting TB, such as close contact with individuals with active 
or latent TB. 
• Patient who received Bacille Calmette Guerin -vaccination within 12 months prior to 
screening. 
E 19. Patients with a history of invasive opportunistic infections, including but not limited to 
histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis jirovecii, 
aspergillosis despite resolution or John Cunningham virus (progressive multifocal 
leukoencephalopathy). 
E 20. Patients with fever (>38°C) associated with infection, or chronic, persistent, or recurring 
infection(s) requiring active treatment with antibiotics, antivirals, or antifungals within 
4 weeks prior to the screening visit or other frequent recurrent infections deemed 
unacceptable as per Investigator judgment. 
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E 21. Patients with uncontrolled diabetes mellitus, defined as glycosylated hemoglobin (HbA1c) 
≥9% at the screening visit. 
E 22. Patients with non-healed or healing skin ulcers. 
E 23. Patients who received any live, attenuated vaccine within 3 months prior to the baseline 
visit, such as varicella-zoster, oral polio or rubella vaccines. 
E 24. Patients who are positive for hepatitis B surface antigen (HBsAg) or are positive for total 
hepatitis B core antibody (HBcAb) with negative hepatitis B surface antibody (HBsAb) or 
are positive for both HBcAb and HBsAb with presence of HBV DNA at screening. 
E 25. Patients who are positive for hepatitis C antibody (HCV Ab). 
E 26. Patients who are positive for human immunodeficiency virus (HIV) antibody test at 
screening or who previously had a positive HIV antibody test, or who are suspected to be 
positive for HIV. 
E 27. Patients with a history of recurrent herpes zoster or active herpes zoster. 
E 28. Patients with a history of prior articular or prosthetic joint infection. 
E 29. Prior or current history of malignancy, including lymphoproliferative diseases, other than 
adequately treated carcinoma in-situ of the cervix, non-metastatic squamous cell or basal 
cell carcinoma of the skin, within 5 years prior to the baseline visit. 
E 30. Prior or current history of other significant concomitant illness(es) that, according to 
Investigator's judgment, would adversely affect the patient's participation in the study. 
These include, but are not limited to, cardiovascular (including Stage III or IV cardiac 
failure according to the New York Heart Association classification), renal, neurological 
(including demyelinating disease), active infectious diseases, endocrinological, 
gastrointestinal, hepato-biliary, metabolic, pulmonary, non-malignant lymphoproliferative 
disease or other lymphatic disease(s). 
E 31. Patients who have had surgery within 4 weeks prior to the screening visit or with planned 
surgery during the course of the study. 
E 32. Patients with a history of a systemic hypersensitivity reaction, other than localized 
injection site reaction, to any biologic drug and known hypersensitivity to any constituent 
of the sarilumab product. 
E 33. Patients with any of the following laboratory abnormalities at the screening visit: 
• Hemoglobin <8.5 g/dL. 
• White blood cells <3000/mm3. 
• Neutrophils <2000/mm3. 
• Platelet count <150 000 cells/mm3. 
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• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 x upper limits 
of normal (ULN). 
• Bilirubin (total) >ULN, unless documented Gilbert's disease diagnosed by genetic testing 
• Presence of severe uncontrolled hypercholesterolemia (>350 mg/dL, 9.1 mmol/L) or 
hypertriglyceridemia (>500 mg/dL, 5.6 mmol/L). 
• Patients with a calculated creatinine clearance <30 mL/minute (using Cockroft-Gault 
formula). 
Note: Laboratory parameters may be repeated once during the open screening period if 
judged to be spurious or due to technical error in order to determine eligibility. 
E 34. Patients with a history of inflammatory bowel disease or severe diverticulitis or previous 
gastrointestinal perforation. 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
Details of investigational medicinal product IMPs are provided in Table 1. 
Table 1 - Summary of investigational medicinal products  
 
Name of 
IMP  
Pharmaceutical 
forms 
Dose of drug 
per 
administration 
Route and 
method of 
administration 
Treatment 
duration 
Double blind 
phase of 
sarilumab 
Sarilumab or 
matching 
placebo 
Single-use 1.14 mL prefilled 
glass syringes containing 
175 mg/mL (200 mg) of 
sarilumab or placebo 
solution for injection 
Sarilumab 200 mg, 
or matching placebo 
Subcutaneous route 
52 weeks 
Double blind 
phase of 
sarilumab 
Sarilumab or 
matching 
placebo 
Single-use 1.14 mL prefilled 
glass syringes containing 
131.6 mg/ml (150 mg) of 
sarilumab solution for 
injection 
Sarilumab 150 mg 
(an option only for 
patients who had lab 
abnormality) or 
matching placebo  
Subcutaneous route 
 
In the case of 
dose reduction 
 
 
 
 
 
 
Double blind 
phase 
Prednisone or 
matching 
placebo 
1 and/ or 5 mg over-
encapsulated tablet or over-
encapsulated placebo 
 
Oral administration 
52 weeks 
(Combination 
of prednisone / 
matching 
placebo per 
Appendix A) 
Open label 
≤5 mg add-
on 
Prednisone  
1 mg  
Commercial TABLETS 
 
Oral administration 
In the case of 
flare within the 
first 12 weeks 
after 
randomization 
Additional detail regarding the method of administration 
8.1.1 Sarilumab or matching placebo:  
Formulation: 
Sarilumab drug product will be provided as single-use 1.14 ml prefilled glass syringes containing 
131.6 mg/mL (150 mg), 175 mg/mL (200 mg) of sarilumab or placebo solution for SC injection. 
No preparation at the clinical site is required. 
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Route of Administration: 
Sarilumab will be administered SC in the abdomen or thigh when self-injections or also in upper 
arm (lateral side) by a professional or a non-professional caregiver. It is preferred that SC 
injection sites be alternated between the 4 quadrants of the abdomen (except the navel or waist 
area) or the thigh (front and side). Each drug administration requires a single injection. 
Patients and/or their non-professional caregivers will be trained to prepare and administer study 
drug at the start of the study. This training must be documented in the subject’s study file. The 
study staff should review the patient’s self-administration technique at Visit 2 (Week 0). For 
doses not given at the study site, diaries will be provided to record information pertaining to those 
injections. If the patient is unable or unwilling to administer study drug, arrangements must be 
made for a qualified site personnel or a caregiver to administer study drug doses that are not 
scheduled to be given at the study site. 
Dose regimen: 
The IMP (sarilumab or matching placebo) should be administered every 14 days as per protocol 
IMP administration schedule; however, an IMP administration time window of ±3 days is 
permitted in exceptional circumstances (eg. laboratory test result pending, or an ongoing AE or 
patient schedule difficulty). For subsequent IMP administrations the initial IMP administration 
schedule should be followed again (see Table 1). 
An interval of at least 11 days between 2 IMP (sarilumab and matching placebo) doses must be 
maintained. 
If the study visit is not performed at the site as scheduled, the dose will be administered as 
described above, either by the patient, qualified site personnel, and/or their caregiver(s). 
On the days when the patient has a study visit, the IMP will be administered following clinic 
procedures and blood collection. 
Patients will be monitored for at least 30 minutes after each dose of sarilumab (or up to 2 hours as 
per country specific requirements) for any signs or symptoms of any medical events. In the case 
that the injection is administered by caregiver or self-injection, patients should be instructed to 
monitor themselves for any signs or symptoms of any medical events.   The total duration of 
treatment is 52 weeks. 
Dose modification/reduction: 
Sarilumab dose may be reduced to 150 mg q2w in a blinded manner to treat neutropenia, 
thrombocytopenia and/or elevated liver transaminases. Please see Section 10.5.6 for further 
details. In addition, sarilumab dose can also be temporarily discontinued as described in 
Section 10.4.1. The decision to reduce the sarilumab dose and/or to temporarily discontinue it will 
be made by the investigator. 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, sarilumab or matching placebo may be supplied from the site to 
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the patient via a Sponsor-approved courier company where allowed by local regulations and 
approved by the subject. 
Post-trial access to sarilumab will be in compliance with all applicable national and local laws and 
regulations, including safety reporting obligations. 
8.1.2 Prednisone or matching placebo:  
Formulation:  
1 and/ or 5 mg over-encapsulated tablet or over-encapsulated matching placebo 
Route of Administration:  
Prednisone or matching placebo will be administered orally.  
Dose regimen: 
All patients will receive prednisone treatment with different regimen depending on the assigned 
group (see Appendix A). Patients will receive prednisone and/or prednisone matching placebo in 
order to ensure the double-blind CS tapering regimen as defined below is maintained. The initial 
dose of prednisone for both groups will be 15 mg/day for the first 2 weeks after randomization. 
• For Group 1: From Week 2 to Week 13, patients will receive gradually decreasing dose 
levels of prednisone (see Appendix A). From Week 14 onwards, patients without flare will 
receive prednisone matching placebo. 
• For Group 2: From Week 2 to Week 51, patients will receive gradually decreasing dose 
levels of prednisone (prednisone or combination of prednisone and placebo to prednisone) 
as shown in Appendix A. 
There will be 2 phases to each double-blind prednisone taper regimen: 
• Phase 1: Initial 2 weeks after randomization (beginning of Week 0 to end of Week 1) 
when all patients will receive prednisone 15 mg/day. 
• Phase 2: 50 weeks (beginning of Week 2 to end of Week 51) following Phase 1. 
Prednisone and matching placebo will be used to maintain the blinding of the tapering 
regimen for both treatment arms.  
During the prednisone taper, patients will be supplied with monthly kit containing 4 weekly 
blister packs which will clearly indicate the number of tablets to be taken per day. The monthly 
kits and blister packs will be numbered, and it is important that the blister packs be used in 
sequential order and that 7 days of prednisone from each blister be taken by the patient before 
starting the next blister pack. If a scheduled study visit occurs before the target date, the patient 
should complete the blister pack assigned for that particularly week before using the sequentially 
numbered blister packs dispensed at the scheduled study visit.  If tablets are missed or skipped, 
patients should not use the missed tablets before resuming on the blister packs as scheduled. 
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Patients will be trained in the use of the prednisone treatment kit and weekly prednisone blister 
packs at the baseline visit. This training will include instruction on use of the blister packs in the 
appropriate order and use of the “spare” row of tablets in the case of loss of a tablet during dosing. 
The training must be documented in the patient’s study file. 
The daily encapsulated dose may contain prednisone, placebo, or a combination of the two. The 
number of tablets to be taken each day will vary but will not be consistent with the dosage of 
prednisone. The number of tablets to be taken daily may increase or decrease during the tapering 
schedule but will not exceed 6 tablets per day. 
In the later stages of the study where visits are more than 1 month apart, an interim visit may be 
required for IMP dispensing between protocol scheduled on-site visits. As an alternative to these 
visits, prednisone may be supplied from the site to the patient via a sponsor-approved courier 
company where allowed by local regulations and approved by the subject. 
Refer to Appendix A for detailed standardized CS taper regimen during the double-blind study 
treatment period. 
8.1.3 Add on prednisone taper in the case of flare within initial 12 weeks  
During the initial 12 weeks of prednisone taper, treatment for one flare before Week 12 is 
permitted if it can be successfully treated with a low dose of prednisone (≤5 mg/day) to add on to 
the CS tapering regimen provided that all other sustained remission parameters are met. The 
add-on prednisone must be completed by Week 12. 
The prednisone for this add-on taper is provided in an open label manner consisting of 30 count 
blister (1 mg each) in a child resistant wallet. It is up to the investigator to decide on the CS 
dosage (with a maximum dose of (≤5 mg/day) and taper schedule/duration according to the 
patient's disease status. The quantity of tablets to be taken daily will be written on the wallet and 
recorded in the eCRF. The patient will need to be monitored and in close communication with the 
site to ensure patients have taken the correct quantity of prednisone until the add-on taper is 
completed prior to Week 12. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
Prednisone for rescue therapy  
If a patient experiences a disease flare or cannot adhere to the per protocol prednisone tapering 
schedule including the 5mg prednisone add-on prior to Week 12, then the patient must stop the 
per protocol prednisone taper and instead may receive commercial CS as a form of rescue therapy, 
per investigator's clinical judgment. The commercial CS will be reimbursed by the Sponsor. The 
patient should continue in the double-blind period of the study for the full 52 weeks and should 
continue to receive blinded sarilumab or matching placebo injections unless contraindicated by 
safety concerns and complete the remainder of the study assessments.  
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Once the patients are on the rescue therapy at the discretion of investigators, it is not allowed for 
them to return to per protocol prednisone taper regimen. 
8.3 
BLINDING PROCEDURES  
8.3.1 Methods of blinding  
8.3.1.1 Blinding of IMP:  
Blinding of Sarilumab 
The list of treatment kit numbers will be generated by the Sanofi Clinical Supplies Department. A 
patient randomization list will be generated by the interactive response technology (IRT). Both the 
randomization and treatment kit lists will be loaded into the IRT. 
Based on the double blinded study design, the investigators and patients will be blinded to the 
allocation of the active sarilumab and placebo treatment arms. 
Sarilumab and matching placebo will be provided in matching glass prefilled syringes in kits. For 
example, every 2 weeks, the patient allocated to Group 1 will receive 1 sarilumab prefilled syringe 
(PFS), the patient allocated to Group 2 will receive a sarilumab matching placebo PFS. 
The treatment kit numbers will be obtained by the Investigator at the time of patient 
randomization and subsequent patient scheduled visits via IRT that will be available 24 hours a 
day. 
In accordance with the double-blind design of the randomized treatment period, Investigators will 
remain blinded to study treatment and will not have access to the randomization (treatment codes) 
except under exceptional medical circumstances. Please refer to Section 10.6 for suspected 
unexpected adverse drug reaction unblinding by the Sponsor. 
A dose reduction from 200mg to 150mg for sarilumab treatment can be requested by the Safety 
Assessor in the case of laboratory abnormalities. IRT system will apply the dose reduction in a 
blinded manner only if the patient is receiving the 200 mg dose such that the Efficacy Assessor is 
unaware of the request for dose reduction. 
Blinding of Prednisone  
Based on the double-blind study design, the investigators and patients will be blinded to the 
allocation of the different protocol defined CS-taper regimens. 
Prednisone will be provided in blister pack suitable for double blinding as per assigned protocol 
defined CS-taper regimen. For example, every week, the patient will take the PS supplied in 
1 blister package. 
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The list of treatment kit numbers will be generated by the Sanofi Clinical Supplies Department. A 
patient randomization list will be generated by the IRT. Both the randomization and treatment kit 
lists will be loaded into the IRT. 
The treatment kit numbers will be obtained by the Investigator at the time of patient 
randomization and subsequent patient scheduled visits via IRT that will be available 24 hours a 
day. 
In accordance with the double-blind design of the randomized treatment period, Investigators will 
remain blinded to study treatment and will not have access to the randomization (treatment codes) 
except under exceptional medical circumstances. 
8.3.2 Randomization code breaking during the study  
In case of an adverse event (AE), the code may only be broken in circumstances when knowledge 
of the IMP (Sarilumab and Prednisone) is required for treating the patient. 
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. If the blind is broken, 
the Investigator must document the date, time of day and reason for code breaking. 
If the blind is broken by the Investigator, for the above stated purpose, the patient must be 
withdrawn from treatment and will be asked to complete an EOT visit (Visit 12) that should be 
scheduled at the time of the treatment discontinuation, if possible. If not possible, the EOT visit 
should be scheduled as soon as possible after treatment discontinuation. The IRT should be 
notified of EOT. 
Knowledge of certain laboratory data may result in inadvertent unblinding of a patient’s 
treatment. In order to maintain the blind, an Independent Safety Assessor, who is the only 
individual who can have access to laboratory data (except post-baseline CRP), will be assigned at 
the study site to perform regular review of the patient’s laboratory data. 
At the facilities where the PK measurements, ADA and selected biomarkers are determined, the 
samples will be analyzed prior to database lock leading to unblinding of responsible bioanalysts. 
Bioanalysts are excluded from the clinical trial team. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
The randomization treatment kit number is generated centrally by Sanofi. The IMPs are packaged 
in accordance with this list. Patients will be randomized to one of the two treatment groups via an 
IRT. Both the randomization and treatment kit lists will be loaded into the IRT. A patient will be 
considered randomized when the treatment number has been provided by the IRT. 
Patients who meet the entry criteria will be randomized to one of the two treatment groups at a 
ratio of 1:1. 
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At the screening Visit 1 (Day -28 to D-1), the site coordinator will contact the IRT to obtain a 
patient number for each patient who gives informed consent. Each patient will be allocated a 
patient number associated with the center and allocated in chronological order in each site. 
At the baseline Visit 2 (Week 0, D1), after confirming the patient is eligible for entry into the 
treatment period, the site coordinator will contact the IRT order to receive the first treatment 
allocation kit numbers. At subsequent visits during the treatment period, the site coordinator will 
call IRT to obtain the next treatment kit numbers. A confirmation fax/e-mail will be sent to the 
site after each assignment. 
Patients may be rescreened once upon investigator discretion.  Upon rescreen, a different patient 
identification will be issued. There is no requirement for a waiting period between the screen-
failure and the re-screening dates. The IRT report will flag rescreened patients. Patients who are 
re-screened must sign a new consent form and the Visit 1 procedures must be repeated (except 
chest X-ray if one was taken within 12 weeks of the new V1 (rescreen date) that clearly 
documents the exclusion of TB or if local guidelines and requirements for active screening of TB 
are followed). Any previously randomized patient cannot be rescreened. 
A randomized patient is defined as a patient who is registered and assigned a randomization 
number from the IRT. 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING  
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
The investigational products will be supplied in treatment kit boxes that are labeled in accordance 
with the local regulatory specifications and requirements and content information, dosing 
instructions and precautionary statement (“for clinical use only”). 
The number of treatment kits allocated to the patient will provide sufficient medication until the 
next clinic visit. An additional treatment kit, to provide medication to randomized patients in 
special circumstances (eg, a damaged kit) will be allocated by IRT if a “replacement call” is made 
to the IRT system. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.  
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound must be 
managed according to the rules provided by the Sponsor. 
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8.7 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMPs will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) must be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure (see Section 10.5.7). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for DTP (direct 
to patient) shipment, for which a courier company has been approved by the Sponsor), allow the 
IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any other 
manner. 
8.7.1 Treatment accountability and compliance  
Measures taken to ensure and document treatment compliance and IMP accountability include: 
• Proper recording of treatment kit number or packaging number as required on appropriate 
electronic case report form (eCRF) page for accounting purposes; 
• All medication treatment kits for sarilumab or matching placebo (whether empty or 
unused) are returned by the patient at each visit when a treatment dispensing is planned. 
- 
Except for the prefilled syringes that 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.  
• All packs of prednisone treatment (whether empty or unused) are returned by the patient at 
each visit when a treatment dispensing is planned. 
• The study coordinator tracks treatment accountability/compliance, either by diary, or by 
counting the number of used treatment kits/tablets/capsules and fills in the appropriate 
page of the patient treatment log.  
The monitor in charge of the study then checks the data entered on the IMP administration page 
by comparing them with the IMP that has been retrieved and the patient treatment log form. 
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8.7.2 Return and/or destruction of treatments  
All used, partially-used or unused treatments will be retrieved by the Sponsor. A detailed 
treatment log of the returned IMP will be established with the Investigator (or the pharmacist) and 
countersigned by the Investigator and the monitoring team. 
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy the used and unused IMP unless the Sponsor provides written authorization. 
8.8 
CONCOMITANT MEDICATION  
A concomitant medication is any treatment received by the patient concomitantly with any 
IMP(s). 
The use of any biologics for treatment of PMR during the study is not permitted throughout the 
study treatment and until 6 weeks following the last sarilumab or matching placebo administration 
unless otherwise indicated. If any of these treatments is used, the patient should be discontinued 
from IMP treatment but the patient will remain in the study and continue to be monitored for 
safety. 
Administration of any live (attenuated) vaccine is contraindicated until 3 months following the 
last sarilumab or matching placebo administration. 
Treatment with non-biological disease modifying anti-rheumatic drugs [DMARDs] (such as 
alkylating agents, hydroxychloroquine, CsA, MMF, AZA, etc) is not permitted during the course 
of the study, unless used for the purpose of rescue therapy. 
During the course of study, for patients in need of rescue therapy as per investigator judgment, 
corticosteroids should be the agent of first choice. Patients may continue SC administration of 
sarilumab or matching placebo only if CS is used as rescue therapy. If the patients remain 
symptomatic despite CS rescue therapy, then other treatment options including non-biological 
immunosuppressive drugs may be used (patient must have symptomatic PMR disease) and the 
patient must be discontinued from the study treatment and considered a non-responder. 
Methotrexate with a dose not exceeding 15 mg per week is permitted if the dose has been stable 
for at least 3 months prior to baseline. The dose should also remain stable (may be reduced or 
discontinued for safety reasons, if necessary), throughout the study treatment duration and until 
6 weeks following the last SC IMP (sarilumab or matching placebo) administration. 
Treatment with any IMP other than sarilumab and CS defined by protocol is not permitted. 
8.8.1 Steroids  
There will be two standardized prednisone-tapering regimens in this study with one that lasts for 
14 weeks (Group 1) and the other one lasting for 52 weeks (Group 2) (Appendix A). The total 
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duration of prednisone therapy for each particular patient will depend on the treatment group to 
which the patient is randomized. 
If the patient develops an AE for a condition not related to PMR that requires the introduction of a 
new systemic CS medication, the new medication and AE must be recorded on the patient eCRF. 
Furthermore, the Sponsor must be notified as soon as possible at the time of the steroid dose 
modification (eg, within 24 hours) in order to discuss the patient’s status with regards to ongoing 
study participation. Intranasal, inhaled, ophthalmic or topical CSs as per label are permitted 
throughout the course of the study. 
8.8.2 Nonsteroidal anti-inflammatory drugs and analgesics  
As there are limited treatment options for pain, all analgesics, including nonsteroidal anti-
inflammatory drugs (NSAIDs), are allowed. These analgesics must be held for 24 hours prior to 
efficacy assessment, including physical function and quality of life assessments. 
Acetaminophen use should be limited to ≤4 g every 24 hours. Specific attention should be paid to 
co-administration of hepatotoxic drugs. 
8.8.3 Treatment for dyslipidemia  
Treatments for dyslipidemia, such as statins, are permitted. Doses of medications for dyslipidemia 
should be stable for at least 6 weeks prior to screening visit. Any change and reason for change 
should be recorded on the patients’ electronic case report form (eCRF). Anti-IL-6 drugs, including 
sarilumab are known to increase serum total cholesterol and this effect will be closely monitored 
during the study. If, during the treatment period of this study, patients are found to have 
significant increase in cholesterol levels, or other lipid abnormalities, then cholesterol lowering 
therapy with statins, or other treatment(s) for dyslipidemia, per local guidelines, should be 
initiated or the dose adjusted. A referral to a specialist should be considered when dyslipidemia is 
difficult to manage, such as patients who have elevated low-density lipoprotein (LDL) in spite of 
being treated with maximum dose of statins. 
8.8.4 Glucocorticoid-Induced Osteopenia/Osteoporosis Prevention and Treatment  
Oral calcium, 25-hydroxy vitamin D supplementation, and bisphosphonate therapy 
(eg, alendronate 70 mg weekly or zolendronate 4 mg annually) for the prevention or treatment of 
glucocorticoid-induced osteoporosis are permitted. The doses and treatment duration should 
comply with local practice or clinical guidelines at the discretion of the Investigator. 
8.8.5 CYP Substrates  
IL-6 has been shown to reduce Cytochrome P450 (CYP)1A2, CYP2C9, CYP2C19, and CYP3A4 
enzyme expression in in vitro studies. Therefore, it is expected that for a molecule that 
antagonizes cytokine activity, such as sarilumab, the formation of CYP450 enzymes could be 
normalized, and as a result drugs that are metabolized by these CYP450 isoforms may have 
decreased levels when PMR patients start receiving sarilumab. As a precautionary measure, drugs 
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which are metabolized via these cytochromes and with a narrow therapeutic index should be 
adjusted if needed: doses should be increased to maintain efficacy after initiation of sarilumab and 
decreased after sarilumab is stopped. Some examples of CYP450 substrates with a narrow 
therapeutic index, requiring monitoring of effect are warfarin or monitoring of drug concentration 
include, but are not limited to, the following: warfarin, 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®). 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
PRIMARY ENDPOINT  
9.1.1 Primary efficacy endpoint  
Proportion of patients achieving sustained remission at Week 52. Sustained remission at Week 52 
is defined by having met all of the following parameters: 
1. Achievement of disease remission no later than Week 12 
AND 
2. Absence of disease flare from Week 12 through Week 52 
AND 
3. Sustained reduction of CRP (to <10 mg/L, with an absence of successive elevations to 
≥10 mg/L) from Week 12 through Week 52 
AND 
4. Successful adherence to the prednisone taper from Week 12 through Week 52. 
Successful adherence to the prednisone taper may include the use of any excess prednisone 
(beyond the per protocol CS tapering regimen) with a cumulative dose of less than or equal to 
100mg (or equivalent), such as those employed to manage an AE not related to PMR. 
Disease remission is defined as resolution of signs and symptoms of PMR, and normalization of 
CRP (<10 mg/L). 
Note: A single CRP elevation (≥10 mg/L) is not considered absence of remission unless CRP 
remains elevated (≥10 mg/L) for two consecutive study visits. 
Signs and symptoms of PMR 
Evaluation for clinical signs and symptoms by the Efficacy Assessor at every study visit 
according to the schedule of assessment should include, but are not limited to, the following: 
• Morning stiffness and/or pain, in the neck, shoulder and/or hip girdles 
• Limited range of motion of the shoulders and/or hip girdles 
• Constitutional symptoms, such as fatigue, weight loss and low-grade fever   
• Other features judged by the clinician-investigator to be consistent with a PMR flare 
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Flare is defined as either 1) recurrence of signs and symptoms attributable to active PMR plus an 
increase in CS dose due to PMR, or 2) elevation of ESR attributable to active PMR plus an 
increase in CS dose due to PMR. 
Increase in CS dose is defined as: 
• Any dose increase during the protocol-defined steroid taper 
• Re-initiation of prednisone therapy after the protocol defined taper has been completed 
Note: During the initial 12 weeks of prednisone taper, treatment for one flare before Week 12 is 
permitted if it can be successfully treated with a low dose (≤5 mg/day) prednisone add-on taper 
regimen (completed prior to Week 12) and provided that all other sustained remission parameters 
are met. 
Blinding of CRP and ESR assessment results 
Investigators including Efficacy Assessors, patients and sponsor will remain blinded on C-reactive 
protein (CRP) and ESR results (except Screening and Baseline). Safety Assessors will also be 
blinded on post-baseline CRP but will have access to ESR results.  ESR kits will be provided by 
the central laboratory while the test will be performed locally at the site. Results (the distance in 
millimeters (mm) that red blood cells has descended in 1 hour) will be blinded to investigators 
including Efficacy Assessors and staff directly involved in the efficacy assessment of study 
patients. 
9.2 
SECONDARY ENDPOINTS  
9.2.1 Secondary efficacy endpoints  
9.2.1.1 Components of sustained remission composite measure at Week 52  
• Patients who achieved of disease remission by Week 12. 
• Patients who have absence of disease flare from Week 12 through Week 52. 
• Patients who have normalization of CRP (decrease to <10 mg/L) with sustained 
normalization from Week 12 through Week 52. 
• Patients who successfully adhere to the prednisone taper from Week 12 through Week 52. 
Successful adherence to the prednisone taper may include the use of any excess prednisone 
(beyond the per protocol CS tapering regimen) with a cumulative dose of less than or equal to 
100mg (or equivalent), such as those employed to manage an AE not related to PMR. 
9.2.1.2 Total cumulative corticosteroid (including prednisone) dose over 52 weeks  
The total cumulative prednisone (or equivalent) dose over the 52-week period for each group will 
be analyzed as a secondary endpoint. 
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9.2.1.3 Time to first PMR flare  
The duration to first PMR flare from clinical remission up to 52 weeks for each group will be 
analyzed. 
9.2.1.4 Composite glucocorticoid toxicity index and components  
Glucocorticoid toxicity index (GTI) is a composite scale designed to assess glucocorticoid related 
morbidity and potential steroid-sparing effect of treatment alternatives. The Composite GTI and 
Specific List constitute the overall GTI. The Composite GTI consists of nine domains and 
31 items that assess the potential side effects of glucocorticoid, and include evaluation of body 
mass index (BMI), glucose tolerance, blood pressure, lipid metabolism, bone mineral density, 
glucocorticoid-induced myopathy, skin toxicity, neuropsychiatric toxicity and infection. These are 
the potential CS toxicities that are likely to occur during the course of a clinical trial and may vary 
depending on the extent of CS exposure, and that are weighted and scored (see Appendix C). 
The domains of the Composite GTI and the specific list of the GTI will be assessed at baseline, 
Week 12 (Visit 6), Week 24 (Visit 9), Week 40 and Week 52 (except bone density which will be 
assessed at Baseline and Week 52 only). Glucocorticoid toxicity or the changes in GC toxicity 
(comparison with baseline data) for each domain will be scored (score range from -36 to 439) 
based on the information from laboratory, vital sign and clinical assessments and review of 
concomitant medications. The composite GTI can be reported as both a total score and domain-
specific scores, in order to account for scenarios when improvements in certain domains 
compensate for worsening in others. 
Bone Mineral Density assessment will be performed at the baseline (Visit 2) and Week 52 
(Visit 12) using a Dual-Energy X-ray Absorptiometry (DXA) scan. The scan can be performed 
within ± 14 days of Visit 2 and within -14 days of Visit 12 and needs to include the lumbosacral 
and femoral neck regions.  However, the baseline visit DXA scan is not required if there is one 
available within 12 weeks of baseline that includes the assessment of the lumbosacral and femoral 
neck regions. In order to minimize variability, the same machine should be used each time to 
obtain the scan and the machine should be well calibrated according to the recommendations of 
the machine’s manual. 
The Specific List consists of 11 domains and 23 items that are not weighted, and captures other 
CS related toxicities not found in the Composite GTI (refer to Appendix C). Information related to 
the domains/items of the Specific List will be collected if available at the scheduled time points 
(baseline, Week 12, Week 24, Week 40 and Week 52), but no pre-specified assessments related to 
the domains in the Specific List (refer to Appendix D), unless for cause, are required within the 
conduct of this study protocol. 
9.2.2 Safety endpoints  
9.2.2.1 Adverse events  
Refer to Section 10.5 to Section 10.5.1.1 for details. 
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9.2.2.2 Laboratory safety variables  
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry) 
and urinalysis. Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. 
The following laboratory tests are performed, at designated visits specified in the study flow 
charts (Section 1.2): 
• Hematology: hemoglobin, hematocrit, red blood cell count and morphology (if red blood 
cell count is abnormal), white blood cell count, white blood cell differential, absolute 
neutrophil count (ANC) and platelet count. 
• Full chemistry profiles: blood urea nitrogen, calcium, chloride, bicarbonate, phosphate, 
creatinine and creatinine clearance, lactate dehydrogenase, sodium, potassium, total 
protein, uric acid, and albumin, alkaline phosphatase, ALT, AST, total bilirubin, 
conjugated bilirubin, and unconjugated bilirubin. 
• ANA will be checked only at screening (Visit 1), baseline (Visit 2) and End of Treatment 
(EOT) visits. 
• Fasting lipids: total cholesterol, high density lipoprotein cholesterol, low density 
lipoprotein cholesterol, and triglycerides. 
• Fasting glucose, insulin and HbA1c. 
• For women of child-bearing potential: serum pregnancy test Beta-HCG at screening 
(Visit 1) and urine pregnancy tests during the remainder of the study. 
• QuantiFERON® -TB Gold evaluation (screening visit only). 
• HIV-1/HIV-2 antibody testing (screening visit only). 
• Hepatitis B and C serology (screening visit, or in case of liver injury): Hepatitis B: 
HBsAg, total HBcAb, HBsAb, and HBV DNA (if necessary); Hepatitis C: HCV Ab. 
• Urinalysis including specific gravity, pH, glucose, ketones, blood, protein, nitrites, 
leukocytes, urobilinogen and bilirubin (by dipstick) at screening visit only. If any 
parameter on the dipstick is abnormal, a urine sample should be sent to the central 
laboratory for testing. If positive for proteins, microscopic analysis is performed by central 
laboratory. 
Anti-sarilumab antibody (see Section 9.5.2) 
Specimens are submitted for analysis as per the instructions of the central laboratory. 
9.2.2.3 Chest x-ray  
A standard PA chest X-ray (lateral view is also recommended but not required) is required during 
the screening period if no chest imaging (X-ray, CT, MRI) is available within the previous 
12 weeks of V1 that clearly documents the exclusion of TB or if it does not follow the local 
guidelines and requirements for active screening of TB. In countries for which a specific approval 
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procedure for the x-ray is required by a different committee than the local EC/IRB, a chest MRI 
between V1 and V2 can be performed. A radiologist or pulmonologist interpretation (signed and 
dated) should note the absence of calcified granulomas and/or pleural scaring and/or any findings 
consistent with TB. The information must be documented in the patient's chart and in the eCRF at 
the screening visit. In case of any symptom suggestive of TB at any time during the course of the 
study, a chest X-ray should be performed and conclusion recorded. 
Repeat chest radiographs should be performed as indicated by local treatment guidelines or 
practice for monitoring while on immunosuppressive/immunomodulatory therapy. If such 
guidelines are not available/applicable, routine chest X-rays should be performed when clinically 
necessary. 
9.2.2.4 Vital signs  
Vital signs include temperature, BP, and heart rate. They will be collected at every site visit prior 
to IMP administration. Weight will be collected at the screening Visit 1 (Day -28 to Day -1), 
Visit 2 (Week 0), Visit 6 (Week 12), Visit 9 (Week 24), Visit 11 (Week 40), and Visit 12 
(Week 52). Weight should be taken with the patient wearing undergarments or very light clothing 
and no shoes and with an empty bladder. The same scale is recommended to be used throughout 
the study. Height will be collected at Visit 1 during screening only. 
Body temperature 
Body temperature must be collected using the same method for a given patient. Any fever (body 
temperature ≥38°C) associated with infections should be recorded as an AE and the Investigator 
should perform all investigations necessary to rule out infection. 
Blood pressure 
Blood pressure must be measured, using the same method consistently. Blood pressure is 
determined at each study visit using the same well-calibrated apparatus. The same arm should be 
used to measure BP throughout the study. The blood pressure should also be obtained with the 
patient in the same position (recumbent preferred) each time. 
9.2.2.5 Physical examination  
A complete physical examination will be performed at the screening Visit 1 (Day -28 to Day -1) 
and Visit 12 (Week 52) or early termination visit, and a targeted physical examination will be 
performed at the baseline visit (Visit 2), Visit 6 (Week 12), Visit 9 (Week 24) and Visit 11 
(Week 40). Any clinically significant abnormalities should be reported in the patient eCRF as 
medical history if observed at Visit 1 or reported as an AE if observed during subsequent visits.  
9.2.2.6 Electrocardiogram variables  
A standard 12-lead electrocardiogram (ECG) will be performed at screening Visit 1. It will be 
used to determine if there is any clinically significant finding that would preclude the patient from 
participating in the study safely per protocol. 
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9.3 
OTHER EFFICACY ENDPOINTS  
9.3.1 Clinical Outcome Assessments  
9.3.1.1 Patient-Reported Outcomes  
Patients are asked to complete the patient-reported outcome (PRO) questionnaires described 
below at Visit 2 (baseline visit), Visit 6 (Week 12), at Visit 9 (Week 24), and Visit 12 (Week 52) 
(see Section 1.1 and Section 1.2). Translations of the PRO questionnaires, where not already 
available, will follow industry best practices (17). 
9.3.1.1.1 The functional assessment of chronic illness therapy fatigue scale  
The functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue) is a generic 
PRO instrument which includes 13 items to measure fatigue. Each item is rated by patients on a 
0 to 4 scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much). Scores 
are summarized to give a total score between 0 and 52. The recall period is the last 7 days (18). 
See Appendix H. 
9.3.1.1.2 EQ-5D-3L  
The EQ-5D-3L is a generic PRO instrument which measures health status. There are two 
components to the EQ-5D; a health utility index score derived from 5 items addressing mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression “today”, and a current (“right 
now”) general health status score derived from a single 0-100 Visual Analog Scale (VAS).  The 
items contributing to the EQ-5D-3L health utility index score each have the same 3-point response 
scale (1 = no problem, 2 = moderate problems, 3 = severe problems). The VAS is anchored with 
‘Best imaginable health state’ and ‘Worst imaginable health state’ (19). Refer to Appendix I. 
9.3.1.1.3 Short form 36v2 (SF-36v2)  
The Short Form 36v2 (SF-36v2) is a short-form generic, 36-item PRO instrument that evaluates 
8 multi-item dimensions of health (20): physical functioning (PF; 10 items), social functioning 
(SF; 2 items), role limitations due to physical problems (RP; 4 items), role limitations due to 
emotional problems (RE; 3 items), mental health (MH; 5 items), energy/vitality (VT; 4 items), 
bodily pain (BP; 2 items), and general health perception (GH; 5 items) . For each dimension, item 
scores are coded, summed, and transformed on to a scale from 0 (worst possible health state 
measured by the questionnaire) to 100 (best possible health state). Two standardized summary 
scores can also be calculated from the SF-36v2; the physical component summary (PCS) and the 
mental health component summary (MCS) on a scale from 0-100 (21). Refer to Appendix J. 
9.3.1.1.4 HAQ-DI  
The HAQ-DI was developed to assess physical functional status in adults with arthritis but is now 
commonly used among many rheumatologic conditions. It contains 25 items: 20 4-point Likert-
scale questions assessing 8 physical dimensions of activities of daily living (dressing and 
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grooming, arising, eating, walking, hygiene, reaching, gripping, and errands and chores), 
13 additional questions assessing use of assistive devices, and 8 additional questions assessing 
help received from another. The recall period is the last week. To calculate the HAQ-DI Score, 
there are 3 steps:  
1. Sum the 8 category scores by using the highest sub-category score from each category. 
2. Adjust for use of aids/devices and/or help from another person when indicated. 
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). 
In addition to the above, the HAQ-DI has two additional questions, measured on 0-100 scales: 
• How much pain have you had IN THE PAST WEEK? 
• Please rate how well you are doing on a scale of 0 to 100 (0 represents “very well” and 
100 represents “very poor” health). 
These questions, measuring pain and global assessment respectively, are independently scored. 
Refer to Appendix K. 
9.3.1.2 Clinician-reported Outcomes  
9.3.1.2.1 Physician global assessment of disease activity- Visual Analog Scale [MD-VAS]  
The efficacy assessor will be requested to rate the patient’s disease activity on an anchored 
100 mm horizontal VAS where 0 is considered not active and 100 is considered the most active 
(refer to Appendix L). 
9.4 
PHARMACODYNAMIC  
9.4.1 Pharmacodynamic variables  
• Changes in ESR and CRP from baseline through Week 52. 
• Changes in IL-6 level and soluble IL-6 receptor (sIL-6R) through Week 52. 
• Changes in markers of inflammation and disease activity over time as assessed in 
circulating immune cell types, circulating proteins, and gene expression changes as 
follows (refer to Appendix M). 
- 
Markers of inflammation will be assessed in a subset of patient population during the 
study at V2 (baseline), V4 (Week 4), V9 (Week 24) as measured by immune cell 
phenotyping.  Approximately 80 patients (40 patients from each treatment arm) will be 
selected for this analysis. Please refer to Lab Manual for details. 
- 
Disease activity assessment of PMR patients will be assessed via evaluation of 
circulating proteins and gene expression. 
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1. Future Use Samples (Optional): Serum or plasma samples will be collected at V2 
(baseline), V3 (Week 2), V6 (Week12), V9 (Week 24), V12 (Week 52 EOT) for 
circulating protein measurements (a separate future use sample informed consent needs to 
be obtained). 
2. Pharmacogenetic (Optional): DNA samples will be collected at V2 (Baseline), or any 
treatment or follow up visit, RNA samples will be collected at V2 (Baseline) and/or pre-
dose at V3 (Week 2) (refer to Section 1.2) for gene expression measurement (a separate 
pharmacogenetics informed consent needs to be obtained; refer to Section 9.6.1). 
For all patients, samples will be collected for assessment of PD parameters including but 
not limited to, CRP, ESR, IL-6 and sIL-6R levels, and immune cell phenotyping. The 
Investigator is discouraged from testing IL-6 locally. Samples will be taken pre-dose if 
taken on a dosing day (see Appendix M). 
9.5 
PHARMACOKINETICS AND ANTI-DRUG ANTIBODIES  
9.5.1 Sampling time  
Pre-dose blood samples at each study visit will be collected for determination of serum sarilumab 
concentration (functional), and antibodies to sarilumab as designated on the randomized treatment 
period study flow chart (see Section 1.2). The date of collection should be recorded in the patient 
eCRF. 
Note: Serum sarilumab concentrations (functional), and anti sarilumab antibodies results are 
blinded to both Investigator and Sponsor. 
If a serious adverse event (SAE) occurs in a patient, blood samples should be collected for 
determination of sarilumab concentration (functional), and antidrug antibody (ADA) assessment 
at or near the onset and completion of the occurrence of the event, if possible. The exact date and 
time of sample collection and last dose must be recorded on the label and the unscheduled PK 
page in the eCRF should be filled in. 
9.5.2 Sample handling procedure  
Special procedures for collection, storage and shipping of serum are described in separate 
operational manuals. 
9.5.3 Bioanalytical method  
Serum samples will be assayed using validated methods as described in Table 2.  
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Table 2 - Summary of bioanalytical methods for functional sarilumab and anti- sarilumab antibody  
Bioanalysis 
Functional sarilumab 
Anti-sarilumab antibody 
Matrix 
Serum 
Serum 
Analytical Technique 
ELISA 
Electrochemiluminescence 
 
 
 
Site of Bioanalysis 
Regeneron 
Regeneron 
ELISA = enzyme-linked immunosorbent assay 
9.5.4 Pharmacokinetics parameters  
Pre-dose serum sarilumab concentrations at Week 0 and sarilumab trough levels at Weeks 2, 4, 
12, 16, 24, 32, 52 and Week 58 will be collected.  In addition, post-dose sample will be taken 
4-7 days after the Week 24 (Visit 9). 
9.6 
PHARMACOGENETIC ASSESSMENT  
9.6.1 Optional stored DNA and RNA samples  
Pharmacogenetic testing is optional and voluntary. Written informed consent must be obtained 
before sampling.  
For those patients who provided written consent to the collection of the optional pharmacogenetic 
samples, blood samples for exploratory genetic analysis of DNA and RNA will be collected at the 
study visit as specified in the study flow chart (Section 1.2), and these samples will be stored for 
future analysis. Specific procedures for collection, storage, and shipping of pharmacogenetic 
samples will be provided in a lab manual (refer Appendix M for further details). 
The blood DNA and RNA sample, and the DNA and RNA that is extracted, will be assigned a 
second number, a Genetic ID (de-identification code) that is different from the patient ID. This 
“double coding” is performed to separate a patient’s medical information and DNA and RNA 
data. 
The clinical study data (coded by patient ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by Genetic ID). The key linking patient ID and 
Genetic ID will be maintained by a third party, under appropriate access control. The matching of 
clinical data and pharmacogenetic data, for the purpose of data analysis, will be possible only by 
using this key, which will be under strict access control. All data will be reported only in coded 
form in order to maintain confidentiality. 
The aliquots of DNA and RNA sent to the bioanalytical laboratories for specific genetic testing 
will be destroyed after completion of that specific analysis and issuance of the related analytical 
data. 
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9.7 
FUTURE USE OF SAMPLES  
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patient(s) who have consented to it, the samples that are archived, unused or left 
over after planned testing may be used for other research purposes (any genetic analysis subject to 
additional consent per Section 9.6.1). For subjects who have consented to it, archival blood 
sample(s) will be collected at the visits specified in the study flow chart (see Section 1.2) for the 
purposes of evaluating circulating proteins. Additional details will be provided in the laboratory 
manual (refer Appendix M for further details). 
These samples will remain labelled with the same identifiers used during the study 
(ie, subject ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be 
located outside of the country where the study is conducted. The Sponsor has included safeguards 
for protecting subject confidentiality and personal data (see Section 14.3 and Section 14.5). 
9.8 
APPROPRIATENESS OF MEASUREMENTS  
The key to assessing the effectiveness of a novel therapy for PMR is to determine its ability to 
reduce the cumulative dose of CS used which in turn results in fewer CS associated toxicities 
while able to maintain disease remission. To this end, the primary endpoint is a composite one 
that assesses the ability to achieve a sustained disease remission by Week 12 with sarilumab while 
adhering to predefined prednisone taper that represents a substantial reduction in prednisone 
exposure compared to the current standard of care. It also assesses the durability of sarilumab’s 
treatment response (maintenance of remission) over an extended period of time compared to the 
current usual prednisone regimen, which is an important factor for a chronic disease like PMR. 
The secondary endpoints evaluate specific components of the primary endpoint. 
One of the other efficacy endpoints utilizes the GTI for the first time in a study of PMR patients to 
assess if there is less CS associated toxicity with sarilumab that employs a substantially shorter 
CS tapering regimen than the conventional CS tapering regimen per standard of care. Lastly, the 
patient and clinician reported outcomes will further evaluate the potential clinical benefits of 
sarilumab for the treatment of PMR. 
The safety assessments are performed in accordance to the known profile of sarilumab and will 
further inform the safety profile of sarilumab when administered to PMR patients. The PK and PD 
assessments will provide additional information related to the exposure of sarilumab and 
biological effect of sarilumab in PMR patients. 
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10 
STUDY PROCEDURES  
10.1 
INDEPENDENT EFFICACY AND SAFETY ASSESSORS  
A dual assessor approach will be required during this study in order to maintain the blind during 
the double-blind treatment period with sarilumab, placebo, and prednisone. The precise 
definitions of the efficacy and safety assessors’ roles and responsibilities are specified in the Dual 
Assessor Guidance Document supplied to the sites.  An overview of those definitions is provided 
below. 
Efficacy Assessor 
The Efficacy Assessor will be primarily responsible for completing the overall evaluation and 
management of PMR disease activity including the following: 
• Assessment of clinical signs and symptoms of PMR (without access to any central 
laboratory data including CRP and ESR) 
• Assessment of adherence to the protocol defined prednisone taper regimen or management 
of investigator-led open-label prednisone use (including the use of prednisone add-on 
and/or rescue corticosteroids per protocol) or other rescue therapy use 
The Efficacy Assessor should not have access to any central laboratory data.  If knowledge of the 
ESR is absolutely required in making a medical decision related to disease activity, the Efficacy 
Assessor may request the last available value obtained per protocol from the Safety Assessor or 
obtain a separate local laboratory value for ESR.  Otherwise it is strongly recommended for the 
Efficacy Assessor not to have access to any laboratory data.  Additionally, if necessary for the 
management of any safety concern for a particular patient that cannot wait to be addressed by the 
Safety Assessor, the Efficacy Assessor may arrange for local laboratory assessments to be 
performed and will have access to the results of these assessments. 
To ensure consistency of assessments, it is encouraged that efficacy evaluations throughout the 
study be conducted by the same Efficacy Assessor for all study visits for a given patient, 
whenever possible. 
It is mandatory that assessments by the Efficacy Assessor be completed before assessments by the 
Safety Assessor. 
The Efficacy Assessor may permanently discontinue oral IMP and initiate rescue CS in order to 
properly manage disease activity, if necessary.   In such a scenario, the SC IMP will continue per 
protocol unless a safety concern is raised by the Safety Assessor. 
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Safety Assessor 
The Safety Assessor will be responsible for assessing and managing any safety concerns of the 
patient during the course of the study. The specific responsibilities include: 
• Eliciting and recording of any clinical and/or laboratory AEs  
• Management of any clinical and/or laboratory AEs 
• Review of all laboratory data (except CRP after baseline) 
• Perform the assessments related to GTI 
The Safety Assessor may temporarily (or permanently) discontinue IMP (SC and/or oral) during 
the management of an AE and only the Safety Assessor may re-initiate the IMP upon his/her 
discretion.  If the IMP is permanently discontinued, both Efficacy and Safety Assessors should be 
informed in order to make subsequent medical management decisions. 
10.2 
VISIT SCHEDULE  
It is preferred that all study visits that require fasting blood samples to take place in the morning. 
The study visits occur on the planned dates (relative to randomization date), as scheduled. The 
visit schedule should be adhered to within the ±3 day visit window. In general, PRO assessments 
should be completed at the study site as part of the visit (per study flow chart) but prior to any 
meaningful communication with a health care professional or any other study procedures, unless 
noted otherwise in the suggested order of the study procedures for each individual visit described 
below. 
10.2.1 Visit 1: Screening from Day -28 to Day -1  
The following activities will be performed: 
• An explanation of the purpose, procedures, potential risks, and benefits of this study will 
be provided to the patient. 
• Informed consent signature and date will be collected. 
• If required locally, the locally provided consent for the required HIV screening test will be 
collected. 
• Call IRT to assign patient number and register screening visit. 
• Assess patient based upon inclusion and exclusion criteria. 
• Record patient demographic data. 
• Review medical, surgical, smoking and alcohol history. 
• Review prior and concomitant medication history. 
- 
For patients who are on >15mg/day (but not exceeding 20mg/day) of prednisone at 
screening and during the screening period, the Investigator should judiciously taper the 
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prednisone down to 15mg/day prior to randomization in order to prevent a disease 
flare upon entering the study at 15mg/day of prednisone. 
- 
Review family cardiovascular history. 
- 
Perform full physical examination. 
- 
Perform PMR clinical assessments. 
- 
If the ultrasound is employed in the diagnosis of PMR, then the ultrasound images 
need to be submitted to the central reader for confirmation that they fulfill the 
ultrasound part of the diagnostic criteria for PMR. 
- 
Perform tuberculosis assessment. 
- 
Perform blood sampling (fasting) for the following tests: 
- 
Hematology, chemistry 
- 
Fasting lipids, fasting glucose or insulin 
- 
HbA1c 
- 
CRP 
- 
ESR 
- 
Virology 
- 
Serum β-hCG pregnancy test (for WOCBP) 
- 
Quantiferon Gold Testing. (Refer to Section 10.8.1 
- 
Urinalysis (dipstick) 
- 
Measure vital signs (including systolic and diastolic BP [mmHg], heart rate [beats per 
minute] and body temperature [° C]. 
- 
Measure body weight [kg]. 
- 
Measure height [cm]. 
- 
Obtain 12-lead ECG. 
- 
Perform chest x-ray. (Refer to Section 9.2.2.3 and Section 10.8.1) 
- 
Schedule a Visit 2 within 28 days (maximum) from Visit 1. 
10.2.2 Double blind period (52 weeks)  
10.2.2.1 Visit 2/Baseline visit (Day 1, Week 0)  
• Review and record concomitant medication use. 
• Confirm eligibility by review of Inclusion/Exclusion Criteria 
• If the patient meets all inclusion criteria and does not meet any exclusion criteria, please 
conduct the following procedures in the recommended order, if possible. 
• Call IRT to randomize the patient and obtain the initial treatment kit assignments. 
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- 
If the patient has been selected to complete the immunophenotyping blood sampling, 
the system will provide this information during the call. 
• Administer PRO questionnaires (EQ-5D, SF-36v2, FACIT-Fatigue, HAQ-DI). 
• Note: PRO questionnaires should be completed prior to any significant interaction with the 
study team and prior to any physical examination or sampling 
• Measure vital signs (including systolic and diastolic BP [mmHg], heart rate [beats per 
minute] and body temperature [°C]. 
• Measure body weight [kg]. 
• Perform PMR clinical assessment for disease activity and flare. 
• Complete physician global assessment (MD-VAS). 
• Inquire about AEs/SAEs. 
• Perform Tuberculosis assessment. 
• Perform targeted physical examination (including head, eyes, ears, neck and throat, skin, 
respiratory, cardiovascular, neurologic, lymphatic examinations and abdominal 
examination). 
• Complete Glucocorticoid Toxicity Index questionnaire. 
• Perform DXA scan (may be performed within ±14 days of this visit) Not required if 
previously performed within 12 weeks of baseline visit. Refer to Section 9.2.1.4 for 
details.  
• Perform blood sampling (fasting, prior to administration of IMP) for the following tests: 
• Hematology and chemistry 
• ANA 
• CRP  
• ESR 
• Serum sarilumab and antibodies to sarilumab 
• Biomarkers IL-6, sIL-6R 
• Immune cell phenotyping (whole blood) 
• Future Use Samples for serum and plasma (Optional - requires separate signed consent 
form) 
• Pharmacogenetic samples for DNA and RNA (Optional - requires separate signed consent 
form) 
• Perform urine pregnancy test (for women of childbearing potential). 
• Dispense patient diary to record injections performed at home (date, time, injection 
location, and local reaction or any medical events pertaining to the injection). 
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• IMP training. Provide instructions on preparation and self-injection of the pre-filled 
syringes and the use of the weekly blister packs of prednisone. Document this training in 
the patient study file. Note: If the patient is unable or unwilling to perform the 
subcutaneous injections themselves, arrangements must be made for qualified site 
personnel and/or caregiver to administer study drug every 2 weeks for doses that are not 
scheduled to be given at the study site. 
• Dispense and administer IMP. 
- 
Patients will be monitored for at least 30 minutes or up to 2 hours as per country 
specific requirements after each dose of SC IMP for any signs or symptoms of a 
hypersensitivity reaction. 
• Schedule an appointment for Visit 3. 
10.2.2.2 Visit 3 (Day 15±3 Week 2)  
• Review concomitant medication. 
• Dispense new patient diary and review last visit patient diary. 
• Measure vital signs (including systolic and diastolic BP [mmHg], heart rate [beats per 
minute] and body temperature [°C]). 
• Perform PMR clinical assessment for disease activity and flare. 
• Inquire about AEs/SAEs. 
• Perform tuberculosis assessment. 
• Perform blood sampling (prior to administration of IMP) for the following tests: 
• CRP 
• ESR 
• Serum sarilumab 
• Biomarkers IL-6, sIL-6R 
• Future Use Samples – Serum and Plasma (Requires separate signed consent form) 
• Pharmacogenetic samples for RNA (Requires separate signed consent form) 
• Dispense and administer IMP. 
• Patients will be monitored for at least 30 minutes or up to 2 hours as per country specific 
requirements after each dose of SC IMP for any signs or symptoms of a hypersensitivity 
reaction 
• Schedule an appointment for next visit. 
10.2.2.3 Visit 4-11 (Day 29±3 Week 4 to Day 281±3, Week 40)  
• Call IRT to register visit. 
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• Administer PRO questionnaires (EQ-5D-3L, FACIT-Fatigue, SF-36v2, HAQ-DI; 
Applicable only at Visits 6 and 9; at these visits PRO questionnaires should be completed 
prior to any significant interaction with the study team and prior to any physical 
examination or sampling). 
• Review of concomitant medication. 
• Dispense new patient diary and review last visit patient diary. 
• Measure vital signs (including systolic and diastolic BP [mmHg], heart rate [beats per 
minute] and body temperature [°C]).  
- 
Measure body weight (kg) (Applicable only at Visits 6, 9 and 11) 
- 
Perform PMR clinical assessment for disease activity and flare. 
- 
Complete physician global assessment (MD-VAS) at Visits 6 and 9 only. 
• Inquire about AEs/SAEs.  
• Perform tuberculosis assessment. 
- 
Perform targeted physical examination (including head, eyes, ears, neck and throat, 
skin, respiratory, cardiovascular, neurologic, lymphatic examinations and abdominal 
examination) (Applicable only at Visits 6, 9, and 11). 
- 
Complete Glucocorticoid Toxicity Index questionnaire. (Applicable only at Visits 6, 9 
and 11). 
• Perform blood sampling at all visits (prior to administration of IMP) for the following 
tests: 
- 
CRP and ESR. 
• Perform blood sampling (fasting, prior to administration of IMP) for the following tests: 
(Applicable only at Visits 4, 6, 9 and 11). 
- 
Hematology and chemistry. 
- 
Fasting lipids, fasting glucose and insulin. 
- 
HbA1c. 
• Perform blood sampling (prior to administration of IMP) for the following tests: 
(Applicable only at Visits 4, 6, 7, and 9). 
- 
Serum sarilumab. 
Note: Additional sample is to be drawn 4-7 days after Visit 9 dosing. May be 
performed at the patient's home, if compatible with local organization. 
• Perform blood sampling (prior to administration of IMP) for the following tests: 
- 
Anti-sarilumab antibody (Applicable only at Visits 6 and 9). 
- 
Biomarkers IL-6, sIL-6R. (Applicable only at Visits 6 and 9). 
- 
Immune Cell Phenotyping – Whole Blood (Applicable only at Visits 4 and 9). 
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- 
Future Use Samples – Plasma and Serum (Optional - requires separate signed consent 
form) (Applicable only at Visits 6 and 9). 
- 
Perform urine pregnancy test (for WOCBP). 
- 
Dispense and administer IMP. 
- 
Patients will be monitored for at least 30 minutes or up to 2 hours as per country 
specific requirements after each dose of IMP for any signs or symptoms of a 
hypersensitivity reaction. 
- 
Schedule an appointment for the next planned study visit. 
10.2.2.4 Visit 12/End of treatment (Day 365±3 Week 52)  
• Call IRT to register visit. 
• Administer PRO questionnaires (EQ-5D, SF-36v2, FACIT-Fatigue, and HAQ-DI). 
Note: PRO questionnaires should be completed prior to any significant interaction with the 
study team and prior to any physical examination or sampling from the patient. 
• Review concomitant medication.  
• Review last visit patient diary. 
• Measure vital signs (including systolic and diastolic BP [mmHg], heart rate [beats per 
minute] and body temperature [°C]. 
• Measure body weight [kg]. 
• Perform PMR clinical assessment for disease activity and flare. 
• Complete physician global assessment (MD-VAS). 
• Inquire about AEs/SAEs. 
• Perform tuberculosis assessment. 
• Perform full physical examination. 
• Complete Glucocorticoid Toxicity Index questionnaire. 
• Perform DXA scan (may be performed within -14 days of this visit). Refer to 
Section 9.2.1.4 for details. 
• Perform blood sampling (fasting) for the following tests: 
- 
Hematology and chemistry. 
- 
ANA. 
- 
Fasting lipids, fasting glucose and insulin. 
- 
HbA1c. 
- 
CRP. 
- 
ESR. 
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- 
Serum sarilumab and antibodies to sarilumab. 
- 
Biomarkers IL-6, sIL-6R. 
- 
Future Use Samples – Plasma and Serum (Requires separate signed consent form). 
- 
Perform urine pregnancy test (for WOCBP). 
- 
Schedule an appointment for Visit 13 (EOS). 
10.2.3  Post-treatment follow-up period (6 weeks)  
10.2.3.1 Visit 13/End of study (Day 407±3, Week 58)  
• Call IRT to register visit. 
- 
Review concomitant medication. 
- 
Perform PMR clinical assessment for disease activity and flare. 
• Inquire about AEs/SAEs. 
- 
Perform tuberculosis assessment. 
- 
Perform blood sampling for the following tests:  
- 
Serum sarilumab and antibodies to sarilumab. 
10.3 
DEFINITION OF SOURCE DATA  
Source data is all information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents. Source documents are 
original documents, data and records such as hospital records, clinic and office charts, laboratory 
notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, etc. 
The following data collected in the CRFs and in device capturing questionnaires and scales will 
be part of source data:  
• Local laboratory reports. 
• EuroQol (EQ-5D). 
• MD-VAS. 
• FACIT-F. 
• HAQ-DI. 
• Erythrocyte sedimentation rate results. 
• SF-36v2. 
Additional data that are considered to be part of source data are: 
• Chest x-ray or signed documented x-ray and reports. 
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• Chest MRI. 
• Ultrasound images. 
• Patient Home Dosing Diaries. 
• ECG tracings and reports. 
• Central lab reports. 
Local lab reports and ESR results 
DXA results  
Diagnostic results from other healthcare professionals, if appropriate, for PMR and GTI 
assessments 
10.4 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation must be fully documented in the eCRF. In any case, the 
patient should remain in the study as long as possible. 
10.4.1 Temporary treatment discontinuation with investigational medicinal product 
(sarilumab or matching placebo)  
Temporary treatment discontinuation may be considered because of suspected AEs. Re initiation 
of treatment with the IMP (SC and/or oral) will be done under close and appropriate clinical/and 
or laboratory monitoring once it is considered that  the responsibility of the IMP(s) in the 
occurrence of the concerned event was unlikely and if the selection criteria for the study are still 
met (refer to Section 7.1 and Section 7.2). 
Temporary SC IMP treatment discontinuation corresponds to ≥1 dose not administered to the 
patient. 
A temporary discontinuation of SC IMP ≥ 31 consecutive days will be considered permanent. 
The following is a list of criteria for temporary discontinuation (refer to Section 10.8 for details): 
• Increase in ALT level to ≥3 x ULN to ≤5 x ULN and total bilirubin≤ 2 x ULN will result 
in temporary IMP discontinuation. The IMP (sarilumab or matching placebo) can be 
resumed only after the ALT has returned to a value <3X ULN and all requirements for 
resumption of study drug administration are met based on investigator’s judgement. The 
IMP may be resumed at the same dose or at a lower dose of 150 mg q2w in such cases if 
the patient was randomized to the 200 mg group (see Section 10.8.2 and Appendix E). 
• Decrease in neutrophil count to a level ≥500/mm3 to <1000/mm3 without signs of 
infection. The IMP (sarilumab or matching placebo) can be resumed only after the 
neutrophils have returned to a value ≥1000/mm3 and all requirements for resumption of 
study drug administration are met based on investigator’s judgement. The IMP may be 
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resumed at the same dose or at a lower dose of 150 mg q2w in such cases if the patient 
was randomized to the 200 mg group (see Section 10.8.3 and Appendix E). 
• Decrease in platelet count to a level of ≥50 000 cells/mm3 to <100 000 cells/mm3 without 
spontaneous bleeding. The IMP can be resumed only after the platelet count is 
≥100 000/mm3 and all requirements for resumption of study drug administration are met 
based on investigator’s judgement. The IMP may be resumed at the same dose or at a 
lower dose of 150 mg q2w in such cases if the patient was randomized to the 200 mg 
group (See Section 10.8.4 and Appendix E). 
• Inter-current infections requiring oral or parenteral treatment with antibacterial, antiviral 
and/or antifungal agents. 
10.4.2 Permanent treatment discontinuation with investigational medicinal product(s)  
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to re-expose the patient to the IMP (sarilumab or 
matching placebo) at any time during the study, or from the patient not to be re-exposed to the 
IMP whatever the reason.  Oral IMP (prednisone) may be permanently discontinued and replaced 
with rescue CS but the IMP may continue in this case upon the discretion of the Dual Assessors as 
long as safety is not compromised.  However, if IMP is permanently discontinued then oral IMP 
must be permanently discontinued as well.   
10.4.3 List of criteria for permanent treatment discontinuation  
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the eCRF. 
All IMP will be permanently discontinued in case of the following events (refer to Section 10.8.2, 
Section 10.8.3, and Section 10.8.4 for details): 
• Opportunistic infections (as assessed by the investigator) including, but not limited to, 
active tuberculosis and non-tuberculosis mycobacteria infections. 
- 
The diagnosis of tuberculosis can be made either on symptoms or on a chest 
radiograph suggestive of active tuberculosis. Patients should be referred to appropriate 
medical specialists and whenever possible, culture confirmation of disease should be 
obtained and recorded in the eCRF. 
- 
Culture positive for non-tuberculosis mycobacteria. 
• The patient is at risk through close contact with a person with active tuberculosis and the 
patient refuses to undergo tuberculosis evaluation. 
• Symptoms of systemic hypersensitivity or anaphylactic reactions. 
• Severe neurologic disease such as demyelinating disease or PML. 
• Significant laboratory abnormalities resulting in permanent IMP discontinuation: 
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- 
ALT>5 x ULN or ALT>3 x ULN with concomitant total bilirubin>2 x ULN (unless 
patient has documented Gilbert's Syndrome). 
- 
Neutrophil count <500/mm3, or neutrophil count <1000/mm3 with evidence of 
infection. 
- 
Platelet count <50 000/mm3, or platelet count <100 000/mm3 with evidence of 
bleeding. 
• Acute renal failure (refer to Section 10.8.8). 
• Pregnancy in female participant. 
• Use of any biologic DMARDs other than IMP. 
• Any AEs, per Investigator's judgment, that may jeopardize the patient's safety. 
• Diagnosis of GCA (eg, persistent or recurrent localized headache, temporal artery or scalp 
tenderness, jaw claudication, extremity claudication, blurry or loss of vision, symptoms of 
stroke). 
Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision of permanent discontinuation of the IMP for the concerned patient. 
10.4.4 Handling of patients after permanent treatment discontinuation  
Every effort should be made to maintain patients in the study after permanent study treatment 
discontinuation. Patients should be followed up according to the study procedures as specified in 
this protocol up to the scheduled date of study completion, or up to recovery or stabilization of 
any AE to be followed-up as specified in this protocol, whichever comes last. The scientific value 
of the complete collection of data will be explained to patients, and site personnel will receive 
training regarding strategies for patient retention, and access to tools to assist with this during the 
study. 
If a patient prematurely and permanently discontinues study treatment, a premature end of 
treatment (EOT) visit (see Section 10.4.2) should be scheduled at the time of treatment 
discontinuation, if possible. If not possible, the EOT should be scheduled as soon as possible after 
treatment discontinuation. The IRT should be notified of EOT. Of note, during this premature 
EOT visit, the bone density test does not need to be performed if it has been less than 6 months 
since the bone density test associated with the baseline visit. 
Following the premature EOT visit, the remaining visits will be performed as scheduled. All 
efforts should be made to follow the patients for safety for at least 6 weeks after last dose of SC 
IMP and for primary endpoint and key secondary endpoints through the remainder of the study 
visits up to Week 52 after premature EOT. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. Details recording the specific 
reasons for discontinuation should be collected. 
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10.4.5  Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Discontinuation of study treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients will be told that they are free to withdraw 
from the study at any time without any adverse effect on their care. However, if patients no longer 
wish to take the IMP, they will be encouraged to remain in the study. The value of critical study 
data collected during their continued involvement will be emphasized as important to the public 
health value of the study. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Should the 
patient or the patient's representatives withdraw from the study without a preferred written 
withdrawal of consent, the site should clearly document and sign the reason for the patient’s 
reason for withdrawal of consent, if known. 
All study withdrawals should be recorded by the Investigator in the appropriate sections of the 
eCRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who withdraw from the study, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to re-contact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.5.1 Definitions of adverse events  
10.5.1.1 Adverse event  
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. Reconciliation of AEs between the GTI and clinical safety 
database will be part of the usual data review surveillance activities. 
10.5.1.2 Serious adverse event  
A SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
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• Is life-threatening, or  
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
• Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm.  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc.) 
• Development of drug dependence or drug abuse. 
• Alanine aminotransferase >3 x ULN and total bilirubin >2 x ULN or asymptomatic ALT 
increase >5 x ULN. 
• Suicide attempt or any event suggestive of suicidality. 
• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
• Bullous cutaneous eruptions. 
• Cancers diagnosed during the study or aggravated during the study. 
• Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study.  
• Suspected transmission of an infectious agent. 
• GCA. 
10.5.1.3 Adverse event of special interest  
An AE of special interest (AESI) is an AE (serious or nonserious) of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
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immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. AESI may be added, modified 
or removed during a study by protocol amendment. 
The following listed events are considered as AESI:  
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.5.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued. 
- 
An attempt to follow-up of the pregnancy in a female participant or in a female partner 
of a male participant is made until the outcome has been determined (see Appendix B). 
• Symptomatic overdose (serious or nonserious) with IMP 
- 
An overdose (accidental or intentional) with the SC IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
intended dose during an interval of <11 days (for sarilumab or matching placebo). 
- 
Of note, both symptomatic and asymptomatic overdoses have to be reported on a 
specific AE page. 
• Increase in alanine transaminase (ALT) ≥3 x ULN (see the “Increase in ALT” flow 
diagram in Appendix E). 
• Clinically significant infections including: 
- 
Confirmed diagnosis of opportunistic infections based on the investigator's assessment 
with appropriate diagnostic workups and consultations. For any infection from the list 
of potential opportunistic infections provided in Appendix F for reporting purpose, 
even if it is not confirmed to be an opportunistic infection based on the Investigator's 
assessment, it should still be reported as AESI. 
- 
Active/latent TB or initiation of medications for suspected TB. 
Note: Parasitic infections are not considered opportunistic infections. Fungal 
infections are not considered opportunistic infections, unless they are systemic and/or 
extensive muco-cutaneous cases. 
- 
Infection requiring prolonged medication (>14 days). These are infections which 
require treatment (continuous or intermittent) for >14 days, with antibiotics, 
antifungals, or antivirals (exclude when medications are only administered topically). 
- 
Infections requiring any parenteral antibiotics, parenteral antifungals, or parenteral 
antiviral agents. 
• The following laboratory abnormalities:  
- 
ALT increase leading to permanent discontinuation  
- 
ANC decrease leading to permanent discontinuation  
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- 
Thrombocytopenia leading to permanent discontinuation  
10.5.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities  
Not applicable. 
10.5.3 General guidelines for reporting adverse events  
• All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that 
patient, are to be recorded on the corresponding page(s) or screen(s) of the eCRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s). 
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
At the pre-specified study end-date, patients who experience an ongoing SAE or an AESI 
should be followed until resolution, stabilization, or death and related data will be 
collected. 
- 
When treatment is prematurely discontinued, the patient’s observations will continue 
until the end of the study as defined by the protocol for that patient. 
- 
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
• Symptomatic and/or  
• Requiring either corrective treatment or consultation, and/or  
• Leading to IMP discontinuation or modification of dosing, and/or  
• Fulfilling a seriousness criterion, and/or  
• Defined as an AESI 
10.5.4 Instructions for reporting serious adverse events  
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
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• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc.) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.5.5 Guidelines for reporting adverse events of special interest  
For AESIs (serious or non-serious), the Sponsor must be informed immediately (ie, within 
24 hours), as per SAE notification guidelines described in Section 10.5.4, even if not fulfilling a 
seriousness criterion, using the screens in the eCRF. 
Instructions for AE reporting are summarized in Section 10.5.3. 
10.5.6 Guidelines for management of specific laboratory abnormalities  
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix E. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 
• Neutropenia. 
• Thrombocytopenia. 
• Increase in ALT. 
10.5.7 Guidelines for reporting product complaints (IMP)  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
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Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
10.6 
OBLIGATIONS OF THE SPONSOR  
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR 
[suspected unexpected serious adverse reaction]), to the regulatory authorities, 
independent ethics committee (IECs)/institutional review boards (IRBs) as appropriate and 
to the Investigators.  
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition (eg, progression of 
disease) and thus will not be considered unexpected. 
For the IMP, any other AE not listed as an expected event in the Investigator’s brochure for 
sarilumab or defined in this protocol or local label summary of product characteristics (SmPC) / 
package insert for prednisone will be considered unexpected. 
For safety, the Sponsor will report to the Health Authorities of any SUSAR and reasonably 
associated with the use of the IMP (sarilumab or matching placebo) according to either the 
judgment of the Investigator and/or the Sponsor. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.7 
SAFETY MONITORING  
Signs and symptoms of GCA 
Additionally, at every study visit signs and symptoms of GCA including but not limited to the 
following should be assessed: 
• Localized headache, temporal artery or scalp tenderness, jaw claudication, extremity 
claudication, blurry or loss of vision, symptoms of stroke. 
• Other features judged by the clinician-investigator to be consistent with a GCA diagnosis. 
If the diagnosis of GCA is highly suspected or confirmed, please discontinue IMP permanently 
and manage the patient appropriately.  The GCA should be reported as an SAE. The patient 
should remain in the study and complete the remainder of the study visits per protocol. 
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10.8 
SAFETY INSTRUCTIONS  
10.8.1 Infections  
Biologics including TNF antagonists and tocilizumab (another IL-6 receptor antagonist similar to 
sarilumab) have been associated with an increased risk of infection, including black box warnings 
for serious infections leading to hospitalization or death. In sarilumab studies, the most commonly 
reported TEAEs were infections (mostly non-serious upper respiratory and urinary tract 
infections), clinically significant infections including life threatening sepsis, have been reported, 
some notably associated with minor trauma. As a precautionary measure, Investigators should 
carefully follow any signs of infection with particular care to identify potential infective 
complications in immune-suppressed individuals where superficial skin wounds or abrasions may 
lead to serious infections including necrotizing fasciitis and/or sepsis. 
Any infection should be reported by the Investigator as an adverse event and a corresponding 
eCRF form should be filled in. If possible, culture should be performed to identify the type of 
infection. The type of infection should be listed in the eCRF form. Treatment with antibiotics if 
any should be recorded including the route of administration. 
Clinically significant infections including opportunistic infections are AESI and should be 
reported accordingly (see Section 10.5.5). Infections requiring prolonged treatment (>14 days) or 
anti-TB medication are considered AESI. Systemic opportunistic infections should be reported as 
SAE. The IMP must be withheld in case of suspicion of a clinically significant infection and a 
complete diagnosis work-up should be performed including but not limited to cultures for 
bacterial infections, fungi and/or mycobacteria, histopathological or cytological evaluation, 
antigen detection and serum antibody titers. 
• Tuberculosis assessment: sarilumab is a biologic treatment that may induce 
immunosuppression, increasing the risk of reactivation of latent TB. A special warning of 
the increased risk of TB is included in the sarilumab label. As a precautionary measure, 
patients at risk for TB will be excluded from the study. For inclusion, patient with a past 
history of TB could be included only if there is a documented confirmation medically 
validated by the Investigator that the patient was adequately treated and does not meet any 
of the TB-related exclusion criteria. 
- 
A clinical examination and history will be performed at every visit to assess any signs 
and symptoms of TB or contact with a patient with active TB.  
- 
A QuantiFERON TB Gold test will be performed at screening and can be repeated at 
any time during the course of the studies in case of suspicion of TB. A repeat chest 
X-ray should be performed in all patients with suspected TB. 
- 
In case of suspicion of TB, the Investigator must refer the patient to a specialist for a 
complete examination. The IMP should be discontinued until TB is ruled out. 
• Chest X-ray: A standard PA chest X-ray (lateral view is also recommended but not 
required) is required during the screening period if no chest imaging (X-ray, CT, MRI) is 
available within the previous 12 weeks  of V1 that clearly documents the exclusion of TB 
or if it does not follow the local guidelines and requirements for active screening of TB. In 
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countries for which a specific approval procedure for the x-ray is required by a different 
committee than the local EC/IRB, a chest MRI between V1 and V2 can be performed. A 
radiologist or pulmonologist interpretation (signed and dated) should note the absence of 
calcified granulomas and/or pleural scaring and/or any findings consistent with TB. The 
information must be documented in the patient's chart and in the eCRF at the screening 
visit. In case of any symptom suggestive of TB at any time during the course of the study, 
a chest X-ray should be performed and conclusion recorded. 
• Repeat chest radiographs should be performed as indicated by local treatment guidelines 
or practice for monitoring while on immunosuppressive/immunomodulatory therapy. If 
such guidelines are not available/applicable, routine chest X-rays should be performed 
when clinically necessary. 
• QuantiFERON TB Gold test will be performed at screening. This is an in vitro TB test that 
measures a memory T-cell mediated response (production of interferon γ) in TB-infected 
patients. This test is unaffected by Bacillus Calmette-Guerin vaccination or 
nontuberculous mycobacteria. The test received regulatory and policy approvals in the US, 
Japan, EU, Canada. Blood samples will be incubated within 16 hours of blood collection 
and sent to the central laboratory for analysis the day after collection or as soon as 
possible. In case of suspicion of TB, those patients will be referred to a specialist for 
follow-up. 
10.8.2 Liver function tests  
Please refer to Section 10.5.5 for liver function test (LFT) abnormalities to be reported as AESI. 
The Sponsor relies on investigators’, particularly Safety Assessors’, judgment for adapting 
concomitant medication in case of LFT abnormalities. 
In order to closely follow LFTs, assessment of ALT, AST, alkaline phosphatase, and bilirubin 
(total, conjugated) are performed per specifications on the study flow charts (see flow chart 
Section 1.2). 
• The IMP (sarilumab or matching placebo) should be permanently discontinued in case of 
confirmed ALT >5 x ULN or in case of confirmed ALT >3 x ULN and total bilirubin 
>2 x ULN (unless the patient has documented Gilbert's disease). A complete serological 
and ultrasonography work-up should be conducted in case of ALT >5 x ULN or ALT 
>3 x ULN and concomitant total bilirubin >2 x ULN (see Appendix E). 
• If ALT is ≥3 x ULN and ≤5 x ULN and bilirubin is ≤2 x ULN, administration of SC IMP 
must be temporarily interrupted, and LFTs must be repeated within 48 hours from the 
study Investigator's awareness for confirmation of transaminase levels. If the elevated 
ALT level is confirmed but stays below the 5 x ULN thresholds, then LFTs must be 
repeated according to the provided guideline and at a minimum of every 7 days until 
conditions for resumption of SC IMP administration are met (see Appendix E). 
• The SC IMP will then be restarted at the Safety Assessor's discretion after conditions for 
resumption of IMP administration are met (ALT <3 x ULN). Safety assessor will have the 
options of either to restart the SC IMP at its current dose or to perform a dose reduction 
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request in a blinded manner through IRT for patients without a previous reduction in dose. 
Dose of sarilumab will then be reduced to 150 mg if the patient was randomized to the 
200 mg group. 
10.8.3 Neutrophils  
Refer to Section 10.5.5 criteria for reporting neutropenia as an AESI.  
In case of a decrease in neutrophil count to a level ≥500/mm3 and <1000/mm3: 
• The IMP (sarilumab or matching placebo) may temporarily discontinued; the patient must 
be assessed for evidence of infection and CBC blood test repeated within 48 hours from 
the Safety Assessor’s awareness of neutrophil count ≥500/mm3 and <1000/mm3. 
• Discontinuation of SC IMP is maintained until the neutrophil count returns to ≥1000/mm3 
(see Appendix E). 
• After the patient meets all requirements for resumption of SC IMP administration, 
including neutrophil count ≥1000/mm3, then SC IMP administration may resume. The 
safety assessor will have the options of either to restart the SC IMP at its original dose or 
to perform a dose reduction request in a blinded manner through IRT. The dose of 
sarilumab will be reduced to 150 mg if the patient was randomized to the 200 mg group. 
In case of a decrease in neutrophil count <1000/mm3 with signs of infection or neutrophil count 
<500/mm3: 
• The IMP must be permanently discontinued. 
• The patient must be re-assessed for evidence of infection and CBC blood test repeated 
within 48 hours from the Safety Assessor’s awareness of neutrophil count <1000/mm3 
with signs of infection or neutrophil count <500/mm3. 
• It is recommended to admit the patient to the hospital in case of neutrophil count 
<1000/mm3 with suspicion of infection or neutrophil count <500/mm3. 
• The neutrophil count <500/mm3 persisting for more than 5 days are reported as an SAE. 
10.8.4 Platelets  
Refer to Section 10.5.5 for criteria for reporting thrombocytopenia as an AESI. 
In case of a decrease in platelet count to a level ≥50 000/mm3 and <100 000/mm3: 
• The IMP (sarilumab or matching placebo) must be temporarily discontinued; the patient 
must be assessed for evidence of spontaneous bleeding and CBC blood test repeated 
within 48 hours from the Safety Assessor’s awareness of platelet count ≥50 000/mm3 and 
<100 000/mm3 
• Discontinuation of SC IMP is maintained until the platelet count returns to ≥100 000/mm3 
(see Appendix E).  
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• After the patient meets all requirements for resumption of SC IMP administration, 
including platelet count ≥100 000/mm3, then SC IMP administration may resume. The 
Safety Assessor will have the option of either to restart the SC IMP at its original dose or 
to perform a dose reduction request in a blinded manner through IRT. The dose of 
sarilumab will be reduced to 150 mg if patient was randomized to the 200 mg group. 
The SC IMP must be permanently discontinued if platelet count is <50 000/mm3 (confirmed by 
repeat testing) or if <100 000/mm3 with spontaneous bleeding (see Section 10.4.2). 
10.8.5 Systemic hypersensitivity reactions/anaphylaxis  
Severe systemic hypersensitivity reactions (in rare cases, fatal anaphylaxis) have been reported 
with biologics, including tocilizumab. Rare, severe non-fatal systemic hypersensitivity reactions 
have been observed with sarilumab. The patient should be monitored for 30 minutes or up to  
2 hours as per country specific requirements after the IMP (sarilumab or matching placebo) 
injection when given at the study site. Also patient should be advised, when IMP is administered 
at home, to self-monitor for potential signs and symptoms that may suggest a hypersensitive 
reaction for 30 minutes or up to 2 hours as per country specific requirements after administration. 
Any problems should be documented in the patient’s Home Dosing Diary or in the medical notes 
and reported as AE. In case of systemic hypersensitivity reaction, the IMP should be discontinued 
and those events meeting seriousness criteria (eg, hospitalization, life threatening, etc.; see 
Section 10.5.1.2) should be reported as SAEs. Appendix G defines clinical criteria for diagnosing 
anaphylaxis. If clinical criteria for anaphylaxis are met, appropriate treatment should be 
administered immediately and the event should be reported as a SAE. 
10.8.6 Diverticulitis and gastrointestinal perforation  
The Investigator should pay particular attention to gastrointestinal symptoms such as, but not 
limited to, abdominal pain, hemorrhage, or unexplained change in bowel habits with fever to 
assure that the diagnosis is not missed and that the conditions are managed appropriately to avoid 
the complication of perforation. If necessary, the patient should be referred to a specialist. 
Corticosteroid use or prior history of diverticulitis is known to increase the risk of gastrointestinal 
perforations. The Investigator should be aware of this potential risk and monitor any sign of 
diverticulitis. 
Gastro-intestinal perforation will be reported as an SAE (see Section 10.5.4). Confirmed 
diverticulitis or gastrointestinal ulceration should be reported as AEs. 
10.8.7 Management of dyslipidemia  
Patients treated with tocilizumab have been observed to have increased elevations of all lipid 
parameters, including LDL cholesterol. A similar finding has been observed for sarilumab. The 
potential cardiovascular effect of the lipid elevations, including LDL levels in this population of 
PMR patients treated with anti-IL-6R antagonists is unknown. 
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As such, patients who are found to have dyslipidemia during the course of the study should be 
treated according to the NCEP/ATP3 or applicable local guideline. Also see Section 8.8.3 under 
concomitant medication rules for lipid lowering therapy. 
10.8.8 Acute renal failure  
Sarilumab is not known to be associated with a clinically significant effect on renal function. 
10.9 
ADVERSE EVENTS MONITORING  
All events will be managed and reported in compliance with all applicable regulations and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS  
11.1 
DETERMINATION OF SAMPLE SIZE  
The sample size calculations are based on the primary efficacy variable of sustained remission at 
Week 52 compared between the sarilumab and placebo groups. There are no prior controlled 
study data to establish the placebo remission rate in PMR. A 25% difference from placebo 
response rate is considered clinically relevant, and the initial sample size of 140 per group 
provides at least 90% power to detect such a difference regardless of the placebo response rate, 
using a two-sided χ2 test at a significance level of 0.01. Data from the GIACTA trial in a related 
population with GCA suggest that such a treatment difference is achievable (22). 
As a result of the inability to recruit due to the COVID19 pandemic, the power calculations have 
been revised for the decreased sample size from 140 per group to 59 per group, and the change in 
statistical significance level from 0.01 to 0.05. 
Table 3 shows the power calculations for sample size of 118 based on a two-sided χ2 test at a 
significance level of 0.05. The sample size of 59 per group provides at least 85% and 95% power 
to detect a 25% and 30% between group difference respectively, assuming placebo response rates 
between 5% to 15%. 
Table 3 - Power calculations based on total sample size of 118 randomized patients  
Assumed sustained 
remission rate for 
placebo + 52-week 
prednisone taper 
Sample Size 
per group 
Power assuming an 
absolute 25% 
between group 
difference 
Power assuming 
an absolute 30% 
between group 
difference 
Minimal 
detectable 
difference 
5% 
59 
95.6% 
98.8% 
11.1% 
10% 
59 
91.2% 
97.2% 
13.5% 
15% 
59 
86.9% 
95.4% 
15.1% 
Calculations were made using nQuery Advisor 7.0. 
11.2 
DISPOSITION OF PATIENTS  
Screened patients are defined as any patient who signed informed consent. 
Randomized patients consist of all patients, with signed informed consent, with a treatment kit 
number allocated and recorded in the IRT database, regardless of whether the treatment kit was 
used or not. These patients form the randomized population. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population. 
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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS  
11.3.1 Efficacy populations  
11.3.1.1 Intent–to-treat /modified intent-to-treat population  
Intent-to-treat (ITT) population: all randomized population analyzed according to the treatment 
group allocated by randomization. All efficacy analyses will use this population. 
11.3.2 Safety population  
Safety population: all randomized patients who have received at least one dose or part of a dose of 
the study medication (IMP) analyzed according to the treatment they have actually received. 
In addition: 
• Non-randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately. 
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• For patients receiving more than 1 study treatment during the trial, the treatment group 
allocation for as-treated analysis will the treatment for which the patient received the 
majority of doses. 
11.3.3  Pharmacokinetic analysis population  
The PK population will consist of all patients in the safety population with at least one post-dose, 
non-missing serum sarilumab concentration. 
The ADA population will consist of all patients in the safety population with at least one non-
missing ADA result in the ADA assay following the first dose of the study medication. 
11.4 
STATISTICAL METHODS  
Analysis of the randomization double-blind phase is described below. The post-treatment follow-
up phase will be presented separately without formal statistical testing, and details of the follow-
up phase will be provided in the SAP. 
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11.4.1 Extent of study treatment exposure and compliance  
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure  
Duration of sarilumab exposure is defined as: last double-blind dose date – first double-blind dose 
date +14 days, regardless of unplanned intermittent discontinuations. 
Duration of exposure to the double-blind IMP (sarilumab or matching placebo) will be 
summarized for each treatment group descriptively as a quantitative variable (N, Mean, standard 
deviation [SD], Median, Min, and Max). 
In addition, the number and percentage of patients randomized and exposed to the double-blind 
IMP will be presented by specific time periods for each treatment group. 
11.4.1.2 Compliance  
Treatment compliance to the double-blind IMP (sarilumab or matching placebo) is defined as the 
actual amount of injections received compared to the scheduled amount of injections during the 
double-blind treatment period. It is calculated according to the following formula: 
100 x total number of injections administered / [nominal number of injections for the duration of 
double-blind exposure]. 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of injection as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, Mean, SD, Median, Min, and Max). The percentage of patients with compliance 
is <80% will be summarized. In addition, number and percentage of patients with at least 1 above-
planned dosing administration will be given, as well as the number and percentage of patients 
with 0, (0, 20%), and >20% under-planned dosing administrations. 
11.4.2 Analyses of efficacy endpoints  
11.4.2.1 Analysis of primary efficacy endpoint(s)  
The primary endpoint (refer to Section 9.1.1) is the proportion of patients achieving sustained 
remission at Week 52 compared between sarilumab and placebo analyzed in the ITT population. 
The primary endpoint will be summarized as counts and proportions in each treatment group and 
analyzed by Fisher's exact test.  Patients who do not achieve remission, receive rescue treatment 
with open label prednisone (or equivalent), withdraw from the study before Week 52, or having 
missing data that prevents assessment of the primary endpoint will be considered as non-
responders. The significance level for all tests will be 0.05 (2-sided). 
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Sensitivity analyses will be performed based on a revised remission definition excluding acute 
phase reactants. 
11.4.2.2 Analyses of secondary efficacy endpoints  
Other binary endpoints (defined in Section 9.2.1) will be analyzed as described for the primary 
endpoint (see Section 11.4.2.1). 
The cumulative prednisone (or equivalent) dose will be analyzed using a non-parametric 
Wilcoxon rank-sum test and the mean and median dose summarized. 
 
Time events will be analyzed by Kaplan-Meier method. Treatment groups will be compared with 
the use of Cox proportional hazards models. Data censoring will be used for patients who 
withdraw from the study.  
The GTI assessment (total score and domain-specific scores) will be analyzed as other secondary 
efficacy endpoint using the mixed model repeated measures (MMRM) approach. The model 
includes treatment, visit, treatment-by-visit interaction as fixed effects, and baseline score as a 
covariate, will be used to test the difference of the least-square means (LS means) between 
treatment groups. Descriptive statistics including number of subjects, mean, standard error and LS 
means will be provided. In addition, difference in LS means, the corresponding 95% CI and the 
p-value will be provided. 
11.4.2.3 Multiplicity considerations  
If the primary endpoint reaches statistical significance, then secondary endpoints will be tested in 
a fixed sequential order to maintain an overall type I error rate of 0.05. Details of the hierarchical 
testing approach will be specified in the statistical analysis plan. 
11.4.3 Analyses of safety data  
The summary of safety results will be presented by treatment group. Incidence rates and exposure 
adjusted event summaries will be provided for categorical safety summaries. 
All safety analyses will be performed on the safety population using the following common rules: 
• The baseline value is defined generally as the last available value before randomization. 
• The observation period to be used for the safety population is the TEAE period. The 
TEAE period is defined as the time from first dose of randomized study treatment to the 
last dose date of IMP +60 days. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group. 
• The analysis of the safety variables will be essentially descriptive and no hypothesis 
testing is planned. 
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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 on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. 
11.4.3.1 Analysis of adverse event data  
Treatment-emergent AEs, treatment-emergent SAEs, TEAEs leading to treatment discontinuation 
and treatment-emergent AESIs will be summarized for each treatment group based on MedDRA 
coding of verbatim terms reported by investigators. 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment period. The denominator for 
computation of percentages is the safety population within each treatment group. 
Treatment-emergent AESI, by AESI category and PT, will show number (%) of patients overall, 
sorted by decreasing incidence of PT within each AESI category. The AESIs include, but are not 
limited to, the following categories and details of the MedDRA coding will be provided in the 
statistical analysis plan: Neutropenia, thrombocytopenia, infections, hepatic disorders, 
diverticulitis/GI ulcerations/GI perforations, elevation in lipids, systemic allergic reactions, 
malignancy, autoimmune or drug-induced lupus like syndrome and demyelinating disorders. 
Death: The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (TEAE, on-study) summarized on the 
safety population by treatment received. 
• Death in nonrandomized patients or randomized and not treated patients. 
• TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT.  
11.4.3.2 Analysis of laboratory data  
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
laboratory variables will be calculated for each visit or study assessment (baseline, each post-
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baseline time point, endpoint) by treatment group. Listings will be provided with flags indicating 
the out of range values as well as the PCSA values. 
The incidence of PCSA at any time will be summarized by treatment group for each laboratory 
parameter. Shift tables showing changes with respect to the baseline status will be provided. 
11.4.3.2.1.1 
Neutropenia  
The incidence of neutropenia by maximal grade (lowest neutrophils value reported) during the 
TEAE period will be summarized. The 4 grades are defined as below: 
• Grade 1: ≥1.5 Giga/L – LLN.  
• Grade 2: ≥1.0 – 1.5 Giga/L 
• Grade 3: ≥0.5 – 1.0 Giga/L. 
• Grade 4: <0.5 Giga/L. 
For patients with Grade 3 or 4 neutropenia, a listing with the individual neutropenia counts, and 
selected laboratory tests at each visit (including unscheduled visits for retest) will be provided. In 
addition, the neutrophil counts at each scheduled visit during the study will be plotted by 
treatment groups. Dose will be reduced to 150 mg if patient was randomized to the 200 mg group. 
11.4.3.2.1.2 
Assessment of potential drug-induced liver injury  
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 
post-baseline visit by baseline status will be displayed by treatment group for each parameter. The 
proportion of patients with PCSA values at any post-baseline visit will also be displayed by 
duration of exposure for each treatment group. 
Time to onset of the initial ALT elevation (>3 x ULN), time to onset of the initial AST elevation 
(>3 x ULN), time to onset of the initial total bilirubin elevation (>2 x ULN), and time to first 
observation of ALT >3ULN or Total Bilirubin >2 ULN (whichever comes first) will be analyzed 
using Kaplan-Meier estimates, using the midpoint of the time interval between the first 
assessment showing the elevation and the previous assessment, presented by treatment group. A 
graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and Total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
Summarize the normalization by parameter (to ≤1 ULN or return to baseline) of elevated LFTs by 
categories of elevation (1-<3 x, 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. 1-3, 3-5, 5-10, 10-20, >20. 
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The incidence of liver-related AEs will be summarized by treatment group. The selection of 
preferred terms will be based on standardized MedDRA query (SMQ) Hepatic disorder. Time to 
liver-related treatment discontinuation and time to liver death may also be provided based on 
hepatic disorder SMQ. 
11.4.3.3 Analysis of vital signs data  
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
vital signs variables will be calculated for each visit or study assessment (baseline, each post-
baseline time point, endpoint) by treatment group. 
The incidence of PCSA at any time will be summarized by treatment group for each vital signs 
variable. Shift tables showing changes with respect to the baseline status will be provided. 
Listings will be provided with flags indicating the out of range values as well as the PCSA values. 
11.4.3.4 Analysis of immunogenicity data  
At each sample time, the result of the ADA assay will be categorized as either positive or 
negative. ADA positive samples will be further characterized as either neutralizing or 
non-neutralizing. Descriptive statistics will be provided for: 
ADA positive patients are defined as: 
• Treatment Emergent Responses: Patients with no positive assay response at baseline but 
with a positive assay response during the TEAE period or 
• Treatment Boosted Responses: Patients with a positive ADA assay response at baseline 
and also have at least a 4-fold increase in titer over baseline titer during the TEAE period. 
ADA negative patients are defined as any evaluable patient that is not an ADA positive patient. 
Descriptive statistics for ADA titers will be provided for patients with positive ADA assay 
response and selected sub-categories. 
Efficacy/safety endpoints will be analyzed for the subgroup of ADA positive patients during the 
TEAE period and compared to ADA negative patients. 
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables  
Serum concentrations of functional sarilumab will be summarized using arithmetic and geometric 
means, SD, standard error of the mean (SEM), coefficient of variation (CV%), minimum, median, 
and maximum by visit. 
IL-6 and sIL-6R will be summarized using arithmetic and geometric means, SD, standard error of 
the mean (SEM), coefficient of variation (CV%), minimum, median, and maximum by visit. 
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11.4.5 Analyses of patient reported outcomes  
Change from baseline in patient reported endpoints at Weeks 12, 24 and 52 will be analyzed with 
a mixed model repeated measures approach (all data is continuous): 
• SF-36v2 physical component summary score.  
• SF-36v2 mental component summary score. 
• Each SF-36v2 domain (n=8). 
• EQ-5D-3L single index utility score.  
• EQ-5D-3L VAS score. 
• FACIT-Fatigue total score. 
• HAQ-DI standardized score. 
• HAQ-DI pain score. 
• HAQ-DI patient global assessment. 
The model, including treatment, visit, treatment-by-visit interaction, as fixed effects and baseline 
score as a covariate, will be used to test the difference of least-square means (LS means) between 
treatment groups in each variable. Descriptive statistics including number of subjects, mean, 
standard error and LS means will be provided. In addition, difference in LS means, the 
corresponding 95% CI and the p-value will be provided. 
11.5 
INTERIM ANALYSIS  
No interim analysis is planned for this study. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS  
12.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Sub-Investigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies,   in particular the Declaration of Helsinki as amended in 1996 for clinical trials with 
medicinal products in the EU, and the International Conference on Harmonisation (ICH) 
guidelines for good clinical practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments. 
12.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (institutional review board/independent 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, if required by local laws, for those who are able to be consented but not able to 
sign the form), and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient. 
If informed consent is obtained under special circumstances (emergency, from a guardian, minor, 
etc.), the method should be specified following the ICH requirements. The first part of the section 
should be adapted, keeping the point as appropriate. 
Prior to the optional collection of blood for pharmacogenetics, the pharmacogenetic informed 
consent form must be obtained from the patient.  This process includes a signing of the form with 
the name spelled out, and personally dated by the patient (or by the patient’s legally acceptable 
representative, if required by local laws, for those who are able to be consented but not able to 
sign the form), and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written optional informed consent form will be provided to the patient. 
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Similarly, prior to the optional collection of blood (plasma/serum) for Future Use Samples the 
informed consent form must be obtained from the patient in the same manner described above.  
Both informed consent forms for pharmacogenetics and Future Use Samples must be reviewed 
and approved by the Sponsor prior to submission to the appropriate ethics committee (IRB/IEC) 
for approval/favorable opinion. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
addenda or labeling documents (summary of product characteristics, package insert) Investigator’s 
curriculum vitae [CV], etc.) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure or 
labeling information, will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial. 
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13 
STUDY MONITORING  
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub-
Investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-Investigators shall be appointed and listed in a timely manner. The Sub-
Investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the pre-identified source data directly recorded in the eCRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
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personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the eCRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc.). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST  
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS  
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file. 
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14 
ADDITIONAL REQUIREMENTS  
14.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES  
The Investigator must maintain confidential all study documentation and take measures to prevent 
accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years (or longer per local 
requirements) after the completion or discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
14.3 
CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure, and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-Investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-Investigators of the confidential nature of the clinical trial. 
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The Investigator and the Sub-Investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS  
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Sub-Investigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-Investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION  
• The patient's personal data, which are included in the Sponsor database, shall be treated in 
compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Subject race or ethnicity will be collected in this study because these data are required by several 
regulatory authorities. 
Analyses of subject genetic data will be conducted as described in the protocol as this is needed 
for pharmacogenetics analyses required for the purposes of the study or by regulatory authorities. 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
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14.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document. 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial protocol, good clinical practice, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio 
• Patient enrollment is unsatisfactory 
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• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• The total number of patients are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator  
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights. 
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The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES  
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12. Cantini F, Salvarani C, Oliveiri I, Macchioni L, Ranzi A, Niccoli L, et al. Erythrocyte 
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24. Van der Geest Disturbed B Cell Homeostasis in Newly Diagnosed Giant Cell Arteritis and 
Polymyalgia Rheumatica A&R 2014;66(7):1927-38. 
25. Dasgupta. Interleukin-6 in serum of patients with polymyalgia rheumatic and giant cell 
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26. Taboada. Clonally Expanded CD8 T Cells in Patients with Polymyalgia Rheumatica and Giant 
Cell Arteritis. Clinical immunology and immunopathology 1996;79(3) 
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Rheumatica patients as predictors of disease remission and steroid withdrawal. British Journal 
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28. Van Sleen. Involvement of Monocyte Subsets in the Immunopathology of GiantCell Arteritis. 
Scientific Reports. 2017;7:6553. 
29. Ribbens. Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: 
relationship with synovitis and steroid treatment. ARD. 2002;61:161-6 
30. Kim. Intercellular adhesion molecule-1 (ICAM-1, CD54) is increased in adhesive capsulitis. J 
Bone Joint Surg Am. 2013;95(23):e181-8 
31. Roche. Correlation of Interleukin-6 production and disease activity in Polymyalgia 
Rheumatica and Giant Cell Arteritis. Arthritis & Rheumatism. 1993;36(9):1286-94 
32. Uddhammer. Cytokines and adhesion molecules in patients with Polymyalgia Rheumatica.  
British Journal of Rheumatology. 1998;37:766-69 
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StudyA&R. 2007;57(8):1514-19 
 
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17 
APPENDICES  
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Appendix A 
Standardized corticosteroid-taper regimen during double-blind 
study treatment period  
Week 
Group 1-Daily PS dose14 weeks taper  
Group 2-Daily PS dose  
52 weeks taper 
0 
Day 1 
15 
15 
1 
15 
15 
2 
14 
14 
3 
12 
12 
4 
10 
12 
5 
9 
12 
6 
8 
10 
7 
7 
10 
8 
6 
9 
9 
5 
9 
10 
4 
9 
 11 
3 
9 
12 
2 
8 
13 
1 
8 
14 
PS placebo 
8 
15 
PS placebo 
8 
16 
PS placebo 
7 
17 
PS placebo 
7 
18 
PS placebo 
7 
19 
PS placebo 
7 
20 
PS placebo 
6 
21 
PS placebo 
6 
22 
PS placebo 
6 
23 
PS placebo 
6 
24 
PS placebo 
5 
25 
PS placebo 
5 
26 
PS placebo 
5 
27 
PS placebo 
5 
28 
PS placebo 
4 
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Week 
Group 1-Daily PS dose14 weeks taper  
Group 2-Daily PS dose  
52 weeks taper 
29 
PS placebo 
4 
30 
PS placebo 
4 
31 
PS placebo 
4 
32 
PS placebo 
3 
33 
PS placebo 
3 
34 
PS placebo 
3 
35 
PS placebo 
3 
36 
PS placebo 
2 
37 
PS placebo 
2 
38 
PS placebo 
2 
39 
PS placebo 
2 
40 
PS placebo 
2 
41 
PS placebo 
2 
42 
PS placebo 
2 
43 
PS placebo 
2 
44 
PS placebo 
1 
45 
PS placebo 
1 
46 
PS placebo 
1 
47 
PS placebo 
1 
48 
PS placebo 
1 
49 
PS placebo 
1 
50 
PS placebo 
1 
51 
PS placebo 
1 
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Appendix B 
Contraceptive guidance and collection of pregnancy information  
DEFINITIONS 
Non reproductive potential 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
2. Postmenopausal 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH)/estradiol level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, a single FSH/estradiol measurement is insufficient. 
• Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
highly effective contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
A WOCBP should avoid pregnancy and should use the highly effective contraceptive methods 
detailed below through the course of the entire study and until 12 weeks after the last dose of 
sarilumab or matching placebo. 
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Female subjects: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 
• 
oral 
• 
intravaginal 
• 
transdermal 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
• 
oral 
• 
injectable 
• 
implantable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• Intrauterine device  
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence if this is the preferred and usual lifestyle of the subject 
 
For UK and Germany Only: Acceptable forms of effective contraception include: 
 
• Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation; 
• Established use of oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation; 
• Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS); 
• Bilateral tubal occlusion; 
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• Male sterilisation (provided that the partner is the sole sexual partner of the woman of 
childbearing potential study participant and that the sterilized partner has received medical 
assessment of the surgical success.); 
• True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception). 
For Denmark Only: Acceptable methods of effective contraception include: 
• Intra-uterine devices (IUD); 
• Hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal 
vaginal devices or injections with prolonged release). 
Male participants with partners of reproductive potential who become pregnant  
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male participant who becomes pregnant while participating in this study. This applies only 
to male participants who receive study treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor. 
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. 
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and the neonate, which will be forwarded 
to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. 
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
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Appendix C 
COMPOSITE Glucocorticoid Toxicity Index  
 
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Appendix D 
Specific list for Glucocorticoid Toxicity Index  
 
 
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Appendix E 
General guidance for the follow-up of laboratory abnormalities by 
Sanofi  
 
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met  
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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met  
 
 
 
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  Total Bilirubin    2X ULN 
 
 
Discontinue Administration of IMP 
Monitor LFTs 48 hours later 
Repeat LFT 7 days later, continue to hold 
until conditions for resumption of IMP 
administration are met (ALT < 3X ULN) 
  
  
  
 
  
 
ALT  X ULN 
 
  
 
  
  
  
 
  ALT   5X ULN 
  
  
 
 ALT  >  5X ULN 
 
  
 
 
  
  
  
 
  
  
  
 
Discontinue Administration 
of IMP 
  
 
 
  
  
 
In ANY CASE, FOLLOW the instructions #1 to #8 listed in the box below. 
1.
INFORM the medical monitor/CRA 
2.
COMPLETE the specific form for “Liver Injury” 
3.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury 
4.
PERFORM the following tests: 
 
-LFTs:  AST, ALT, alkaline phosphatase, total and conjugated bilirubin, and prothrombin time /INR 
 
-CPK, serum creatinine, complete blood count 
 
-Anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA, anti-CMV IgM and anti-HEV IgM antibodies 
 
-Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM 
 
-Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma 
 
-Hepatobiliary ultrasonography (can be completed by other imaging investigations if needed) 
5.
CONSIDER consulting with hepatologist 
6.
CONSIDER patient hospitalization if INR >2 (or PT <50%) and/or central nervous system disturbances 
suggesting hepatic encephalopathy 
7.
MONITOR LFTs 
-If investigational medicinal product is discontinued due to ALT increases as closely as possible to 
every 48 hours until stabilization, then every 2 weeks until return to normal (<2 x ULN) or baseline for at 
least 3 months, whichever comes last 
8.
FREEZE serum (5 mL x 2) 
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test could be proposed 
ALT > 3X ULN and  
Total Bilirubin  2X ULN 
Note: in addition, as soon as a seriousness criterion is met, the event should be notified within 24 hours  to the monitoring team 
ALT increase 
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Appendix F 
List of opportunistic infections  
• Aspergillosis 
• Blastomyces dermatitidis (endemic in the south-eastern and south-central Unites States, 
along Mississippi and Ohio rivers) 
• Systemic candidiasis and extensive cutaneous cases 
• Coccidioides immitis (endemic Southwestern US and Central and South America) 
• Cryptococcus infection 
• Cytomegalovirus infection 
• Herpes simplex (severe/disseminated) 
• Herpes zoster infection 
• Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-
Ohio-Mississippi river basins) 
• Listeriosis 
• Malaria (developing world) 
• Infection with mycobacterium avium and other nontuberculosis mycobacteria 
• Pneumocystis Carinii pneumonia (PCP) 
This list is indicative and not exhaustive. 
 
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Appendix G  
Definition of Anaphylaxis  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death." 
(Adapted from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , Branum A, et al.  Second 
symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391-7) 
Clinical criteria for diagnosing anaphylaxis 
 
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Appendix H 
FACIT- Fatigue (Paper Version)*  
FACIT-Fatigue Scale (Version 4), English (Universal) - Copyright 1987, 1997 
- 
*This version will be adapted for use in the electronic format.  
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Appendix I 
EuroQol Questionnaire (EQ-5D-3L) (Paper Version)*  
 
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*This version will be adapted for use in the electronic format. 
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Appendix J 
SF-36v2 (Paper Version)*  
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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) 
*This version will be adapted for use in the electronic format. 
 
 
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Appendix K 
HAQ-DI – Health Assessment Questionnaire (Paper Version)*  
 
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Appendix L 
Physician’s Global Assessment of Disease Activity (Paper Version)*  
 
PHYSICIAN’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
Place a vertical mark on the line for how you would assess your patient’s current disease activity 
 
 
 
 
Not active 
 
 
 
 
Very active  
0 mm 
 
100 mm 
 
 
 
 
*This version will be adapted for use in the electronic format. 
 
 
 
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Appendix M 
Biomarker Objectives  
The objectives of the Precision Medicine Plan are to characterize the disease activity of PMR 
patients while on steroid taper or sarilumab treatment. Both treatment arms will be exposed to 
anti-inflammatory agents so evaluation of baseline inflammation and changes over time will be 
evaluated using comprehensive approaches to evaluating circulating cell types, circulating 
proteins, genetics and evaluation of gene expression changes in an optional sub study. 
Whole blood for immunophenotyping of circulating immune cell types 
The contribution of the innate and adaptive immune systems to PMR disease activity and 
treatment response are not well understood. In order to better characterize alterations of the innate 
and adaptive immune system pre-dose and after steroid taper or sarilumab treatment, whole blood 
collections at pre-dose at V2, V4 and V9 are proposed to characterize T cell subsets that are 
purported to be dysregulated in PMR patients (CD8 cytotoxic lymphocytes) (23, 24, 25, 26) and 
(27) or cells that produce or are activated by IL6 signaling (monocytes (28) and Th17 cells, 
respectively). A total of 80 patients (40 patients/arm) will be selected at random by IRT for this 
blood sampling and subsequent analysis. 
Optional Future Use Sample - Biomarker Serum and Plasma  
The purpose of storing serum and plasma is to analyze at a later time point proteins at baseline 
and after treatment that may be associated with disease progression of PMR and related diseases, 
severity and treatment response to anti IL-6R therapy. Although acute phase reactants have been 
well described in PMR patients, proteins that associate with PMR symptoms of morning stiffness 
and shoulder and hip pain have not been explored in the other studies. Proteins that may be 
explored include but not limited to the following: proteins involved in the IL6 signaling pathway 
(IL-6, soluble IL-6R, fibrinogen, serum amyloid A, synovitis and bursitis (adhesion and proteases 
(29, 30)), cytokines involved in TH1/Th17 pathway and the HPA axis (cortisol) (31, 32, 33). 
Optional Pharmacogenetics substudy for DNA and RNA 
For the optional pharmacogenetics substudy, DNA will be collected at a single visit to analyze the 
sequence to determine if there are genetic variants that predict disease flare, remission or response 
to anti-IL-6R therapy.  RNA will be collected pre-dose at V2 and then pre-dose at V3 2 weeks 
after the first study drug administration to determine if anti-IL6R therapy changes gene expression 
patterns in circulating blood cells compared to steroid taper + placebo. DNA and RNA samples 
for the genomics sub-study will be double-coded as defined by the International Council for 
Harmonisation (ICH) guideline E15. The DNA and RNA will be stored for up to 15 years from 
the completion of the clinical study report (CSR), or as otherwise required by local regulations. 
Specific procedures for collection, shipping and storage of pharmacogenetics samples will be 
provided in a separate manual. The purpose of the genomic analyses is to identify genomic 
associations with clinical or biomarker response, other clinical outcome measures and possible 
AEs.  In addition, associations between genomic variants and prognosis or progression of as well 
as related diseases may also be studied. These data may be used or combined with data collected 
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from other studies to identify and validate genomic markers related to the study drug or and 
related diseases. Analyses may include sequence determination or single nucleotide 
polymorphism studies of candidate genes and surrounding genomic regions.  Other methods, 
including whole-exome sequencing, whole-genome sequencing, DNA copy number variation, and 
transcriptome sequencing may also be performed. 
The list of methods may be expanded to include novel methodology that may be developed during 
the course of this study or sample storage period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix N 
Protocol amendment history  
Amended protocol 01 (19 Sep 2018) 
This amended protocol (amendment 01) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it neither significantly impacts the safety or physical/mental integrity 
of participants nor the scientific value of the study. 
Overall rationale for amendment 1 and amended protocol 01 (19 Sep 2018) 
The overall rationale for the changes implemented in the protocol amendment is to address several 
comments raised by the European Regulatory Authorities during the initial protocol review. 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
Section 7.2.2 
Exclusion 
Criterion 15 
The initial wording of this criteria was modified with 
the elimination of, “Based on investigators’ 
judgment,” and addition of, “Patient who meets any 
of the following”.  
The modification was made based upon request from the 
European Regulatory Authorities.  The underlying 
criterion has not changed. 
Sections 
10.4.1 and 
10.4.3 
Additional wording was added to both sections 
pertaining to ALT discontinuation criteria.  
The modification was made based upon the 
recommendation from the European Regulatory 
Authorities to improve clarity. The underlying criteria in 
both sections have not changed.  
Section 12.2 
Language pertaining to the use of legal 
representative was modified.  
The modification, made based upon an inquiry from the 
European Regulatory Authorities, explains the specific 
use of a legal representative that may be required for 
certain countries in obtaining the informed consent when 
a patient may be able to give consent but not able to sign 
the document. 
 
 
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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 
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According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
A randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of sarilumab in patients with polymyalgia rheumatica 
SAR153191-EFC15160 
STATISTICIAN: 
 
DATE OF ISSUE: 20-May-2021 
Total number of pages: 
88 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.2.3 
Other objectives ............................................................................................................................... 8 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 12 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 12 
2.1.1 
Demographic and baseline characteristics .................................................................................... 12 
2.1.2 
Prior or concomitant medications ................................................................................................... 14 
2.1.3 
Efficacy endpoints .......................................................................................................................... 14 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 14 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 16 
2.1.3.3 
Exploratory endpoint(s) .................................................................................................................. 21 
2.1.4 
Safety endpoints ............................................................................................................................ 21 
2.1.4.1 
Adverse events variables ............................................................................................................... 22 
2.1.4.2 
Deaths ............................................................................................................................................ 23 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 23 
2.1.4.4 
Vital signs variables ....................................................................................................................... 24 
2.1.4.5 
Antinuclear antibodies .................................................................................................................... 24 
2.1.5 
Immunogenicity endpoints ............................................................................................................. 24 
2.1.6 
Pharmacokinetic variables ............................................................................................................. 25 
2.1.7 
Pharmacodynamic/genomics endpoints ........................................................................................ 25 
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2.1.8 
Other efficacy endpoints ................................................................................................................ 25 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 29 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 31 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 31 
2.3.1 
Efficacy populations ....................................................................................................................... 32 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 32 
2.3.2 
Safety population ........................................................................................................................... 32 
2.3.3 
Pharmacokinetics and ADA populations ........................................................................................ 32 
2.3.4 
Population with and without trial impact (disruption) due to COVID-19 ......................................... 32 
2.4 
STATISTICAL METHODS ............................................................................................................. 33 
2.4.1 
Demographics and baseline characteristics .................................................................................. 33 
2.4.2 
Prior or concomitant medications ................................................................................................... 33 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 34 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 34 
2.4.3.2 
Compliance .................................................................................................................................... 34 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 35 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 35 
2.4.4.2 
Analyses of secondary efficacy endpoint(s) .................................................................................. 37 
2.4.4.3 
Analyses of exploratory endpoint(s) ............................................................................................... 38 
2.4.4.4 
Multiplicity issues ........................................................................................................................... 39 
2.4.5 
Analyses of safety data .................................................................................................................. 39 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 39 
2.4.5.2 
Deaths ............................................................................................................................................ 42 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 42 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 44 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 44 
2.4.7 
Analyses of quality of life variables ................................................................................................ 44 
2.4.8 
Analysis of immunogenicity endpoints ........................................................................................... 45 
2.4.9 
DNA/RNA ....................................................................................................................................... 47 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 47 
2.5.1 
General conventions ...................................................................................................................... 47 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 47 
2.5.3 
Missing data ................................................................................................................................... 47 
2.5.4 
Windows for time points ................................................................................................................. 49 
2.5.5 
Unscheduled visits ......................................................................................................................... 49 
2.5.6 
Remote Assessment ...................................................................................................................... 49 
2.5.7 
Pooling of centers for statistical analyses ...................................................................................... 49 
2.5.8 
Statistical technical issues ............................................................................................................. 50 
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3 
INTERIM ANALYSIS ..................................................................................................................... 51 
4 
DATABASE LOCK ........................................................................................................................ 52 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 53 
6 
REFERENCES ............................................................................................................................... 54 
7 
LIST OF APPENDICES ................................................................................................................. 55 
APPENDIX A 
STUDY FLOW CHART ........................................................................................................ 56 
APPENDIX B 
STANDARDIZED CORTICOSTEROID-TAPER REGIMEN DURING DOUBLE-
BLIND STUDY TREATMENT PERIOD ......................................................................................... 61 
APPENDIX C 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA ......... 63 
APPENDIX D 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 69 
APPENDIX E 
SF-36 V2 SCORING ............................................................................................................ 72 
APPENDIX F 
FACIT-FATIGUE SCORING GUIDELINES (VERSION 4) .................................................. 74 
APPENDIX G 
SAS CODE FOR EQ-5D-3L INDEX UTILITY SCORING ................................................... 75 
APPENDIX H 
SAS CODE FOR SF-36 SCORING ..................................................................................... 76 
APPENDIX I 
VISIT WINDOWS BASED ON DAY RANGES...................................................................... 84 
APPENDIX J 
BASELINE GLUCOCORTICOID TOXICITY ........................................................................ 87 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADA: 
antidrug antibody 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANA: 
antinuclear antibodies 
AST: 
asparate aminotransferase 
BMI: 
body mass index 
CRF: 
case report form 
CSR: 
clinical study report 
ds-DNA: 
double-stranded DNA 
HbA1c: 
hemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol 
HLGT: 
high level group term 
HLT: 
high level term 
ID: 
identification 
IMP: 
investigational medicinal product 
LDH: 
lactate dehydrogenase 
LDL-C: 
low density lipoprotein cholesterol 
LLN: 
lower limit of normal 
LLOQ: 
lower limit of quantification 
LLT: 
lower level term 
LS: 
least square, least square 
MD-VAS: 
physician global assessment of disease activity- visual analog scale 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NCEP ATPIII: 
National Cholesterol Education Program Adult Treatment Panel III 
PT: 
preferred term 
RBC: 
red blood cell 
SAEs: 
serious adverse events 
SMQ: 
standardized MedDRA query 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
WBC: 
white blood cell 
WHO-DD: 
World Health Organization - Drug Dictionary 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of 
statistical strategy and methodology to be used to analyze the data from sarilumab EFC15160 
study in patients with active polymyalgia rheumatica (PMR). 
Due to the ongoing pandemic of COVID-19 (the disease caused by the novel coronavirus), the 
operations of sarilumab (Kevzara®) clinical trial EFC15160 have been significantly disrupted in 
various countries and sites. Consequently, the screening/recruitment activities for this study have 
been suspended since March 2020. Due to the protracted recruitment timeline and internal 
portfolio reprioritization, in July 2020, Sanofi decided not to re-open the screening/recruitment 
activities and to discontinue the study. This decision is not related to any safety issues arising 
from the administration of sarilumab. 
A total of 118 patients (out of 280 planned patients) have been randomized in the study. Despite 
the decision to discontinue the study, all patients already recruited will be allowed to continue in 
the study to complete the 52-week treatment period and the 6 weeks post-treatment follow up per 
protocol. 
1.1 
STUDY DESIGN AND RANDOMIZATION  
Original study design 
This is a multicenter, randomized, double-blind, placebo-controlled 52-week Phase 3 study with a 
6-week post-treatment follow-up phase, evaluating the efficacy and safety of sarilumab in patients
with active polymyalgia rheumatica (PMR).
Patients with active PMR who meet the entry criteria will be randomized in a 1:1 ratio to either 
−
Group 1: sarilumab 200 mg every two weeks (q2w) with a 14-week prednisone taper, or
−
Group 2: sarilumab matching placebo q2w with a 52-week prednisone taper.
All patients will receive sarilumab 200 mg or its matching placebo for 52 weeks, while the initial 
dose of prednisone for both groups will be 15 mg/day for the first 2 weeks after randomization 
(baseline). To ensure the double blinding of the corticosteroid (CS) regimen thereafter, once daily 
prednisone and/or prednisone matching placebo will be provided according to the protocol 
defined CS tapering regimen (Appendix B) as summarized below. 
−
Group 1: From Week 2 to Week 13, patients will receive gradually decreasing dose levels
of prednisone (prednisone or combinations of prednisone and its matching placebo). From
Week 14 onwards, patients without flare will receive prednisone matching placebo.
−
Group 2: From Week 2 to Week 51, patients will receive gradually decreasing dose levels
of prednisone (prednisone or combinations of prednisone and its matching placebo).
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During the initial 12 weeks of prednisone taper, treatment for one flare before Week 12 is 
permitted if it can be successfully treated with a low dose (≤5 mg/day) prednisone add-on taper 
regimen (completed prior to Week 12) and provided that all other sustained remission parameters 
are met. For patients who experience a disease flare and are in need of rescue therapy (such as CS) 
as per investigator judgment, during the course of the study, they may continue administration of 
sarilumab or matching placebo in a double-blinded fashion for the full duration of the 52-week 
treatment period only if CS are used as rescue therapy. Treatment with non-biological 
immunosuppressive drugs (such as alkylating agents, hydroxychloroquine, CsA, MMF, AZA, 
etc.) is not permitted during the study, unless used for the purpose of rescue therapy. 
For the management of pre-defined laboratory abnormalities, investigators may temporarily hold 
the study drug (sarilumab or its matching placebo) and/or permanently reduce the dose of 
sarilumab (or its matching placebo) to 150 mg q2w in a continuous blinded manner. 
There will be a post treatment follow-up visit 6 weeks after the end of treatment visit. All patients 
who prematurely and permanently discontinue study treatment will be asked to return to the site 
for study assessments as per protocol until end of study (EOS) evaluation. The last patient last 
visit will occur when the last patient has completed the 6-week follow up period (EOS). The end 
of the clinical trial is defined as the last patient’s last visit. 
Approximately 280 patients are planned to be randomized into 2 treatment groups of 140 patients 
per group. 
Study discontinuation plan 
As mentioned in Section 1, due to the protracted recruitment timeline and internal portfolio 
reprioritization, Sanofi decided to terminate the EFC15160 study in July 2020. All randomized 
patients continued to complete the study per protocol, and the last patient last visit (EOS) was 
achieved on May 19, 2021. 
1.2 
OBJECTIVES  
1.2.1 Primary objectives 
The primary objective of this study is to evaluate the efficacy of KEVZARA® (sarilumab) in 
patients with PMR as assessed by the proportion of patients with sustained remission at Week 52 
for sarilumab with a 14-week CS tapering regimen as compared to placebo with a 52-week CS 
tapering regimen (see Section 2.1.3.1 for definition of sustained remission). 
1.2.2 Secondary objectives 
•
To demonstrate the efficacy of sarilumab (14 week taper of CS) compared to placebo
(52 week taper of CS) in patients with PMR with regards to:
-
Clinical responses (such as components of sustained remission, disease remission
rates, time to first disease flare) over time.
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-
Cumulative CS (including prednisone) exposure.
•
To assess the safety (including immunogenicity) and tolerability of sarilumab in patients
with PMR.
•
To measure sarilumab concentrations from serum of patients with PMR.
•
To assess the effect of sarilumab on reducing glucocorticoid toxicity as measured by the
composite glucocorticoid toxicity index (GTI) questionnaire.
1.2.3 Other objectives 
•
To assess the effect of sarilumab on physician assessment of disease activity as measured
by a visual analogue scale (MD-VAS).
•
To assess the effect of sarilumab on a variety of patient-reported outcome (PRO) concepts,
including fatigue (as measured by FACIT-fatigue scale), health status (as measured by
EQ-5D-3L and SF-36v2), physical function (as measured by HAQ-DI, pain (as measured
via HAQ-DI by a visual analogue scale [VAS]) and patient assessment of disease activity
(as measured via HAQ-DI by a VAS).
•
To assess the correlation between the ESR/CRP levels on remission status.
•
To characterize the disease activity of PMR patients while on steroid taper or sarilumab
treatment in a subset of patients using comprehensive approaches to evaluate circulating
immune cell types.
•
To characterize the disease activity of PMR patients while on steroid taper or sarilumab
treatment by evaluating circulating proteins, genetics and gene expression.
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations are based on the primary efficacy variable of sustained remission at 
Week 52 compared between the sarilumab + 14-week prednisone taper and placebo + 52-week 
prednisone taper groups. There are no prior controlled study data to establish the placebo + 
52-week prednisone taper remission rate in PMR. The hypothesis to be tested on the primary
endpoint is that sarilumab + 14-week prednisone taper is superior to placebo + 52-week
prednisone taper based on the proportion of patients achieving sustained remission at Week 52. A
25% difference from placebo + 52-week prednisone taper response rate is considered clinically
relevant, and the sample size of 140 per group provides at least 90% power to detect such a
difference regardless of the placebo + 52-week prednisone taper response rate (i.e., assuming 5%
to 50% placebo + 52-week prednisone taper response rates), using a two-sided χ2 test at a
significance level of 0.01. Data from the GiACTA trial in a related population with GCA suggest
that such a treatment difference is achievable (1).
The above sample size calculation was performed for the full enrollment (140 per group). The 
total number of randomized patients is 118 at the time of the premature termination of the study. 
Randomized patients could continue in the study to complete the 52-week treatment period per 
protocol. 
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Based on protocol amendment 2, the alpha level has been changed from 0.01 to 0.05. The power 
calculations provided in Table 1 below are based on a sample size of 118 and alpha level of 0.05. 
The sample size of 59 per group provides at least 85% and 95% power to detect a 25% and 30% 
difference in response rates between sarilumab + 14-week prednisone taper and placebo 
+ 52-week prednisone taper groups respectively, assuming response rates between 5% to 15% in
the placebo + 52-week prednisone taper group based on two-sided χ2 test at a significance level of
0.05.
Table 1: Power calculations based on total sample size of 118 randomized patients 
Assumed sustained remission 
rate for placebo+ 52-week 
prednisone taper 
Sample Size per group 
Power assuming an 
absolute 25% between 
group difference 
Power assuming an 
absolute 30% between 
group difference 
5% 
59 
95.6% 
98.8% 
10% 
59 
91.2% 
97.2% 
15% 
59 
86.9% 
95.4% 
Calculations were made using nQuery Advisor 7.0 based on two-sided χ2 test at a significance 
level of 0.05. 
1.4 
STUDY PLAN 
The schedule of the safety, efficacy, pharmacokinetic (PK), and immunogenicity assessments 
from Section 1.2 of the study protocol is provided in Appendix A. The graphical study design is 
provided in Figure 1. 
Figure 1 – Graphic study design 
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL 
In general, the statistical methods remain unchanged by the protocol amendment 02 except for 
revisions made to sample size and power calculations as listed below: 
Amended protocol 02 (19 April 2021): 
As a result of the inability to recruit due to the COVID19 pandemic, the study was terminated 
prematurely resulting in a change in the total expected number of patients from 280 to 118 
(Section 1.3). 
•
Statistical significance level changed from 0.01 to 0.05 due to the change in total expected
number of patients.
•
Power calculations revised due to the change in total expected sample size to 118, and the
change in statistical significance level to 0.05.
•
99% confidence intervals revised to 95% confidence intervals associated with the change
in statistical significance level to 0.05.
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Due to the premature termination of the study, a total of 118 patients (42%) of the 280 patients 
planned were randomized. The randomized patients could continue in the study to complete the 
treatment period and the 6 weeks post-treatment follow up per protocol. Hence, there are no 
changes to the efficacy analysis plan per protocol. 
The COVID-19 pandemic has also impacted data collection as patients may not be able to visit 
clinical sites for endpoint assessments. Additional patient level information at visits that were 
impacted by the pandemic situations were captured for assessments performed in visits that were 
delayed, not done, partially done on site, or partially done by phone. Major or critical COVID-19 
impacted deviations per protocol were also recorded.  
To assess the impact of the pandemic on the study, COVID-19 related summaries are added as 
below. 
a)
Patients who permanently discontinue study treatment or study due to COVID-19 reasons will
be summarized in patient disposition table
b)
Patient disposition by visit according to trial impact due to COVID-19
c)
Critical or major deviations summary according to COVID-19 impact
d)
Number (%) of patients experiencing at least one treatment-emergent COVID-19 related
adverse event by primary SOC and PT
In addition, if > 10% patients are impacted by the COVID-19 pandemic, below 
summaries/analyses will be generated by COVID-19 impacted population (Yes, No): 
a)
Extent of exposure to SC IMP
b)
Treatment compliance for SC IMP
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c)
Number (%) of patients with TEAEs by primary SOC and PT, and
d)
Analysis of the primary endpoint of sustained remission at Week 52.
The population with and without trial impact (disruption) due to COVID-19 is defined in 
Section 2.3.4. 
In addition, upon meeting with Japan Health Authorities (PMDA) in April 2019, data for the 
components to calculate the PMR activity score (PMR-AS) were subsequently collected and the 
analysis plan is described in Section 2.4.4.3.  
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
Data analyses will be performed in the double-blind (DB) 52-week treatment period and presented 
by two treatment groups (sarilumab 200 mg q2w with 14-week CS taper, and placebo with 
52-week CS taper). Safety data will be summarized for the treatment and 6-week follow-up
period.
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value prior to the first dose of study medication, 
SC IMP. For patients randomized but not treated, the baseline value is the last available value up 
to randomization. For PRO assessments, baseline value is defined as the last available value up to 
and including the day of administration of the first dose of SC IMP. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the efficacy and safety sections (Section 2.4.4 and 
Section 2.4.5). 
Demographic characteristics 
The following demographic characteristics will be summarized separately by treatment and 
overall: 
•
Sex (Male, Female)
•
Race (White, Black or African American, Asian, Native Hawaiian or Other Pacific
Islander, American Indian or Alaska Native, Unknown, Not reported)
•
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Not reported)
•
Region (Region 1 [Western countries], Region 2 [South America], and Region 3 [Rest of
the World]); definitions of the regions are provided in Section 2.5.7
•
Age (years)
•
Age group (≥50 and <65, ≥65 and <75, ≥75 and <85, ≥85 years)
•
Weight (kg)
•
Weight group (<60, ≥60 and <100, ≥100 kg)
•
Body mass index (BMI, kg/m2)
•
BMI group (<25, ≥25 and < 30, ≥30 kg/m2)
•
Smoking status (never, former, current)
•
Alcohol habits (never, occasional, monthly, weekly, daily)
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Medical or surgical history 
Medical or surgical history includes all the relevant findings within the lifetime of the patient. 
This information will be coded to a “Lower Level Term (LLT)”, “Preferred Term (PT)”, “High 
Level Term (HLT)”, “High Level Group Term (HLGT)”, and associated primary “System Organ 
Class (SOC)” using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Sanofi at the time of database lock. 
Disease characteristics at baseline  
The following baseline disease characteristics as well as the other baseline characteristics will be 
summarized separately by treatment group: 
•
PMR signs and symptoms:
-
Morning stiffness (≤ 45 minutes, > 45 minutes)
-
Pain in the shoulders, neck and/or hip girdles
-
Limited range of motion of the shoulders and /or hip girdles (no upper limb elevation,
elevation below the shoulder girdle, elevation up to the shoulder girdle, elevation
above the shoulder girdle)
-
Constitutional symptoms (low grade fever, unintentional weight loss, fatigue, malaise,
loss of appetite)
-
Other features judged by the investigator to be consistent with PMR disease activity
•
Number of patients with prior PMR flares (≤6 months, 6 to 12 months or >12 months prior
to screening) and number of prior flares per patient
•
Prednisone dose at baseline
•
Highest dose and duration of corticosteroid taper taken for PMR from 24 weeks prior to
screening up to baseline
•
Physician global assessment of disease activity (MD-VAS)
•
C-reactive protein (CRP) at baseline
•
ESR at baseline
•
Glucocorticoid toxicity at baseline*
*The baseline glucocorticoid toxicity is established by a composite index calculated from
weighted scores assigned by toxicities. The scores are described in Appendix J.
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 2.5. 
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2.1.2 Prior or concomitant medications 
All medications taken within a certain period of time before randomization and until the end of 
the study, including vaccines taken before screening, biological/non-biological disease modifying 
anti-rheumatic drugs [DMARDs] and immunosuppressive agents taken for patients with 
symptomatic PMR disease are to be reported in the case report form (CRF) pages. The highest 
dose and duration of all corticosteroids taper taken for PMR from 24 weeks prior to screening up 
to baseline and all corticosteroids taken during the study are also reported. 
All medications will be coded using the World Health Organization – Drug Dictionary 
(WHO-DD) version currently in effect at Sanofi at the time of database lock. 
•
Prior medications are those the patient used prior to first investigational medicinal product
(IMP) intake. Prior medications can be discontinued before first dosing or can be ongoing
during treatment phase.
•
Concomitant medications are any treatments received by the patient concomitantly to the
IMP, during the treatment-emergent adverse event period (Section 2.1.4).
A given medication can be classified as a prior medication, as a concomitant medication, and/or 
as a post-treatment medication. 
For patients who experience a disease flare and are in need of rescue therapy, study patients 
prescribed with rescue corticosteroids (non-investigational medicinal product) per investigator 
judgement during the course of the study will continue administration of subcutaneous (SC) IMP 
(sarilumab or its matching placebo) for the full duration of the 52-week treatment period. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints  
2.1.3.1 Primary efficacy endpoint(s) 
The primary endpoint is the proportion of patients achieving sustained remission at Week 52, 
where the sustained remission at Week 52 is defined as having met all of the following 
parameters: 
1. Achievement of disease remission not later than Week 12,
2. Absence of disease flare from Week 12 through Week 52,
3. Sustained reduction of CRP (to <10 mg/L, with an absence of successive elevations to
≥10 mg/L) from Week 12 through Week 52, and
4. Successful adherence to the prednisone taper from Week 12 through Week 52.
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Components of primary endpoint are described as below: 
1.
Achievement of disease remission not later than Week 12
Disease remission is defined as resolution of signs and symptoms of PMR, and normalization of 
CRP (<10 mg/L). Note that a single CRP elevation (≥10 mg/L) is not considered absence of 
remission unless CRP remained elevated (≥10 mg/L) at the next study visit. 
The status of normalization of CRP (<10 mg/L) will be determined based on the last two non-
missing post-baseline CRP values measured up to Week 12. If at least one of them is <10 mg/L, 
then it is considered as normalization of CRP. 
Signs and symptoms of disease 
Evaluation of clinical signs and symptoms by the Efficacy Assessor at every study visit according 
to the schedule of assessment will include the following: 
•
Morning stiffness and/or pain, in the neck, shoulder and/or hip girdles
•
Limited range of motion of the shoulders and/or hip girdles
•
Constitutional symptoms, such as fatigue, weight loss and low-grade fever
•
Other features judged by the clinician-investigator to be consistent with a PMR flare
The resolution of signs and symptoms of PMR is identified in eCRF “PMR Assessment” page 
with the question “Based upon the patient’s relevant medical history and the clinical assessment 
and responses provided above, does the patient have active PMR?” ticked as “No”. The resolution 
of signs and symptoms of PMR by Week 12 will be determined based on the last non-missing 
post-baseline PMR assessment measured up to Week 12. 
Patients who took rescue CS due to active PMR prior to Week 12 or who permanently withdraw 
from the study treatment prior to Week 12 will be considered as not achieved disease remission by 
Week 12. 
Note that during the initial 12 weeks of prednisone taper, treatment for one flare before Week 12 
is permitted if it can be successfully treated with a low dose (≤5 mg/day) prednisone add-on taper 
regimen (completed prior to Week 12) and provided that all other sustained remission parameters 
are met. 
2. Absence of disease flare from Week 12 through Week 52.
Flare is defined as either 1) recurrence of signs and symptoms attributable to active PMR plus an 
increase in CS dose due to PMR, or 2) elevation of ESR attributable to active PMR plus an 
increase in CS dose due to PMR. Increase in CS dose is defined as: 
•
Any dose increase during the protocol defined steroid taper, or
•
Re-initiation of prednisone therapy after the protocol defined taper has been completed.
Patients with disease flare are identified as those with the reason for treatment ticked “rescue 
therapy” in eCRF “Steroid Medication” page and to the question “If Rescue Therapy, please 
specify” ticked either “Active PMR” or “Elevated ESR Attributable to Active PMR”. 
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3. Sustained reduction of CRP (to <10 mg/L, with an absence of successive elevations to
≥10 mg/L) from Week 12 through Week 52
The status of normalization of CRP from Week 12 through Week 52 will be determined based on 
the CRP values measured at Week 16, Week 20, Week 24, Week 32, Week 40 and Week 52. If 
there are two or more consecutive visits with CRP≥10 mg/L, then it is categorized as no 
normalization of CRP. Intermittent missing CRP at Week 16, Week 20, Week 24, Week 32, Week 
40 or Week 52 will be imputed using last value carried forward (LOCF) approach up to the last 
non-missing measurement. 
4. Successful adherence to the prednisone taper from Week 12 through Week 52
Successful adherence to the prednisone taper from Week 12 through Week 52 is defined as 
patients who did not take rescue therapy from Week 12 through Week 52 and any excess 
prednisone (beyond the per protocol CS tapering regimen) with a cumulative dose of ≤100 mg (or 
equivalent), such as those employed to manage AE not related to PMR. The cumulative dose of 
excess prednisone use will be counted from baseline to Week 52 (does not include add-on 
prednisone taken prior to Week 12). 
In addition, patients who permanently withdraw from the study treatment prior to Week 52 will be 
considered as not having achieved component 2, 3, or 4 for the primary endpoint. 
Blinding of CRP and ESR assessment results 
Investigators, including Efficacy Assessors, and patients will remain blinded to CRP and ESR 
results (except screening and baseline). Safety Assessors will also be blinded on post baseline 
CRP but will have access to ESR results. 
ESR kits will be provided by the central laboratory while the test will be performed locally at site, 
results (the distance in millimeters (mm) that red blood cells has descended in 1 hour) will be 
blinded to Investigators including Efficacy Assessors and staff directly involved in efficacy 
assessment of study patients. 
2.1.3.2 Secondary efficacy endpoint(s)  
The following efficacy variables will be assessed: 
•
Components of sustained remission composite measure at Week 52
•
Total cumulative corticosteroid (including prednisone) dose over during the treatment
period
•
Time to first PMR flare during the treatment period
•
GTI Cumulative worsening score (CWS) and Aggregate improvement score (AIS) at
Week 52.
Below are descriptions of these variables. Details related to imputation of GTI scores are 
described in Section 2.5.2. 
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Components of sustained remission composite measure at Week 52 
1. Proportion of patients who achieved disease remission by Week 12.
2. Proportion of patients who have no disease flare from Week 12 through Week 52.
3. Proportion of patients who have normalization of CRP (to <10 mg/L, with an absence of
successive elevations to ≥10 mg/L) from Week 12 through Week 52.
4.
Proportion of patients who successfully adhere to the prednisone taper from Week 12
through Week 52.
Total cumulative corticosteroid (including prednisone) dose during the treatment period 
The total cumulative corticosteroid includes prednisone taper regimen per protocol, add-on 
prednisone prior to Week 12 or use of commercial prednisone during the study treatment period 
such as those employed to manage AE not related to PMR, and rescue corticosteroids dose 
prescribed for rescue therapy over the treatment period for PMR disease only. 
Time to first PMR flare during the treatment period 
The duration (in days) from randomization to first PMR flare after clinical remission and up to 
52 weeks. Patients who never achieve remission will be censored at randomization day; and those 
who achieved clinical remission and never flared will be censored at the end of treatment 
assessment date up to Week 52. 
The definition of PMR flare is provide in Section 2.1.3.1 primary efficacy endpoint. 
Clinical remission is defined as resolution of signs and symptoms and normalization of CRP 
(<10 mg/L). Intermittent missing CRP at visit will be imputed using last value carried forward 
(LOCF) approach. If missing signs and symptoms, then clinical remission is not achieved. 
Glucocorticoid toxicity index (GTI) scores and components 
The GTI is intended to capture glucocorticoid (GC)-related morbidity and GC-sparing ability of 
other therapies (2). 
The GTI is composed of two components, the Composite GTI and the Specific List (Table 2). 
The Composite GTI consists of nine domains (body mass index (BMI), glucose tolerance, blood 
pressure,  Hyperlipidemia,  Bone Health (BMD), steroid myopathy,  Skin steroid-related Toxicity, 
Neuropsychiatric – steroid related symptoms and infection) on common steroid-related adverse 
events anticipated to occur in ≥5% of patients treated in a clinical trial involving glucocorticoids. 
The Specific List consists of 23 items (11 domains) that are mainly less common but serious 
adverse effects, serving as a complementary tool to the Composite GTI to ensure that all 
important elements of glucocorticoid toxicity were captured. 
The domains of the Composite GTI and the specific list of the GTI will be assessed at baseline, 
Week 12, Week 24, Week 40 and Week 52, except for bone density (BMD) which will be 
assessed at Baseline and Week 52 only. 
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For patients who withdraw from the study prior to Week 24, BMD will not be measured at the 
EOT visit as no substantial changes are expected within 6 months of treatment. As a result, 
missing BMD score will be imputed as ‘no change’. The BMD measured at the end of treatment 
(EOT) visit will be included in the definition of cumulative GTI scores (i.e., CWS and AIS as 
defined below) at Week 52 regardless when the EOT visit occurred. 
Scoring of the Glucocorticoid Toxicity Index (GTI) 
Domain-specific score for each patient at a visit is defined as the weight assigned based on the 
change in severity level as described for each domain in Table 2. 
Composite GTI score for each patient at a visit is the sum of 9 domain-specific scores at each 
visit. 
Cumulative GTI score is the sum of composite GTI score across visits. Two cumulative GTI 
scores, CWS and AIS, will be defined. 
•
Cumulative worsening score (CWS)
CWS is designed to assess cumulative GC toxicity, regardless of whether the toxicity has
lasting effects or is transient. New toxicities that occur are added, but toxicities that appear
to resolve on follow-up are not removed. Thus, the CWS serves as a lasting record of GC
toxicity observed and can only increase or remain the same over time.
CWS will be lower in the treatment arm compared to the placebo arm at the end of trial, if
the treatment is effective at decreasing GC toxicity over time.
•
Aggregate improvement score (AIS)
Patients are anticipated to have some GC toxicity at baseline, the AIS would be important
in establishing that the new therapy is effective at diminishing any baseline GC toxicity
over time. With the AIS, toxicities can be removed if improvement occurs, and added if
worsening occurs.
AIS decrease over time means that the treatment is effective in decreasing GC toxicity
level, compared to placebo which may show fluctuation of CIS over time. Negative score
reflects that toxicities present at baseline (or occurring during the trial) resolved over the
treatment period.
The steps to calculate the CWS and AIS at Week 52 are described below. 
Step 1: Calculate domain-specific worsening score (for computing CWS in Step 2) and 
improvement score (for computing AIS in Step 2) at each visit. 
For Domains without sub-items (Body Weight, Glucose Metabolism, Blood Pressure, Lipid 
Metabolism, Bone Health and Steroid Myopathy), 
a)
For worsening score, only consider positive domain-specific score at each visit. For domain
with a negative domain-specific score, the worsening score will be 0.
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b) For improvement score, all domain-specific scores (could be positive or negative) at each visit 
will be considered. 
The Skin and Neuropsychiatric domains both have sub-items. For the Skin domain, these are 
Acneiform Rash, Easy Bruising, Hirsutism, Atrophy/Striae, and Erosions/tears/ulcerations. For 
the Neuropsychiatric domain, these are Insomnia, Depression, Mania, and Cognitive Impairment. 
a) For worsening score, only the item with the highest weight is scored for any GTI interval 
(typically three months) with the CWS.  As an example, if neither insomnia nor depression 
were present at the baseline visit but there is now mild Insomnia and moderate depression 
present at follow-up, then only the moderate depression is scored (+63 points). 
b) For improvement score, improvement as well as worsening can be recorded. Because it is 
conceivable that one item might improve while another worsens, the item of greatest 
improvement (highest absolute weight) and the item of greatest worsening (highest weight) 
are recorded for given GTI interval. 
For Infection Domain, the worsening score and improvement score handle the scoring of 
infections differently, because the CWS and AIS reflect reciprocal measures of GC toxicity. 
a) For worsening score, the most severe infection in every GTI interval is scored. 
b) For improvement score, only the most severe infection occurring over the course of the entire 
trial is scored. 
Step 2: Calculate composite worsening score and improvement score at each visit by summing 
the 9 domain-specific score. 
a) For composite worsening score, sum the 9 domain-specific worsening scores. 
b) For composite improvement score, sum the 9 domain-specific improvement scores. 
Step 3: Calculate cumulative GTI scores by summing composite scores across visits.  
a) For CWS at Week 52, summing composite GTI worsening score at Week 12, Week 24, Week 
40, and Week 52. 
b) For AIS at Week 52, summing composite GTI improvement score at Week 12, Week 24, 
Week 40, and Week 52.  
Table 2 – The Glucocorticoid Toxicity Index 
Composite GTI 
Item 
weight 
Specific List1 
1.BMI 
 
  
  Decrease by >/= 5 BMI units 
-36 
Major increase in BMI 
  Decrease by >2 but <5 BMI units 
-21 
  
  No significant change (+/- 2 BMI units) 
0 
  
  Increase of >2 to <5 BMI units 
21 
  
  Increase of 5 or more BMI units 
36 
  
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Composite GTI 
Item 
weight 
Specific List1 
2.Glucose tolerance
Improvement in HbA1c AND decrease in medication
-44
Diabetic retinopathy 
Improvement in HbA1c OR decrease in medication
-32
Diabetic nephropathy 
No significant change
0
Diabetic neuropathy 
Increase in HbA1c OR increase in medication
32
Increase in HbA1c AND increase in medication
44
3.Blood pressure
Improvement in BP AND decrease in medication
-44
Hypertensive emergency 
Improvement in BP OR decrease in medication
-19
Posterior reversible encephalopathy 
syndrome 
No significant change
0
Increase in BP OR increase in medication
19
Increase in BP AND increase in medication
44
4.Hyperlipidemia
Decrease in LDL AND decrease in medication
-30
Decrease in LDL OR decrease in medication
-10
No significant change
0
Increase in LDL OR increase in medication
10
Increase in LDL AND increase in medication
30
5.Bone Health (BMD)
Increase in BMD (gain of more than 3%)
-29
Major decrease in bone density 
No significant change in BMD (+/- 3%)
0
Insufficiency fracture 
Decrease in BMD (loss of more than 3%)
29
6.Steroid myopathy
Moderate weakness to none
-63
Severe steroid myopathy 
Moderate to Mild weakness
-54
Mild weakness to none
-9
No significant change
0
None to Mild weakness (without functional limitation)
9
Mild to Moderate weakness
54
None to Moderate weakness (with functional limitation)
63
7.Skin steroid-related Toxicity
Decrease in Skin Toxicity – Moderate to None
-26
Severe skin toxicity 
Decrease in Skin Toxicity – Moderate to Mild
-18
Decrease in Skin Toxicity – Mild to None
-8
No significant change
0
Increase in Skin Toxicity – None to Mild
8
Increase in Skin Toxicity – Mild to Moderate
18
Increase in Skin Toxicity – None to Moderate
26
8.Neuropsychiatric – steroid related symptoms
Decrease in NP Toxicity – Moderate to None
-74
Psychosis 
Decrease in NP Toxicity – Moderate to Mild
-63
GC-induced violence 
Decrease in NP Toxicity – Mild to None
-11
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Composite GTI 
Item 
weight 
Specific List1 
  No significant change 
0 
Other severe neuropsychiatric 
symptoms 
  Increase in NP Toxicity – None to Mild 
11 
  Increase in NP Toxicity – Mild to Moderate 
63 
  Increase in NP Toxicity – None to Moderate 
74 
9.Infection
No infection
0 
Grade IV infection 
Oral or vaginal candidiasis or non-complicated zoster
(<Grade3)
19 
Grade V infection 
Grade 3, 4, or 5 infection
93 
1 Maximum weight is given for specific list events in Blood pressure, Steroid myopathy, Skin toxicity, Neuropsychiatric and Infection domains at 
each visit. For the rest of domains, specific list events will not affect the corresponding domain specific score. 
2.1.3.3 Exploratory endpoint(s) 
Following recommendation from the meeting with Japan Health Authority (PMDA) in April 
2019, exploratory analysis will be performed for disease activity in PMR, quantified by the PMR 
activity score (PMR-AS). 
PMR-AS is calculated as: CRP (mg/dl) + VAS p (0-10) + VAS ph (0-10) + (MST (min) x 0.1) + 
EUL (3-0). 
Visual analogue scale for pain (VAS p) is the patient’s assessment of pain from HAQ-DI 
assessment, and the visual analogue scale for physician’s assessment (VAS ph) is the physician’s 
global assessment of disease activity, MD-VAS. The exact duration of morning stiffness (MST) 
and the ability to elevate the upper limbs (EUL: 3 = none, 2 = below shoulder girdle, 1 = up to 
shoulder girdle, 0 = above shoulder girdle) are captured in the “PMR assessment” eCRF. CRP 
value is from laboratory measurements. 
PMR-AS will be assessed at baseline, Week 12, Week 24, and Week 52. 
Note that only binary MST duration was collected (≤ 45mins OR > 45mins) prior to the collection 
of exact MST duration implemented in June 2019. Missing exact MST duration will be imputed 
using the median of MST duration at visit for each MST category (≤45mins and >45mins). 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events (AEs), serious AEs (SAEs) and 
adverse events of special interest (AESIs) including but not limited to neutropenia, 
thrombocytopenia, elevations in hepatic enzymes leading to permanent discontinuation and 
tuberculosis, and other opportunistic infections. Other safety information, such as clinical 
laboratory data and vital signs will also be assessed. 
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Observation period  
The observation period will be divided into 4 epochs: 
• The screening epoch is defined as the time from the signed informed consent date up to 
the time prior to first dose of SC IMP. 
• The treatment epoch is defined as the time from the first dose of the IMP to the last dose 
of the SC IMP in the DB period +13 days. 
• The residual treatment epoch is defined as the time from the end of TREATMENT 
epoch to the last dose of the SC IMP +60 days. 
• The post-treatment epoch is defined as the time after the last dose of SC IMP +60 days. 
The rationale of having “last dose of SC IMP +60 days” as the end of follow-up in the residual 
treatment epoch is to capture the events observed within an approximately 5 half-lives of the last 
sarilumab SC IMP. 
The treatment-emergent adverse event (TEAE) period includes both treatment and residual 
treatment epochs. 
2.1.4.1 Adverse events variables  
Adverse event observation period  
• Pre-treatment AEs are AEs that developed or worsened or became serious from the signed 
informed consent date up to first administration of SC IMP 
• TEAEs are AEs that developed or worsened or became serious during the TEAE period 
• Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period 
All AEs (including SAEs and AESIs) will be coded to a “LLT”, “PT”, “HLT”, “HLGT”, and 
associated primary “SOC” using the version of MedDRA currently in effect at Sanofi at the time 
of database lock. 
The occurrence of AEs (including SAEs and AESIs) will be recorded from the time of signed 
informed consent until the end of the study. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
Adverse event of special interest (AESI) 
Adverse events of special interest will be flagged in the database. The AESIs and its search 
criteria are listed in Table 3 below: 
 
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Table 3 – Protocol defined AESIs and search criteria 
AESI flag 
Search criteria 
Clinically significant infections including: 
• 
Opportunistic infections 
• 
Tuberculosis 
• 
Infections requiring prolonged medication 
• 
Infections requiring parenteral treatment 
Reported by the investigators on the AE CRF page 
with AESI box ticked. 
Lab abnormalities including: 
• 
ALT increase leading to permanent discontinuation 
• 
ANC decrease leading to permanent discontinuation 
• 
Thrombocytopenia leading to permanent discontinuation 
ALT >= 3xULN 
Pregnancy 
CRF checkbox: Pregnancy 
Symptomatic Overdose 
CRF checkbox: Symptomatic Overdose 
2.1.4.2 Deaths  
The deaths per the observation period will be summarized.  
• Death on-treatment: deaths occurring during the treatment period (i.e., treatment Epoch)  
• Death during follow-up: deaths occurring during the residual treatment period 
• Death post-treatment: deaths occurring during the post-treatment period  
2.1.4.3 Laboratory safety variables  
Clinical laboratory data will include hematology, clinical chemistry, and urinalysis. Clinical 
laboratory values will be converted to standard international units; international units will be used 
in all listings and tables. In addition, the lipids parameters will also be summarized in US units. 
Hematology and chemistry data will be collected at screening, baseline, Weeks 4, 12, 24, 40, and 
52, and/or early termination unless otherwise specified. The laboratory parameters will be 
classified as follows: 
• Hematology 
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, platelet 
count, red blood cell (RBC) count, and RBC morphology (if RBC count is abnormal). 
- 
White blood cells: white blood cell (WBC) count and WBC differential (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils). 
• Clinical chemistry  
- 
Metabolism: fasting lipids (total cholesterol, high density lipoprotein cholesterol 
(HDL-C), low density lipoprotein cholesterol (LDL-C), ratio of HDL-C versus LDL-C 
(HDL-C:LDL-C), triglycerides), total proteins, CRP, fasting glucose, and  hemoglobin 
A1c (HbA1c). 
- 
Electrolytes: sodium, potassium, chloride, calcium, phosphate, and bicarbonate. 
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- 
Renal function: creatinine, creatinine clearance, uric acid, and blood urea nitrogen 
(BUN). 
- 
Liver function: alanine aminotransferase (ALT)/SGPT, aspartate aminotransferase 
(AST)/SGOT, alkaline phosphatase (ALP), albumin, total bilirubin, conjugated and 
unconjugated bilirubin, and lactate dehydrogenase (LDH). 
- 
Pregnancy test: Serum β-hCG for all women of childbearing potential (screening 
only). 
- 
TB screen:  QuantiFERON®-TB Gold evaluation. 
- 
Hepatitis screen: Hepatitis B and C serology, human immunodeficiency virus 
serology. 
Urine samples will be collected as follows: 
• Urinalysis – dipstick: pH, specific gravity, blood, glucose, protein, nitrates, leukocyte 
esterase, and bilirubin.  If any parameter on the dipstick is abnormal, a urine sample was to 
be sent to the central laboratory for testing.  
A urine pregnancy test was done for all women of childbearing potential at baseline, all visits up 
to Week 52 or early termination.  
2.1.4.4 Vital signs variables  
Vital signs variables include: heart rate, systolic blood pressure, and diastolic blood pressure, 
height, weight, and body temperature. 
2.1.4.5 Antinuclear antibodies  
Antinuclear antibodies (ANA) will be measured at baseline and EOT visits. 
2.1.5 Immunogenicity endpoints  
The immunogenicity blood samples will be collected before injection during the same visit 
according to the Study Flow Chart (Appendix A). 
Samples analyzed in the antidrug antibody (ADA) assay will be categorized as either positive or 
negative, and in the case of a positive result will be further characterized as either neutralizing or 
non-neutralizing. 
ADA positive patient is defined as patient with at least one treatment-emergent or 
treatment-boosted ADA positive sample during the TEAE period, where 
• Treatment-emergent ADA positive patient is defined as a patient with non-positive assay 
(meaning negative or missing) response at baseline but with a positive assay response 
during the TEAE period. 
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• Treatment-boosted ADA positive patient is defined as a patient with a positive ADA assay 
response at baseline and with at least a 4-fold increase in titer compared to baseline during 
the TEAE period. 
ADA negative patient is defined as patient without a treatment-emergent or treatment-boosted 
ADA positive sample during the TEAE period. 
A treatment-emergent positive response is further classified as persistent or transient. 
Persistent ADA response: treatment-emergent ADA detected at two or more consecutive 
sampling time points during the TEAE period, where the first and last ADA positive samples are 
separated by a period of at least 16 weeks. Also persistent in case last sample analyzed is positive. 
Transient ADA response: A treatment-emergent response that is not determined to be persistent. 
2.1.6 Pharmacokinetic variables  
The blood samples for the determination of functional sarilumab concentrations in serum will be 
collected before injection during the same visit according to the Study Flow Chart (refer to 
Section 1.2 in the study protocol) and at or near the onset and completion of the occurrence of a 
SAE. In addition, post-dose sample will be taken 4-7 days after the Week 24 (Visit 9). 
2.1.7 Pharmacodynamic/genomics endpoints  
Blood samples (DNA and genetic RNA) will be collected from each consenting patient to 
participate in the pharmacogenomics substudy. Details of any analysis will be described in a 
separate plan.  
2.1.8 Other efficacy endpoints  
Quality-of-life endpoints 
Other efficacy endpoints in the clinical outcome assessments will be summarized. Patients are 
asked to complete the following patient-reported outcome (PRO) questionnaires described below 
at Visit 2 (baseline visit), Visit 6 (Week 12), Visit 9 (Week 24), and Visit 12 (Week 52). 
Patient-Reported Outcomes 
Short Form 36 Version 2 (SF-36 V2) 
The SF-36 V2 is a multi-purpose, short-form health survey with 36 questions. It yields scores for 
eight domains (Physical Functioning, Role-Physical, Bodily pain, General health, Vitality, Social 
Functioning, Role-Emotional, and Mental Health, each scale is scored from 0 to 100 where higher 
scores indicate better health and well-being), as well as two summary measures of physical and 
mental health: the Physical Component Summary (PCS) and Mental Component Summary 
(MCS). 
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The scoring process is summarized below: 
• Enter item response data. 
• Recode item response values. 
• Determine health domain scale raw scores. 
• Transform health domain scale raw scores to 0 to 100 scores. 
• Transform health domain scale 0 to 100 to normal-based scores. 
• Score physical and mental component summary measures. 
The following table shows the construction and summary measures of the SF-36 scales: 
Table 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 H provides the SAS code to 
calculate the eight scales, the two summary measure scores and the standardized summary scores.  
The PCS and MCS summary measure scores will be computed if at least 50% of the component 
scales are available. The scale scores will be computed if at least 50% of items are available 
within the corresponding scale. The missing items will be imputed by the mean of available items. 
Change from baseline in SF-36 scores (physical component summary score and mental 
component summary score as well as the eight domains) at each visit will be analyzed. 
Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue) 
The FACIT-Fatigue will be used to assess fatigue. The FACIT-Fatigue is a 13-item questionnaire 
rated 0 to 4 originally developed to measure fatigue in patients with cancer and is widely used in 
rheumatoid arthritis patients to demonstrate good consistency and sensitivity to change. The 
patient will be asked to answer 13 questions rated 0 to 4 (0 = not at all, 1 = a little bit, 
2 = somewhat, 3 = quite a bit, 4 = very much). The fatigue scale has 13 items, with 52 as the 
highest possible score. A higher score in the fatigue scale corresponds to a lower level of fatigue 
and indicates better Quality of Life. 
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To calculate the FACIT-fatigue score, the response scores on negatively phrased questions are 
reversed and then the 13 item responses are added. Eleven items with responses have their scores 
reversed (item score = 4 – response, if the response is not missing), and two items (items 7 and 8) 
have their responses unchanged (Appendix 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 and 8)] / number of answered items 
EuroQol 5 Dimension 3 Level (EQ-5D-3L) 
The EQ-5D-3L is a standardized, generic measure of health outcome (3). EQ-5D is designed for 
self-completion by patients. Instructions to respondents are included in the questionnaire. The 
EQ5D is specifically included to address concerns regarding the health economic impact of RA, 
which have been considered in cost effectiveness arguments. The EQ-5D-3L comprises five 
questions on mobility, self-care, pain, usual activities, and psychological status with three possible 
answers for each item (1 = no problem, 2 = moderate problems, 3 = severe problems) and a 
vertical visual analog scale that allows the patients to indicate their health state today that can 
range from 0 (worst imaginable) to 100 (best imaginable). 
The 5 dimensional 3-level systems are converted into a single index utility score. Values for the 
243 theoretically possible health states defined by the EuroQol classification are calculated using 
a regression model and weighted according to the social preferences of the GB population. The 
minimum value for the single index utility score is -0.594, which corresponds to a level 3 (severe 
problems) for mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 
maximum value for this index is 1.0, which corresponds to a full health (level 1 [no problem] for 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression). 
The VAS records the respondent’s self-rated health on a vertical visual analogue scale. The VAS 
“thermometer” has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst 
imaginable health state) at the bottom. This information can be used as a quantitative measure of 
health outcomes as judged by the individual respondents. EQ 5D self-reported VAS data 
generates information on the self-perceived overall health-related quality of life. 
Appendix G provides the SAS code to derive the index utility score using GB based population. 
Health Assessment Questionnaire Disease Index (HAQ-DI) 
•
Patient’s Assessment of Physical function
The HAQ-DI is a standardized questionnaire developed to assess physical functional status in 
adults with arthritis but is now commonly used among many rheumatologic conditions. The 
HAQ-DI, with the past week as the time frame, focuses on whether the respondent “is able to…” 
do the activity and covers eight categories in 20 items: dressing and grooming, arising, eating, 
walking, hygiene, reach, grip and activities, for which there are at least two questions by category. 
The four responses for the HAQ-DI questions are graded as follows: without any difficulty=0; 
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with some difficulty=1; with much difficulty=2; and unable to do=3. To calculate the Standard 
HAQ-DI Score (With Aids/Devices), there are 3 steps: 
1. Sum the eight category scores by using the highest sub-category score from each category. 
• For example, in the category EATING there are three sub-category items. A patient 
responds with a 1, 2, and 0, respectively; the category score is 2. 
2. Adjust for use of aids/devices and/or help from another person when indicated. 
• When there are NO aids or devices or help indicated for a category, the category’s score is 
not modified. 
• When aids or devices or help ARE indicated by the patient: 
- 
Adjust the score for a category by increasing a 0 or a 1 to a 2. 
- 
If a patient’s highest score for that sub-category is a 2 it remains a 2, and if a 3, it 
remains a 3. 
- 
The data entered at field “Other specify” will not be used for score adjustment. 
3. Divide the summed category scores by the number of categories answered (must be a 
minimum of 6) to obtain a HAQ-DI score of 0 to 3 (3=worst functioning). 
A HAQ-DI score cannot be calculated validly when there are scores for less than six of the 
eight categories. If there are less than 6 categories completed, a HAQ-DI cannot be computed, 
whether the missing categories are due to missing values or they do not apply to the 
respondent. HAQ-DI disability index scoring ranges between 0 and 3 with higher score 
indicating greater disability. A high HAQ-DI score has been found to be a strong predictor of 
morbidity and mortality in RA. A 0.22 unit difference is considered clinically meaningful. 
In addition to the above, the HAQ-DI has two additional questions to measure pain and global 
assessment described below. 
• Patient’s Assessment of Pain 
Patients will be requested to indicate their pain intensity due to PMR using a 100 mm horizontal 
VAS to the question “How much pain have you had IN THE PAST WEEK?”, where 0 is 
considered “No pain” and 100 “the worst pain you can imagine”. 
To obtain the patient score, using a metric ruler, measure the distance in centimeters from the left 
anchor (at base zero) to their mark and multiply by 0.2. This converts the number of centimeters 
into the appropriate score and yields a score from 0 to 3. For example, the mark is at 8 centimeters 
– 8 x 0.2 = a pain score of 1.6. 
In case a 0-100 mm scale is used, pain severity coding translations follow below:  
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PAIN SEVERITY CODING TRANSLATIONS  
 
Measurement (m) = Score 
Measurement (m) = Score [continue] 
0 = 0  
7.8 – 8.2 = 1.6  
0.1 – 0 .7 = 0.1  
8.3 – 8.7 = 1.7  
0.8 – 1.2 = 0.2  
8.8 – 9.2 = 1.8  
1.3 – 1.7 = 0.3  
9.3 – 9.7 = 1.9  
1.8 – 2.2 = 0.4  
9.8 – 10.2 = 2.0  
2.3 – 2.7 = 0.5  
10.3 – 10.7 = 2.1  
2.8 – 3.2 = 0.6  
10.8 – 11.2 = 2.2  
3.3 – 3.7 = 0.7  
11.3 – 11.7 = 2.3  
3.8 – 4.2 = 0 .8  
11.8 – 12.2 = 2.4  
4.3 – 4.7 = 0 .9  
12.3 – 12.7 = 2.5  
4.8 – 5.2 = 1.0  
12.8 – 13.2 = 2.6  
5.3 – 5.7 = 1.1  
13.3 – 13.7 = 2.7  
5.8 – 6.2 = 1.2  
13.8 – 14.2 = 2.8  
6.3 – 6.7 = 1.3  
14.3 – 14.7 = 2.9  
6.8 – 7.2 = 1.4  
14.8 – 15.0 = 3.0  
 
• Patient’s Global Assessments of Disease Activity 
Patient’s global assessments of their current disease activity will be rated on an anchored 100 mm 
horizontal VAS, with the given instruction to “Please rate how well you are doing on a scale of 
0 to 100 (0 represents “very well” and 100 represents “very poor” health)”. 
It is scored similarly to the VAS Pain Scale. 
Clinician-Reported Outcomes 
Physician’s Global Assessments of Disease Activity – Visual Analog Scale [MD-VAS] 
Physician’s global assessments of the patient’s current disease activity will be assessed on an 
anchored 100 mm horizontal VAS where 0 is considered the best disease activity (no disease 
activity) and 100 the worst (most disease activity). 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient status and the patient populations. 
Screened patients are defined as all patients who signed the informed consent. 
Randomized patients consist of all patients who signed informed consent with a treatment kit 
number allocated and recorded in the Interactive Voice Response System/Interactive Web 
Response System database, regardless of whether the treatment kit was used or not. 
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For patient status in the DB treatment period, the total number of patients for each one of the 
following categories will be presented in the clinical study report (CSR) using a summary table: 
• Screened patients 
• Screen failure patients and reasons for screen failure 
• Non-randomized but treated patients 
• Randomized patients 
• Randomized but not treated patients 
• Randomized and treated patients 
• Patients who completed 52-week SC IMP study treatment period 
• Patients who discontinued from 52-week study treatment period and the reasons for 
permanent SC IMP treatment discontinuation 
• Patients who completed the study 
• Patients who discontinued the study and the reasons for study discontinuation 
• Patients who took CS rescue therapy 
• Patients who took add-on prednisone 
• Subject status at end of study visit 
For all categories of patients (except for the screened and non-randomized categories) percentages 
will be calculated using the number of randomized patients as the denominator. Reasons for SC 
IMP treatment or study discontinuation, such as if it is related to COVID-19 will be presented in 
tables giving numbers and percentages by treatment group. Patient disposition by visit according 
to trial impact due to COVID-19 (visits that were delayed, not done, partially done on site, or 
partially done by phone, or not impacted) will also be provided. 
A patient is considered as lost to follow-up at the end of the study if he/she is not assessed at the 
end of study visit. 
All critical or major deviations potentially impacting efficacy analyses, randomization and drug 
dispensing irregularities and other major/critical deviations will be summarized in tables giving 
numbers and percentages of deviations by treatment groups. Critical or major deviations 
according to COVID19 impact will also be summarized. 
Additionally, the analysis populations for safety, efficacy, PK and immunogenicity will be 
summarized in a table by patient counts based on the randomized populations (See definitions in 
Section 2.3). 
• Efficacy population 
• Safety population 
• PK population 
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• ADA population 
2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error.  
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis. 
All randomization and drug-dispensing irregularities will be considered as protocol deviations and 
documented in the CSR.  If the number of irregularities is large enough to make a tabular 
summary useful, the irregularities will be categorized and summarized among randomized 
patients (number and percentages).  Nonrandomized, treated patients will be described separately. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to: 
Table 5 – Randomization and Drug Allocation Irregularities 
Randomization and Drug Allocation Irregularities 
Kit dispensation without IVRS transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Subject randomized twice 
Forced randomization 
Subject switched to another site 
IVRS=Interactive Voice Response System 
2.3 
ANALYSIS POPULATIONS  
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population. 
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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 Efficacy populations  
The primary analysis population will be the ITT population as defined in Section 2.3.1.1. 
2.3.1.1 Intent–to-treat population  
The intent-to-treat (ITT) population is the randomized population analyzed according to the 
treatment group allocated by randomization. 
2.3.2 Safety population  
The safety population is defined as randomized population who received at least 1 dose or part of 
a dose of the SC IMP, analyzed according to the treatment actually received.In addition: 
• 
Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately 
• 
Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
• 
For patients receiving more than one SC IMP during the trial, the treatment group 
allocation for as-treated analysis will be the treatment group for which the patient received 
the majority of doses.  In such cases, individual patient listings will be provided for each 
treatment group with treatment start and end date for each treatment exposed. 
2.3.3 Pharmacokinetics and ADA populations  
The PK population will consist of all patients in the safety population with at least one post-dose, 
non-missing serum sarilumab concentration value. The ADA population will consist of all 
patients in the safety population with at least one post-dose, evaluable ADA sample. Patients will 
be analyzed according to the treatment actually received. 
2.3.4 Population with and without trial impact (disruption) due to COVID-19  
The population without trial impact (disruption) due to COVID-19 is defined as patients without 
any critical or major deviation related to COVID-19 or did not permanently discontinue study 
treatment due to COVID-19. Population with trial impact due to COVID-19 are patients with any 
critical or major deviation related to COVID-19 or permanently discontinue study treatment due 
to COVID-19. These populations will be used to summarize treatment exposure, treatment 
compliance, subgroup analysis of primary endpoint and safety only if > 10% patients are impacted 
by the COVID-19 pandemic. 
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2.4 
STATISTICAL METHODS  
2.4.1 Demographics and baseline characteristics  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group. 
Parameters will be summarized based on the randomized populations. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall using 
descriptive statistics. 
Medical and surgical history will be summarized by SOC and PT sorted by internationally agreed 
order of SOC and by the decreasing frequency of PT within SOC in total group (including all the 
randomized patients). P-values on demographic and baseline characteristic data will not be 
calculated. 
No specific description of the safety parameters will be provided at baseline. If relevant, the 
baseline values will be described along with each safety analysis. 
2.4.2 Prior or concomitant medications  
The prior and concomitant medications will be summarized based on the randomized populations 
as follows:  
• Prior medications discontinued before the first dose of IMP in the DB period 
• Prior medications that continued at the time of the first dose of IMP in the DB period 
• Concomitant medications 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the 
generic names.  All ATC codes corresponding to a medication will be summarized. Patients will 
be counted once in each ATC category (anatomic or therapeutic) linked to the medication; 
therefore, patients may be counted several times for the same medication.  
In addition, the following summaries will also be provided: 
• Vaccines (prior) 
• Other prior DMARDs/immunosuppressive agents taken since diagnosis of PMR and 
discontinued before the first dose of IMP 
The table for prior medications will be sorted by decreasing frequency of anatomic category 
followed by all other generic names based on the overall incidence across treatment groups.  In 
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case of equal frequency regarding anatomic categories (respectively, generic names), alphabetical 
order will be used. 
The tables for concomitant medications will be sorted by decreasing frequency of anatomic 
category followed by all other generic names based on the incidence of the total group (including 
all the randomized patients). In case of equal frequency regarding anatomic categories 
(respectively, generic names), alphabetical order will be used. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of SC IMP exposure and compliance will be assessed and summarized by actual 
treatment group within the safety population and in populations with and without trial impact due 
to COVID-19 (Section 2.3.2 and Section 2.3.4). 
2.4.3.1 Extent of investigational medicinal product exposure  
The extent of SC IMP exposure will be assessed by the duration of SC IMP exposure and actual 
dose information. 
The duration of SC IMP exposure is defined as last DB dose date – first DB dose date +14 days, 
regardless of unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of 
missing or incomplete data).Duration of SC IMP exposure will be summarized descriptively as a 
quantitative variable (number, mean, SD, median, minimum, and maximum).  In addition, 
duration of treatment exposure will also be summarized categorically by numbers and percentages 
for each of the following categories and cumulatively according to these categories: ≤4 weeks, >4 
and ≤8 weeks, >8 and ≤12 weeks, >12 and ≤16 weeks, >16 and ≤20 weeks, >20 and ≤24 weeks, 
>24 and ≤32 weeks, >32 and ≤40 weeks, >40 and ≤52 weeks and >52 weeks. The cumulative 
duration of treatment exposure, defined as the sum of patients’ duration of treatment exposure and 
expressed in patient years, will also be provided. 
2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Percentage of compliance for SC IMP will be defined as the number of administrations the patient 
was compliant divided by the total number of administrations the patient was planned to take on 
or before the last dose date during the DB treatment period. 
Percentage of compliance for oral IMP compliance rate will be defined as the total number of 
days patient with partial or complete oral IMP intake divided by total number of days between the 
first oral IMP intake date and day prior to rescue therapy start date or EOT date which is earlier. 
Treatment compliance percentages will be summarized descriptively as quantitative variables 
(number, mean, SD, median, minimum, and maximum). The percentage of patients whose 
compliance is <80% will be summarized. 
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Cases of overdose (administering two or more doses of sarilumab or its matching placebo in less 
than 11 calendar days) will constitute AESI and will be listed as such.  More generally, dosing 
irregularities will be listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints  
The primary and secondary efficacy endpoints will be analyzed using the ITT population. For 
patients who reduced dose to sarilumab 150mg during the course of the study, a listing of key 
efficacy endpoint variables will be provided. 
2.4.4.1 Analysis of primary efficacy endpoint(s)  
Fisher’s exact test at 5% significance level will be performed to test the null hypothesis that the 
proportion of patients who achieved sustained remission at Week 52 in each treatment group 
(Group 1 = sarilumab + 52-week prednisone taper; Group 2 = placebo + 14-week prednisone 
taper) is the same, against the alternative hypothesis that the proportion is not the same between 
the treatment groups: 
𝐻0: 𝜌𝐺𝑟𝑜𝑢𝑝1 −𝜌𝐺𝑟𝑜𝑢𝑝2 = 0 
𝐻1: 𝜌𝐺𝑟𝑜𝑢𝑝1 −𝜌𝐺𝑟𝑜𝑢𝑝2 ≠0 
The number and proportion of patients achieving sustained remission at Week 52 in each 
treatment group will be presented, with the 95% exact confidence interval for the proportion 
difference and p-value from Fisher’s exact test (2-sided). 
Sensitivity analysis excluding acute phase reactants:  
Sensitivity analysis will be performed for the primary endpoint by removing the acute phase 
reactants (CRP and ESR) from the definition to mitigate against the possibility of biasing the 
results due to the known PD effect of sarilumab on acute phase reactants. 
Patients achieving sustained remission at Week 52 excluding acute phase reactants is defined 
by having met all of the following parameters: 
• Achievement of disease remission not later than Week 12. Disease remission is defined as 
resolution of signs and symptoms of PMR. 
• Absence of disease flare from Week 12 through Week 52. Flare is defined as recurrence 
of signs and symptoms attributable to active PMR plus an increase in CS dose due to 
PMR. 
• Successful adherence to the prednisone taper from Week 12 through Week 52. 
The sensitivity analysis will be performed in the same fashion as for the primary endpoint. 
Descriptive statistics (i.e., counts and percentages) will be provided for the three individual 
components. 
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Sensitivity analysis excluding patients who discontinued treatment as they were incorrectly 
diagnosed as PMR or newly diagnosed as RA while on study: 
The diagnosis of PMR can be challenging as symptom characteristics often overlap, making it 
difficult to decipher differential diagnosis of PMR. Sensitivity analysis of primary endpoint will 
be performed to remove patients who discontinued study treatment due to a change in PMR 
disease diagnosis. 
Sensitivity analyses for missing data in the primary endpoint: 
Tipping point analysis will be performed. The number of responders to impute in each treatment 
group will vary from zero to up to the total number of patients with missing primary endpoint 
outcomes. For each imputation combination, a p-value based on Fisher’s exact test will be 
calculated. The goal is to identify scenarios leading to non-significant results (p-value ≥0.05). 
Patients who receive rescue therapy will be considered as non-responders. Withdrawn patients 
who had a disease flare prior to withdrawal will also be considered as non-responders as this 
represents the true outcome had they remained in the study. Withdrawn patients who did not 
experience a disease flare prior to withdrawal will be considered as missing and will be 
sequentially imputed for the tipping point analysis. 
Subgroup analyses: To assess the consistency in treatment effects across subgroup levels, 
subgroup analyses will be conducted for the primary endpoint with respect to: 
• Gender (Male versus Female) 
• Race (Caucasian/White versus all other races) 
• Region (Region 1 [Western countries], Region 2 [South America], Region 3 [Rest of the 
world]) 
• Age (<70, ≥70) 
• Baseline weight (<60, ≥60 and <100, ≥100 kg) 
• BMI (<25, ≥25 and <30, ≥30 kg/m2) 
• Baseline CRP (≤median, >median) 
• Baseline ESR (≤median, >median) 
• Baseline CS dose (≤median, >median) 
• Number of relapses prior to screening (1, > 1 relapse) 
• COVID-19 impacted population (Yes, No) – will only be performed if >10% of patients 
were impacted by COVID-19. The population without trial impact (disruption) due to 
COVID-19 is defined as patients without any critical or major deviation related to 
COVID-19 or did not permanently discontinue study treatment due to COVID-19. 
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Within each subgroup, the number and proportion of patients achieving sustained remission at 
Week 52 by treatment groups will be presented together with the proportion difference between 
sarilumab and placebo groups and its 95% confidence interval. 
Subgroup analyses will also be performed with logistic regression models for binary status of 
patients achieving sustained remission at Week 52, with treatment group, subgroup variable and 
the subgroup-by treatment interaction as covariates. A p-value for the test of interaction will be 
provided. 
Forest plots of treatment differences (proportion difference) between sarilumab and placebo at 
Week 52 and corresponding CIs for each subgroup will be provided. 
2.4.4.2 Analyses of secondary efficacy endpoint(s)  
Components of sustained remission composite measure at Week 52 
Descriptive statistics (i.e., counts and percentages) will be provided for the following binary 
variables by treatment groups:  
• Patients who achieve disease remission by Week 12 
• Patients who have absence of disease flare from Week 12 through Week 52 
• Patients who have normalization of CRP (decrease to <10 mg/L) with sustained 
normalization from Week 12 through Week 52 
• Patients who successfully adhere to the prednisone taper from Week 12 through Week 52 
Total cumulative corticosteroid (including prednisone) dose 
Descriptive statistics including the number of subjects, mean, and median of the total cumulative 
prednisone (or equivalent) dose will be presented for each treatment group. The difference 
between the medians and the corresponding 95% non-parametric confidence interval along with 
p-value from the non-parametric Wilcoxon rank-sum test between the treatment groups will also 
be provided. 
Both expected and actual cumulative CS dose will be presented. The expected cumulative dose is 
based on CS tapering regimen up to end of treatment, assuming that the taper was continued 
without error while actual cumulative CS dose will be calculated as the total cumulative CS used 
for PMR disease up to the end of treatment, including expected prednisone in tapering regimen 
per protocol, add-on prednisone, CS used in rescue therapy and the use of commercial prednisone. 
Patients who received increased prednisone or equivalent in rescue therapy will be included in 
their original treatment groups. 
In the scenario that a patient has already taken external CS for the disease before randomization 
on the day of randomization, the CS dose taken will be considered as the first dose of oral IMP. 
The first dose of prednisone per tapering regimen will be skipped, and the patient will take the 
second dose of prednisone on the next day. 
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Time to first PMR flare during the treatment period 
Time (from randomization) to the first PMR flare after clinical remission up to Week 52 will be 
analyzed by Kaplan-Meier method providing the median, 25th and 75th percentiles (where 
possible) along with the 95% CI for the median. The comparison between the treatment groups 
will be performed using Cox proportional hazards model. Hazard ratio and the corresponding 95% 
CI and p-value will be provided. 
Composite GTI and Specific List 
GTI analyses 
Descriptive statistics including number, mean, SD, SE, median, minimum, and maximum will be 
provided by treatment group and by visit for domain-specific GTI score, composite GTI total 
score, composite worsening score and composite improvement score. For CWS and AIS at Week 
52, analysis of covariance (ANCOVA) model with treatment groups and baseline glucocorticoid 
toxicity score as fixed effects, will be used to test the difference of the least-square means (LS 
means) between the treatment groups. Difference in LS means and the corresponding 95% CI 
along with the p-value will be provided. 
In addition, descriptive statistics (i.e., counts and percentages) will be provided for not worsening 
(CWS = 0), worsening (CWS > 0), improved (AIS < 0) and not improved (AIS ≥ 0) at Week 52. 
Odds ratios and exact 95% CIs of not worsening versus worsening and improved versus not 
improved will be provided for the comparison between the sarilumab and placebo groups. 
Analyses of items in Specific list 
Number and percentage of patients with each item in specific list will be summarized by treatment 
groups and by visit. 
2.4.4.3 Analyses of exploratory endpoint(s)  
Descriptive statistics will be provided for PMR-AS and its components at baseline, Week 12, 
Week 24, and Week 52. 
The change from baseline at Week 52 for PMR-AS will be analyzed with mixed model repeated 
measures (MMRM) approach. The repeated-measures analysis will be based on the restricted 
maximum likelihood method assuming an unstructured covariance structure to model the within-
subject errors. The model, including treatment, visit, and treatment -by -visit interaction, baseline 
and baseline -by -visit interaction as covariates, will be used to test the difference of least square 
means (LS means) between treatment groups in the change from baseline for PMR-AS at Week 
52. The difference in LS means between treatment groups, the corresponding 95% CI and the 
p-value will be provided. No imputations will be performed for missing values. 
Change from baseline at each visit will be plotted by treatment group for PMR-AS.  
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2.4.4.4 Multiplicity issues  
If the primary endpoint reaches statistical significance, the secondary endpoint for total 
cumulative CS dose will be tested next.  
2.4.5 Analyses of safety data  
The summary of safety results will be presented by treatment groups. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately 
• 
The baseline value is defined as the last available value prior to the first dose of study 
medication. 
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (PCSA in BTD-009536 version 3, see Appendix C. 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the on-treatment PCSA percentage 
• 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population. 
• 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group.  Summaries will include the endpoint value. The endpoint value 
is commonly defined as the value collected at the same day/time of the last dose of 
investigational product. If this value is missing, this endpoint value will be the closest one 
prior to the last dose intake. 
• 
Analyses of the safety variables will be essentially descriptive, and no systematic testing is 
planned. 
2.4.5.1 Analyses of adverse events  
Generalities 
The primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-treatment AEs will 
be described separately.  
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If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, or TEAE, or post-treatment 
AE.  The algorithm for imputing date/time of onset will be conservative and will classify an AE as 
treatment-emergent unless there is definitive information to determine it is pre-treatment or post-
treatment. Details on classification of AEs with missing or partial onset dates are provided in 
Section 2.5.3. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in SOC 
internationally agreed order and then alphabetical order, and present the number (n) and 
percentage (%) of patients experiencing an AE by treatment group. Multiple occurrences of the 
same event in the same patient will be counted only once in the tables within a treatment phase.  
The denominator for computation of percentages is the safety population within each treatment 
group. 
The tables by primary SOC and PT will be sorted by internationally agreed order of SOC and 
decreasing frequency of PT within SOC.  Sorting will be based on results for the sarilumab 
200mg arm. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 
• 
Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE 
- 
Serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
• All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least one TEAE sorted by SOC internationally agreed order. The other level (HLGT, 
HLT, PT) will be presented in an alphabetic order. 
• All TEAEs by primary SOC and PT, showing number (%) of patients with at least one 
TEAE, sorted by SOC internationally agreed order and decreasing incidence of PTs within 
SOC. This sorting order will be applied to all other tables, unless otherwise specified.  
• If > 10% patients are impacted by the COVID-19 pandemic: All TEAEs by primary SOC 
and PT by COVID-19 impact subgroup, showing number (%) of patients with at least one 
TEAE by COVID-19 impact subgroup. 
• All COVID-19 TEAEs by primary SOC and PT, showing number (%) of patients with at 
least one COVID-19 related TEAE. 
• All TEAEs by primary SOC, showing number (%) of patients with at least one TEAE, 
sorted by internationally agreed order of primary SOC. 
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• All TEAEs by relationship, presented by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least one TEAE, sorted by SOC internationally agreed 
order. The other level (HLGT, HLT, PT) will be presented in an alphabetic order. 
• All TEAEs by maximal severity, presented by primary SOC and PT, showing number (%) 
of patients with at least one TEAE by severity (ie, mild, moderate, or severe), sorted by 
sorting order defined above.  
Analysis of all treatment emergent serious adverse event(s) 
• All treatment-emergent SAEs by primary SOC, HLGT, HLT, and PT, showing number 
(%) of patients with at least one serious TEAE, sorted by SOC internationally agreed 
order. The other level (HLGT, HLT, PT) will be presented in an alphabetic order. 
• All treatment-emergent SAEs by primary SOC and PT, showing number (%) of patients 
with at least one TEAE 
• All treatment-emergent SAEs by primary SOC, showing number (%) of patients with at 
least one TEAE, sorted by internationally agreed order of primary SOC 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT, 
showing number (%) of patients sorted by SOC internationally agreed order. The other 
level (HLGT, HLT, PT) will be presented in an alphabetic order. 
• All TEAEs leading to treatment discontinuation, by primary SOC and PT, showing 
number (%) of patients with at least one TEAE 
• All TEAEs leading to treatment discontinuation, by primary SOC, showing number (%) of 
patients with at least one TEAE, sorted by internationally agreed order of primary SOC 
Analysis of all treatment-emergent adverse event(s) leading to dose reduction 
• 
For the management of pre-defined laboratory abnormalities, sarilumab dose can be 
reduced to 150 mg q2w.  All treatment-emergent adverse events leading to dose reduction, 
by primary SOC, HLGT, HLT and PT, showing the number (%) of patients, sorted by the 
sorting order defined above 
Analysis AESI  
Summaries of AESI defined by the search criteria: 
• All treatment-emergent AESIs, by AESI category and PT, showing number (%) of 
patients, sorted by decreasing incidence of PT within each AESI category. 
• Within each treatment-emergent AESI category, at a minimum the data display will 
include: 
- 
Overview summary 
- 
Treatment duration summary 
- 
Incidence by patient and by event 
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- 
Serious TEAEs 
- 
TEAEs leading to treatment discontinuation 
- 
TEAEs leading to death 
- 
Possibly related TEAEs 
2.4.5.2 Deaths  
The incidence of death will be generated on the safety populations. 
• Number (%) of patients who died by study period (on-treatment, treatment residual, and 
post-treatment). 
• Death in non-randomized patients or randomized but not treated patients. 
• TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC and PT, showing number (%) of patients sorted by 
internationally agreed order of SOC and decreasing frequency of PT within a SOC in the 
Sarilumab 200mg q2w treatment group.  
Listings will be provided for all deaths with flags indicating during treatment or post-treatment 
status. 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
laboratory variables (central laboratory values and changes from baseline) will be calculated for 
each visit or study assessment (baseline, each post baseline time point, endpoint) by treatment 
group.  This section will be organized by biological function as specified in Section 2.1.4.3. 
In addition, for all laboratory parameters, the mean value and mean change from baseline at each 
scheduled visit during the treatment period will be plotted by treatment group.  
The incidence of PCSAs (list provided in Appendix C) at any time during TEAE period will be 
summarized by biological function and treatment group whatever the baseline level and/or 
according to the following baseline status categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
For lipids, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) 
classification will be used for the baseline. 
The incidence of abnormal laboratory values at any time during the TEAE period will be 
summarized in shift tables by biological function and treatment group whatever the baseline level 
and/or according to the following baseline status categories:  
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• Normal/Missing 
• Abnormal high according to the normal range 
• Abnormal low according to the normal range 
Time to onset of the initial LDL-C elevation (≥4.1 mmol/L, ≥4.9 mmol/L), time to onset of the 
initial total cholesterol elevation (≥6.2 mmol/L), time to onset of the initial Grade 3 or Grade 4 
neutropenia (neutrophil count <1.0 Giga/L), time to onset of the initial platelet count 
<100 Giga/L, time to onset of the initial lymphocyte count <1.0 Giga/L, time to onset of the initial 
ALT elevation (>3 x ULN, >5 x ULN), time to onset of the initial AST elevation (>3 x ULN, >5 x 
ULN), and time to onset of initial total bilirubin >2 x ULN will be analyzed using Kaplan-Meier 
estimates, using the midpoint of the time interval between the first assessment showing the 
elevation and the previous assessment, presented by treatment group. 
Listings will be provided with flags indicating the out of range values as well as the PCSA values. 
Neutrophils 
The incidence of neutropenia by maximal grade (lowest absolute neutrophil count reported during 
the TEAE period) will be summarized. The 4 grades are defined as below: 
• Grade 1: ≥1.5 Giga/L-LLN. 
• Grade 2: ≥1.0 Giga/L- <1.5 Giga/L. 
• Grade 3: ≥0.5 Giga/L- <1.0 Giga/L. 
• Grade 4: <0.5 Giga/L. 
Thrombocytopenia 
The incidence of thrombocytopenia by maximal grade (lowest platelet count reported during the 
TEAE period) as defined below will be summarized.  
• ≥75 Giga/L-100 Giga/L. 
• ≥50 Giga/L-<75 Giga/L. 
• ≥25 Giga/L-<50 Giga/L. 
• <25 Giga/L. 
Hepatic disorders 
The liver function tests, namely AST, ALT, ALP, and total bilirubin are used to assess possible 
drug-induced liver toxicity. The proportion of patients with PCSA values at any post-baseline visit 
by baseline status will be displayed by treatment group for each parameter. The proportion of 
patients with PCSA values at any post baseline visit may be displayed by duration of exposure for 
each treatment group. 
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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 3x ULN for ALT and 
a horizontal line corresponding to 2x ULN for total bilirubin. 
2.4.5.4 Analyses of vital sign variables  
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
vital signs variables (vital signs values and changes from baseline) will be calculated for each visit 
or study assessment (baseline, each post baseline time point, endpoint) by treatment group. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group whatever the baseline level and/or according to the following baseline status categories: 
• Normal/Missing 
• Abnormal according to PCSA criterion or criteria 
Listings will be provided with flags indicating the PCSA values. 
2.4.6 Analyses of pharmacokinetic variables  
All the PK analyses will be performed using the PK populations including only the sarilumab 
treated patients. 
Serum concentrations of functional sarilumab (both pre-dose and post-dose) will be summarized 
using descriptive statistics (including number, arithmetic and geometric means, SD, standard error 
of the mean, coefficient of variation, minimum, median, and maximum) for each visit. The 
pre-dose samples will be considered non-eligible for these analyses if the previous dosing time is 
<11 days or >17 days before the sampling time for every other week regimens.  Concentrations 
below the lower limit of quantification (LLOQ) will be set to zero for samples at baseline 
(i.e., pre-dose at Week 0). Other post-treatment concentrations below LLOQ will be replaced by 
LLOQ/2. In addition, serum concentrations of functional sarilumab will be summarized using 
descriptive statistics mentioned above by immunogenicity status for each visit. 
2.4.7 Analyses of quality of life variables  
Descriptive statistics including number of subjects, mean, median, SD, minimum, maximum will 
be provided by treatment groups for the value and change from baseline at each visit (baseline, 
Week 12, Week 24 and Week 52) for the 2 summary measures of SF-36 (physical component 
summary score and mental component summary score) and the 8 domains, the quantitative 
variables of EQ-5D-3L (visual analog scale and single index utility), FACIT-Fatigue, HAQ-DI 
(standardized score, pain score and patient global assessment) and MD-VAS. Change from 
baseline at each visit will also be plotted by treatment groups. 
The change from baseline at Week 52 for the above measures will be analyzed with mixed model 
repeated measures (MMRM) approach. The repeated-measures analysis will be based on the 
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restricted maximum likelihood method assuming an unstructured covariance structure to model 
the within-subject errors. The model, including treatment, visit, and treatment -by -visit 
interaction, baseline and baseline -by -visit interaction as covariates, will be used to test the 
difference of least square means (LS means) between treatment groups in the change from 
baseline in each variable. Descriptive statistics including number of subjects, mean, standard error 
and LS means will be provided. In addition, difference in LS means between treatment groups, the 
corresponding 95% CI and the p-value will be provided. 
2.4.8 Analysis of immunogenicity endpoints  
The following summary will be provided separately for ADA positive patients, ADA negative 
patients, patients with persistent ADA response, and patients with transient ADA responses. 
ADA prevalence and titer 
The following summary will be provided based on the ADA populations: 
• Number (%) of patients with an ADA positive sample at baseline: 
- 
Number (%) of neutralizing antibody. 
- 
Number (%) of non-neutralizing antibody. 
- 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) 
of the titer for the baseline ADA positive patients. 
• Number (%) of patients with an ADA negative sample at baseline. 
ADA incidence and titer 
The following summary will be provided based on the ADA populations during TEAE period: 
• Number (%) of ADA-negative patients. 
• Number (%) of ADA-positive patients: 
- 
Number (%) of patients with neutralizing antibody. 
- 
Number (%) of patients with non-neutralizing antibody. 
- 
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) 
of the peak post-baseline titer for all ADA-positive patients. 
• Number (%) of treatment-emergent ADA-positive patients: 
- 
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) 
of the peak post-baseline titer for treatment-emergent ADA-positive patients. 
- 
Number (%) of transient treatment-emergent ADA-positive patients: 
- 
Number (%) of patients with neutralizing antibody. 
- 
Number (%) of patients with non-neutralizing antibody. 
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- 
Number (%) of persistent treatment-emergent ADA positive patients: 
- 
Number (%) of patients with neutralizing antibody. 
- 
Number (%) of patients with non-neutralizing antibody. 
- 
Number (%) of persistent treatment-emergent ADA positive patients because last 
sample was positive. 
• Number (%) of treatment-boosted ADA positive patients:  
- 
Number (%) of patients with neutralizing antibody. 
- 
Number (%) of patients with non-neutralizing antibody. 
- 
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) 
of the peak post-baseline titer for all treatment-boosted ADA-positive patients. 
In addition, number (%) of patients with ADA positive or negative response at each visit will be 
summarized by treatment group. 
ADA and PK 
By visit descriptive summary of functional sarilumab concentrations in serum will be provided by 
ADA patient classifications (positive or negative) for the sarilumab treatment groups. 
ADA and clinical safety 
The safety assessment will focus on the following events: 
• Hypersensitivity (standardized MedDRA query (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) for the sarilumab treatment group. The relationship between the timing and 
the titer of the positive ADA and events may also be explored as necessary. 
ADA and clinical efficacy 
The following efficacy endpoints will be analyzed by ADA patient classifications (positive or 
negative; persistent, transient; neutralizing, non-neutralizing): 
• Proportion of patients achieving sustained remission at Week 52 
• Number (%) of patients with lack of efficacy. 
Lack of efficacy is defined as permanent treatment discontinuation due to lack of efficacy. 
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2.4.9 DNA/RNA  
The DNA test is optional and patients need to sign a separate informed consent for DNA testing.  
Exploratory analysis of DNA/RNA will be addressed in a separate document by a separate 
biomarker analysis group. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computations of parameters. 
Demographic formulas: 
BMI is calculated as follows: 
BMI = Weight in kg/(height2 in meters). 
2.5.2 Data handling conventions for secondary efficacy variables  
GTI 
General Considerations 
For vital signs and laboratory data used together with the GTI CRF to derive the scoring the 
scheduled measurements at the time of the visit should generally be used, but if any of these are 
missing they can be replaced by the last available measurement in the corresponding time window 
for that parameter. 
GTI missing domains 
The missing lab measurement for any GTI domain at a visit will be imputed by last observation 
carried forward (LOCF) method, and missing medication information for Glucose, Blood Pressure 
and Hyperlipidemia domains will be imputed as ‘no change’ in order to calculate the composite 
and cumulative GTI scores. For patients who discontinued study treatment prematurely (prior to 
Week 52), domain scores after treatment discontinuation visit will be considered as ‘no change’ 
for the calculation of cumulative GTI scores at Week 52. No imputation will be performed for 
cumulative GTI scores at Week 52 for patients with no post-randomization measurements 
(i.e. will not carry forward from baseline). 
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. 
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Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missingFor the calculation of the treatment duration, the date of the last dose of 
SC IMP is equal to the date of last administration reported on the SC IMP administration CRF 
page.  If this date is missing, the exposure duration should be left as missing.  
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior and concomitant medication. 
Handling of AEs with missing or partial date/time of onset 
Missing or partial missing AE onset dates and times will be imputed so that if the partial AE onset 
date/time information does not indicate that the AE started prior to treatment or after the TEAE 
period, the AE will be classified as treatment-emergent.  No imputation of AE end dates/times 
will be performed.  These data imputations are for categorization purpose only and will not be 
used in listings.  No imputation is planned for date/time of AE resolution. 
Handling of AEs when date and time of first investigational medicinal product administration 
is missing 
When the date and time of the first IMP administration is missing, all AEs that occurred on or 
after the day of randomization should be considered as TEAE.  The exposure duration should be 
kept as missing. 
Handling of missing relationship of adverse events to investigational medicinal product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the AE considered as such in the frequency tables of possibly related AEs, but no 
imputation should be done at the data level. 
Handling of missing severity of AEs 
If the severity is missing for one of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences a “missing” category will be added in summary table. 
Handling of PCSA  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
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For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
2.5.4 Windows for time points  
Visit windows based on days relative to the first IMP dose will be used to map the efficacy, lab, 
vital signs, PK and ADA measurements to each scheduled visit (see Appendix I). The following 
rule will be applied when mapping the measurements to the visit: 
• For the same parameter (i.e., efficacy, lab, or vital signs), if a patient has more than one 
measurement at different dates within the same visit window, the scheduled measurement 
that is closest to the target date will be used (in case of tie select the latest). If there is no 
scheduled measurement within the visit window, the unscheduled measurement that is 
closest to the target date will be used (in case of tie select the latest).  
• When a patient has more than one measurement on the same parameter on the same date, 
then the one with the later/largest sample ID will be used. 
• If there is no measurement for a given parameter in an analysis window, data will be 
considered missing for the corresponding visit.  
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory parameters and vital signs will be used for 
computation of baseline, the last on-treatment value, analysis according to PCSA analysis, and the 
shift summaries for safety. They will also be included in the by-visit summaries if they are re-
allocated to scheduled visits. 
2.5.6 Remote Assessment  
Due to the nature of the COVID-19 pandemic, related travel restrictions, and on-site visits 
limitations, some efficacy assessments and laboratory parameters have been taken remotely or 
locally. All the measurements will be used in the analyses. 
2.5.7 Pooling of centers for statistical analyses  
Countries are pooled by region: Western countries, South American and Rest of the world.   
• Region 1 (Western countries): Australia, Belgium, Canada, Estonia, France, Germany, 
Hungary, Italy, Netherlands, Spain, Switzerland, United Kingdom, United States. 
• Region 2 (South American): Argentina. 
• Region 3 (Rest of the world): Russia, Israel, Japan. 
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2.5.8 Statistical technical issues  
Not applicable. 
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3 
INTERIM ANALYSIS  
No interim analysis is planned for this study. 
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4 
DATABASE LOCK  
The database lock will occur approximately 4 weeks after the last patient has completed the EOS 
Visit.  
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
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6 
REFERENCES  
 
1. J.H. Stone, K. Tuckwell, S. Dimonaco, et al. Trial of Tocilizumab in Giant-Cell Arteritis. The 
New England Journal of Medicine. 2017;377(4):317–28 
2. Eli M. Miloslavsky, Ray P. Naden, Johannes W.J. Bijlsma, et al. Development of a 
Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. Annals of the 
rheumatic diseases. 2017;76(3):543–6 
3. EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199-208 
 
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7 
LIST OF APPENDICES  
 
Appendix A 
Study flow chart 
Appendix B 
Standardized corticosteroid-taper regimen during double-blind study treatment 
period 
Appendix C 
Appendix D  
Potentially clinically significant abnormalities (PCSA) criteria 
Summary of statistical analyses 
Appendix E 
SF-36 V2 Scoring 
Appendix F 
FACIT-Fatigue scoring guidelines (Version 4) 
Appendix G 
SAS code for EQ-5D-3L index utility scoring 
Appendix H 
SAS code for SF-36 scoring  
Appendix I 
Visit windows based on day ranges 
Appendix J 
Baseline glucocorticoid toxicity 
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Appendix A 
Study flow chart  
 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
 
V11 
V12  
(EOT) 
V13 
(EOS) 
DAY 
D-28 to 
D-1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85  
(±3) 
D113 
(±3) 
D141 
(±3) 
D169 
(±3) 
D225 
(±3) 
D281 
(±3) 
D365    
(±3) 
D407 
(±3) 
WEEK 
 
Week 
0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 
32 
Week 
40 
Week 
52 
Week 58 
Eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriat 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound central readingv 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical/smoking-alcohol 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Family cardiovascular history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
Targeted physical examinationa 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Confirm eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Call IRT 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial treatment kit assignment (IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IMP administrationb 
 
Xw 
X 
X 
X 
X 
X 
X 
Xs 
Xs 
Xs 
 
 
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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
 
V11 
V12  
(EOT) 
V13 
(EOS) 
DAY 
D-28 to 
D-1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85  
(±3) 
D113 
(±3) 
D141 
(±3) 
D169 
(±3) 
D225 
(±3) 
D281 
(±3) 
D365    
(±3) 
D407 
(±3) 
WEEK 
 
Week 
0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 
32 
Week 
40 
Week 
52 
Week 58 
Concomitant medication review 
Xu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense patient diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance/review patient diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature, heart rate, blood 
pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
PMR clinical assessments       
(including disease flare) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician global assessment         
(MD-VAS)  
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Patient reported outcomesc 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Glucocorticoid toxicity index (excl. 
bone density assessment) 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Bone density assessmentd 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE recording 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QuantiFERON® 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
 
V11 
V12  
(EOT) 
V13 
(EOS) 
DAY 
D-28 to 
D-1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85  
(±3) 
D113 
(±3) 
D141 
(±3) 
D169 
(±3) 
D225 
(±3) 
D281 
(±3) 
D365    
(±3) 
D407 
(±3) 
WEEK 
 
Week 
0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 
32 
Week 
40 
Week 
52 
Week 58 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyf 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
Chemistryg 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
ANAh 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Fasting lipidsi and fasting 
glucose/insulinj 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
HbA1c 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
hs-CRPk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESRk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysisl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Virologym 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testn 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sarilumabj 
 
X 
X 
X 
 
X 
X 
 
Xr 
 
 
X 
X 
Antibodies to sarilumab/ADAj 
 
X 
 
 X 
  
 
 X 
  
 
X 
X 
Genotyping and biomarkersj 
 
 
 
 
 
 
 
 
 
 
 
 
 
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VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9  
V10 
 
V11 
V12  
(EOT) 
V13 
(EOS) 
DAY 
D-28 to 
D-1 
D1 
D15 
(±3) 
D29 
(±3) 
D57 
(±3) 
D85  
(±3) 
D113 
(±3) 
D141 
(±3) 
D169 
(±3) 
D225 
(±3) 
D281 
(±3) 
D365    
(±3) 
D407 
(±3) 
WEEK 
 
Week 
0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 
32 
Week 
40 
Week 
52 
Week 58 
Biomarkers-IL-6 and sIL-6R 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Immune Cell Phenotyping (Whole 
Blood)o 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
Future Use Samples (Serum and 
Plasma)lp – Optional 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
DNAq- Optional 
 
X 
 
 
 
 
 
 
 
 
 
 
 
RNAq- Optional 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
AE = Adverse event; D = Day; DNA = Deoxyribonucleic acid; ECG = Electrocardiogram; EOT = End of treatment; EOS = End of study; EQ-5D = EuroQol; ESR = erythrocyte sedimentation rate; EUL = elevate 
upper limb; FACIT-Fatigue = Functional assessment of chronic illness therapy fatigue scale; GCA = Giant cell arteritis; GTI = Glucocorticoid toxicity index; HbA1c = Hemoglobin A1c; HbsAg = Hepatitis B 
surface antigen; Hbcore Ab = Hepatitis B core antibodies; HCV = Hepatitis C virus; hs-CRP = High-sensitivity C-reactive protein; IL = Interleukin; IMP = Investigational medicinal product; IRT = Interactive voice 
response system; MD-VAS = Physician global assessment of disease activity- visual analog scale; Pain VAS = Pain visual analog scale; Pt-VAS = Patient global assessment of disease activity– visual analog 
scale; RNA = Ribonucleic acid; SAE = Serious adverse event; SF-36v2 = Short form 36v2; V = Visit; Wk = Week. 
a Targeted physical examination: head, eyes, ears, neck and throat, skin, respiratory, cardiovascular, neurologic, lymphatic examinations and abdominal examination. 
b Last administration of sarilumab is at Week 50. 
c Patient Reported Outcomes include EQ-5D-3L, FACIT-Fatigue, SF-36v2, HAQ-DI 
d Bone Mineral Density assessment will be performed at the baseline (Visit 2) and Week 52 (Visit 12) using a DXA scan. The scan can be performed within ± 14 days of Visit 2 and within -14 days of Visit 12 and 
needs to include the lumbosacral and femoral neck regions.   
e Chest X-ray is required during the screening period if no chest imaging (X-ray, CT, MRI) is available within the previous 12 weeks of V1 that clearly documents the exclusion of TB or if it does not follow the local 
guidelines and requirements for active screening of TB.  In countries for which a specific approval procedure for the x-ray is required by a different committee than the local EC/IRB, a chest MRI between V1 and 
V2 can be performed. 
f 
Hematology (blood should be drawn before drug administration): Hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential, platelet count, 
absolute neutrophil count (ANC). 
g Chemistry(blood should be drawn before drug administration): Sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine and creatinine clearance, calcium, phosphate, total protein, albumin, 
alanine aminotransferase (ALT) (SGPT), aspartate aminotransferase (AST) (SGOT), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated bilirubin, lactate dehydrogenase (LDH), uric acid 
h Anti-nuclear antibody (ANA) will be collected at baseline, Visit 2 and EOT visits only. 
i 
Lipids (blood should be drawn before drug administration): Triglycerides (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol. Fasting is defined as having no 
food or liquid intake (except water/ice) for six hours or more.  
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j 
Blood should be drawn before drug administration. Fasting is defined as having no food or liquid intake (except water/ice) for six hours or more. 
k CRP and ESR results will be blinded to both Investigator and Sponsor (except screening and baseline). ESR kits will be provided by the central laboratory while the test will be performed locally at the site; results 
will be blinded to Investigator and staff directly involved in management of study patient except the safety assessor. 
l 
Urinalysis dipstick: specific gravity, pH, glucose, blood, protein, nitrites, leukocytes, ketones, urobilinogen and bilirubin (by dipstick) at screening visit only. If any parameter on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for testing. If positive for proteins, microscopic analysis is performed by central laboratory. 
m Human immunodeficiency virus antibodies; Hepatitis B: Hep B surface antigen, total Hep B core antibody, Hep B surface antibody, and Hep B viral DNA (if necessary); Hepatitis C: HCV-antibody. 
n In women of child-bearing potential. 
o Immune Cell Phenotyping (Whole Blood): Approximately 40 patients from each of the two treatment arms will be selected for this whole blood draw and immune cell phenotyping analysis.   
p A separate Future Use Samples Informed Consent has to be obtained before any sampling.  Both serum and plasma will be drawn and the samples will be used for future analysis (e.g, circulating proteins). 
q A separate Pharmacogenetic Research Informed Consent for collecting and sequencing DNA and RNA samples has to be obtained before any sampling. One DNA (at baseline or any treatment or follow up visit) 
and RNA sample for sequencing sampling time point at baseline and pre-dose (V3) are needed. 
r 
Additional sample is to be drawn 4-7 days after Week 24 dosing. 
s Since the visit interval exceeds 4 weeks, interim shipments of IMP to patients home may be performed using direct to patient (DTP) shipping in order to provide the patient with only 4 weeks IMP at a time in order 
to minimize compliance errors. 
t 
If the ultrasound is employed in the diagnosis of PMR, then the ultrasound images need to be submitted to the central reader for confirmation that they fulfill the ultrasound part of the diagnostic criteria for PMR. 
u For patients who are on >15mg/day (but not exceeding 20mg/day) of prednisone at screening and during the screening period, the Investigator should judiciously taper the prednisone down to 15mg/day prior to 
randomization in order to prevent a disease flare upon entering the study at 15mg/day of prednisone. 
v If the ultrasound is being used as a diagnostic tool of PMR, the image needs to be submitted to the central reader for confirmation of eligibility. 
w IMP training. Prior to the first dose of IMP, provide instructions on preparation and self-injection of the pre-filled syringes and the use of the weekly blister packs of prednisone. Document this training in the patients 
study file. Note: If the patient is unable or unwilling to perform the subcutaneous injections themselves, arrangements must be made for qualified site personnel and/or caregiver to administer study drug every 2 
weeks for doses that are not scheduled to be given to the study site.  
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Appendix B 
Standardized corticosteroid-taper regimen during double-blind 
study treatment period  
Week 
Group 1-Daily PS dose14 weeks taper  
Group 2-Daily PS dose  
52 weeks taper 
0 
Day 1 
15 
15 
1 
15 
15 
2 
14 
14 
3 
12 
12 
4 
10 
12 
5 
9 
12 
6 
8 
10 
7 
7 
10 
8 
6 
9 
9 
5 
9 
10 
4 
9 
 11 
3 
9 
12 
2 
8 
13 
1 
8 
14 
PS placebo 
8 
15 
PS placebo 
8 
16 
PS placebo 
7 
17 
PS placebo 
7 
18 
PS placebo 
7 
19 
PS placebo 
7 
20 
PS placebo 
6 
21 
PS placebo 
6 
22 
PS placebo 
6 
23 
PS placebo 
6 
24 
PS placebo 
5 
25 
PS placebo 
5 
26 
PS placebo 
5 
27 
PS placebo 
5 
28 
PS placebo 
4 
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Week 
Group 1-Daily PS dose14 weeks taper  
Group 2-Daily PS dose  
52 weeks taper 
29 
PS placebo 
4 
30 
PS placebo 
4 
31 
PS placebo 
4 
32 
PS placebo 
3 
33 
PS placebo 
3 
34 
PS placebo 
3 
35 
PS placebo 
3 
36 
PS placebo 
2 
37 
PS placebo 
2 
38 
PS placebo 
2 
39 
PS placebo 
2 
40 
PS placebo 
2 
41 
PS placebo 
2 
42 
PS placebo 
2 
43 
PS placebo 
2 
44 
PS placebo 
1 
45 
PS placebo 
1 
46 
PS placebo 
1 
47 
PS placebo 
1 
48 
PS placebo 
1 
49 
PS placebo 
1 
50 
PS placebo 
1 
51 
PS placebo 
1 
 
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Appendix C 
Potentially clinically significant abnormalities (PCSA) criteria  
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Additional analysis*: 
>1 – 1.5 ULN 
>1.5 – 3 ULN 
>3 – 5 ULN 
>5 – 8 ULN 
> 8 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
AST 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Additional analysis*: 
>1 – 1.5 ULN 
>1.5 – 3 ULN 
>3 – 5 ULN 
>5 – 8 ULN 
> 8 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative  
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
 
Additional analysis*: 
>1.5 ULN 
>2 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
PCSA to be retrieved manually 
Unconjugated bilirubin 
Additional analysis*: 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
CPK** 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on the 
Cokcroft-Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR** (mL/min/1.73m2) 
(Estimate of GFR based 
on an MDRD equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
≥6.2 mmol/L* 
Threshold for therapeutic intervention. 
LDL 
≥4.1 mmol/L* 
≥4.9 mmol/L 
 
Triglycerides 
≥4.6 mmol/L 
≥5.6 mmol/L* 
Threshold for therapeutic intervention. 
Lipasemia** 
≥3 ULN 
 
Amylasemia** 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
<0.5 Giga/L* 
≥0.5 Giga/L – LLN* 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
<1.0 Giga/L* 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are 
more relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of 
Hb. 
Otherwise, consider FDA criteria. 
Platelets 
< 50 Giga/L* 
≥ 50 – 100 Giga/L* 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 “ Analysis and reporting of safety data from clinical trials through the Clinical Study Report”– Version 3 –
21-MAY-2014) 
Parameter 
PCSA 
Comments 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
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Appendix D 
Summary of statistical analyses  
 
Analysis 
 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Population 
Primary Analysis 
Method 
Analysis* 
Analysis* 
Analyses* 
Primary Endpoint 
Patients who achieved 
sustained remission at 
Week 52 
ITT 
Proportion of patients achieving 
sustained remission at Week 52 
Fisher’s exact test 
Tipping point analysis 
and primary endpoint 
excluding acute phase 
reactants and excluding 
incorrectly diagnosed 
PMR patients. 
Yes 
Subgroups: Gender, 
race, region, age, 
baseline weight, 
BMI, baseline CRP, 
baseline ESR, 
baseline CS dose, 
prior relapse, 
COVID-19 impacted 
population. 
No 
Secondary Endpoints 
Patients who achieved of 
disease remission by Week 
12 
ITT 
Proportion of patients who achieved of 
disease remission by Week 12 
Descriptive 
No 
No 
No 
Patients who have absence 
of disease flare from Week 
12 through Week 52 
ITT 
Proportion of patients who have 
absence of disease flare from Week 
12 through Week 52 
Descriptive 
No 
No 
No 
Patients who have 
normalization of CRP 
(decrease to <10 mg/L) 
with sustained 
normalization from Week 
12 through Week 52 
ITT 
Proportion of patients who have 
normalization of CRP (decrease to 
<10 mg/L) with sustained 
normalization from Week 12 through 
Week 52 
Descriptive 
No 
No 
No 
Patients who successfully 
adhere to the prednisone 
ITT 
Proportion of patients who 
successfully adhere to the prednisone 
taper from Week 12 through Week 52 
Descriptive 
No 
No 
No 
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Analysis 
 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Population 
Primary Analysis 
Method 
Analysis* 
Analysis* 
Analyses* 
taper from Week 12 
through Week 52 
Total cumulative 
prednisone (or equivalent) 
dose 
ITT 
Total cumulative prednisone (or 
equivalent) dose over 52-week 
treatment period 
Wilcoxon rank-sum 
test 
No 
No 
No 
Time to the first PMR flare 
after clinical remission up to 
Week 52 
ITT 
Time (from randomization) to the first 
GCA flare after clinical remission up to 
Week 52  
Kaplan-Meier 
estimates and Cox 
proportional hazards 
model  
No 
No 
No 
Total composite GTI total 
score  
ITT 
Cumulative GTI scores (CWS and 
AIS) at Week 52 
Analysis of 
covariance 
(ANCOVA) model 
No 
No 
Summaries of domain 
specific scores and 
specific list events at 
Week 12, 24, 40 and 
52. 
PMR activity score 
ITT 
PMR-AS at Week 52 
MMRM model 
No 
No 
Summaries of PMR-
AS and components 
at baseline, Week 12, 
24, and 52. 
SF-36, EQ-5D-3L, FACIT-
Fatigue, HAQ-DI, MD-VAS 
ITT 
Change from baseline at Week 52 
MMRM model 
No 
No 
No 
Safety 
 
 
 
 
 
 
Adverse Events 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
No 
Laboratory 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
No 
Vital signs and ECGs 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
No 
PK 
 
 
 
 
 
 
Sarilumab serum 
concentration 
PK 
By visit 
Descriptive 
No 
No 
No 
Immunogenicity 
 
 
 
 
 
 
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Analysis 
 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Population 
Primary Analysis 
Method 
Analysis* 
Analysis* 
Analyses* 
ADA positive patients 
ADA 
NA 
Descriptive 
No 
No 
No 
ADA negative patients 
ADA 
NA 
Descriptive  
No 
No 
No 
Persistent ADA response 
ADA 
NA 
Descriptive 
No 
No 
No 
Transient ADA response 
ADA 
NA 
Descriptive 
No 
No 
No 
 
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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 the 10 items that require recoding, 
• Step 2. Computing scale scores by summing across items in the same scale (raw scale 
scores); and, 
• Step 3. Transforming raw scale scores to a 0-100 scale (transformed scale). 
Item recoding 
• All 36 items should be checked for out-of-range values prior to assigning the final item 
value. All out-of-range values should be recoded as missing data. 
• The following tables show the recoding of response choice. 
How to treat missing data 
A scale score is calculated if a respondent answered at least half of the items in a multi-item scale 
(or half plus one in the case of scales with an odd number of items). 
The recommended algorithm substitutes a person-specific estimate for any missing item when the 
respondent answered at least 50 percent of the items in a scale. A psychometrically sound estimate 
is the average score, across completed items in the same scale, for that respondent. For example, if 
a respondent leaves one item in the 5-item mental Health scale blank, substitute the respondent’s 
average score (across the 4 completed mental health items) for that one item. When estimating the 
respondent’s average score, use the respondent’s final item values. 
Computing raw scale scores 
After item recoding, including handling of missing data, a raw score is computed for each scale. 
This score is a simple algebraic sum of responses for all items in that scale. 
If the respondent answered at least 50% of the items in a multi-items scale, the score can be 
calculated. If the respondent did not answer at least 50% of the items, the score for that scale 
should be set to missing. 
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Transformation of the scale scores 
The next step involves transforming each raw score to a 0 to 100 scale using the following 
formula: 
Transformed scale = [(actual raw score – lowest possible raw score) / possible raw score range] x 
100 
This transformation converts the lowest and highest possible scores to zero and 100, respectively. 
Table 6 - 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)  
Instructions:* 1. Record answers in "item response" column. If missing, mark with an X 
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by the  
number of items answered. This produces the subscale score. 
4. The higher the score, the better the QOL. 
Subscale 
         Item Code       Reverse item?            Item response         
 Item Score  
FATIGUE 
 
HI7 
      
4 
- 
________ 
 
=________ 
SUBSCALE 
 
HI12 
 
4 
- 
________ 
 
=________ 
    
 
 
An1 
 
4 
- 
________ 
 
=________ 
An2 
 
4 
- 
________ 
 
=________ 
An3 
 
4 
- 
________ 
 
=________ 
An4 
 
4 
- 
________ 
 
=________ 
An5 
 
0 
+ 
________ 
 
=________ 
An7 
 
0 
+ 
________ 
 
=________ 
An8 
 
4 
- 
________ 
 
=________ 
An12 
 
4 
- 
________ 
 
=________ 
An14 
 
4 
- 
________ 
 
=________ 
An15 
 
4 
- 
________ 
 
=________ 
An16 
 
4 
- 
________ 
 
=________ 
              Sum individual item scores:________   
 
 
 
                   Multiply by 13: ________ 
           Divide by number of items answered: ________=Fatigue Subscale score 
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring Guidelines in the manual or on-line 
at www.facit.org. 
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Appendix G 
SAS code for EQ-5D-3L index utility scoring  
 
 
/*==================================================================*/; 
/* Aim : Derive the EQ5-D index (utility) */; 
/* Source for the algorithm : scoring EQ-5D health states (
*/; 
/* (cf. G:\_HE\PRO questionnaire\EQ5D\scoring\YorkTariffx.doc) */; 
/* Note : UK based population (Dolan, 1997) */; 
/* Author :
*/; 
/*==================================================================*/; 
 
data EUROQOL; set temp; 
profil= (10000*eqq1cd)+(1000*eqq2cd)+(100*eqq3cd)+(10*eqq4cd)+eqq5cd; 
eq5d=1; 
**********Mobility*********; 
if eqq1cd=2 then eq5d=eq5d-0.069; 
if eqq1cd=3 then eq5d=eq5d-0.314; 
********Self-care**********; 
if eqq2cd=2 then eq5d=eq5d-0.104; 
if eqq2cd=3 then eq5d=eq5d-0.214; 
******Usual activities*****; 
if eqq3cd=2 then eq5d=eq5d-0.036; 
if eqq3cd=3 then eq5d=eq5d-0.094; 
*****Pain/discomfort******; 
if eqq4cd=2 then eq5d=eq5d-0.123; 
if eqq4cd=3 then eq5d=eq5d-0.386; 
*****Anxiety/depression*****; 
if eqq5cd=2 then eq5d=eq5d-0.071; 
if eqq5cd=3 then eq5d=eq5d-0.236; 
 
if (eqq1cd ne 1 or eqq2cd ne 1 or eqq3cd ne 1 or eqq4cd ne 1 or eqq5cd ne 1) 
then eq5d=eq5d-0.081; 
 
if (eqq1cd=3 or eqq2cd=3 or eqq3cd=3 or eqq4cd=3 or eqq5cd=3) 
then eq5d=eq5d-0.269; 
 
if (eqq1cd=. or eqq2cd=. or eqq3cd=. or eqq4cd=. or eqq5cd=.) 
then eq5d=.; 
 
run; 
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Version number: 1 
 
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Page 76 
Appendix H 
SAS code for SF-36 scoring  
 
******************************************************************** 
*  PROGRAM: SF36 V2                                                * 
*  PURPOSE: SAS SCORING PROGRAM FOR THE SF-36 VERSION2             * 
*                                                                  * 
*******************************************************************; 
 
*****************************************************************; 
***               STEP 1: INPUT DATA                          ***; 
*****************************************************************; 
 
DATA SF36DATA; 
INFILE IN; 
INPUT ID $ 1-3 
      @ 5 (GH1 HT PF01-PF10 RP1-RP4 RE1-RE3 SF1 
      BP1-BP2 VT1 MH1 MH2 MH3 VT2 MH4 VT3 MH5 
      VT4 SF2 GH2 GH3 GH4 GH5) (1.); 
RUN; 
 
 
*****************************************************************; 
***               STEP 2: SF-36 SCALE CONSTRUCTION            ***; 
*****************************************************************; 
 
 
****************************************************************** 
*  USING THE SAS DATASET CREATED IN PART 1, CHANGE OUT-OF-RANGE 
*  VALUES TO MISSING FOR EACH ITEM.  RECODE AND RECALIBRATE ITEMS 
*  AS NEEDED.  AN 'R' PREFIX MEANS THE VARIABLE IS RECODED. 
*****************************************************************; 
 
DATA SF36SCAL; 
  SET SF36DATA; 
 
 
****************************************************************** 
*  THE SF-36 PHYSICAL FUNCTIONING INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM 
*  VALUE, THE BETTER THE PHYSICAL HEALTH. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE PHYSICAL FUNCTIONING. 
******************************************************************; 
 
ARRAY PFI(10) PF01-PF10; 
 
DO I = 1 TO 10; 
   IF PFI(I) < 1 OR PFI(I) > 3 THEN PFI(I) = .; 
END; 
 
PFNUM = N(OF PF01-PF10); 
PFMEAN = MEAN(OF PF01-PF10); 
 
DO I = 1 TO 10; 
  IF PFI(I)= . THEN PFI(I) = PFMEAN; 
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Page 77 
END; 
 
IF PFNUM GE 5 THEN RAWPF = SUM(OF PF01-PF10); 
PF = ((RAWPF - 10)/(30-10)) * 100; 
 
LABEL  PF = 'SF-36 PHYSICAL FUNCTIONING (0-100)' 
       RAWPF = 'RAW SF-36 PHYSICAL FUNCTIONING'; 
 
 
****************************************************************** 
*  THE SF-36 ROLE-PHYSICAL INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM VALUE, 
*  THE BETTER THE ROLE-PHYSICAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE ROLE-PHYSICAL. 
*****************************************************************; 
 
ARRAY RPA(4) RP1-RP4; 
 
DO I = 1 TO 4; 
   IF RPA(I) < 1 OR RPA(I) > 5 THEN RPA(I) = .; 
END; 
 
ROLPNUM = N(OF RP1-RP4); 
ROLPMEAN = MEAN(OF RP1-RP4); 
 
DO I = 1 TO 4; 
   IF RPA(I) = . THEN RPA(I) = ROLPMEAN; 
END; 
 
IF ROLPNUM GE 2 THEN RAWRP = SUM(OF RP1-RP4); 
RP = ((RAWRP - 4)/(20-4)) * 100; 
LABEL  RP = 'SF-36 ROLE-PHYSICAL (0-100)' 
       RAWRP = 'RAW SF-36 ROLE-PHYSICAL'; 
 
 
***************************************************************** 
*  THE SF-36 PAIN ITEMS. 
*  ITEM RECODING DEPENDS ON WHETHER BOTH PAIN1 AND PAIN2 
*  ARE ANSWERED OR WHETHER ONE OF THE ITEMS HAS MISSING DATA. 
*  AFTER RECODING, ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER 
*  THE SCORE, THE LESS PAIN (OR THE MORE FREEDOM FROM PAIN). 
* 
*   THIS SCALE IS POSITIVELY SCORED.  THE HIGHER THE 
*   SCORE THE LESS PAIN OR THE MORE FREEDOM FROM PAIN. 
*****************************************************************; 
 
IF BP1 < 1 OR BP1 > 6 THEN BP1 = .; 
IF BP2 < 1 OR BP2 > 5 THEN BP2 = .; 
 
*  RECODES IF NEITHER BP1 OR BP2 HAS A MISSING VALUE; 
 
IF BP1 NE . AND BP2 NE . THEN DO; 
 
   IF BP1 = 1 THEN RBP1 = 6; 
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Page 78 
   IF BP1 = 2 THEN RBP1 = 5.4; 
   IF BP1 = 3 THEN RBP1 = 4.2; 
   IF BP1 = 4 THEN RBP1 = 3.1; 
   IF BP1 = 5 THEN RBP1 = 2.2; 
   IF BP1 = 6 THEN RBP1 = 1; 
 
   IF BP2 = 1  AND BP1 = 1 THEN RBP2 = 6; 
   IF BP2 = 1  AND 2 LE BP1 LE 6 THEN RBP2 = 5; 
   IF BP2 = 2  AND 1 LE BP1 LE 6 THEN RBP2  = 4; 
   IF BP2 = 3  AND 1 LE BP1 LE 6 THEN RBP2  = 3; 
   IF BP2 = 4  AND 1 LE BP1 LE 6 THEN RBP2  = 2; 
   IF BP2 = 5  AND 1 LE BP1 LE 6 THEN RBP2  = 1; 
 
END; 
 
*  RECODES IF BP1 IS NOT MISSING AND BP2 IS MISSING; 
 
IF BP1 NE . AND BP2 = . THEN DO; 
   IF BP1 = 1 THEN RBP1 = 6; 
   IF BP1 = 2 THEN RBP1 = 5.4; 
   IF BP1 = 3 THEN RBP1 = 4.2; 
   IF BP1 = 4 THEN RBP1 = 3.1; 
   IF BP1 = 5 THEN RBP1 = 2.2; 
   IF BP1 = 6 THEN RBP1 = 1; 
   RBP2 = RBP1; 
 
END; 
 
*  RECODES IF BP1 IS MISSING AND BP2 IS NOT MISSING; 
 
IF BP1 = . AND BP2 NE . THEN DO; 
 
   IF BP2 = 1 THEN RBP2 = 6; 
   IF BP2 = 2 THEN RBP2 = 4.75; 
   IF BP2 = 3 THEN RBP2 = 3.5; 
   IF BP2 = 4 THEN RBP2 = 2.25; 
   IF BP2 = 5 THEN RBP2 = 1; 
   RBP1 = RBP2; 
 
END; 
 
BPNUM = N(BP1,BP2); 
 
IF BPNUM GE 1 THEN RAWBP = SUM(RBP1,RBP2); 
BP = ((RAWBP - 2)/(12-2)) * 100; 
 
LABEL  BP = 'SF-36 PAIN INDEX (0-100)' 
       RAWBP = 'RAW SF-36 PAIN INDEX'; 
 
 
****************************************************************** 
*  THE SF-36 GENERAL HEALTH PERCEPTIONS INDEX. 
*  REVERSE TWO ITEMS AND RECALIBRATE ONE ITEM.  AFTER RECODING 
*  AND RECALIBRATION, ALL ITEMS ARE POSITIVELY SCORED --  THE 
*  HIGHER THE SCORE, THE BETTER THE PERCEIVED GENERAL HEALTH. 
* 
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
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*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE HEALTH PERCEPTIONS. 
*****************************************************************; 
 
ARRAY GHP(5) GH1-GH5; 
 
DO I= 1 TO 5; 
  IF GHP(I) < 1 OR GHP(I) > 5 THEN GHP(I) = .; 
END; 
 
IF GH1 = 1 THEN RGH1 =   5; 
IF GH1 = 2 THEN RGH1 = 4.4; 
IF GH1 = 3 THEN RGH1 = 3.4; 
IF GH1 = 4 THEN RGH1 =   2; 
IF GH1 = 5 THEN RGH1 =   1; 
 
RGH3 = 6 - GH3; 
RGH5 = 6 - GH5; 
 
GHNUM = N(GH1,GH2,GH3,GH4,GH5); 
GHMEAN = MEAN(RGH1,GH2,RGH3,GH4,RGH5); 
 
ARRAY RGH(5) RGH1 GH2 RGH3 GH4 RGH5; 
 
DO I= 1 TO 5; 
  IF RGH(I) = . THEN RGH(I) = GHMEAN; 
END; 
 
IF GHNUM GE 3  THEN RAWGH = SUM(RGH1,GH2,RGH3,GH4,RGH5); 
GH = ((RAWGH - 5)/(25-5)) * 100; 
 
LABEL  GH = 'SF-36 GENERAL HEALTH PERCEPTIONS (0-100)' 
       RAWGH = 'RAW SF-36 GENERAL HEALTH PERCEPTIONS'; 
 
 
***************************************************************** 
*  THE SF-36 VITALITY ITEMS. 
*  REVERSE TWO ITEMS.  AFTER ITEM REVERSAL, ALL ITEMS ARE 
*  POSITIVELY SCORED -- THE HIGHER THE SCORE, THE LESS THE FATIGUE 
*  AND THE GREATER THE ENERGY. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE GREATER THE VITALITY. 
****************************************************************; 
 
ARRAY VI(4) VT1-VT4; 
 
DO I = 1 TO 4; 
  IF VI(I) < 1 OR VI(I) > 5 THEN VI(I) =.; 
END; 
 
RVT1 = 6-VT1; 
RVT2 = 6-VT2; 
 
VITNUM = N(VT1,VT2,VT3,VT4); 
VITMEAN = MEAN(RVT1,RVT2,VT3,VT4); 
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Statistical Analysis Plan  
20-May-2021 
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 80 
 
ARRAY RVI(4) RVT1 RVT2 VT3 VT4; 
 
DO I = 1 TO 4; 
  IF RVI(I) = . THEN RVI(I) = VITMEAN; 
END; 
 
IF VITNUM GE 2 THEN RAWVT= SUM(RVT1,RVT2,VT3,VT4); 
VT = ((RAWVT-4)/(20-4)) * 100; 
 
LABEL  VT = 'SF-36 VITALITY (0-100)' 
       RAWVT = 'RAW SF-36 VITALITY'; 
 
 
**************************************************************** 
*  THE SF-36 SOCIAL FUNCTIONING INDEX. 
*  REVERSE ONE ITEM SO THAT BOTH ITEMS ARE POSITIVELY SCORED -- 
*  THE HIGHER THE SCORE, THE BETTER THE SOCIAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE SOCIAL FUNCTIONING. 
*****************************************************************; 
 
ARRAY SOC(2) SF1-SF2; 
 
DO I = 1 TO 2; 
   IF SOC(I) < 1 OR SOC(I) > 5 THEN SOC(I) = .; 
END; 
 
RSF1 = 6 - SF1; 
SFNUM = N(SF1,SF2); 
SFMEAN = MEAN(RSF1,SF2); 
 
ARRAY RSF(2) RSF1 SF2; 
 
DO I = 1 TO 2; 
  IF RSF(I) = . THEN RSF(I) = SFMEAN; 
END; 
 
IF SFNUM GE 1 THEN RAWSF = SUM(RSF1,SF2); 
SF = ((RAWSF - 2)/(10-2)) * 100; 
 
LABEL  SF = 'SF-36 SOCIAL FUNCTIONING (0-100)' 
       RAWSF = 'RAW SF-36 SOCIAL FUNCTIONING'; 
 
 
****************************************************************** 
*  THE SF-36 ROLE-EMOTIONAL INDEX. 
*  ALL ITEMS ARE POSITIVELY SCORED -- THE HIGHER THE ITEM VALUE, 
*  THE BETTER THE ROLE-EMOTIONAL FUNCTIONING. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE, THE BETTER THE ROLE-EMOTIONAL. 
*****************************************************************; 
 
ARRAY RM(3) RE1-RE3; 
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 81 
 
DO I = 1 TO 3; 
   IF RM(I) < 1 OR RM(I) > 5 THEN RM(I) = .; 
END; 
 
ROLMNUM = N(OF RE1-RE3); 
ROLMMEAN = MEAN(OF RE1-RE3); 
 
DO I = 1 TO 3; 
   IF RM(I) = . THEN RM(I) = ROLMMEAN; 
END; 
 
IF ROLMNUM GE 2 THEN RAWRE = SUM(OF RE1-RE3); 
RE = ((RAWRE - 3)/(15-3)) * 100; 
 
LABEL  RE = 'SF-36 ROLE-EMOTIONAL (0-100)' 
       RAWRE = 'RAW SF-36 ROLE-EMOTIONAL'; 
 
 
***************************************************************** 
*  THE SF-36 MENTAL HEALTH INDEX. 
*  REVERSE TWO ITEMS.  AFTER ITEM REVERSAL, ALL ITEMS ARE 
*  POSITIVELY SCORED -- THE HIGHER THE SCORE, THE BETTER THE 
*  MENTAL HEALTH. 
* 
*  THIS SCALE IS POSITIVELY SCORED. 
*  THE HIGHER THE SCORE THE BETTER THE MENTAL HEALTH. 
****************************************************************; 
 
ARRAY MHI(5) MH1-MH5; 
 
DO I = 1 TO 5; 
   IF MHI(I) < 1 OR MHI(I) > 5 THEN MHI(I)=.; 
END; 
 
RMH3 = 6-MH3; 
RMH5 = 6-MH5; 
 
MHNUM=N(MH1,MH2,MH3,MH4,MH5); 
MHMEAN=MEAN(MH1,MH2,RMH3,MH4,RMH5); 
 
ARRAY RMH(5) MH1 MH2 RMH3 MH4 RMH5; 
 
DO I = 1 TO 5; 
   IF RMH(I) = . THEN RMH(I) = MHMEAN; 
END; 
 
IF MHNUM GE 3 THEN RAWMH = SUM(MH1,MH2,RMH3,MH4,RMH5); 
MH = ((RAWMH-5)/(25-5)) * 100; 
 
LABEL  MH = 'SF-36 MENTAL HEALTH INDEX (0-100)' 
       RAWMH = 'RAW SF-36 MENTAL HEALTH INDEX'; 
 
 
***************************************************************** 
*  THE SF-36 HEALTH TRANSITION ITEM. 
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Statistical Analysis Plan  
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 82 
*  THIS ITEM SHOULD BE ANALYZED AS CATEGORICAL DATA, 
*  PENDING FURTHER RESEARCH. 
****************************************************************; 
 
IF HT < 1 OR HT > 5 THEN HT = .; 
 
LABEL  HT='RAW SF-36 HEALTH TRANSITION ITEM'; 
RUN; 
 
 
*****************************************************************; 
***               STEP 3: SF-36 SCALE CONSTRUCTION            ***; 
*****************************************************************; 
 
 
 
DATA SF36INDX; 
  SET SF36SCAL; 
 
  
*******************************************************************; 
*  purpose: create physical and mental health index scores 
*           standardized but not normalized 
*           and standard deviations calculated with vardef=wdf 
*******************************************************************; 
 
         
/********************************************************************/ 
/* NORM-BASED SCORING OF SF-36, STANDARD RECALL (4 WEEKS)           */ 
/* USING  WEIGHTED MEANS AND SD'S FROM 1998 GENERAL US POPULATION   */ 
/* FROM COMBINED SAMPLES                                            */ 
/********************************************************************/ 
 
********************************************************** 
**********************1998 US NORMS*********************** 
**********************************************************; 
 
*CREATING SF-36 STANDARDIZED SCORES (0-100 Means/SD's from 1998 General 
Population)*; 
 
pf_z=(pf-83.29094)/23.75883; 
rp_z=(rp-82.50964)/25.52028; 
bp_z=(bp-71.32527)/23.66224; 
gh_z=(gh-70.84570)/20.97821; 
vt_z=(vt-58.31411)/20.01923; 
sf_z=(sf-84.30250)/22.91921; 
re_z=(re-87.39733)/21.43778; 
mh_z=(mh-74.98685)/17.75604; 
 
 
**************************************************************; 
*     COMPUTE SAMPLE RAW FACTOR SCORES                       *; 
*     Z SCORES ARE FROM ABOVE                                *; 
*     SCORING COEFFICIENTS ARE FROM U.S. GENERAL POPULATION  *; 
*     FACTOR ANALYTIC SAMPLE N=2393: HAVE ALL EIGHT SCALES   *; 
**********************************************************; 
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Page 83 
 
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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Statistical Analysis Plan  
20-May-2021 
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 84 
Appendix I 
Visit windows based on day ranges  
Visit windows based on days relative to the first IMP dose will be used to map the efficacy, lab, 
vital signs, PK, and immunogenicity data to each scheduled visit (see Table 7). 
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Statistical Analysis Plan  
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Page 85 
Table 7 - Day range for each scheduled visit in the DB period for efficacy, lab, vital sign, PK and ADA summaries 
Visit Label 
Target 
Day 
Schedule 
Aa
Schedule 
Bb
Schedule 
Cc
Schedule 
Dd
Schedule 
Ee
Schedule 
Ff
Schedule 
Gg
Schedule 
Hh 
Schedule 
Ii 
Schedule 
Jj 
Double-Blind Period 
Baseline 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 2  
15 
>1*-21 
>1* - 21 
>1* - 49 
Week 4  
29 
22-42 
>1* - 56 
>1* - 56 
>1* - 42 
22 - 56 
>1* - 98 
Week 8 
57 
43-70 
43 - 70 
Week 12 
85 
71-98 
>1* - 126 
>1* - 126 
57 - 126 
57 - 126 
71 - 98 
57 - 98 
50 - 126 
Week 16 
113 
99-126 
99 - 126 
99 - 140 
Week 20 
141 
127-154 
127 - 154 
Week 24 
169 
155-196 
127 - 224 
127 - 266 
127 - 224 
127 - 224 
155 - 196 
141 - 266 
127 - 266 
≥ 99 
Week 32 
225 
197-252 
197 - 252 
Week 40 
281 
253-322 
225 - 322 
225 - 322 
225 - 322 
253 - 322 
Week 52 
365 
≥323 
≥ 323 
≥ 267 
>1* 
≥ 323 
≥ 323 
≥ 323 
≥ 267 
≥ 267 
a Includes temperature, heart rate, blood pressure, PMR clinical assessments (including disease flare), CRP, ESR 
b Includes weight, glucocorticoid toxicity index (excluding bone density assessment) 
c Includes physician global assessments (MD-VAS), patient reported outcomes and antibodies to sarilumab/ADA 
d Includes bone density assessment, ANA 
e Includes hematology: hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential, platelet count, absolute 
neutrophil count (ANC) and chemistry: sodium, potassium, calcium, chloride, bicarbonate, total protein, creatinine and clearance, blood urea nitrogen (BUN), uric acid, lactate 
dehydrogenase (LDH), phosphate, albumin, ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, and unconjugated bilirubin 
f 
Includes HbA1c, fasting glucose, fasting lipids: triglycerides (TG), total cholesterol, HDL, LDL  
g Includes urine pregnancy test 
h Includes serum sarilumab 
i 
Includes biomarkers-IL-6 and sIL-6R 
j 
Includes immune cell phenotyping (whole blood) 
* Includes value measured on day 1 but after the first IMP dose
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For PK and ADA, the follow-up (i.e., 6-week post-treatment) measurement will be defined based 
on the sample collected at the follow-up visit (ie, Visit 13). The rest of PK and ADA 
measurements will be mapped to each visit using the visit window defined in Table 7. 
 
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Statistical Analysis Plan  
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Page 87 
Appendix J 
Baseline glucocorticoid toxicity 
Approach to calculating the Baseline glucocorticoid toxicity score:  Toxicities assigned weighted scores 
from the Composite Index to establish a baseline glucocorticoid toxicity score 
Toxicity Domain 
Points 
Body Mass Index (BMI) 
BMI < 27 
0 
BMI ≥ 27 but < 30 
21 
BMI ≥ 30 
36 
Glucose Metabolism 
HgbA1c < 5.7 
0 
HgbA1c < 5.7 but on medication 
32 
Hgb A1c ≥ 5.7 
32 
HgbA1c ≥ 5.7 and on medication 
44 
Diabetic retinopathy, nephropathy, or neuropathy (count only one) 
44 
Blood pressure 
Normotensive: systolic ≤ 120 and diastolic ≤ 85 no medications 
0 
Systolic ≤ 120 and diastolic ≤ 85 but on medications 
19 
Systolic > 120 and diastolic > 85 no medications 
19 
Systolic ≤ 120 and diastolic > 85 no medications 
44 
Hypertensive emergency or PRES (count only one) 
44 
Lipid Metabolism 
LDL ≤ targeta 
0 
LDL ≤ targeta but on medications 
10 
LDL > targeta on no medications 
10 
LDL > targeta on treatment 
30 
Bone/Tendon 
Normal BMD or no known history of osteoporosis 
0 
Osteoporosis 
29 
Insufficiency fracture secondary to osteoporosis 
29 
Osteonecrosis 
29 
Tendon rupture while on corticosteroid 
29 
Glucocorticoid 
Myopathy 
No myopathy 
0 
Minor glucocorticoid myopathy 
9 
Moderate glucocorticoid myopathy 
63 
Severe glucocorticoid myopathy 
63 
Skin 
No skin toxicity 
0 
Minor skin toxicity (one or more than one minor skin item) 
8 
Moderate skin toxicity (one or more than one moderate skin item) 
26 
Severe skin toxicity (one or more than one moderate skin item) 
26 
Neuropsychiatric 
No neuropsychiatric toxicity 
0 
Minor (one or more than one minor NP item: insomnia, mania, 
depression, cognitive) 
11 
Moderate (one or more than one moderate NP item: insomnia, mania, 
depression, cognitive) 
74 
Severe (one or more than one severe NP item: insomnia, mania, 
depression, cognitive) 
74 
Psychosis 
74 
Glucocorticoid-induced violence 
74 
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Infection 
No GTI-relevant infections within the pre-baseline GTI interval of the 
study  
0 
Oral or vaginal candidiasis or non-complicated zoster (<Grade3) within 
the pre-baseline GTI interval of the study 
19 
Grade 3 or Grade 4 infection within the pre-baseline GTI interval of the 
study 
93 
Ocular 
Increased IOP 
33 
Posterior subcapsular cataract 
33 
Central serous retinopathy 
33 
Gastrointestinal 
GI perf absence of NSAIDs 
33 
PUD without H. pylori 
33 
Endocrine 
Adrenal insufficiency  
33 
a Target range of <70 mg/dL will be used for LDL domain. 
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