Conditions: Corona Virus Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 420
Healthy volunteers: no

Brief summary:
Primary Objective:

To evaluate the clinical efficacy of sarilumab relative to the control arm in adult participants hospitalized with severe or critical Coronavirus Disease 2019 (COVID-19).

Secondary Objectives:

* Evaluate the 28-day survival rate.
* Evaluate the clinical efficacy of sarilumab compared to the control arm by clinical severity.
* Evaluate changes in the National Early Warning Score 2.
* Evaluate the duration of predefined symptoms and signs (if applicable).
* Evaluate the duration of supplemental oxygen dependency (if applicable).
* Evaluate the incidence of new mechanical ventilation use during the study.
* Evaluate the duration of new mechanical ventilation use during the Study.
* Evaluate the proportion of participants requiring rescue medication during the 28-day period.
* Evaluate need for admission into intensive care unit.
* Evaluate duration of hospitalization (days).
* The secondary safety objectives of the study were to evaluate the safety of sarilumab through hospitalization (up to Day 29 if participant was still hospitalized) compared to the control arm as assessed by incidence of:

  * Serious adverse events.
  * Major or opportunistic bacterial or fungal infections in participants with grade 4 neutropenia.
  * Grade greater than or equal to (\>=) 2 infusion related reactions.
  * Grade \>=2 hypersensitivity reactions.
  * Increase in alanine transaminase (ALT) \>=3X upper limit of normal (ULN) (for participants with normal baseline) or greater than 3X ULN AND at least 2-fold increase from baseline value (for participants with abnormal baseline).
  * Major or opportunistic bacterial or fungal infections.

Detailed description:
An individual participant would complete the study approximately 60 days from screening to follow-up on day 60 ±7 days.

Arms:
arm 1: Sarilumab 200 milligrams (mg), single dose of intravenous (IV) injection on Day 1. Participants could receive a second dose of sarilumab 200 mg 24 to 48 hours after the first dose if first and any one of last three criteria was met as compared to Day 1 (as per following protocol amendment 2 \[dated 08-Apr-2020\]):

* Benefit risk assessment by the investigator favored the administration of another dose of study drug without compromising safety and
* Increase/recurrence of fever or
* Increase/no change in fraction of inspired oxygen (FiO2) requirement or
* Required vasopressors, extracorporeal membrane oxygenation (ECMO) or development of multi-organ dysfunction. arm 2: Sarilumab 400 mg, single dose of IV injection on Day 1. Participants could receive a second dose of sarilumab 400 mg 24 to 48 hours after the first dose if first and any one of last three criteria was met as compared to Day 1 (as per following protocol amendment 2 \[dated 08-Apr-2020\]):

* Benefit risk assessment by the investigator favored the administration of another dose of study drug without compromising safety and
* Increase/recurrence of fever or
* Increase/no change in FiO2 requirement or
* Required vasopressors, ECMO or development of multi-organ dysfunction. arm 3: Placebo (for sarilumab), single dose of IV injection on Day 1. Participants could receive a second dose of placebo (for sarilumab) 24 to 48 hours after the first dose if first and any one of last three criteria was met as compared to Day 1 (as per following protocol amendment 2 \[dated 08-Apr-2020\]):

* Benefit risk assessment by the investigator favored the administration of another dose of study drug without compromising safety and
* Increase/recurrence of fever or
* Increase/no change in FiO2 requirement or
* Required vasopressors, ECMO or development of multi-organ dysfunction.

Interventions: intervention 1: Sarilumab SAR153191 intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion intervention 2: Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion

Protocol document:
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 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 04 
Protocol title: 
An adaptive phase 3, randomized, double-blind, 
placebo-controlled study assessing efficacy and safety of 
sarilumab for hospitalized patients with COVID-19 
Protocol number: 
EFC16844 
Amendment number: 04 
Compound number 
(INN/Trademark): 
SAR153191 
Sarilumab/Kevzara® 
Study phase: 
Phase 3 
Short title: 
Sarilumab COVID-19  
Sponsor name: 
sanofi-aventis Recherche & Développement  
 
Legal registered 
address: 
1 avenue Pierre Brossolette 
91385 Chilly Mazarin Cedex 
France 
Monitoring Team’s 
Representative Name 
and Contact 
Information 
 
Regulatory agency identifier number(s): 
IND:  
Not available at the time of protocol preparation 
EudraCT: 
2020-001162-12 
NCT: 
NCT04327388 
WHO: 
U1111-1249-6021 
EUDAMED 
Not available at the time of protocol preparation 
Other: 
Not available at the time of protocol preparation 
 
Date: 
11-Jun-2020 
Total number of pages: 86 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 04 
All 
11-Jun-2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
29-Apr-2020, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
08-Apr-2020, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
26-Mar-2020, version 1 (electronic 1.0) 
Original Protocol 
All 
18-Mar-2020, version 1 (electronic 1.0) 
 
Amended protocol [04] (11-Jun-2020) 
This amended protocol 04 (amendment 04) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The main purpose of the amendment is to close enrollment into the sarilumab 200 mg IV arm 
while maintaining the original 2:1 ratio of sarilumab 400 mg IV to placebo. This amendment also 
clarifies instructions and provides additional guidance to investigators regarding follow-up and 
reporting of adverse events of special interest (AESI). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 2.1 Study 
Rationale, Section 4.1 
Overall Design, Section 
4.2 Scientific Rationale for 
Study Design, Section 4.3 
Justification for Dose, 
Section 6.1. Study 
Interventions administered 
(Table 3) 
Closed enrollment to the sarilumab 200 mg 
IV arm 
Based on anticipation of a more favorable 
benefit-risk profile in the 400 mg arm versus the 
200 mg arm, enrollment in the 200 mg arm will 
be closed upon implementation of amended 
protocol 04. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 3 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities 
Urinalysis and urine culture results, serum IL-
6, adverse events 
The timing of urinalysis, urine culture results, 
serum IL-6, and adverse events assessments 
was clarified. No changes were made to the 
collection schedule. 
Section 5.2 
E04 was modified to clarify that oral 
corticosteroids were a type of systemic 
corticosteroids. 
Clarification of definition. 
Section 10.3.1 Definition 
of AE 
Events meeting the AE definition: 
Removed: “Lack of efficacy” or “failure of 
expected pharmacological action” per se will 
not be reported as an AE or SAE. Such 
instances will be captured in the efficacy 
assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or 
SAE if they fulfil the definition of an AE or 
SAE. 
This bullet is duplicated in error. The same 
information is included in the first bullet. 
 
 
 
 
 
 
Section 10.3.1 Definition 
of AE 
Events meeting the AE definition: 
The signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfil the 
definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected 
pharmacological action” also constitutes an 
AE or SAE. 
This bullet is contradictory to the information 
provided, stating “Lack of efficacy” or “failure of 
expected pharmacological action” per se will not 
be reported as an AE or SAE. 
 
 
 
Section 10.3.2.1 
Recording and follow-up 
of AE and/or SAE 
Added tables for assessment of intensity for 
infusion related reactions, hypersensitivity 
reactions, and neutropenia.  
Added guidance for the follow-up of AESIs of 
ALT increase and Grade 4 Neutropenia. 
Provide guidance to the investigator. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 4 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE CHANGES ............................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 8 
LIST OF FIGURES .......................................................................................................................................... 8 
1 
PROTOCOL SUMMARY ................................................................................................................. 9 
1.1 
SYNOPSIS ....................................................................................................................................... 9 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 16 
2 
INTRODUCTION ............................................................................................................................ 20 
2.1 
STUDY RATIONALE...................................................................................................................... 20 
2.2 
BACKGROUND ............................................................................................................................. 21 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 22 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 24 
4 
STUDY DESIGN ............................................................................................................................ 27 
4.1 
OVERALL DESIGN ........................................................................................................................ 27 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 28 
4.2.1 
Participant input into study design ................................................................................................. 29 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 29 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 30 
5 
STUDY POPULATION .................................................................................................................. 31 
5.1 
INCLUSION CRITERIA .................................................................................................................. 31 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 32 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 34 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 5 
5.4 
SCREEN FAILURES...................................................................................................................... 34 
6 
STUDY INTERVENTION ............................................................................................................... 35 
6.1 
STUDY INTERVENTIONS ADMINISTERED ................................................................................ 35 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 36 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 36 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 37 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 37 
6.6 
RESCUE THERAPY ...................................................................................................................... 38 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 38 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 39 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 39 
7.1.1 
Definitive discontinuation ............................................................................................................... 39 
7.1.2 
Temporary discontinuation ............................................................................................................. 39 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 40 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 41 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 42 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 42 
8.1.1 
Clinical data collection ................................................................................................................... 42 
8.1.2 
Oxygen Administration and Oxygenation ...................................................................................... 43 
8.1.3 
Body temperature ........................................................................................................................... 44 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 44 
8.2.1 
Vital signs ....................................................................................................................................... 45 
8.2.2 
Targeted Physical Examination ..................................................................................................... 45 
8.2.3 
Electrocardiograms ........................................................................................................................ 45 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 45 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 45 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 46 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 46 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 46 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 46 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 6 
8.3.5 
Pregnancy ...................................................................................................................................... 47 
8.3.6 
Adverse event of special interest ................................................................................................... 48 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 48 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 49 
8.5 
PHARMACOKINETICS .................................................................................................................. 49 
8.5.1 
Sampling times ............................................................................................................................... 49 
8.5.2 
Sample handling procedure ........................................................................................................... 49 
8.5.3 
Bioanalytical methods .................................................................................................................... 50 
8.5.4 
Pharmacokinetic parameters ......................................................................................................... 50 
8.6 
PHARMACODYNAMICS ............................................................................................................... 50 
8.6.1 
Pharmacodynamic parameters ...................................................................................................... 50 
8.6.2 
Assessment methods ..................................................................................................................... 50 
8.7 
GENETICS ..................................................................................................................................... 51 
8.8 
BIOMARKERS ............................................................................................................................... 51 
8.9 
HEALTH ECONOMICS/MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 51 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 52 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 52 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 52 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 52 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 53 
9.4.1 
General considerations .................................................................................................................. 53 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 54 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 54 
9.4.3.1 
Efficacy ........................................................................................................................................... 54 
9.4.3.2 
Safety ............................................................................................................................................. 55 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 56 
9.4.5 
Other safety analyse(s) .................................................................................................................. 56 
9.4.5.1 
Vital Signs ...................................................................................................................................... 56 
9.4.5.2 
Laboratory Tests ............................................................................................................................ 56 
9.4.5.3 
Assessment of anti- sarilumab antibodies ..................................................................................... 57 
9.4.6 
Pharmacokinetics ........................................................................................................................... 57 
9.4.6.1 
Analysis of Drug Concentration Data ............................................................................................. 57 
9.4.6.2 
Analysis of Pharmacodynamic and Exploratory Biomarker Data .................................................. 57 
9.4.7 
Other analyse(s) ............................................................................................................................. 57 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 7 
9.5 
INTERIM ANALYSES .................................................................................................................... 57 
9.6 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ....................................................... 58 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 59 
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ...... 59 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 59 
10.1.2 
Financial disclosure........................................................................................................................ 60 
10.1.3 
Informed consent process .............................................................................................................. 60 
10.1.4 
Data protection ............................................................................................................................... 61 
10.1.5 
Dissemination of clinical study data ............................................................................................... 61 
10.1.6 
Data quality assurance .................................................................................................................. 62 
10.1.7 
Source documents ......................................................................................................................... 63 
10.1.8 
Study and site start and closure ..................................................................................................... 63 
10.1.9 
Publication policy ........................................................................................................................... 64 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 64 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 66 
10.3.1 
Definition of AE .............................................................................................................................. 66 
10.3.2 
Definition of SAE ............................................................................................................................ 67 
10.3.2.1 Recording and follow-up of AE and/or SAE ................................................................................... 68 
10.3.3 
Reporting of SAEs.......................................................................................................................... 72 
10.3.4 
Management of Acute Reactions ................................................................................................... 73 
10.3.4.1 Acute Intravenous Infusion Reactions ........................................................................................... 73 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 74 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 76 
10.6 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 76 
10.7 
APPENDIX 9: ABBREVIATIONS ................................................................................................... 76 
10.8 
APPENDIX 10: PROTOCOL AMENDMENT HISTORY ................................................................ 78 
10.8.1 
Amended protocol [01] (26 March 2020) ....................................................................................... 78 
10.8.2 
Amended protocol [02] (08 April 2020) .......................................................................................... 80 
10.8.3 
Amended protocol [03] (29 April 2020) .......................................................................................... 82 
11 
REFERENCES ............................................................................................................................... 84 
 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 8 
LIST OF TABLES  
Table 1 - Objectives ....................................................................................................................................... 24 
Table 2 - Endpoints ....................................................................................................................................... 25 
Table 3 - Overview of study interventions administered ............................................................................... 35 
Table 4 - The NEWS2 Scoring System ......................................................................................................... 43 
Table 5 - Body temperature assessment ...................................................................................................... 44 
Table 6 - Summary of handling procedures for samples for sarilumab and sample for anti-sarilumab 
antibody ......................................................................................................................................................... 49 
Table 7 - Summary of bioanalytical method for sarilumab ............................................................................ 50 
Table 8 - List of pharmacokinetic parameters and definitions ....................................................................... 50 
Table 9 - Summary of handling procedures for sIL-6 and IL-6 ..................................................................... 50 
Table 10 - Populations for analyses .............................................................................................................. 52 
Table 11 - Protocol-required laboratory assessments .................................................................................. 64 
Table 12 - Grading of infusion related reactions (NCI-CTCAE v3) ............................................................... 69 
Table 13 - Grading of hypersensitivity reactions (NCI-CTCAE v3) ............................................................... 69 
Table 14 - Grading of neutropenia (NCI-CTCAE v3) .................................................................................... 69 
Table 15 - Grading System for Adverse Events Not Listed in NCI-CTCAE .................................................. 70 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 15 
 
 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 9 
1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: An Adaptive Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients with 
COVID-19 
Short title: 
Sarilumab COVID-19 
Rationale: 
See Section 2.1 
Objectives and endpoints 
 
Objectives 
 
Primary 
• 
To evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with severe or 
critical COVID-19 
Secondary 
• 
Evaluate the 28-day survival rate 
• 
Evaluate the clinical efficacy of sarilumab compared to the control arm by clinical severity 
• 
Evaluate changes in the National Early Warning Score 2 (NEWS2) 
• 
Evaluate the duration of predefined symptoms and signs (if applicable) 
• 
Evaluate the duration of supplemental oxygen dependency (if applicable) 
• 
Evaluate the incidence of new mechanical ventilation use during the study 
• 
Evaluate the duration of new mechanical ventilation use during the Study 
• 
Evaluate the proportion of patients requiring rescue medication during the 28-day period  
• 
Evaluate need for admission into intensive care unit (ICU) 
• 
Evaluate duration of hospitalization (days) 
• 
The safety objectives of the study are to evaluate the safety of sarilumab through hospitalization (up to day 29 if 
patient is still hospitalized) compared to the control arm as assessed by incidence of: 
- 
Serious adverse events (SAEs) 
- 
Major or opportunistic bacterial or fungal infections in patients with grade 4 neutropenia  
- 
Grade ≥2 infusion related reactions 
- 
Grade ≥2 hypersensitivity reactions 
- 
Increase in alanine transaminase (ALT) ≥3X ULN (for patients with normal baseline) or >3X ULN AND at 
least 2-fold increase from baseline value (for patients with abnormal baseline) 
- 
Major or opportunistic bacterial or fungal infections 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 10 
Tertiary/exploratory  
• 
Evaluate the virologic changes in the treatment arms compared to the control arm as assessed by 
nasopharyngeal (NP) and blood quantitative SARS-CoV-2 counts 
• 
To evaluate the cytokine profile and additional biomarkers that may be associated with efficacy and safety 
associated with sarilumab treatment 
• 
To evaluate the incidence of new or worsening laboratory-confirmed serious secondary infections in the treatment 
arms as compared to the control arm 
• 
To characterize the concentrations of sarilumab in serum over time 
• 
Patients will not be recalled after discharge for any missing exploratory assessments. 
Overall design: 
This study is an adaptive, multi-national, multi-center, phase 3, randomized, double-blind, 
placebo-controlled trial to evaluate the efficacy and safety of sarilumab in hospitalized adults with 
severe or critical COVID-19. Patients were randomized in a 2:2:1 ratio to sarilumab 400 mg 
intravenous (IV), 200 mg IV, or matching placebo IV in a stratified manner prior to Amended 
Protocol 04. The sarilumab 200 mg IV dose arm will be closed for patients enrolled after 
Amended Protocol 04 is implemented.   
Patients will receive a single dose of study drug on Day 1.  Patients may receive a second dose 
with study drug (based on the original treatment group assigned) 24 to 48 hours after the first 
dose, if they meet prespecified criteria (see Section 4.1). Randomization will be stratified by 
severity of illness (severe OR critical) and use of systemic corticosteroids (Yes OR No). 
Study duration: An individual patient will complete the study approximately 60 days from 
screening to follow-up on day 60 ±7 days. Patients will not be required to return to the hospital 
once discharged. 
End of study definition: The end of study (EOS) is defined as the date the last patient completes 
the last study assessment (in the hospital or via a follow-up phone call if the patient was 
discharged from the hospital before day 60), withdraws from the study, or is lost to follow-up (ie, 
the study patient can no longer be contacted by the investigator). 
Population: Hospitalized adult (≥ 18 years old) male and female patients with COVID-19. 
Disclosure Statement: This is a parallel group treatment study with 3 arms that is participant and 
Investigator blinded. 
Number of participants: 
Approximately 400 patients randomized and treated with study medication.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 11 
Intervention groups and duration: 
Study intervention(s) 
Participants who satisfy the inclusion and exclusion criteria will be randomized (2:2:1) to one of 
the following IMP treatment groups: 
• 
Sarilumab 400 mg IV 
• 
Sarilumab 200 mg IV  
• 
Matching placebo IV 
Investigational medicinal product(s) 
• 
Formulation: a 175 mg/ml sarilumab solution in a pre-filled syringe to deliver 200 mg in a 
1.14 ml solution 
• 
Route of administration: intravenous (IV) 
• 
Dose regimen: 
- 
One infusion of sarilumab 400 mg IV, (two sarilumab 200 mg, single dose prefilled 
syringes (PFS), mixed in
 0.9% sodium chloride solution for IV use) 
- 
One infusion of sarilumab 200 mg IV, (one sarilumab, single dose PFS, mixed in 
 0.9% sodium chloride solution for IV use)  
- 
One infusion of matching placebo 
 0.9% sodium chloride solution for IV use). 
For each treatment group, patients will receive a single dose of study drug on Day 1. 
Patients may receive a second dose with study drug (based on the original treatment group 
assigned) 24 to 48 hours after the first dose, if they meet prespecified criteria (see  
Section 4.1).  
Statistical considerations: 
Primary endpoint: 
The primary endpoint is the time to improvement of 2 points in clinical status assessment from 
baseline using the 7-point ordinal scale.  
The 7-point ordinal scale is an assessment of the clinical status. The scale is as follows: 
1. Death; 
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO); 
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 12 
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care 
7. Not hospitalized  
 
Secondary endpoints: 
Key secondary endpoint: 
• 
Percent of patients alive at Day 29 
The other secondary efficacy endpoints are: 
• 
Proportion of patients with one point improvement from baseline in clinical status 
assessment at days 4, 7, 15, 21, 29 using the 7-point ordinal scale 
• 
Mean change in the 7-point ordinal scale from baseline to days 4, 7, 15, 21, 29 (or until 
discharge) 
• 
Time to resolution of fever defined as body temperature (≤36.6°C [axilla], or ≤37.2°C 
[oral], or ≤37.8°C [rectal or tympanic]) for at least 48 hours without antipyretics or until 
discharge, whichever is sooner,  
• 
Time to resolution of fever (as defined above) and improvement in oxygenation (as 
defined below)  
• 
Days with fever (>37.4°C [axilla], or >38.0°C [oral], or >38.4°C [rectal or tympanic]) 
based on maximum value observed during a 24-hour period  
• 
Time to change in National Early Warning Score 2 (NEWS2) from baseline 
• 
Time to NEWS2 of <2 and maintained for 24 hours 
• 
Mean change from baseline to days 4, 7, 15, 21, 29 in NEWS2 
• 
Time-to-improvement in oxygenation ([SpO2]/[FiO2] of 50 or greater) compared to the 
nadir for at least 48 hours, or until discharge, whichever is sooner 
• 
Alive off supplemental oxygen at day 29 
• 
Days of hypoxemia (SpO2 <93% on room air, or requiring supplemental oxygen, or 
mechanical ventilatory support)  
• 
Days of supplemental oxygen use  
• 
Days of resting respiratory rate >24 breaths/min (maximum value if recorded at more than 
once a day)  
• 
Time to oxygen saturation ≥94% on room air  
• 
Ventilator free days in the first 28 days (to day 29) 
• 
Initiation of mechanical ventilation, non-invasive ventilation, or use of high flow nasal 
cannula (for those not requiring these interventions at baseline)  
• 
Proportion of patients requiring rescue medication during the 28-day period 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 13 
• 
ICU status (among those not in an ICU at baseline, record if transferred to the ICU or the 
need to transfer to the ICU [if the ICU is not available])  
• 
Days of hospitalization among survivors 
 
Safety 
The secondary safety endpoints are: 
• 
Incidence of serious adverse events 
• 
The incidence of major or opportunistic bacterial or fungal infections 
• 
The incidence of major or opportunistic bacterial or fungal infections in patients with 
grade 4 neutropenia 
• 
The incidence of hypersensitivity reactions, infusion reactions, gastrointestinal perforation 
• 
White blood cell count, hemoglobin, platelets, creatinine, total bilirubin, alanine 
aminotransferase (ALT) on days 1, 4, 7, 15, 21, 29 (if still hospitalized) 
Procedures and assessments 
Efficacy procedures and assessments include clinical data collection, body temperature, oxygen 
delivery and oxygenation, resting SpO2, and National Early Warning Score2. 
Safety procedures and assessments include laboratory testing, vital signs, targeted physical 
examination, and concomitant medication review. 
Statistical plan 
Assuming that accrual duration is 3 months (~90 days) with each patient followed for a period of 
at least 29 days, the proportions of patients with two points improvement from baseline in clinical 
status assessment at day 15 are 45% and 70% for placebo and sarilumab, respectively, a total 
sample size of approximately 400 patients with a 2:2:1 randomization ratio provides at least 90% 
power for pairwise comparisons between each sarilumab dose (400 mg IV or 200 mg IV; n~160 
each) and placebo (n~80), using a log-rank test for superiority at a two-sided significance level of 
0.05. Sample size calculation was performed using PASS 14.  
The primary analysis is planned when the last patient randomized reaches Day 29 (or planned 
Day 29 if the patient is discharged or leaves the study early). Final analysis will be performed at 
study end at Day 60.  
The primary endpoint, which is the time to improvement of 2 points in clinical status assessment 
from baseline using the 7-point ordinal scale, will be analyzed using a log-rank test stratified by 
randomization stratum with treatment as a fixed factor in the mITT population. P-value for the 
pairwise treatment comparison versus placebo will be provided. Estimation of treatment effect of 
each sarilumab dose will be provided as hazard ratio (sarilumab versus placebo) using Cox 
proportional hazards model stratified by the randomization stratum with treatment as a covariate, 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 14 
along with 2-sided confidence intervals. Kaplan-Meier (KM) plot and the median time-to- 
improvement of 2 points will also be provided.   
The key secondary endpoint, which is percent of patients alive at Day 29, will be analyzed using a 
Cochran-Mantel-Haenszel (CMH) test stratified by randomization stratum in the mITT 
population. Estimation of treatment effect of each sarilumab dose will be reported as difference in 
proportion of patients alive at Day 29 (sarilumab - placebo), along with 95% confidence levels. 
P-value for the pairwise treatment comparison versus placebo will be provided. 
For the primary and key secondary endpoints, multiplicity will be controlled via a hierarchical 
testing procedure in the following order:  
 
1. Primary endpoint sarilumab 400 mg versus placebo 
2. Key secondary endpoint sarilumab 400 mg versus placebo 
3. Primary endpoint sarilumab 200 mg versus placebo 
4. Key secondary endpoint sarilumab 200 mg versus placebo 
If one sarilumab dose is discontinued for safety reasons, then all comparisons versus placebo for 
that dose will be removed and the remaining comparisons will be tested in the order specified 
above.  
An interim analysis is planned to be performed when approximately 50% of total planned number 
of patients (~200) are randomized. The purpose of the interim analyses is to obtain an 
understanding of the possible drug effect in the population under study. An administrative alpha 
of 0.001 will be spent at interim analysis (1). 
The interim analyses will be performed by an external statistical analysis center and are separated 
from personnel involved in the trial conduct. The unblinded results can only be viewed by a small 
group of senior sponsor individuals, who are separate from sponsor personnel involved in the 
conduct of the study. People involved in the conduct of the study (Patients, Investigators, Study 
Team, and Project Team) will have no access to the interim analysis results. 
Independent Data Monitoring Committee: Yes 
An independent data monitoring committee (IDMC) is established to oversee the welfare of 
patients in the study and to monitor all data to make recommendations to continue the study, to 
modify the protocol, or to terminate the study. The IDMC members include 2 to 4 independent 
expert physicians with relevant medical specialist training and 1 statistician.
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 15 
1.2 
SCHEMA  
Figure 1 - Graphical study design  
  
VV-CLIN-0579585 4.0






Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 18 
ESO: end of study, SpO2: oxygen saturation, CT-scan: computed tomography ECG: electrocardiogram, WOCBP: women of childbearing 
potential, PK: pharmacokinetic, ADA: antidrug antibodies, sIL-6R: soluble interleukin 6 receptor, Il: interleukin, PCR: polymerase chain 
reaction, SARS-Cov-2: Severe acute respiratory syndrome coronavirus 2, DNA: deoxyribonucleic acid, RNA: ribonucleic acid, 
SAE: serious adverse event, AESI: adverse event of special interest. 
1. Laboratory-confirmed SARS-CoV-2 infection (eg by PCR), or other commercial or public health assay in any specimen within  
2 weeks prior to randomization and no alternative explanation for current clinical condition is required for inclusion. 
2. Screening and baseline may occur within 24 hours. Assessments that are noted for both visits should only be assessed once if 
the baseline visit is within 24 hours of the screening visit. All baseline samples, if obtained, should be collected before study 
drug administration at baseline visit except post-infusion PK and sIL-6R samples. 
3. Patients will have an end of study (EOS) assessment to collect data on survival, adverse events, and history of hospital re-
admission. This assessment may be performed by phone. This visit may be performed earlier if a patients withdraws from the 
study. 
4. Patients discharged prior to Day 29 will have a follow-up phone call on Day 29 to collect data on all adverse events, and history 
of hospital re-admission.  
5. Patients discharged prior to Day 29 should have a sample collected on or before day of discharge. Any sample collected within 
24 hours of the day of discharge do not need to be repeated. 
6. Patients may receive a second dose with study drug 24 to 48 hours after the first dose, if the patient meets prespecified criteria 
in Section 4.1. Day 2 or 3 samples are only taken from patients who are administered a second dose of study treatment. They 
should be drawn prior to administration of the second dose of study drug to aid in benefit/risk assessment. 
7. Sites are required to capture the history of chronic hypercapnic respiratory failure.  
8. Body temperature is described in Section 8.1.2 (up to 4 times a day at screening). Retrospective temperature within the previous 
24 hours can be considered for screening. Body temperature to be reported in the CRF should be the maximum value observed 
during any time period or window (Section 8.1.2). 
9. Oxygen delivery and oxygenation: refer to Section 8.1.2 of the protocol for details (up to 4 times a day at screening). 
Retrospective readings within the previous 24 hours can be considered for screening.  
10. Must be measured after 5 minutes of rest (sitting or supine), and must be measured simultaneously with oxygen delivery and 
ventilation data. 
11. Clinical Data Assessments (including 7-point ordinal scale, status of intubation, Intensive care unit admission/discharge, CT 
scan, X-rays, and any other imaging performed during hospitalization, daily consciousness for NEWS2 scoring system [2]): refer 
to Section 8.1.1 of the protocol for details. 
12. Results as reported to be recorded in arterial blood gas results electronic case report form (CRF) (as available). 
13. Vital signs include height (screening only), weight (screening only), blood pressure, pulse, and respiration rate, See  
Section 8.2.1 
14. The ECG is optional. Historical ECG from current hospital admission is acceptable. 
15. Concomitant therapy: refer to Section 6.5 of the protocol for details.  
16. Adverse events: All AEs will be recorded in CRF. Note: any abnormal physical findings requiring medical or surgical intervention 
must be recorded as an AE. 
17. Pregnancy testing to be performed locally in women of childbearing potential (WOCBP) only. Serum or urine pregnancy test are 
both acceptable. 
18. Hematology: refer to Table 11  for details.   
19. Blood Chemistry: refer to Table 11 for details.  
20. Urinalysis is performed at screening (if feasible) and should be collected one additional time (optional) during the treatment 
period. 
21. SARS-COV-2 detection will be performed locally. This test is optional. 
22. Sarilumab concentration  
• Day 1 sampling: 2 samples with one taken pre dose, and 1 taken within 30 min after the end of infusion; end of infusion 
sample should be collected from the arm contralateral to that used for IV infusion 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 19 
• For patients administered a 2nd dose, Day 2 or Day 3 sampling is performed with 2 samples taken on the day of the 2nd 
dose, with 1 taken pre dose, and 1 taken within 30 min after the end of infusion; end of infusion sample should be collected 
from the arm contralateral to that used for IV infusion 
• Day 4 (approximately 72 hours post first dose) 
• The Day 29 or Early Discharge PK sample may be used for ADA analysis 
23. In the event of any SAE of severe infusion reaction, or any AESI of anaphylactic reaction or systemic allergic reaction that is 
related to IMP, ADA samples will be collected at or near the onset of the event for any additional analysis. 
24. Serum IL-6 samples must be taken pre-dose. Samples are mandatory for baseline/Day 1, Discharge before Day 29 and Day 29. 
It is optional on Day 4, 7, 15, and 21.  
25. Serum sIL-6R: 
• Day 1 sample taken pre dose (as close to initiation of treatment as reasonable) 
26. Blood collected will be shipped for the central analysis of SARS-CoV-2 viral load and is not for determining the inclusion criteria. 
27. Separate consent is required for participation in the optional genomic sub-study and collection of a blood sample for (DNA/RNA). 
The sample for genomic DNA/RNA should be collected on Day 1 or may be collected at any visit.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 20 
2 
INTRODUCTION  
This study protocol describes an adaptive Phase 3 multi-center, randomized, placebo-controlled 
trial of sarilumab for the treatment of severe COVID-19 to assess efficacy in reducing time to 
alleviation of COVID-19 predefined symptoms and safety in administering an interleukin-6 
receptor (IL-6R) blocker during an acute viral pneumonia. 
2.1 
STUDY RATIONALE  
As there are no treatments with proven efficacy for treatment of patients with severe or critical 
COVID-19 in the current SARS-CoV-2 pandemic, investigation of novel or repurposed 
medication is clearly warranted to minimize the impact of COVID-19 on infected patients and 
society as a whole. 
Rationale for Study Design 
There are currently no approved treatments for COVID-19. With an increasing amount of people 
affected by COVID-19 worldwide, it is essential to identify safe treatments quickly. This study 
utilizes an adaptive phase 3 design aimed at gathering this efficacy data quickly while also closely 
monitoring safety for all participants. Because the optimal dose regimen of sarilumab IV is 
unknown for treatment of patients with severe or critical COVID-19, the study includes two dose 
levels. In addition, a second infusion of sarilumab 200 mg IV, sarilumab 400 mg IV, or placebo 
can be administered under the conditions specified in Section 4.1.  Enrollment to the sarilumab 
200 mg IV dose arm will be closed for patients after implementation of Amended Protocol 04 
(See Section 4.3).   
As the 2 doses of sarilumab (200 mg IV or 400 mg IV) have not been evaluated formally in a 
phase 3 clinical trial, the study will have close monitoring by the IDMC. This Phase 3 study 
utilizes a double-blind to minimize potential for bias on the part of the investigator, patient, or 
sponsor.  Whilst the double-blind is maintained the protocol allows for adaptation of the primary 
endpoint based on new or emerging information to manage the uncertainties regarding 
assessment, course and prognosis of pandemic COVID-19. 
In the absence of treatments with demonstrated efficacy, a placebo control is warranted to 
distinguish the safety and tolerability of sarilumab from the background signs and symptoms of 
COVID-19 infection as well as evaluate its potential to reduce fever, reduce oxygen requirements, 
and improve clinical outcomes. Due to the severity of COVID-19, in this study 2 patients will be 
randomized to each sarilumab arm for every 1 patient randomized to placebo in order to minimize 
the number of patients exposed to placebo. 
Because there remains uncertainty regarding appropriate choice of primary endpoint for efficacy 
trials in hospitalized patients with COVID-19, clinical status represented on a 7-point ordinal 
scale has been proposed as an endpoint with face-validity and interpretability without regard to 
the type or target of an investigational treatment.  A 7-point ordinal scale clinical assessment has 
been utilized in a randomized open-label trial of lopinavir-ritonavir in hospitalized adult patients 
with COVID-19 (3).  In this study (3) a 7-point ordinal scale with anchors similar to those 
included in the current protocol did exhibit sensitivity to change over time and results were 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 21 
reported in sufficient detail to estimate COVID-19 clinical progression over a 14 to 28-day 
observation period. 
A change in 2 points on the 7-point clinical scale included in the current protocol has face validity 
as a pragmatic measure of clinical status in hospitalized patients with COVID-19 because it is 
anchored by the intensity of the intervention needed to support respiration. 
The key secondary endpoint is percent of patients alive at Day 29, because patients with severe or 
critical COVID-19 have elevated risk of non-survival related to conditions not captured in the 
primary endpoint (eg, myocardial infarction, acute kidney injury, coagulopathy, or secondary 
infection). 
2.2 
BACKGROUND  
Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2), a protein-enveloped RNA virus (4) related to severe acute respiratory syndrome 
coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-
CoV)(5). COVID-19 presents with influenza-like symptoms (fever, cough, dyspnea, nausea, 
vomiting, diarrhea) and radiographic features of diffuse pneumonia (5, 6, 7, 8, 9), with more 
severe cases characterized by neutrophilia, lymphopenia, thrombocytopenia, elevations in acute 
phase reactants and inflammatory cytokines (8), including IL-6 (9). Over 25% of patients develop 
acute respiratory distress during the second week of hospitalization (7). Acute, life-threatening 
respiratory injury induced by coronavirus infection is associated with an over-exuberant cytokine 
release (also known as “cytokine storm”) (10, 11). Case series of patients afflicted with SARS-
Cov and MERS-Cov pneumonia indicate that elevations in IL-6 and other pro-inflammatory 
cytokines are correlated with clinical and radiographic severity (12, 13) and that in SARS-Cov 
pneumonia, peak viral load precedes peak IL-6 concentration and subsequent peak radiographic 
severity (14). As of 14 March 2020, there are many efforts to develop vaccines, anti-virals, and 
therapeutics against COVID-19, but none have yet demonstrated meaningful efficacy. 
Clinical management of hospitalized patients with COVID-19 includes supportive therapy: 
supplemental oxygen therapy to target SpO2, empiric antimicrobials, empiric neuraminidase 
inhibitor for treatment of influenza when there is local circulation, and intensive care as required 
(WHO, 2020) (15).  
Both SARS-CoV-2 (16, 17) and SARS-CoV (18) exploit angiotensin converting enzyme II 
(ACE2) to infect pulmonary and intestinal epithelial cells (18, 19, 20) and activate NF-kappa B 
upregulation of proinflammatory cytokines such as IL-6 (21, 22). SARS-CoV infected pulmonary 
epithelial cells, pneumocytes, and macrophages (Mφ) produce elevated levels of IL-6, MCP-1, 
TGF-β1, and other proinflammatory cytokines and chemokines (23).  
SARS-CoV infected human bronchial epithelial cells secrete IL-6, IL-8, and gamma interferon 
(IFN-γ)-inducible protein 10 (IP-10) which stimulates monocyte-derived Mφ and dendritic cells 
(DC) to also produce, IL-6, IL-8, IL-1β, G-CSF, MIP-1α/β, and TNF-α.  These cytokines from 
SARS-Cov-infected pulmonary epithelial cells interfere with receptor-mediated endocytosis and 
DC priming of T cells. In vitro anti-IL-6 or anti-IL-8 antibodies restored DC capacity to prime T 
cells inhibited by cytokines produced by SARS-Cov-infected pulmonary epithelial cells (24). 
Excessive pulmonary and systemic cytokine release, sustained, in part by IL-6 signaling, 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 22 
potentially results in infiltration of activated neutrophils into the alveolar space, followed by a 
fibroproliferative phase characterized by findings of alveolar hyaline membranes, with varying 
degrees of interstitial fibrosis, and eventual resolution (25, 26, 27). 
These findings related to SARS-CoV support the possibility that systemic inhibition of IL-6 
signaling can be used to therapeutic advantage when treating COVID-19. 
In the setting of infection, IL-6 is an important mediator of fever induction (28). The pyrogenic 
role of IL-6 was delineated in patients receiving T cell based-immunotherapy (specifically, 
chimeric antigen receptor-expressing T cells or a CD19/CD3-bispecific antibody) where treatment 
with the IL-6 receptor antagonist, tocilizumab, quickly reversed the high fevers and other 
symptoms that developed as part of a cytokine release syndrome (CRS) over several days (29). 
During the current COVID-19 outbreak, tocilizumab has been used in 21 patients with severe 
COVID-19 infection and described in a retrospective study (30). All patients had fever prior to 
treatment, baseline mean CRP was 75±66.80, and mean IL-6 level was 132±278 pg/mL. One day 
after treatment with tocilizumab all patients had normal body temperature. Before treatment, 20 of 
21 patients required oxygen therapy. After tocilizumab 15 (75%) lowered oxygen intake after 
treatment and by Day 3 all patients had SpO2 >94%, including 1 patient who was breathing 
without supplemental oxygen. 
While evidence of efficacy of tocilizumab in COVID-19 remains unproven, early reports 
suggested that systemic inhibition of IL6 signaling may have value as a supportive therapy. 
Sarilumab (KEVZARA®) is a recombinant human IgG1 kappa monoclonal antibody (mAb) 
directed against soluble and membrane-bound IL-6 receptor (IL-6Rα). Sarilumab, formulated as a 
solution for subcutaneous (SC) injection at doses of 150 and 200 mg every 2 weeks (q2w), was 
first approved for the treatment of adult patients with rheumatoid arthritis (RA) in Canada on 
12 January 2017, the United States (US) on 22 May 2017, the European Union (EU), Norway, 
Iceland, and Liechtenstein on 23 June 2017, and Japan on 27 September 2017. Sarilumab is 
currently approved for the treatment of moderate to severe RA in multiple countries across the 
globe. Sarilumab inhibition of  IL-6 signaling leads to a decrease in concentration of free sIL-6Rα 
and normalization of levels of acute phase proteins and markers of inflammation, such as 
C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen (31). Because sarilumab 
inhibits both soluble and membrane bound forms of IL-6Rα, thereby suppressing pro-
inflammatory signaling by both pulmonary epithelial and immune cells, it has the potential to 
reduce the severity of pulmonary COVID-19 complications, including respiratory failure. There is 
no evidence that sarilumab has anti-viral potential. 
2.3 
BENEFIT/RISK ASSESSMENT  
For patients with RA, sarilumab 150 mg and 200 mg every 2 weeks by SC injection has 
demonstrated clinically meaningful reductions of inflammatory joint swelling and tenderness of 
RA, improvements in physical function, and reduced progression of joint damage as measured by 
radiography. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 23 
However, in clinical trials of patients with RA sarilumab was associated with an increased risk of 
infections, including serious infections. As with other immunomodulatory therapies for RA, 
serious and sometimes fatal infections have been reported on sarilumab. 
For this study it is proposed to administer sarilumab IV to patients with a confirmed viral 
pneumonia for which no antiviral therapy has demonstrated effectiveness. However, the potential 
benefit of sarilumab for patients with COVID-19 is suppression of the cytokine storm which may 
be a more important and long-lasting contributor to lung damage than the viral infection itself. 
One of the features of coronavirus pneumonia is a local and systemic increase in activated 
neutrophils which function to eliminate the viral infection but also inflict collateral damage to the 
pulmonary epithelium (26). In this context the dose-related reduction of absolute neutrophil count 
(ANC) associated with IL-6rα inhibition may help to mitigate the coronavirus-induced 
neutrophilia. 
Uncertainties associated with this study include the route of administration, IV, and the sarilumab 
400 mg dose; both intended to increase Cmax and decrease tmax compared to SC route. Given that 
changes in ANC of antibody-mediated sIL-6Rα are dose-dependent, irrespective of route of 
administration, it is anticipated that sarilumab delivered IV will rapidly suppress ANC. Based on 
analyses of 7985.5 patient-years of sarilumab exposure collected over 7.3 years from 3358 clinical 
trial patients with RA, the incidence of infection and serious infection did not increase with 
increasing severity of neutropenia. ANC values on sarilumab were normal for the majority of 
infections occurring within 12 weeks after sample collection (3452/3943 [88%] and 370/434 
[85%] of patients reporting infections from patients treated with sarilumab plus conventional anti-
rheumatic disease-modifying drug and sarilumab monotherapy, respectively. Both observations 
support the consistent finding that low ANC is not associated with an increased rate of infection 
for patients treated with sarilumab. 
To mitigate the uncertainty around safety and tolerability of sarilumab IV, review of safety data 
by an independent data monitoring committee (IDMC) after the dosing of the first 12 patients will 
be required. 
Although risks of treatment with sarilumab are established and benefits for patients with 
COVID-19 are potential, the absence of effective treatments of COVID-19 complications 
associated with excessive cytokine release during this ongoing pandemic, investigations such as 
this study are warranted. 
A recently published retrospective cohort study (n=191) of hospitalized patients with COVID-19 
reports that patients with multi-organ dysfunction (MOD), as quantified using the Sequential 
Organ Failure Assessment (SOFA) score have a 5.65 odds ratio for non-survival (16). Because the 
potential benefit is marginal relative to the burden of study-related procedures and established 
risks of sarilumab, patients with multi-organ dysfunction, along with patients who, in the opinion 
of the investigator are unlikely to survive after 48 hours will not be included in the study. 
A risk-benefit statement with respect to the overall development program is provided in the IB 
and associated addendum. 
VV-CLIN-0579585 4.0






Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 26 
• 
ICU status (among those not in an ICU at baseline, record if transferred to the ICU or the need to transfer to the 
ICU [if the ICU is not available]) 
• 
Days of hospitalization among survivors 
Secondary Endpoints (Safety) 
The safety endpoints are: 
• 
Incidence of serious adverse events 
• 
The incidence of major or opportunistic bacterial or fungal infections 
• 
The incidence of major or opportunistic bacterial or fungal infections in patients with grade 4 neutropenia 
• 
The incidence of hypersensitivity reactions, infusion reactions, gastrointestinal perforation 
• 
White cell count, hemoglobin, platelets, creatinine, total bilirubin, ALT on days 1, 4, 7, 15, 21, 29 (if still 
hospitalized) 
Tertiary/exploratory  
• 
Evaluate the virologic changes in the treatment arms compared to the control arm as assessed by: 
- 
Percent of patients with SARS-CoV-2 detectable in nasopharyngeal (NP) sample at days 7, 15, 21, and 29 
- 
Quantitative SARS-CoV-2 virus in the NP sample at days 7, 15, 21, and 29 
- 
Development of SARS-CoV-2 variants in NP sample at day 7, 15, 21, and 29 
- 
Quantitative SARS-CoV-2 virus in blood at days 7, 15, 21, and 29 
• 
To evaluate the cytokine profile and additional biomarkers that may be associated with efficacy and safety 
associated with sarilumab treatment 
• 
To evaluate the incidence of new or worsening laboratory-confirmed serious secondary infections in the treatment 
arms as compared to the control arm 
• 
To characterize the concentrations of sarilumab in serum over time 
• 
Patients will not be recalled after discharge for any missing exploratory assessments. 
 
 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 27 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This study is an adaptive phase 3, randomized, double-blind, placebo-controlled trial to evaluate 
the efficacy and safety of sarilumab in hospitalized adults with severe or critical COVID-19. The 
study will be conducted in Europe and other countries except in the United States (US) in up to 
100 sites. 
Patients will be randomized in a 2:2:1 allocation ratio to sarilumab 400 mg IV, sarilumab 200 mg 
IV, or placebo.  The sarilumab 200 mg IV dose arm will be closed for patients enrolled after 
Amended Protocol 04 is implemented. Patients enrolled after implementation of Amended 
Protocol 04 will be randomized in a 2:1 allocation ratio to sarilumab 400 mg IV or placebo 
(Section 4.3). All patients will receive a single dose of study drug on Day 1. Patients may receive 
a second dose with study drug (based on the original treatment group assigned) 24 to 48 hours 
after the first dose, if  
 
1. The Benefit Risk assessment by the investigator favors the administration of another dose 
of study drug without compromising safety (e.g., increase in LFTs, neutropenia)  
 
AND 
 
2. And least one of the following criteria is met: 
- 
Increase in fever or recurrence of fever compared to Day 1 OR 
- 
Increase or no change in FiO2 requirement compared to Day 1 OR 
- 
Requiring vasopressors, ECMO, or development of multi-organ dysfunction  
The safety data from approximately the first 12 patients randomized (assuming a total of ~10 
patients are dosed on the sarilumab doses of 200 mg IV or 400 mg IV) will be reviewed by an 
independent data monitoring committee (IDMC) after the last of these patients dosed reaches 
Day 7. Data on approximately the first 12 and 50 patients (regardless of severity of illness) with at 
least 7-days follow-up will be reviewed by the IDMC to determine if the study can continue with 
or without modification. Subsequently, the frequency of IDMC meetings will be determined 
following the first 2 IDMC meetings. In addition to these specific assessment times, the IDMC 
will actively monitor interim data to make recommendations about early study closure, changes to 
study arms, and/or the eligible patient population throughout the course of the study.  
Patients will be assessed daily while hospitalized. Discharged patients will be contacted by 
telephone on Day 29 to assess status and occurrence of re-admission to a hospital. Patients will 
undergo a series of efficacy, safety and laboratory assessments while in the hospital. Serum IL-6 
and other markers will be collected and analyzed in a central laboratory. Nasopharyngeal (NP) 
samples to monitor viral infection and blood samples will be requested on day 1 (pre-dose), 4, 7, 
15, 29 (or up until the day of discharge if the patient is discharged from the hospital before 
day 29). 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 28 
Randomization will be stratified by: 
• 
Severity of illness  
- 
Severe disease 
- 
Critical disease 
• 
Systemic corticosteroids (Yes/No) 
The severity categories are: 
• 
Severe disease: 
- 
Requires supplemental oxygen administration by nasal cannula, simple face mask, or 
other similar oxygen delivery device 
• 
Critical disease: 
- 
Requires supplemental oxygen requiring delivered by non-rebreather mask or high-
flow nasal cannula  
- 
OR Use of invasive or non-invasive ventilation, 
- 
OR Requiring treatment in an intensive care unit. 
Note: Participants meeting criteria for both severity categories will be stratified according to the 
more severe category. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Rationale for Study Design 
This Phase 3 study utilizes a double-blind to minimize potential for bias on the part of the 
investigator, patient, or sponsor.  Whilst the double-blind is maintained the protocol allows for 
adaptation of the primary endpoint based on new or emerging information to manage the 
uncertainties regarding assessment, course and prognosis of pandemic COVID-19. 
Because of the novelty of the SARS-CoV-2 pathogen, the ease with which it spreads within a 
community, the current absence of effective anti-viral therapies or vaccines, and still evolving 
knowledge regarding course of disease and risk factors for progression, there is no criterion of 
efficacy validated by health authorities to support authorization for use.  An adaptive design is 
necessary to accommodate these multiple uncertainties during this global health crisis to make 
most efficient use of valuable participant data and investigator resources in the context of an 
ongoing pandemic while maintaining the rigor of a double-blind placebo-controlled comparison. 
In the absence of treatments with demonstrated efficacy, a placebo control is warranted to 
distinguish the safety and tolerability of sarilumab from the background signs and symptoms of 
COVID-19 infection as well as evaluate its potential to reduce fever, reduce oxygen requirements, 
and improve clinical outcomes.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 29 
4.2.1 Participant input into study design  
Due to the urgency of the SARS-CoV-2 pandemic potential participants have not been involved in 
the design of this clinical trial.  
4.3 
JUSTIFICATION FOR DOSE  
Rationale for dose selection 
The sarilumab IV doses of 200 mg and 400 mg for this study are based similar pharmacokinetic 
(PK), pharmacodynamic (PD), and safety profiles between sarilumab and tocilizumab and the 
dose of tocilizumab 400 mg IV included in (32) mentioned in Xinhua press release dated 
7 March 2020 (32) based on a case series of 20 patients treated in China (30). The PK, PD and 
safety of sarilumab and tocilizumab were compared in several randomized trials. In a single-dose, 
open-label randomized trial the PK and PD were assessed in patients with RA randomized 1:1:1:1 
to either 150 mg or 200 mg (SC) of sarilumab, or 4 mg/kg or 8 mg/kg (IV) of tocilizumab. In a 
single dose PK/PD study, 150 mg of sarilumab (SC) was compared to 162 mg of tocilizumab (SC) 
in Japanese patients with RA randomized 1:1 (33). In these single dose studies, consistent with 
saturation of the target-mediated pathway for sarilumab and tocilizumab, all dose levels regardless 
of the route of administration demonstrated similar maximal effect in suppression in CRP and 
ANC lowering. Higher dose levels and the associated higher concentrations beyond that need to 
achieve saturation, resulted in a longer duration of the maximal PD response, but did not result in 
a deeper response. Subcutaneous single doses of sarilumab (150 mg) or tocilizumab (162 mg) 
resulted in similar concentration time profiles and yielded nearly identical PD response in CRP 
and ANC, as well as changes in sIL-6R and IL-6 over time (34). Although PK/PD modeling 
suggested that the higher binding affinity to IL-6Rα of sarilumab compared to tocilizumab 
translates to greater receptor occupancy (35), there is currently no detailed information available 
on sIL-6Rα concentrations in patients with COVID-19. It is possible (perhaps probable) that peak 
concentrations of sIL-6Rα in patients with COVID-19 may greatly exceed what has been 
measured in patients with RA; therefore, dose-finding above exposures yielded by SC of 
sarilumab are needed given the urgency to identify useful therapeutics for COVID-19. 
Because the optimal dose regimen of sarilumab IV is unknown for treatment of patients with 
severe or critical COVID-19, the study includes two dose levels.  In addition, a second infusion of 
sarilumab 200 mg IV, sarilumab 400 mg IV, or placebo can be administered under the conditions 
specified in Section 4.1.  
Senior management, who are separate from the blinded team involved in study management and 
are not involved in any study related activities, reviewed a pre-specified, one time, unblinded 
interim analysis report (Section 9.5). Subsequent to this review, a scheduled IDMC reviewed 
additional unblinded data that is not available to this senior management team (Section 9.6). Both 
groups suggested to stop enrollment in the 200 mg arm. Thus, based on anticipation of a more 
favorable benefit-risk profile in the 400 mg arm versus the 200 mg arm, enrollment in the 200 mg 
arm will be closed upon implementation of amended protocol 04. The ratio of 2:1 will continue to 
be maintained for sarilumab 400 mg IV versus placebo after Amended Protocol 04 is 
implemented. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 30 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities. 
The end of study is defined as the date the last patient completes the last study assessment (in the 
hospital or via a follow-up phone call if the patient was discharged from the hospital before day 
60), withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be 
contacted by the investigator). 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 31 
5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be ≥18 years of age inclusive, at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Hospitalized for less than or equal to 7 days (or documentation of a plan to admit to the 
hospital if the patient is in an emergency department) with illness of any duration with 
evidence of pneumonia by chest radiograph, chest computed tomography or chest 
auscultation (rales, crackles)  
AND meets at least one of the following prior to randomization (patients meeting more 
than one criterion will be categorized in the most severely affected category). 
Participants who are with a: 
• 
Severe disease: 
Requires supplemental oxygen administration by nasal cannula, simple face mask, or 
other similar oxygen delivery device (ie. increase in oxygen requirement following 
COVID infection).  
• 
Critical disease: 
- 
Requires supplemental oxygen delivered by non-rebreather mask or high-flow 
nasal cannula 
OR 
- 
Use of invasive or non-invasive ventilation 
OR 
- 
Requiring treatment in an intensive care unit. 
I 03. Laboratory-confirmed SARS-CoV-2 infection (eg, by PCR), or other commercial or public 
health assay in any specimen within 2 weeks prior to randomization and no alternative 
explanation for current clinical condition. 
I 04. Willing and/or able to comply with study-related procedures/assessments 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 32 
Sex 
I 05. Male and/or female 
Contraceptive use by men or women should be consistent with the prescribing information 
for Kevzara and with local regulations regarding the methods of contraception for those 
participating in clinical studies. 
Informed Consent 
I 06. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of 
the protocol which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol.  
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions and prior/concomitant therapy 
E 01. In the opinion of the investigator, unlikely to survive after 48 hours, or unlikely to remain 
at the investigational site beyond 48 hours.  
Note: Multi-organ dysfunction patients (defined as dysfunction of 2 or more organ 
systems) and patients requiring extracorporeal life support or renal replacement therapy are 
excluded.  
E 02. Presence of any of the following abnormal laboratory values at screening: absolute 
neutrophil count (ANC) less than 2000/mm3, AST or ALT greater than 5 x ULN, platelets 
<50,000 per mm3. 
E 03. Any prior (within the defined periods below) or concurrent use of immunosuppressive 
therapies at screening including but not limited to the following:  
• 
Anti-IL-6, anti-IL-6R antagonists or with Janus kinase inhibitors (JAKi) in the past 
30 days or plans to receive during the study period (other than interventional drug). 
• 
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 or 
methotrexate within 4 weeks of baseline.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 33 
• 
Intravenous immunoglobulin (IVIG) within the past 5 months or plans to receive during 
the study period 
Please consult sponsor if the patient has taken any other immunosuppressant therapy not 
described above within 6 months of screening.  
E 04. Use of systemic chronic (e.g. oral) corticosteroids for a non-COVID-19-related condition 
in a dose higher than prednisone 10 mg or equivalent per day at screening. 
E 05. Exclusion criteria related to tuberculosis (TB) 
• 
Known active TB or a history of incompletely treated TB 
• 
Suspected or known extrapulmonary tuberculosis 
E 06. Patients with suspected or known active systemic bacterial or fungal infections within 
4 weeks of screening. 
Prior/concurrent clinical study experience 
E 07. Participation in any clinical research study, including any double-blind study, evaluating 
an investigational product or therapy within 3 months and less than 5 half-lives of 
investigational product prior to the screening visit. 
Note: The use of unblinded investigational medications for the treatment of COVID-19 is 
permitted unless these medications are otherwise prohibited in the protocol.  
Other exclusions 
E 08. Patient who withdraws consent during the screening period (following signing of the 
informed consent form). 
E 09. Any physical examination findings and/or history of any illness that, in the opinion of the 
study investigator, might confound the results of the study or pose an additional risk to the 
patient by their participation in the study. 
E 10. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 11. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 12. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals (in 
conjunction with section 1.61 of the ICH-GCP Ordinance E6). 
E 13. Any specific situation during study implementation/course that may rise ethics 
considerations. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 34 
E 14. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
5.3 
LIFESTYLE CONSIDERATIONS  
No restrictions are required. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
reasons, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a different participant number. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 35 
6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTIONS ADMINISTERED  
Table 3 - Overview of study interventions administered  
ARM name 
Sarilumab 200* 
Sarilumab 400 
Placebo 
Intervention name 
Sarilumab 
Sarilumab 
Placebo 
Type  
Drug 
Drug 
Drug 
Dose formulation 
One single-dose pre-filled 
syringe containing 200 mg 
sarilumab in 1.14 ml solution 
(175 mg/ml) added to 
 
0.9% sodium chloride for a 
1-hour intravenous infusion. 
Instructions on dose 
preparation are provided in the 
pharmacy manual. 
Two single-dose pre-filled 
syringes, each containing 
200 mg sarilumab in 1.14 ml 
solution (175 mg/ml) added 
to 
 0.9% sodium 
chloride for a 1-hour 
intravenous infusion. 
Instructions on dose 
preparation are provided in 
the pharmacy manual. 
 0.9% sodium 
chloride for a 1-hour 
intravenous infusion. 
Instructions on 
preparation are provided 
in the pharmacy manual. 
Unit dose strength(s) 
200 mg 
400 mg 
 
Dosage level(s) 
1 injection 
1 injection 
1 injection 
Route of 
administration 
IV injection 
IV injection 
IV injection 
Use 
experimental 
experimental 
placebo  
IMP and NIMP 
IMP  
IMP  
IMP  
Packaging and 
labeling 
Study Intervention will be 
provided in box by the 
Sponsor. Each box will contain 
2 prefilled syringes and will be 
labeled as required per country 
requirement. 
Each box will be stored at the 
site at a temperature of 2ºC to 
8ºC. 
 
Study Intervention will be 
provided in box by the 
Sponsor. Each box will 
contain 2 prefilled syringes 
and will be labeled as 
required per country 
requirement. 
Each box will be stored at 
the site at a temperature of 
2ºC to 8ºC. 
 
NA 
Tradename 
Kevzara® 
Kevzara® 
NA 
*Enrollment into the sarilumab 200 mg arm will be closed after implementation of Amended Protocol 04.  
Instructions on the ancillary supplies needed for IV injection (IV infusion bags, IV infusion sets 
and IV infusion pumps) are provided in the pharmacy manual. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 36 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
Detailed instructions are provided for the un-blinded pharmacist in the pharmacy manual. 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
RANDOMIZATION 
Randomization will occur only after patient has signed informed consent, completed screening 
procedures, and screening data has been reviewed by the investigator to assess patient eligibility. 
Randomization will be performed according to a central randomization scheme using an 
interactive response technology (IRT). 
Once the randomization procedure has been completed, the patient will be considered as 
randomized, whether or not IMP is administered. 
BLINDING 
Investigators will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. In order to maintain this blind, an otherwise uninvolved 3rd party, the 
pharmacist, will be responsible for the reconstitution and dispensation of all study interventions 
(sarilumab 400 mg, sarilumab 200 mg, or placebo). The pharmacist will endeavor to ensure that 
there are no differences in time taken to dispense following randomization. Once prepared, the 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 37 
IMP will be identical in appearance when delivered for infusion. The unblinded pharmacist will 
be responsible for documentation of treatment as per pharmacy manual. 
The study team directly involved with the study conduct will be blinded. In case of an adverse 
event, if knowledge of study drug is required for treating the patient, emergency unblinding to 
study drug can be performed. Code breaking can be performed through using the proper module 
of the IRT and/or by calling any other phone number provided by the Sponsor for that purpose. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Measures taken to ensure and document treatment compliance and IMP accountability include:  
• 
As participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. 
• 
The date and time of each dose administered will be recorded in the source documents and 
recorded in the CRF. 
• 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
6.5 
CONCOMITANT THERAPY  
Concomitant medications in a hospitalized population change daily and are difficult to collect and 
attribute to success and failure of therapy and impact on safety. Therefore, only select 
concomitant medications will be required to be captured in this trial (All other relevant 
concomitant medications are recommended to be captured as well, if feasible). The select list of 
medications that will be assessed from screening to Day 60 (or until day of discharge from 
hospital if before day 60) include:  
• 
Corticosteroids, NSAIDs, and any other anti-pyretics 
• 
Antivirals (eg. remdesivir), antifungals, antibacterials, antimycobacterials, antiprotozoans, 
antihelminthics, antimalarials (eg. chloroquine and hydroxychloroquine) 
• 
Interferon beta and convalescent serum. 
• 
Angiotensin converting enzyme and Angiotensin receptor blocking 
• 
Agents that may affect the CYP450 substrate. See CYP substrates below for further detail.   
• 
Any rescue medication that is used during the course of the study. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 38 
Information that should be gathered on these medications include: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The Sponsor can be contacted if there are any questions regarding concomitant or prior therapy. 
CYP Substrates  
Interleukin-6 has been shown to reduce cytochrome CYP1A2, CYP2C9, CYP2C19, and CYP3A4 
enzyme expression in in vitro studies. Therefore, it is expected that for a molecule that 
antagonizes cytokine activity, such as sarilumab, the formation of cytochrome P450 (CYP450) 
enzymes could be normalized, and as a result drugs that are metabolized by these CYP450 
isoforms may have decreased levels when patients start receiving sarilumab. As a precautionary 
measure, drugs which are metabolized via these cytochromes and with a narrow therapeutic index 
should be closely monitored and adjusted if needed. Some examples of CYP450 substrates with a 
narrow therapeutic index requiring monitoring of effect are warfarin; examples of substrates that 
require monitoring of drug concentration include, but are not limited to, the following: warfarin, 
CsA, theophylline, digoxin, antiepileptics, such as carbamazepine (Carbatrol®, Tegretol®), 
divalproex (Depakote®), phenytoin (Dilantin®), or valproic acid (Depakene®); or antiarrhythmics, 
such as disopyramide (Norpace®), procainamide (Procan®, Pronestyl®), or quinidine (Quinidex®, 
Quin Release Quin- G®). 
6.6 
RESCUE THERAPY  
During the course of the study, for patients requiring rescue therapy as per the judgement of the 
study physician, additional medications may be utilized. The benefit/risk of using additional 
medications in combination with study medication should be carefully considered. It is 
recommended that site-specific rescue therapy be identified and reserved for use prior to 
randomization. Administer rescue medication only 48 hours after the last infusion of study 
medication.  
Rescue medications are defined as the immunosuppressive therapies (described in the exclusion 
criteria E 03 and E 04). 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
No intervention will be provided at the end of the study. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 39 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion.  
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no 
longer in the interest of the patient to continue in the study, or if the patient’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of patients should be avoided.  
Patients who opt to withdraw from the study may be asked to provide a final blood draw sample 
for PK analysis before withdrawing from the study.   
Patients prematurely discontinued from the study will not be replaced. 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for 60 days. See Section 1.3 for data to be 
collected at the time of discontinuation of study intervention and follow-up and for any further 
evaluations that need to be completed. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Dose modification for an individual patient is not allowed.  
Study drug discontinuation does not apply for this study.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 40 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
Individual Patient Stopping Rules 
For an individual patient, infusion rate should be slowed or stopped if they have a suspected 
drug-related event of hypersensitivity (Grade 2 or higher) during the infusion. Patients who have 
an IV infusion stopped for a safety related issue will not continue with dosing nor receive a 
subsequent dose.  
Study Level Stopping Rules 
An independent data monitoring committee (IDMC) will actively monitor the ongoing safety of 
patients and can make recommendations about early study closure or changes to the conduct of 
the study. The Sponsor may decide to stop or make changes to the study based on the 
recommendations of the IDMC.  
A treatment arm may be discontinued if there is a clinically meaningful imbalance between 
treatment arms in any of the following safety criteria: 
1. Incidence of SAEs 
2. Incidence of AESIs 
3. Progression of COVID-19 to more severe, critical or multi-organ dysfunction 
4. Incidence of clinically significant recurrence of severe or critical disease after clinical 
improvement 
End of study definition 
The end of study is defined as the date the last patient completes the last study assessment (in the 
hospital or via a follow-up phone call if the patient was discharged from the hospital before day 
60), withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be 
contacted by the investigator). 
• 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
At the time of discontinuing from the study, if possible, an early EOS visit should be 
conducted. 
• 
The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent to the 
extent allowed by local regulation. 
• 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 41 
If participants no longer wish to take the intervention, they will be encouraged to remain in the 
study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate CRF forms and in 
the participant’s medical records. In the medical record, at least the date of the withdrawal and the 
reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant is discharged and cannot be reached by phone 
for the Day 60 EOS for a required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule.  
• 
Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 42 
8 
STUDY ASSESSMENTS AND PROCEDURES  
• 
Study procedures and their timing are summarized in Section 1.3. Protocol waivers or 
exemptions are not allowed. 
• 
Adherence to the study design requirements, including those specified in Section 1.3, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in Section 1.3. 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Clinical data collection  
Clinical status of patient (7-point ordinal scale) (36) is described below: 
1. Death; 
2. Hospitalized, on invasive mechanical ventilation or ECMO; 
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care 
7. Not hospitalized  
Additional clinical assessments that should be collected, if available, and performed as standard-
of-care include, but are not limited to: 
• 
Status of intubation 
• 
Intensive care unit admission/discharge 
• 
CT scan, X-rays, and any other imaging performed during hospitalization 
• 
NEWS2 scoring system (2) 
Consisting of Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), 
SpO2 Scale 2 (%), Air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), 
Consciousness, Temperature (°C). 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 43 
 Table 4 - The NEWS2 Scoring System  
 
CVPU: confusion, voice responsive, pain responsive, unresponsive. 
Note: Consciousness will be assessed as per the ACVPU scale. 
A training document and web-based educational tools to support the implementation of the 
NEWS in a variety of formats are available at http://tfinews.ocbmedia.com. This training is not 
mandatory. These include additional training modules on hypercapnic respiratory failure and the 
use of supplemental oxygen, the significance of new confusion, and the importance of the NEWS 
in the consideration of potential sepsis as a cause for acute clinical deterioration. 
Chronic hypercapnic respiratory failure will be defined as the presence of both of the following 
criteria: 
1. Documented current or historical PaCO2 > 45 mm Hg (measured from arterial blood gas 
analysis), and  
2. A clinician has documented a history of chronic hypercapnic respiratory failure in the 
medical record. 
8.1.2 Oxygen Administration and Oxygenation  
Supplemental oxygen/FiO2 use will be measured to monitor the patient’s status regarding gas 
exchange per the schedule in Section 1.3. As applicable, the following will be recorded: 
• 
Oxygen delivery device (eg, nasal cannula, simple face mask, non-rebreather mask, high 
flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, 
extracorporeal life support, etc) 
• 
Oxygen flow rate in Liters/min 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 44 
• 
FiO2 (if receiving high flow nasal cannula, non-invasive ventilation, invasive mechanical 
ventilation, or extracorporeal life support) 
If a patient is using more than one device (eg, extracorporeal life support and invasive 
ventilation), information from both devices will be recorded separately.   
Resting SpO2 will be measured to assess arterial oxyhemoglobin saturation. SpO2 will be 
measured using a fingertip or similar non-invasive device following 5 minutes of rest (inactivity) 
while supine, semi-recumbent, or sitting and will only be measured in the presence of a good 
SpO2 wave form. SpO2 must be measured simultaneously with recorded supplemental 
oxygen/FiO2 data.  
Additional data to be collected include (when available from the medical record): arterial pH, 
partial pressures of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide in arterial 
blood (PaCO2), oxyhemoglobin saturation in arterial blood from arterial blood gas analysis 
(SaO2). 
8.1.3 Body temperature  
Body temperature will be measured to monitor the patient’s status regarding fever per the 
schedule in Table 5. Temperature may be measured using the following methods: axilla, oral, 
rectal, or tympanic according to local hospital protocols and according to the manufacturer’s 
instructions for use of the device. Body temperature should be measured using the same method 
each time. Temperature should be measured after at least 5 minutes of rest (supine or sitting). 
Temperature will be measured according to timepoints and time period described (or as close as 
possible) in Table 5. Body temperature measurement will occur before taking antipyretics or more 
than 4 hours after the last dose of antipyretics. Clinically indicated body temperature 
measurements between scheduled assessments should be recorded.  
Body temperature to be reported in the CRF should be the maximum value observed during any 
time period or window. 
 Table 5 - Body temperature assessment  
Assessment period 
Time period of a day 
Time window as a guide 
Screening, Day 1 – Day 3 
Morning 
Before 10:00 
Noon 
10:00 – 14:59 
Evening 
15:00 – 19:59 
Bedtime 
20:00 and after 
Day 4 – Day 29 
Morning 
Before 12:00 
Evening 
18:00 and after 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in Section 1.3. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 45 
8.2.1 Vital signs  
Vital signs, including height (screening only), weight (screening only), blood pressure, pulse, and 
respiration rate, will be collected and recorded at the time points according to Section 1.3. 
Any new finding or worsening of previous finding should be reported as a new adverse event. 
8.2.2 Targeted Physical Examination  
A targeted physical examination including lung auscultation and assessment of consciousness will 
be performed at time points according to Section 1.3. Care should be taken to examine and assess 
any abnormalities that may be present, as indicated by the patient’s medical history. 
8.2.3 Electrocardiograms  
A standard 12-lead ECG will be performed optionally at time points according to Section 1.3. 
Heart rate will be recorded from the ventricular rate and the PR, QRS, and QT (identify QTcB or 
QTcF) intervals will be recorded in the eCFR. The ECG strips or reports will be retained with the 
source.   
8.2.4 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to 
Section 1.3 for the timing and frequency. Additional clinical laboratory tests may be performed 
based on the investigator’s clinical judgement. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant’s condition.  
A laboratory manual will be provided to study sites with additional information for laboratory 
parameters assessed centrally.  
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 60 days of the last dose of study intervention should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Sponsor. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE (see Section 10.3.1) or SAE (Section 10.3.2) 
and remain responsible for following up AEs that are serious, considered related to the study 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 46 
intervention or study procedures, or that caused the participant to discontinue the study (see 
Section 7). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the informed consent form (ICF) until the 
follow-up visit at the time points specified in the SoA (Section 1.3). 
All AE will be collected from the signing of the ICF at the time points specified in the SoA 
(Section 1.3). 
All SAEs and AESI (Section 8.3.6) will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in Appendix 3 
(Section 10.3). The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and AESI 
(as defined in Section 8.3.6), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information 
on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 47 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• 
Adverse events that are considered expected will be specified in the reference safety 
information (IB and associated addendum).  
• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 7 
days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days 
- 
For SUSARs, other than those that are life-threatening or result in death, reporting 
is no later than 15 days after first knowledge by the Sponsor 
• 
An Investigator who receives an Investigator safety report describing a SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure and associated 
addendum and will notify the IRB/IEC, if appropriate according to local requirements. It is 
the responsibility of the Sponsor to assess whether an event meets the criteria for a 
SUSAR, and therefore, is expedited to regulatory authorities. 
8.3.5 Pregnancy  
It is the responsibility of the investigator to report to the sponsor (or designee), any pregnancy 
occurring in a female study patient, during the study. 
• 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until the outcome of 
the pregnancy. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. 
• 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 48 
8.3.6 Adverse event of special interest  
Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
The AESI require reporting to the sponsor (or designee) within 24 hours of learning of the event: 
• 
Adverse Events of Special Interest (AESI; serious and nonserious) include the 
following: 
- 
Grade ≥2 infusion related reactions (Infusion related reactions are defined as any signs 
or symptoms experienced by patients who receive IMP within 24 hours of the start of 
infusion) 
- 
Grade ≥2 hypersensitivity reactions 
- 
Grade 4 neutropenia (ANC <500/mm3) 
- 
Grade 4 neutropenia with concurrent invasive infection (ANC <500/mm3) 
- 
Increase in alanine transaminase (ALT) ≥3X ULN (for patients with normal baseline) 
or >3X ULN AND at least 2-fold increase from baseline value (for patients with 
abnormal baseline) 
- 
Invasive bacterial or fungal infections of clinical significance with confirmed diagnosis 
based on the Investigator’s assessment with appropriate diagnostic workups and 
consultations 
- 
Symptomatic overdose (serious or nonserious) with IMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic 
pills count) and defined as an increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in less than 
half the recommended duration of administration. 
Management of acute reactions is described in Section 10.3.4. 
8.3.7 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 49 
8.4 
TREATMENT OF OVERDOSE  
Sponsor does not recommend specific treatment for an overdose. In the event of an overdose, the 
Investigator should: 
1. Contact the Sponsor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
sarilumab can no longer be detected systemically (at least 60 days). 
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of 
study intervention if requested by the Sponsor (determined on a case-by-case basis). 
4. Document appropriately in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
8.5.1 Sampling times  
The sampling times for blood collection can be found in the schedule of activities (Section 1.3). 
8.5.2 Sample handling procedure  
The sample handling procedure is summarized in Table 6 Special procedures for collection, 
storage and shipping of serum are described in separate operational manuals. 
Table 6 - Summary of handling procedures for samples for sarilumab and sample for anti-sarilumab 
antibody  
 
Sarilumab 
 
Anti-sarilumab antibody 
Blood Sample Volume 
5 mL 
 
5 mL 
Anticoagulant 
none 
 
none 
Handling Procedures 
See operation manual 
 
See operation manual 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 50 
8.5.3 Bioanalytical methods  
A brief outline of the bioanalytical assay is given in Table 7. Also, see operational manual. 
Table 7 - Summary of bioanalytical method for sarilumab  
Bioanalysis 
Sarilumab 
 
Anti-sarilumab antibody 
Matrix 
Serum 
 
Serum 
Analytical 
Technique 
ELISA 
 
Electrochemiluminescence 
Site of Bioanalysis 
Regeneron 
 
Regeneron 
8.5.4 Pharmacokinetic parameters  
The following pharmacokinetic parameters will be calculated, using a non-compartmental method 
for serum concentrations of sarilumab after a single dose or two doses. The parameters will 
include, but may not be limited to, the following listed in Table 8. 
Table 8 - List of pharmacokinetic parameters and definitions  
Cmax 
Maximum serum concentration observed  
tmax 
First time to reach Cmax  
8.6 
PHARMACODYNAMICS  
8.6.1 Pharmacodynamic parameters  
Pharmacodynamic effects of sarilumab will be assessed through measurement of the following 
biomarkers: CRP, IL-6, sIL-6R 
8.6.2 Assessment methods  
The sample handling procedure is summarized in Table 9. Special procedures for collection, 
storage and shipping of serum are described in separate operational manuals. 
Table 9 - Summary of handling procedures for sIL-6 and IL-6  
 
sIL-6R 
IL-6 
Blood sample volume 
3 mL 
3 mL 
Anticoagulant 
none 
none 
Handling procedures 
refer to Lab Manual 
refer to Lab Manual 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 51 
8.7 
GENETICS  
Genetics is an optional sub-study. Separate consent is required for participation in the optional 
genomic sub-study and collection of a blood sample for (DNA/RNA). 
A 4 mL blood sample for DNA isolation will be collected from participants who have consented 
to participate in the genetic analysis component of the study. Participation is optional. Participants 
who do not wish to participate in the genetic research may still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
For the sub-study, samples will be stored and analysis may be performed on biomarker variants 
thought to play a role in COVID-19 including, but not limited to, genome-wide analysis for RNA, 
serum analytes, or tissue biomarkers to evaluate their association with observed clinical responses 
to demographic and disease characteristics and to sarilumab. 
See Appendix 5 (Section 10.5) for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in central laboratory 
manual. 
8.8 
BIOMARKERS  
Samples will be tested for IL-6, soluble IL-6Rα, and SARS-CoV-2 to evaluate their association 
with the observed clinical responses (eg, body temperature, clinical status, NEWS2) to sarilumab. 
8.9 
HEALTH ECONOMICS/MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 52 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The hypothesis to be tested are superiority of sarilumab versus placebo with respect to the primary 
endpoint, which is the time to improvement of two points in clinical assessment from baseline in 
clinical status assessment using the 7-point ordinal scale. The statistical hypothesis (null H0 versus 
alternative H1) are stated below.  
H0: S1 (t)= S2 (t) for all time t    versus     H 1: S1 (t)≠ S2 (t) for some time t 
where S1 (t) and S2 (t) are the survival probability functions of the primary endpoint for sarilumab 
and placebo treatment groups, respectively. 
9.2 
SAMPLE SIZE DETERMINATION  
The sample size calculations are performed based on the primary endpoint, the time to 
improvement of 2 points in clinical status assessment from baseline using the 7-point ordinal 
scale. 
Assuming that accrual duration is 3 months (~90 days) with each patient followed for a period of 
at least 29 days, the proportions of patients with two points improvement from baseline in clinical 
status assessment at day 15 are 45% and 70% for placebo and sarilumab, respectively, a total 
sample size of approximately 400 patients with a 2:2:1 randomization ratio provides at least 90% 
power for pairwise comparisons between each sarilumab dose (400 mg IV or 200 mg IV; n~160 
each) and placebo (n~80), using a log-rank test of superiority at a two-sided significance level of 
0.05. Sample size calculation was performed using PASS 14. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 10): 
Table 10 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who sign the ICF 
Randomized 
All randomized patients 
mITT population:   
The modified intention-to-treat (mITT) population includes all randomized patients 
treated with study medication. Analysis of the mITT population will be done 
according to the initial treatment assigned to the patient (as randomized). The mITT 
population will be the primary population for analysis of primary and secondary 
efficacy endpoints, as well as for data including (but not limited to) demographics 
and baseline characteristics. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 53 
Population 
Description 
PPS 
The Per Protocol population set (PPS) includes all ITT patients who did not have 
any relevant major protocol deviations, eg, patients who are randomized and 
treated, but do not have laboratory-confirmed SARS-CoV-2 infection will be 
excluded from PPS. The final determination of the exclusion of patients from the 
PPS will be made prior to the primary database lock. Analysis of the PPS will be 
done according to the treatment the patient actually received (as treated). The PPS 
will be used for sensitivity analysis of the primary efficacy endpoint. 
Safety 
Safety population: The safety population includes all randomized patients treated 
with study medication. Analysis of the Safety population will be done according to 
the treatment received (as treated). 
PK population 
The PK analysis population includes all patients who received any study drug and 
who had at least 1 non-missing result following the first dose of study drug. 
9.4 
STATISTICAL ANALYSES  
The primary analysis is planned when the last patient randomized reaches Day 29 (or planned  
Day 29 if the patient is discharged or leaves the study early). Final analysis will be performed at 
study end (ie, Day 60).  
The SAP will be finalized prior to the interim analysis and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and key 
secondary endpoints. 
9.4.1 General considerations  
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category.  
Subgroups will be defined by key baseline factors (eg, demographics, disease characteristics). 
Subgroup analyses will be performed on efficacy endpoints and safety endpoints, as needed. 
Details will be described in the SAP.  
Statistical analyses will be performed using Statistical Analysis Software (SAS) version 9.4 or 
higher. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 54 
9.4.2 Primary endpoint(s)  
The primary endpoint is the time to improvement of 2 points in clinical status assessment from 
baseline using the 7-point ordinal scale. Patient who discharged early will be considered as 
meeting the two points improvement criteria. 
The primary endpoint will be analyzed using a log-rank test stratified by randomization stratum 
with treatment as a fixed factor in the mITT population. P-value for the pairwise treatment 
comparison versus placebo will be provided. Estimation of treatment effect of each sarilumab 
dose will be provided as hazard ratio (sarilumab versus placebo) using Cox proportional hazards 
model stratified by the randomization stratum with treatment as a covariate, along with 2-sided 
confidence intervals. Kaplan-Meier (KM) plot and the median time-to- improvement of 2 points 
will also be provided.   
Superiority of sarilumab over placebo will be declared if the null hypothesis is rejected at the 5% 
(2-sided) significance level following the multiplicity control procedure specified in  
Section 9.4.3.1. 
Patients who have an improvement of 2-points in clinical assessment or discharge will be 
considered as events, while patients who do not experience improvement of 2-points will be 
censored at the last observation time point. Patients who die or take rescue medication in the study 
without improvement of 2-points before that will be censored at the earlier date of Day 29 (for the 
primary analysis) or rescue medication started. 
9.4.3 Secondary endpoint(s)  
9.4.3.1 Efficacy  
Analysis for Key Secondary Endpoint: 
The key secondary endpoint is the percent of patients alive at Day 29. 
The key secondary endpoint will be analyzed using a Cochran-Mantel-Haenszel (CMH) test 
stratified by randomization stratum in the mITT population. Estimation of treatment effect of each 
sarilumab dose will be reported as difference in proportion of patients alive at Day 29 
(sarilumab - placebo), along with 95% confidence levels. P-value for the pairwise treatment 
comparison versus placebo will be provided.  
 
Superiority of sarilumab over placebo will be declared if the null hypothesis is rejected at the 5% 
(2-sided) significance level following the multiplicity control procedure specified in  
Section 9.4.3.1. 
Analysis for Other Secondary Endpoints: 
• 
Differences in time-to-event endpoints by treatment will be summarized with 
Kaplan-Meier estimates and 95% confidence intervals. 
• 
Change in ordinal scale at specific time points will be summarized by proportions (eg, 
proportion who have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-point worsening). 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 55 
• 
Duration of event (eg, duration of mechanical ventilation) will be summarized according 
to median days with quartiles. 
• 
Incidence data (eg, incidence of new oxygen use) will be summarized as a percent with 
95%confidence intervals. 
• 
Continuous endpoints and their changes from baseline will be summarized through 
descriptive statistics including mean, standard deviation, median and quartiles, and 95% 
confidence intervals of means, as needed. 
• 
Categorical data (eg, ordinal scale by day) will be summarized according to proportions 
with confidence intervals on the difference or odds ratios for a binary or multiple category 
scale, respectively. 
Missing data procedures will be described in the SAP. 
Control of multiplicity 
Multiplicity will be controlled for the primary analysis (i.e. Day 29), final analysis (i.e. Day 60) 
will be supportive. 
For the primary and key secondary endpoints, multiplicity will be controlled via a hierarchical 
testing procedure in the following order:  
1. Primary endpoint sarilumab 400 mg versus placebo 
2. Key secondary endpoint sarilumab 400 mg versus placebo 
3. Primary endpoint sarilumab 200 mg versus placebo 
4. Key secondary endpoint sarilumab 200 mg versus placebo 
If one sarilumab dose is discontinued for safety reasons, then all comparisons versus placebo for 
that dose will be removed and the remaining comparisons will be tested in the order specified 
above.  
9.4.3.2 Safety  
9.4.3.2.1 Adverse events  
Definitions  
For safety variables, the following observation period is defined: 
The on-treatment period is defined as the day from first dose of study drug to the last dose of 
study drug plus 60 days. 
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment period.  
In addition, there will be an end of study (EOS) phone call follow-up to determine the vital status 
(alive or dead) of the patient and to assess for SAEs and AESI.   
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 56 
Analysis  
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level terms. The 
preferred term (PT), and the primary system organ class (SOC) will be listed.  
Summaries of all TEAEs by treatment group will include: 
• 
The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• 
TEAEs by severity, presented by SOC and PT 
• 
TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• 
Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group.  
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
9.4.4 Tertiary/exploratory endpoint(s)  
Tertiary and exploratory endpoints analyses will be described in the SAP. 
9.4.5 Other safety analyse(s)  
9.4.5.1 Vital Signs  
Vital signs (height, weight, temperature, pulse, blood pressure, and respiration rate) will be 
summarized by baseline and change from baseline to each scheduled assessment time with 
descriptive statistics.  
9.4.5.2 Laboratory Tests  
Laboratory test results, including but not limited to white blood cell count, hemoglobin, platelets, 
creatinine, total bilirubin, alanine aminotransferase (ALT), will be summarized by baseline and 
change from baseline to each scheduled assessment time with descriptive statistics.  
Number and percentage of patients with a potentially clinically significant abnormality (PCSA) at 
any post-randomization time point will be summarized for each clinical laboratory test for all 
patients and separately for patients in whom the PCSA criterion was normal or missing at 
baseline.   
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 57 
9.4.5.3 Assessment of anti- sarilumab antibodies  
Anti-sarilumab antibody levels will be listed as negative and positive (titer-based) by patient and 
visit. Data will also be summarized as number of patients (counts and percents) with negative and 
positive levels by treatment group. 
9.4.6 Pharmacokinetics  
9.4.6.1 Analysis of Drug Concentration Data  
The concentrations of sarilumab over time and pharmacokinetic parameters, as appropriate, will 
be summarized using descriptive statistics by treatment group and number of sarilumab doses.  
No formal statistical hypothesis testing will be performed. 
9.4.6.2 Analysis of Pharmacodynamic and Exploratory Biomarker Data  
The concentrations of CRP, IL-6, and sIL-6R over time will be summarized using descriptive 
statistics by treatment group and number of sarilumab doses. 
9.4.7 Other analyse(s)  
Treatment Exposure  
Exposure to study drug will be examined for each patient. The total number of treatments 
administered to each patient and exposure related parameters (eg, duration of exposure) will be 
analyzed and summarized using descriptive statistics by treatment group in the Safety population. 
The number of patients with two treatment doses will be summarized by treatment group. 
Treatment Compliance  
Percentage of compliance is defined as the number of patients who fully completed infusions of 
the first study drug divided by number who received study drug.   
9.5 
INTERIM ANALYSES  
An interim analysis is planned to be performed when approximately 50% of total planned number 
of patients (~200) are randomized. The efficacy endpoints will be analyzed using the same 
methods described in the efficacy analyses section (Section 9.4). The key secondary endpoint will 
be modified to be the percent of patients alive at Day 15. 
The purpose of the interim analyses is to obtain an understanding of the possible drug effect in the 
population under study.  An administrative alpha of 0.001 will be spent at interim analysis (1). 
Due to the conservative amount of alpha spent at interim, no alpha adjustment will be made for 
the primary analysis when the last patient randomized of the whole study reaches Day 29 (or 
planned Day 29 if the patient is discharged or leaves the study early), or the supportive final 
analysis at Day 60. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 58 
The interim analyses will be performed by an external statistical analysis center and are separated 
from personnel involved in the trial conduct. The unblinded results can only be viewed by a small 
group of senior sponsor individuals, who are separate from sponsor personnel involved in the 
conduct of the study. People involved in the conduct of the study (Patients, Investigators, Study 
Team, and Project Team) will have no access to the interim analysis results. Sponsor may decide 
to make changes to the dose and/or alter disease category based on the interim results. 
9.6 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC)  
An independent data monitoring committee (IDMC) will actively monitor the ongoing safety of 
patients and can make recommendations about early study closure or changes to the conduct of 
the study. The Sponsor may decide to stop or make changes to the study based on the 
recommendations of the IDMC.  
A treatment arm may be discontinued if there is a clinically meaningful imbalance between 
treatment arms in any of the following safety criteria: 
• 
Incidence of SAEs 
• 
Incidence of AESIs 
• 
Progression of COVID-19 to more severe, critical or multi-organ dysfunction 
• 
Incidence of clinically significant recurrence of severe or critical disease after clinical 
improvement 
The first analysis of data is planned for safety monitoring when the first approximately 12 patients 
are randomized and receive study drug. Data on these first 12 patients regardless of severity of 
illness will be reviewed by an IDMC after the last of these patients dosed reaches Day 7. Data on 
approximately the first 12 and 50 patients regardless of severity of illness will be reviewed by 
IDMC to determine if the study can continue with or without modification. Subsequent frequency 
of IDMC meetings will be determined following the first two IDMC meetings.  
IDMC will continue to monitor the safety of patients throughout the study as specified in the 
IDMC charter.  
 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 59 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• 
This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• 
The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC Determining whether an incidental finding should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the finding is 
returned (an incidental finding is a previously undiagnosed medical condition that is 
discovered unintentionally and is unrelated to the aims of the study for which the tests 
are being performed). The following should be considered when determining the return 
of an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 60 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial  that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• 
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized/acceptable representative.  
Participants who are rescreened are required to sign a new ICF. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 61 
The ICF will contain a separate section that addresses the use of remaining mandatory samples or 
new extra samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate consent will be required to document a participant's 
agreement to allow any remaining specimens to be used for exploratory research. Participants who 
decline to participate in this optional research will not provide this separate consent. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (General Data Protection Regulation).  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study, unless prohibited by local regulation, 
because these data are required by regulatory agencies (eg, on afro American population for the 
FDA or on Japanese population for the Pharmaceuticals and Medical Devices Agency in Japan). 
• 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred to the Sponsor. 
• 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant as described in the informed consent.  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
• 
Participant data are intended to be used for the whole drug development program from 
collection to reimbursement. 
10.1.5 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 62 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials.   Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com.  
10.1.6 Data quality assurance  
• 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations) 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 63 
10.1.7 Source documents  
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• 
Definition of what constitutes source data can be found in the monitoring plan 
10.1.8 Study and site start and closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• 
For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• 
For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 64 
10.1.9 Publication policy  
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• 
The tests detailed in Table 11 will be performed.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.  
• 
Pregnancy testing: Pregnancy testing to be performed locally in women of childbearing 
potential (WOCBP) only. Serum or urine pregnancy test are both acceptable. 
Table 11 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
MCV 
 
MCH 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Blood chemistrya 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose (fasting or nonfasting) 
 
Potassium 
 
Sodium 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 65 
Laboratory assessments 
Parameters 
 
Calcium 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT)a 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) a 
 
Alkaline phosphatase 
 
Total and direct bilirubin 
 
Total protein 
Ferritin 
D-dimer 
C reactive protein (CRP) 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
Other tests 
• 
Highly sensitive [Serum or urine] human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)b  
• 
Bacterial and fungal blood culture 
• 
PK sarilumab  
• 
ADA 
• 
Serum IL-6  
• 
Serum sIL-6R  
• 
SARS-CoV-2 (Blood sample)  
• 
SARS-CoV-2 (NP swab) 
• 
Blood for DNA/RNA (optional) 
• 
The results of each test must be entered into the CRF. 
NOTES: 
a Details of liver chemistry and other follow-up assessments are given in Section 8.3.6.  
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 66 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg:  
- 
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 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
Events NOT meeting the AE definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 67 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
10.3.2 Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant 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. 
c) Requires “a new” inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 68 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE 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 participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive:  
▪ Intensive treatment in an emergency room or at home for:  
- Allergic bronchospasm  
- Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),   
- Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
▪ Development of drug dependence or drug abuse  
▪ ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 × 
ULN  
▪ Suicide attempt or any event suggestive of suicidality  
▪ Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling)  
▪ Bullous cutaneous eruptions   
▪ Cancers diagnosed during the study or aggravated during the study  
▪ Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the 
study 
10.3.2.1 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor or Representative in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor or Representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor or Representative. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 69 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The severity of neutropenia, hypersensitivity, and infusion related reactions will be graded using 
the NCI-CTCAE v3 (see Table 12, Table 13, Table 14).   
Table 12 - Grading of infusion related reactions (NCI-CTCAE v3)  
Grade 
Description 
1 
Mild reaction; infusion interruption not indicated; intervention not indicated 
2 
Requires therapy or infusion interruption but responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for ≤24 hrs 
3 
Prolonged (ie, not rapidly responsive to symptomatic medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
(eg, renal impairment, pulmonary infiltrates) 
4 
Life-threatening; pressor or ventilatory support indicated 
5 
Death 
 
Table 13 - Grading of hypersensitivity reactions (NCI-CTCAE v3)  
Grade 
Description 
1 
Transient flushing or rash; drug fever 
2 
Rash; flushing; urticaria; dyspnea; drug fever ≥38°C (≥100.4°F) 
3 
Symptomatic bronchospasm, with or without urticaria; parenteral medication(s) indicated; allergy-related 
edema/angioedema; hypotension 
4 
Anaphylaxis 
5 
Death 
 
Table 14 - Grading of neutropenia (NCI-CTCAE v3)  
Grade 
Description 
1 
<LLN – 1500/mm3 or <LLN – 1.5 X 109/L 
2 
<1500 – 1000 /mm3 or <1.5 – 1.0 X 109/L 
3 
<1000 – 500/mm3 or <1.0 – 0.5 X 109/L 
4 
<500/mm3 or < 0.5 X 109/L 
5 
Death 
 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 70 
Adverse events not listed in Table 12, Table 13, Table 14 or in the NCI-CTCAE v5 will be graded 
according to the following scale (Table 15): 
Table 15 - Grading System for Adverse Events Not Listed in NCI-CTCAE  
Grade 
Severity 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.   
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*.   
3  
Severe 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5  
Death 
Death related to AE 
 
* 
Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• 
The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and associated 
addendum and/or Product Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor or Representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor or 
Representative. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 71 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor or 
Representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Sponsor or Representative with a copy of any post-
mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor or Representative 
within 24 hours of receipt of the information. 
Follow-up of AESIs  
The following guidance should be considered for patients with AESI of ALT increase and Grade 
4 Neutropenia 
For AESI of ALT increase: 
Inpatient:  
• 
Confirmation of initial AESI by retesting within 24 -72 hours (ALT, AST, ALP, Total 
bilirubin, etc.). 
• 
Follow up every 24 -72 hours until stabilization (ie, ALT does not continue to increase 
and/or trends towards baseline).  
• 
If a patient is discharged before Day 29, test for ALT, AST, ALP, Total bilirubin, etc. at 
discharge. 
Outpatient (if possible):  
• 
If not stabilized at discharge, follow up every 24 -72 hours, then every 2 weeks (when 
possible) until return to baseline and no manifestation of associated signs and symptoms. 
• 
If stabilized, retest every 2 weeks if possible until results return towards baseline assuming 
no associated signs and symptoms. 
• 
Consider consultation with a hepatologist and additional tests. 
 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 72 
For AESI of Grade 4 Neutropenia (absolute neutrophil count less than <500/mm3): 
Inpatient:  
• 
Confirmation of initial ANC within 24 -72 hours. Monitor patients for signs or symptoms 
of an opportunistic or nosocomial infection. Retest at least twice a week for the first week 
and then per standard of care until return to baseline or normal.  
• 
If discharged, obtain neutrophil count on day of discharge and recommend follow-up with 
family doctor.  
Outpatient (if possible):  
• 
If the lab result has not stabilized at discharge, continue to monitor at least twice a week 
for the first week and then twice a month until return to baseline or normal as possible. 
Monitor patients for signs of infection. 
10.3.3 Reporting of SAEs  
SAE reporting to the Sponsor (or Representative) via an electronic data collection tool 
• 
The primary mechanism for reporting an SAE to the Sponsor or Representative will be the 
electronic data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor (or Representative) by fax or email. 
• 
Contacts for SAE reporting can be found in the study manual. 
SAE reporting to the Sponsor (or Representative) via paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor (or Representative) if electronic data collection tool is not 
available. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in the study manual. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 73 
10.3.4 
Management of Acute Reactions  
10.3.4.1 Acute Intravenous Infusion Reactions   
Emergency equipment and medication for the treatment of infusion reactions must be available 
for immediate use.  All infusion reactions must be reported as AEs (as defined in Section 10.3.1 
and Section 10.3.2) and graded using the grading scales as instructed in Section 10.3.2.1. 
10.3.4.1.1 Interruption of the Intravenous Infusion  
The infusion should be interrupted if any of the following AEs are observed: 
• 
Sustained/severe cough 
• 
rigors/chills 
• 
rash, pruritus (itching) 
• 
urticaria (hives, welts, wheals) 
• 
diaphoresis (sweating) 
• 
hypotension 
• 
dyspnea (shortness of breath) 
• 
vomiting 
• 
flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of 
the original rate.  
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
10.3.4.1.2 Termination of the Intravenous Infusion  
The infusion should be terminated and NOT restarted if any of the following adverse events 
occur: 
• 
anaphylaxis* 
• 
laryngeal/pharyngeal edema 
• 
severe bronchospasm 
• 
chest pain 
• 
seizure 
• 
severe hypotension 
• 
other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc.) 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 74 
• 
any other symptom or sign that, in the opinion of the investigator, warrants termination of 
the IV infusion 
* Consider anaphylaxis if the following is observed (37): acute onset of an illness (minutes to 
several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, 
pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING: 
• 
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• 
Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence). 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 75 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT before the end of the study. 
CONTRACEPTION GUIDANCE: 
Contraceptive use by men or women should be consistent with the prescribing information for 
Kevzara and with local regulations regarding the methods of contraception for those participating 
in clinical studies. 
COLLECTION OF PREGNANCY INFORMATION:  
Female participants who become pregnant  
• 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
• 
The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information 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 the procedure. 
• 
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• 
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in  
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 76 
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA 
• 
Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants. 
• 
DNA samples will be used for research related to sarilumab or COVID-19 and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related 
to sarilumab and or COVID-19 related diseases. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers throughout the 
genome. 
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to sarilumab or study interventions of this class to understand 
study disease or related conditions. 
• 
The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary. 
• 
The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• 
The samples will be retained while research on sarilumab and COVID-19 diseases 
continues but no longer than 15 years or other period as per local requirements. 
10.6 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.7 
APPENDIX 9: ABBREVIATIONS  
ADA Anti-drug antibody 
AE Adverse event 
AESI Adverse event of special interest 
ALT Alanine aminotransferase 
ANC Absolute neutrophil count 
ARDS Acute respiratory distress syndrome 
AST Aspartate aminotransferase 
BUN Blood urea nitrogen 
CDC Center for Disease Control 
CMH Cochran-Mantel-Haenszel  
COVID-19 Coronovirus Disease 2019 
CPK Creatine phosphokinase 
CRF Case report form (electronic or paper) 
CRO Contract research organization 
CRP C-reactive protein 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 77 
CRS Cytokine release syndrome 
ECG Electrocardiogram 
ECMO Extracorporeal membrane oxygenation 
EDC Electronic data capture 
FAS Full analysis set 
FDA Food and Drug Administration 
FiO2 fraction of inspired oxygen  
GCP Good Clinical Practice 
HDL High-density lipoprotein 
ICF Informed consent form 
ICH International Council for Harmonisation 
ICU Intensive care unit 
IL-6 Interleukin 6 
IRB Institutional Review Board 
IV Intravenous 
KM Kaplan-Meier   
LDH Lactate dehydrogenase 
LDL Low-density lipoprotein 
MOD Multi-organ dysfunction 
NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Events 
NEWS2 National Early Warning Score2 
NP Nasopharyngeal 
PCSA potentially clinically significant abnormality  
PK Pharmacokinetic(s) 
RBC Red blood cell 
Regeneron Regeneron Pharmaceuticals, Inc. 
SAE Serious adverse event 
SAF Safety analysis set 
SAP Statistical analysis plan 
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 
SAS Statistical Analysis System 
SC Subcutaneous 
SOC System organ class 
SOFA Sequential Organ Failure Assessment   
SpO2 Oxygen saturation 
SUSAR Suspected unexpected serious adverse reaction 
TEAE Treatment-emergent adverse event 
WBC White blood cell 
WHO World Health Organization 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 78 
10.8 
APPENDIX 10: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.8.1 Amended protocol [01] (26 March 2020)  
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis and 
Section 9.4.3 
Secondary Endpoints 
Clarified statistical analysis for the control of 
multiplicity 
 
Provided in response to Health Authority 
recommendation 
Section 1.1 
Synopsis and 
Section 3 Objectives 
and Endpoints 
Phase 2 primary endpoint changed to:  
The primary endpoint is the time to resolution of 
fever for at least 48 hours without antipyretics 
or until discharge, whichever is sooner 
Clarified primary endpoint collection                            
 
Section 1.1 
Synopsis and 
Section 3 Objectives 
and Endpoints 
Phase 3 Primary endpoint:  
Added the timepoint as Day 15 for the primary 
endpoint of Phase 3 
Provided to clarify description of Phase 3 default 
primary endpoint 
Section 1.1 
Synopsis and 
Section 3 Objectives 
and Endpoints 
Phase 2 and Phase 3 endpoints: 
Added an endpoint to evaluate the proportion of 
patients requiring rescue medication during the 
28-day period 
Added to accommodate analysis of rescue 
medication use 
Section 1.1 
Synopsis Overall 
Design 
Added that screening will be limited to severe 
patients until approximately 100 patients have 
reached Day 15, after which screening can be 
considered for patients of the same or greater 
severity. 
Clarifies time point at which patients with critical 
disease or multi-system organ dysfunction can be 
considered for screening 
Section 1.1 
Synopsis Overall 
Design 
Stratification changed to systemic 
corticosteroids (Yes, No). 
Broadened scope to include systemic corticosteroid 
use for any reason 
Section 1.1 
Number of patients 
and Section 9.2 
Sample size 
determination 
Modified to:  
Sample size may be re-estimated for Phase 3 
based on results from Phase 2 
Clarification of potential impact of Phase 2 analyses 
on Phase 3 sample size. 
Section 1.1 
Statistical Plan and 
Section 9.2 Sample 
size determination 
Modified accrual duration to 3 months (~90 
days)  
 
Adapted accrual duration to account for change in 
accelerated rates of local transmission of SARS-
CoV-2 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 79 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Statistical Plan  
For phase 2 the primary analysis of time-to-
fever-resolution will be conducted on data from 
patients with fever within the 24 hours prior to 
randomization 
Clarification of starting time for time-to-fever-
resolution analysis 
Section 1.1 
Statistical Plan and 
Section 9.2 Sample 
size determination 
Added details for the Phase 2 analyses cut-off. 
Clarified control of multiplicity for Phase 2 
 
Clarification in response to health authority 
comment 
 
Section 1.3 
Schedule of Activities 
Clarified the inclusion criteria for a positive 
SARS-CoV-2 test. 
 
Allowed for inclusion based on positive SARS-CoV-
test recorded prior to screening visit 
Section 1.3 
Schedule of Activities 
Clarified that the blood is collected for the 
central analysis of SARS-CoV-2 viral load. 
Clarify that the blood is collected for the central 
analysis of SARS-CoV-2 viral load and is not for 
determining the inclusion criteria. 
Section 1.3 
Schedule of Activities 
Clarified patients who discontinue early should 
complete the End of Study Visit, if possible. 
 
Operational clarification 
Section 1.3 
Schedule of Activities 
Clarified that All AEs will be recorded in CRF. 
Note: any abnormal physical findings requiring 
medical or surgical intervention must be 
recorded as an AE. 
Operational clarification 
Section 1.3 
Schedule of Activities 
And Section 8.1.1 
Body Temperature 
Clarified that the body temperature to be 
reported in the CRF should be the maximum 
value observed during any time period or 
window. 
Operational clarification 
Section 2.3 
Benefit/Risk 
Assessment 
The review of safety data by an independent 
data monitoring committee (IDMC) after the 
dosing of the first 12 patients will not be 
required prior to enrolling additional patients 
and through the duration of the study 
Modified in response to accelerated pace of local 
transmission 
Section 5.1 
Inclusion Criteria 
Fever has been removed as a necessary 
criterion for definition of pneumonia 
Because body temperature may be altered by anti-
pyretic medication, fever may not be evident in 
patients with pneumonia 
Section 5.1 
Inclusion Criteria 
Laboratory-confirmed SARS-CoV-2 infection 
(eg by PCR), or other commercial or public 
health assay in any specimen within 2 weeks 
prior to randomization and no alternative 
explanation for current clinical condition 
Modified to account for regional variability in SARS-
CoV-2 testing recommendations 
Section 5.2 
Exclusion Criteria 
Modified E01 to: In the opinion of the 
investigator, unlikely to survive after 48 hours, 
or unlikely to remain at the investigational site 
beyond 48 hours. 
Clarification 
Section 6.3 
Blinding 
Added code breaking rules 
Operational clarification 
Section 6.6 
Rescue Therapy 
Added:  
Administer rescue medication only 48 hours 
after the initial infusion of study medication.  
Rescue medications are defined as the 
immunosuppressive therapies (described in the 
exclusion criteria E 03 and E 04 ). 
Added to mitigate risk of potential lack of benefit 
from investigational intervention 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 80 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.2.2 
Limited Physical 
Examination 
Changed to 8.2.2 Targeted Physical 
Examination 
Added: assessment of consciousness 
Added to ensure assessment. Necessary to 
complete NEWS2 score 
Section 9.2  
Sample size 
determination 
Detailed sample size determination of the 
primary endpoint of Phase 3 
Provided in response to Health Authority 
recommendation 
Section 9.4.2  
Primary Endpoint(s) 
Added: 
The primary endpoint of time to fever resolution 
will be performed on patients with fever 
(defined as temperature > 37.4°C [axilla], or > 
38.0 °C [oral], or >38.4°C [rectal or tympanic]) 
documented in the medical record, within the 
24 hours prior to randomization. 
Clarification of definition of fever for analysis of time 
to fever resolution. 
All sections 
Minor edits 
Minor corrections, corrections and formatting of 
bibliography 
 
10.8.2 Amended protocol [02] (08 April 2020)  
This amended protocol 02 (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. 
OVERALL RATIONALE FOR THE AMENDMENT  
The unanticipated and rapid enrollment into this study for COVID -19 patients renders a staged 
approach to analysis unfeasible; consequently the Phase 2 analysis will not be performed. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title and throughout 
the protocol 
An adaptive phase 3, randomized, double-blind, 
placebo-controlled study assessing efficacy and 
safety of sarilumab for hospitalized patients 
with COVID-19. 
The unanticipated and rapid enrollment into the 
study renders a staged approach to analysis 
unfeasible; consequently the Phase 2 analysis will 
not be performed. 
Section 1.1  
Synopsis  
Section 3  
Objectives and 
Endpoints 
Section 9  
Statistical 
Considerations 
The primary endpoint is the time to 
improvement of 2 points in clinical status 
assessment from baseline using the 7-point 
ordinal scale. 
 
 
The 7-point clinical status scale has face validity 
and a two point change in status is considered 
large enough to demonstrate a meaningful 
difference between treatment groups. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 81 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1  
Synopsis  
Section 3  
Objectives and 
Endpoints 
Section 9  
Statistical 
Considerations 
The key secondary endpoint is percent of 
patients alive at Day 29. 
Captures non pulmonary mortality. 
Section 1.1  
Synopsis  
Section 3  
Objectives and 
Endpoints 
Section 9  
Statistical 
Considerations 
A secondary endpoint is the proportion of 
patients with one point improvement from 
baseline in clinical status assessment at days 
4, 7, 15, 21, 29 using the 7-point ordinal scale. 
The 7-point clinical status scale has face validity 
and a one point change in status will demonstrate a 
meaningful difference between treatment groups. 
Section 1.1 
Synopsis Overall 
Design 
Removed that screening will be limited to 
severe patients until approximately 100 patients 
have reached Day 15, after which screening 
can be considered for patients of the same or 
greater severity. 
100 patients comprised the initial phase 2 cohort. 
This is removed as phase 2 analysis will not be 
performed. 
Section 1.1 
Synopsis Overall 
Design 
Section 4.1  
Overall Design 
Added that patients may receive a second dose 
of study treatment if they meet prespecified 
criteria. 
Optimal dose of sarilumab IV for patients with 
severe or critical COVID-19 is unknown. 
Section 1.1 
Synopsis Overall 
Design 
Section 4.1  
Overall Design 
Section 5.1  
Inclusion Criteria 
Removed the severity category of multi-system 
organ dysfunction, and removed stratification 
by multi-system organ dysfunction. 
Clarified which patients can be considered for 
screening. 
Section 1.1 
Synopsis Overall 
Design 
Section 4.1  
Overall Design 
Section 9.5 
Interim Analysis 
An interim analysis has been specified when 
approximately 50% of total planned number of 
patients (~200) would have reached Day 15. 
Obtain an understanding of the possible drug effect 
in the population under study. 
Section 1.3 
Schedule of Activities 
Separated urinalysis from urine culture results. 
Clarify that urinalysis is required for all patients, and 
urine culture results are only requested if available.  
Section 5.1  
Inclusion Criteria 
Added: 
Further clarify Exclusion Criterion 01. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 82 
Section # and 
Name 
Description of Change 
Brief Rationale 
Note: patients requiring extracorporeal life 
support, vasopressors, or renal replacement 
therapy are excluded. 
Section 6.6  
Rescue Therapy 
Removed sarilumab as rescue therapy. 
Specified that rescue therapy may be given 48 
hours after the last infusion of study treatment. 
Clarify time for the administration and type of 
rescue therapy. 
Section 8.3.6 
Adverse event of 
Special Interest 
Added: 
Infusion related reactions are defined as any 
signs or symptoms experienced by patients 
who receive IMP within 24 hours of the start of 
infusion. 
Provide a definition for Infusion related reactions. 
Section 10.3.2 
Definition of SAE 
Modified: Requires inpatient hospitalization or 
prolongation of existing hospitalization 
To: Requires a “new” inpatient hospitalization or 
prolongation of existing hospitalization. 
 
Added the list of medically important events 
intended to serve as a guideline for determining 
which condition has to be considered as a 
medically important event. 
Clarified SAE, as patients enrolled are hospitalized 
patients. 
 
 
 
Clarification for the Investigator. 
Protocol Amendment 
history  
 
Removed that the use of immunosuppressive 
therapy following infusion of study drug, 
besides corticosteroids and anti-malarial 
medication, is not permitted for Section 6.5 
Concomitant therapy. 
Correction. 
All sections 
Minor edits 
Minor corrections, corrections and formatting of 
bibliography. 
 
10.8.3 Amended protocol [03] (29 April 2020)  
This amended protocol 03 (amendment 03) 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. 
OVERALL RATIONALE FOR THE AMENDMENT  
To clarify language regarding interim analysis.  
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 83 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1  
Synopsis and  
Section 10.2: Clinical 
Laboratory Tests 
Remove requirement that the interim 
analysis requires data up to Day 15. 
Clarifies the scope of adaptations the Sponsor 
may make based on the interim analysis results  
1.3 Schedule of Activities 
(SoA) 
Clarified PK sample collection for Day 2 and 
Day 3. 
Removed ‘optional’ for the serum sIL-6R. 
Provided clarity on PK and serum sIL-6R 
collection 
 
Section 2.3 Benefit/Risk 
Assessment 
Changed multisystem organ dysfunction to 
multi-organ dysfunction 
Corrected to align with the publication where it is 
described (16) 
Section 4.1  
Overall design 
Clarified that IDMC will actively monitor 
interim data, and also make 
recommendations pertaining to the eligible 
population throughout the course of the 
study.  
Clarification 
Section 5.2  
Exclusion criteria 
Removes the use of vasopressors as a factor 
to be considered for selection criterion E01. 
Vasopressors are also used by critical patients 
and not primarily patients with multi organ 
disease (who are excluded). 
And Section 9.5 Interim 
analysis 
Specify the type of modifications that the 
Sponsor may make based on the interim 
analysis results. 
Clarifies the scope of adaptations the Sponsor 
may make based on the interim analysis results  
 
 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 84 
11 
REFERENCES  
 
1. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Brit J 
Radiology 1971, 44:793-7 
2. Williams B. The National Early Warning Score 2 (NEWS2) in patients with hypercapnic 
respiratory failure. Clin Med (Lond) 2019; 19(1):94-5.  
3. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G et al. A Trial of Lopinavir-Ritonavir in 
Adults Hospitalized with Severe Covid-19. The New England journal of medicine. 2020. doi: 
10.1056/NEJMoa2001282. Accessed 06 April 2020. 
4. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients 
with pneumonia in China, 2019. N Engl J Med. 2020;382:727-33. 
5. Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, et al. Clinical characteristics of novel 
coronavirus cases in tertiary hospitals in Hubei Province. 2020; Chin Med J (Engl), Feb 7 
[Epub ahead of print]. 
6. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical 
characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a 
descriptive study. Lancet. 2020 Feb 15;395(10223):507-13. 
7. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 
2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. 
8. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 
Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. 
2020; Jama, Feb 7 [Epub ahead of print]. 
9. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. 2020. Clinical characteristics 
of 140 patients infected by SARS-CoV-2 in Wuhan, China, Allergy, Feb 19 [Epub ahead of 
print]. 
10. Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al. An interferon-gamma-related 
cytokine storm in SARS patients. J Med Virol. 2005 Feb;75(2):185-94. 
11. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the 
cytokine storm. Microbiol Mol Biol Rev. 2012 Mar;76(1):16-32. 
12. Chien JY, Hsueh PR, Cheng WC, Yu CJ, Yang PC. Temporal changes in cytokine/chemokine 
profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology 
(Carlton, Vic) 2006;11:715-22. 
13. Kim ES, Choe PG, Park WB, Oh HS, Kim EJ, Nam EY, et al. Clinical progression and 
cytokine profiles of Middle East respiratory syndrome coronavirus infection. J Korean Med 
Sci. 2016 Nov;31(11):1717-25. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 85 
14. Wang WK, Chen SY, Liu IJ, Kao CL, Chen HL, Chiang BL, et al. Temporal relationship of 
viral load, ribavirin, interleukin (IL)-6, IL-8, and clinical progression in patients with severe 
acute respiratory syndrome. Clin Infect Dis. 2004 Oct 1;39(7):1071-5. 
15. World Health Organization (WHO). Clinical management of severe acute respiratory infection 
when novel coronavirus (nCoV) infection is suspected [Internet]. 2020. [cited 2020 Mar 10]. 
Retrieved from: https://www.who.int/publications-detail/clinical-management-of-severe- 
acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. 
16. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality 
of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 
2020 Mar 11. pii: S0140-6736(20)30566-3. [Epub ahead of print]. 
17. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for 
SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020 Feb 24. [Epub 
ahead of print]. 
18. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting 
enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 
27;426(6965):450-4. 
19. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of 
ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding 
SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7. 
20. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting 
enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-
9.  
21. Wang W, Ye L, Ye L, Li B, Gao B, Zeng Y, et al. Up-regulation of IL-6 and TNF-alpha 
induced by SARS-coronavirus spike protein in murine macrophages via NF-kappaB pathway. 
Virus Res. 2007 Sep;128(1-2):1-8. 
22. Zhang X, Wu K, Wang D, Yue X, Song D, Zhu Y, et al. Nucleocapsid protein of SARS-CoV 
activates interleukin-6 expression through cellular transcription factor NF-kappaB. Virology. 
2007 Sep 1;365(2):324-35. 
23. He L, Ding Y, Zhang Q, Che X, He Y, Wang H et al.  Expression of elevated levels of pro-
inflammatorycytokines in SARS-CoV-infected ACE2 cells in SARSpatients: relation to the 
acute lung injury andpathogenesis of SARS. J Pathol. 2006;210:288-97. 
24. Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) 
coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating 
intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009 
Apr;83(7):3039-48. 
25. Tsushima K, King LS, Aggarwal NR, De Gorordo A, D'Alessio FR, Kubo K. Acute lung 
injury review. Intern Med. 2009;48(9):621-30. 
VV-CLIN-0579585 4.0


Amended Clinical Trial Protocol 04 
SAR153191-EFC16844 - sarilumab 
11-Jun-2020 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 86 
26. Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, et al. Acute 
respiratory distress syndrome. Nat Rev Dis Primers. 2019 Mar 14;5(1):18. 
27. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 
4;342(18):1334-49. 
28. Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune 
system feels the heat. Nat Rev Immunol. 2015 Jun;15(6):335-49. 
29. Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine 
release syndrome after blinatumomab treatment related to abnormal macrophage activation 
and ameliorated with cytokine-directed therapy. Blood. 2013 Jun 27;121(26):5154-7. 
30. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 
patients with Tocilizumab. [Internet]. 2020. [cited 2020 Mar 25]. Retrieved from: 
http://www.chinaxiv.org/abs/202003.00026. 
31. Lamb YN, Deeks ED. Sarilumab: a review in moderate to severe rheumatoid arthritis. Drugs. 
2018 Jun;78(9):929-40. 
32. National Health Commission of the People’s Republic of China. China Optimizes Treatment 
for COVID-19 [Internet]. 2020. [cited 2020 Mar 25]. Retrieved from: 
http://en.nhc.gov.cn/2020-03/07/c_77438.htm. 
33. Ishii T, Sato Y, Munakata Y, Kajiwara M, Takahashi Y, Anwar F, et al. Pharmacodynamic 
effect and safety of single-dose sarilumab SC or tocilizumab intravenous or subcutaneous in 
patients with rheumatoid arthritis. Clinical Pharmacology in Drug Development. 2018;7:31-
33. 
34. Emery P, Rondon J, Parrino J, Lin Y, Pena-Rossi C, van Hoogstraten H et al. Safety and 
tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with 
rheumatoid arthritis. 2019;58(5):849-58, 
35. Xu C, Su Y, Paccaly A, Kanamaluru A. Population pharmacokinetics of sarilumab in patients 
with rheumatoid arthritis. Clin Pharmacokinet. 2019 Nov;58(11):1455-67. 
36. Peterson RL, Vock DM, Powers JH, Emery S, Cruz EF, Hunsberger S, et al. Analysis of an 
ordinal endpoint for use in evaluating treatments for severe influenza requiring hospitalization. 
Clin Trials. 2017;14(3):264-76.  
37. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., 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(2):391-7. 
 
VV-CLIN-0579585 4.0


Signature Page for VV-CLIN-0579585 v4.0
efc16844-16-1-1-amended-protocol04
Approve & eSign
Clinical
Approve & eSign
Clinical
VV-CLIN-0579585 4.0

SAP_001.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 7.0 (20-FEB-2019) 
Page 1 
 
STATISTICAL ANALYSIS PLAN  
An adaptive phase 3, randomized, double-blind, placebo-controlled study 
assessing efficacy and safety of sarilumab for hospitalized patients with COVID-19 
SAR153191-EFC16844 
STATISTICIANS: 
 
DATE OF ISSUE: 05-May-2020 
 
 
Total number of pages: 
52 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objective .............................................................................................................................. 6 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 8 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 11 
2.1 
ANALYSIS ENDPOINTS................................................................................................................ 11 
2.1.1 
Demographic and baseline characteristics .................................................................................... 11 
2.1.2 
Concomitant medications ............................................................................................................... 13 
2.1.3 
Efficacy endpoints .......................................................................................................................... 13 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 13 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 14 
2.1.4 
Safety endpoints ............................................................................................................................ 15 
2.1.4.1 
Adverse events variables ............................................................................................................... 15 
2.1.4.2 
Deaths ............................................................................................................................................ 16 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 16 
2.1.4.4 
Vital signs variables ....................................................................................................................... 17 
2.1.4.5 
Physical Examination ..................................................................................................................... 17 
2.1.4.6 
Electrocardiogram variables .......................................................................................................... 17 
2.1.4.7 
Anti-sarilumab antibodies ............................................................................................................... 17 
2.1.5 
Pharmacokinetics variables ........................................................................................................... 18 
2.1.6 
Biomarker and other variables ....................................................................................................... 18 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 18 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 19 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 3 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 20 
2.3.1 
Efficacy populations ....................................................................................................................... 20 
2.3.1.1 
Intent–to-treat/Modified intent-to-treat population .......................................................................... 20 
2.3.1.2 
Per-protocol population .................................................................................................................. 20 
2.3.2 
Safety population ........................................................................................................................... 20 
2.3.3 
PK population ................................................................................................................................. 21 
2.3.4 
ADA population .............................................................................................................................. 21 
2.4 
STATISTICAL METHODS ............................................................................................................. 21 
2.4.1 
Demographics and baseline characteristics .................................................................................. 21 
2.4.2 
Concomitant medications ............................................................................................................... 21 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 22 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 22 
2.4.3.2 
Compliance .................................................................................................................................... 22 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 23 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 23 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 26 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 30 
2.4.5 
Analyses of safety data .................................................................................................................. 30 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 31 
2.4.5.2 
Deaths ............................................................................................................................................ 33 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 33 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 34 
2.4.5.5 
Analyses of physical examination .................................................................................................. 34 
2.4.5.6 
Analyses of electrocardiogram variables ....................................................................................... 34 
2.4.5.7 
Analyses of anti-sarilumab antibodies ........................................................................................... 34 
2.4.6 
Analysis of pharmacokinetics ......................................................................................................... 35 
2.4.7 
Analysis of Pharmacodynamic and Exploratory Biomarker Data: ................................................. 36 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 36 
2.5.1 
General conventions ...................................................................................................................... 36 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 36 
2.5.3 
Missing data ................................................................................................................................... 39 
2.5.4 
Windows for time points ................................................................................................................. 40 
2.5.5 
Unscheduled visits ......................................................................................................................... 40 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 40 
3 
INTERIM ANALYSIS ..................................................................................................................... 41 
4 
DATABASE LOCK ........................................................................................................................ 42 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 43 
6 
REFERENCES ............................................................................................................................... 44 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 4 
7 
LIST OF APPENDICES ................................................................................................................. 45 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 46 
APPENDIX B 
VISIT WINDOWS BASED ON DAY RANGES .................................................................... 51 
APPENDIX C 
AESIS AND SEARCH CRITERIA ........................................................................................ 52 
 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CDC 
Center for Disease Control 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IL-6 
Interleukin 6 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IV 
Intravenous 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NEWS2 
National Early Warning Score2 
NP 
Nasopharyngeal 
PK 
Pharmacokinetic(s) 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
sIL-6R 
Soluble interleukin-6 receptor 
SpO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood cell 
WHO 
World Health Organization 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 6 
1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This study is a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy 
and safety of sarilumab in hospitalized adults with severe or critical COVID-19. The study will be 
conducted in Europe and other countries except in the United States (US) in up to 100 sites. 
Approximately 400 patients will be randomized via interactive response technology (IRT) in a 
2:2:1 allocation ratio to sarilumab 400 mg IV, sarilumab 200 mg IV, or placebo. Randomization 
will be stratified by severity of illness (severe, critical) and use of systemic corticosteroids (yes, 
no), and balanced by region. All patients will receive a single dose of study drug on Day 
1. Patients may receive a second dose with study drug (based on the original treatment group 
assigned) 24 to 48 hours after the first dose, if they meet prespecified criteria in protocol. 
Severity of illness categories: 
• 
Severe disease: 
- Requires supplemental oxygen administration by nasal cannula, simple face mask, or other 
similar oxygen delivery device 
• 
Critical disease: 
- Requires supplemental oxygen requiring delivered by non-rebreather mask or high flow 
nasal cannula, or 
- Use of invasive or non-invasive ventilation, or 
- Requiring treatment in an intensive care unit. 
Patients will be assessed daily while hospitalized. Patients discharged from the hospital prior to 
Day 29 will be contacted with a follow-up phone call on Day 29 to assess status and occurrence of 
re-admission to a hospital. Patients will undergo a series of efficacy, safety and laboratory 
assessments while in the hospital. Serum IL-6 and other markers will be collected and analyzed in 
a central laboratory. Nasopharyngeal (NP) samples to monitor viral infection and blood samples 
may be obtained on Day 1 (pre-dose), 4, 7, 15,29 (or up until the day of discharge if the patient is 
discharged from the hospital before Day 29). An individual patient will complete the study 
approximately 60 days from screening to follow-up on day 60 ±7 days. Patients will not be 
required to return to the hospital once discharged. 
1.2 
OBJECTIVES  
1.2.1 Primary objective  
To evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients 
hospitalized with severe or critical COVID-19. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 7 
1.2.2 Secondary objectives  
• 
Evaluate the 28-day survival rate 
• 
Evaluate the clinical efficacy of sarilumab compared to the control arm by clinical severity 
• 
Evaluate changes in the National Early Warning Score 2 (NEWS2) 
• 
Evaluate the duration of predefined symptoms and signs (if applicable) 
• 
Evaluate the duration of supplemental oxygen dependency (if applicable) 
• 
Evaluate the incidence of new mechanical ventilation use during the study 
• 
Evaluate the duration of new mechanical ventilation use during the Study 
• 
Evaluate the proportion of patients requiring rescue medication during the 28-day period 
• 
Evaluate need for admission into intensive care unit (ICU) 
• 
Evaluate duration of hospitalization (days) 
• 
The secondary safety objectives of the study are to evaluate the safety of sarilumab through 
hospitalization (up to Day 29 if patient is still hospitalized) compared to the control arm as 
assessed by incidence of: 
- 
Serious adverse events (SAEs) 
- 
Major or opportunistic bacterial or fungal infections in patients with grade 4 
neutropenia 
- 
Grade ≥2 infusion related reactions 
- 
Grade ≥2 hypersensitivity reactions 
- 
Increase in alanine transaminase (ALT) ≥3X ULN (for patients with normal baseline) 
or >3X ULN and at least 2-fold increase from baseline value (for patients with 
abnormal baseline) 
- 
Major or opportunistic bacterial or fungal infections 
1.3 
DETERMINATION OF SAMPLE SIZE  
The sample size calculations are performed based on the primary endpoint, the time to 
improvement of 2 points in clinical status assessment from baseline using the 7-point ordinal 
scale. 
Assuming that accrual duration is 3 months (~90 days) with each patient followed for a period of 
at least 29 days, the proportions of patients with two points improvement from baseline in clinical 
status assessment at Day 15 are 45% and 70% for placebo and sarilumab, respectively, a total 
sample size of approximately 400 patients with a 2:2:1 randomization ratio provides at least 90% 
power for pairwise comparisons between each sarilumab dose (400 mg IV or 200 mg IV; n~160 
each) and placebo (n~80), using a log-rank test of superiority at a two-sided significance level of 
0.05. Sample size calculation was performed using PASS 14. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 8 
1.4 
STUDY PLAN  
The schedule of activities can be found in Section 1.3 of the study protocol. The graphical study 
design is provided in Figure 1.  
Figure 1 - Graphical study design  
 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The original protocol (dated: 18 March 2020) was updated to amendment 01 (dated: 
26 March 2020), and amendment 02 (dated: 8 April 2020). The Table 1 below gives the timing, 
rationale, and key details of major changes to the protocol statistical section. 
Table 1 – Protocol amendment statistical changes  
 
Amendment 
Number 
Date 
Approved 
Rational 
Description of statistical 
changes 
01 
26-Mar-2020 
To provide power 
calculation for both 
phase 2 and phase 3 
primary endpoints 
• The power calculation 
for phase 3 primary 
endpoint was added 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 9 
 
 
To specify the 
multiplicity control 
method 
• Details of the 
multiplicity control 
method were added 
 
 
To specify interim 
analysis 
• A planed analysis at the 
end of Phase 2 was 
added in Interim 
Analysis section 
02 
08-Apr-2020 
Study design was 
changed from adaptive 
phase 2/3 to adaptive 
phase 3, and new 
primary and key 
secondary endpoints 
were specified 
• Updated the sample 
size/power calculation 
based on the new 
primary endpoint,  
• Change total number of 
patients needed from 
300 to 400 in sample 
size section 
• Updated the analyses of 
the primary and key 
secondary endpoints 
• Multiplicity control 
method was revised 
• Interim analysis at 
~50% of total planned 
number of patients 
(~200) was added to 
replace the end of phase 
2 analysis 
03 
29-Apr-2020 
To clarify the scope of 
adaptations the 
Sponsor may make 
based on the interim 
analysis results 
• Remove requirement 
that the interim analysis 
requires data up to 
Day 15  
• Specify the type of 
modifications that the 
Sponsor may make 
based on the interim 
analysis results 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
The statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan and/or protocol. 
 
SAP version 
Number 
Date 
Approved 
Rational 
Description of statistical 
changes 
1 
30-Apr-2020 
 
Original SAP 
2 
05-May-2020 
Change the interim 
analysis timing and 
clarify the scope of 
adaptations the 
Sponsor may make 
based on the interim 
analysis results 
according to Protocol 
Amendment 3 
• Remove requirement 
that the interim analysis 
requires data up to 
Day 15 in section 3 
Interim analysis. 
• Specify the type of 
modifications that the 
Sponsor may make 
based on the interim 
analysis results in 
section 3 Interim 
analysis. 
 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 11 
2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
In general, the baseline value is defined as the last available value prior to the first dose of 
investigational medicinal product (IMP) or the last available value on or before the date of 
randomization for patients who were randomized but never exposed to IMP, unless otherwise 
specified.   
Demographic characteristics 
The following demographic characteristics will be summarized separately by treatment and 
overall: 
• 
Age at screening (years) 
• 
Age group (≥18 and <64, ≥65 and <84, ≥85 years) 
• 
Sex (Male, Female) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Not Reported, Unknown). Note: Japanese will 
be included in Asian 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• 
Baseline height (cm) 
• 
Baseline weight (kg) 
• 
Baseline weight category (<50, 50 to <100, ≥100 kg) 
• 
Baseline body mass index (BMI, kg/m2) (<18.5, 18.5 to <25, 25 to <30, ≥30) 
Disease characteristics at baseline   
The following baseline disease characteristics will be summarized: 
• 
Severity of illness (per IRT) (Severe, Critical) 
• 
Severity of illness (as recorded on CRFs) (Severe, Critical) 
• 
Systemic corticosteroids use (per IRT) (Yes, No) 
• 
Systemic corticosteroids use (as recorded on CRFs) (Yes, No) 
• 
Clinical status using 7-point ordinal scale 
• 
Body temperature prior to dosing (oC) (defined as the highest temperature at any time prior 
to first dose)  
• 
Fever (Yes, No) 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 12 
• 
SARS-CoV-2 virus detected (Positive, Negative) 
• 
CRP level 
The other baseline disease characteristic includes 
• 
Pneumonia status 
− 
Pneumonia present based on historical chest X-Ray, CT scan or MRI or lung 
auscultation (Yes, No) 
− 
Signs and symptoms: Fever, Cough, Dyspnea (Yes, No) 
− 
Time from dyspnea onset to baseline  
− 
Type of oxygen delivery device (Nasal cannula, simple face mask, non-rebreather face 
mask, high-flow nasal cannula, non-invasive ventilation, invasive mechanical 
ventilation, other) 
− 
Use of extracorporeal life support life support (Yes, No) 
− 
Use of renal replacement therapy (Yes, No) 
− 
Use of vasopressors (Yes, No)  
• 
Oxygen administration and oxygenation 
− 
Supplemental Oxygen or mechanical ventilation used (Yes, No) 
− 
Oxygen flow rate (L/min) 
− 
Oxygen saturation (SpO2 %) (range is 0% to 100%) 
− 
FiO2 (fraction of inspired oxygen) (range is 0.0 to 1.0) – see Section 2.5.2 for 
derivations 
− 
SpO2/FiO2 ratio – see Section 2.5.2 for derivations 
• 
Hospitalization and ICU admission 
− 
Duration of hospitalization prior to dosing 
− 
ICU required (Yes, No) 
− 
If yes, ICU admitted (Yes, No) 
− 
Duration of ICU admission prior to dosing 
Medical history 
Medical history, concomitant diseases or past surgeries or surgical history are recorded.  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 13 
2.1.2 Concomitant medications  
All medications taken from screening to day 60 (or until day of discharge from hospital if before 
Day 60) captured include:  
• 
Corticosteroids, NSAIDs, and any other anti-pyretics 
• 
Antivirals (eg, remdesivir), antifungals, antibacterials, antimycobacterials, antiprotozoans, 
antihelminthics, antimalarials (eg, chloroquine and hydroxychloroquine) 
• 
Interferon beta and convalescent serum. 
• 
Angiotensin converting enzyme and Angiotensin receptor blocking 
• 
Agents that may affect the CYP450 substrate.   
• 
Any rescue medication that is used during the course of the study. 
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. 
Concomitant medications are any treatments received by the patient concomitantly to the IMP, 
during the treatment-emergent period (as defined in the observation period in Section 2.1.4).  
During the study, for patients requiring rescue therapy as per the judgement of the study 
physician, additional medications may be utilized. Rescue medications are defined as the 
immunosuppressive therapies (described in the exclusion criteria E03 and E04).  
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 time to improvement of 2 points in clinical status assessment from 
baseline using the 7-point ordinal scale. 
The 7-point ordinal scale is an assessment of the clinical status. The scale is as follows: 
- 
1. Death; 
- 
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO); 
- 
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
- 
4. Hospitalized, requiring supplemental oxygen; 
- 
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
- 
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing 
medical care 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 14 
- 
7. Not hospitalized 
2.1.3.2 Secondary efficacy endpoint(s)  
The key secondary endpoint is the proportion of patients alive at Day 29. 
Other secondary endpoints are: 
1. Proportion of patients with one-point improvement from baseline in clinical status 
assessment at days 4, 7, 15, 21, 29 using the 7-point ordinal scale 
2. Mean change in 7-point ordinal scale from baseline to days 4, 7, 15, 21, 29 (or until 
discharge) 
3. Time to resolution of fever defined as body temperature (≤36.6°C [axilla], or ≤37.2 °C 
[oral], or ≤37.8°C [rectal or tympanic]) for at least 48 hours without antipyretics or until 
discharge, whichever is sooner 
4. Time to resolution of fever (as defined above) and improvement in oxygenation (as 
defined below) 
5. Days with fever (>37.4°C [axilla], or >38.0 °C [oral], or >38.4°C [rectal or tympanic]) 
based on maximum value observed during a 24-hour period. 
6. Time to change in National Early Waring Score 2 (NEWS2) from baseline 
7. Time to NEWS2 of <2 and maintained for 24 hours 
8. Mean change from baseline to Day 4, 7, 15, 21, 29 in NEWS2 
9. Time to improvement in oxygenation (SpO2/FiO2 of 50 or greater) compared to the nadir 
for at least 48 hours, or until discharge, whichever is sooner 
10. Alive off supplemental oxygen at Day 29 
11. Days of hypoxemia (SpO2 <93% on room air, or requiring supplemental oxygen, or 
mechanical ventilatory support) 
12. Days of supplemental oxygen use 
13. Days of resting respiratory rate >24 breaths/min (maximum value if recorded at more than 
once a day) 
14. Time to saturation ≥94% on room air 
15. Ventilator free days in the first 28 days (to Day 29) 
16. Initiation of mechanical ventilation, non-invasive ventilation, or use of high flow nasal 
cannula (for those not requiring these interventions at baseline)  
17. Proportion of patients requiring rescue medications during the 28-day period 
18. ICU status (among those not in an ICU at baseline, record if transferred to the ICU or the 
need to transfer to the ICU [if the ICU is not available]) 
19. Days of hospitalization among survivors 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 15 
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). Other safety information, such as clinical laboratory 
data, and vital signs will also be assessed as applicable. 
Observation period  
There are 3 parts in the observation period: 
• 
Screening period is defined as the time from the signed informed consent date up to the 
time prior to first dose of IMP. 
• 
On-treatment period is defined as the day from the first dose of the IMP to the last dose 
of the IMP + 60 days. 
• 
Post-treatment period is defined as the time after the last dose of IMP +60 days.   
The treatment-emergent adverse event (TEAE) period is the on-treatment period. 
The on-study observation period is defined as the time from start of treatment until the end of the 
study (defined as last protocol planned visit or the resolution/stabilization of all serious adverse 
events and AESI).  
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 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. 
Adverse events of special interest (AESI; serious and nonserious) include the following:  
− 
Grade ≥2 infusion related reactions (Infusion related reactions are defined as any signs 
or symptoms experienced by patients who receive IMP within 24 hours of the start of 
infusion) 
− 
Grade ≥2 hypersensitivity reactions 
− 
Grade 4 neutropenia (ANC<500/mm3) 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 16 
− 
Grade 4 neutropenia with concurrent invasive infection (ANC<500/mm3) 
− 
Increase in alanine transaminase (ALT) ≥3X ULN (for patients with normal baseline) 
or >3X ULN AND at least 2-fold increase from baseline value (for patients with 
abnormal baseline) 
− 
Invasive bacterial or fungal infections of clinical significance with confirmed diagnosis 
based on the Investigator’s assessment with appropriate diagnostic workups and 
consultations 
− 
Symptomatic overdose (serious or nonserious) with IMP 
− 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic 
pills count) and defined as an increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in less than 
half the recommended duration of administration. 
AESIs will be flagged in the database using search criteria.  All AEs captured on the general AE 
form, the ALT increase form, infusion reaction symptoms form, and the infection event form will 
be searched.  The list of search criteria is provided in Appendix C. 
2.1.4.2 Deaths  
The deaths observation periods are per the observation periods defined above.  
• 
Death on-study:  deaths occurring during the on-study period  
• 
Death post-study:  deaths occurring after the end of study  
2.1.4.3 Laboratory safety variables  
Clinical laboratory data will include hematology, clinical chemistry, urinalysis and infection tests. 
Clinical laboratory values will be converted to standard international units; international units will 
be used in all listings and tables.  
Hematology and chemistry data will be collected at screening, baseline, days 2 or 3 (only for 
patients with second dose), 4, 7, 15, 21 and 29 or discharge. 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 indices (MCV, MCH, %Reticulocytes). 
- 
White blood cells: white blood cell (WBC) count and WBC differential (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils) 
• 
Clinical chemistry  
- 
Metabolism: total proteins, CRP, and glucose (fasting or non-fasting) 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 17 
- 
Electrolytes: sodium, potassium, and calcium. 
- 
Renal function: creatinine, and blood urea nitrogen (BUN). 
- 
Liver function: alanine aminotransferase (ALT)/SGPT, aspartate aminotransferase 
(AST)/SGOT, alkaline phosphatase (ALP), total and direct bilirubin 
- 
Ferritin 
- 
D-dimer 
Urine samples will be collected as follows: 
• 
Urinalysis - dipstick: pH, blood, glucose, protein, ketones, nitrates, leukocyte esterase, 
and bilirubin.  
• 
Specific gravity  
Infection tests include: 
• 
Bacterial and fungal blood culture 
2.1.4.4 Vital signs variables  
Vital signs variables include heart rate, respiratory rate, systolic blood pressure, diastolic blood 
pressure (daily until discharge). It also includes height and weight at screening only.  
2.1.4.5 Physical Examination  
A targeted physical examination including lung auscultation and assessment of consciousness will 
be performed at time points specified in protocol. 
2.1.4.6 Electrocardiogram variables  
A standard 12-lead ECG will be performed optionally at time points specified in protocol. Heart 
rate will be recorded from the ventricular rate and the PR, QRS, and QT (identify QTcB or QTcF) 
intervals will be recorded in the eCRF.  
2.1.4.7 Anti-sarilumab antibodies  
Samples analyzed in the antidrug antibody (ADA) assay will be categorized as either positive or 
negative. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 18 
ADA positive patient is defined as patient with at least 1 treatment-emergent or 
treatment-boosted ADA positive sample during the TEAE period, where 
• Treatment-emergent ADA positive patient is defined as a patient with non-positive assay 
(meaning negative or missing) response at baseline but with a positive assay response 
during the TEAE period. 
• Treatment-boosted ADA positive patient is defined as a patient with a positive ADA assay 
response at baseline and with at least a 4-fold increase in titer 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.  
2.1.5 Pharmacokinetics variables  
Sarilumab concentration will be collected at Day 1, 2 or 3 (only for patients with second dose), 
Day 4, 7, 15, 21 and 29 or early discharge.   
2.1.6 Biomarker and other variables  
Measurement of SARS-CoV-2 (Blood sample) or SARS-CoV-2 (NP swab), and the concentration 
of CRP, IL-6 and sIL-6R will be collected by schedule specified in protocol.  
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who met the inclusion criteria and signed the 
informed consent. 
Randomized patients consist of all patients with a signed informed consent form and randomized, 
regardless of whether the study drug was used. 
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 
• 
Randomized patients 
• 
Randomized but not treated patients 
• 
Randomized and treated participants  
• 
Patients who reached Day 29 (while still hospitalized) 
• 
Patients who did not reach Day 29 and the reasons 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 19 
• 
Patients who completed the follow-up (Day 60) 
• 
Patients who did not complete follow-up (Day 60) and main reason for not completing 
follow-up.  
In addition, the number (%) of patients screened, randomized, reached Day 29 and completed 
follow-up to Day 60 will be provided by country and site. 
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 group. 
Additionally, the analysis populations for safety, efficacy, per protocol, and 
PK/PD/Immunogenicity will be summarized in a table by patient counts based on the randomized 
populations (see definitions in Section 2.3). 
• 
ITT population (Randomized population)  
• 
Efficacy population (modified intention-to-treat (mITT)) 
• 
Per protocol population (PPS) 
• 
Safety population 
• 
PK population 
• 
ADA population 
2.2.1 Randomization and drug dispensing irregularities  
Randomization will be monitored throughout the study and reviewed on an ongoing basis. Any 
drug-dispensed wrongly will be identified and documented by manual deviation. 
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  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 2 - Randomization and Drug Allocation Irregularities  
Randomization and Drug Allocation Irregularities 
Erroneous treatment dispensation (will be identified by manual deviation) 
Kit not available 
Randomization by error 
Subject randomized twice 
Forced randomization 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 20 
2.3 
ANALYSIS POPULATIONS  
Enrolled population are all patients who sign the inform consent form (ICF). 
Randomized population are all randomized patients regardless of IMP was administered.  
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  
2.3.1.1 Intent–to-treat/Modified intent-to-treat population  
The intent-to-treat population (ITT) is the randomized population analyzed according to the 
treatment group allocated by randomization.  
The modified intention-to-treat (mITT) population includes all randomized patients who received 
at least one dose of the study drug. Analysis of the mITT population will be done according to the 
initial treatment assigned to the patient (as randomized). The mITT population will be the primary 
population for analysis of primary and secondary efficacy endpoints, as well as for data including 
(but not limited to) demographics and baseline characteristics. 
2.3.1.2 Per-protocol population  
The Per Protocol population set (PPS) includes all ITT patients who did not have any relevant 
major protocol deviations, eg, patients who are randomized and treated, but do not have 
laboratory-confirmed SARS-CoV-2 infection will be excluded from PPS. The final determination 
of the exclusion of patients from the PPS will be made prior to the primary database lock.  
Analysis of the PPS will be done according to the treatment the patient received. The PPS will be 
used as sensitivity analysis for the primary efficacy endpoint. 
2.3.2 Safety population  
The safety population includes all randomized patients who received at least one dose of the study 
drug. Analysis of the Safety population will be done according to the treatment received (as 
treated). 
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 1 IMP during the trial, the treatment group allocation for 
as-treated analysis will be the treatment group for which the patient received the first dose.  
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 21 
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 PK population  
The PK analysis population includes all patients who received any study drug and who had at 
least 1 non-missing serum concentration available for PK analysis following the first dose of 
study drug. 
2.3.4 ADA population  
The ADA population includes all patients who had at least 1 post-baseline valid ADA sample 
following the first dose of study drug. 
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 mITT populations. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups 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 Concomitant medications  
Concomitant 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.  
Investigational medications are not coded, a category ‘Investigational medications’ will be used 
for these medications if applicable. The tables for concomitant medications will be sorted by 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 22 
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.  
A listing of rescue medications will be provided including the following information:  
• 
Start and end dates 
• 
WHODD Preferred term 
• 
Dose, unit and route 
• 
ATC level 2 and ATC level 4 
2.4.3 Extent of investigational medicinal product exposure and compliance  
2.4.3.1 Extent of investigational medicinal product exposure  
Patients will receive a single dose of study drug on Day 1.  Patients may receive a second dose 
with study drug (based on the original treatment group assigned) 24 to 48 hours after the first 
dose, if they meet prespecified criteria. 
Duration of IMP exposure will be analyzed by summarizing the number of doses patient received 
by treatment group in the safety population.  
A listing will be provided for all study drug administered including the following information: 
• Infusion rate (units: mL/h) 
• Side and location of drug administration 
• Start and end time 
• Duration of intravenous infusion 
• total dose injected (yes/no) 
− If no and not related to any AE, reason for not administration of total planned dose 
(Device problem, patient decision, other) 
• Evidence of infusion reaction 
• infusion interruptions 
− If yes, whether re-administered (yes/no) 
2.4.3.2 Compliance  
The percentage of compliance, defined as the number of patients who fully completed infusion of 
the first study drug divided by number who received study drug, will be presented by treatment 
group based on the safety population.  
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 23 
2.4.4 Analyses of efficacy endpoints  
Table 3 below summarizes the analyses for each type of efficacy endpoints in general. 
Table 3 – Summary of analyses for each type of efficacy endpoint  
Type of endpoint 
Statistical method 
Graphical presentation 
Time-to-event 
Log-rank test (stratified) 
Cox-PH model (stratified) 
KM curve 
% of patients over time 
CMH test (stratified) 
Descriptive statistics 
Bar plot over time 
% of patients at end 
CMH test (stratified) 
Descriptive statistics 
Bar plot 
Continuous variable over time ANCOVA model 
Descriptive statistics 
Line plot over time 
Continuous variable at end 
ANCOVA model 
Descriptive statistics 
 
Histogram 
For time to event analysis, the time to event duration is calculated as:  
 
Date of first occurrence/episode of the event – date of first dose + 1. 
2.4.4.1 Analysis of primary efficacy endpoint(s)  
The primary efficacy analysis will be pairwise comparisons between sarilumab doses (400 mg and 
200 mg) and placebo with respect to the primary endpoint, time to improvement of 2 points in 
clinical status assessment from baseline using the 7-point ordinal scale, using a log-rank test 
stratified by randomization stratum with treatment as a fixed factor in the mITT population. 
P-values for the pairwise comparison of each sarilumab dose versus placebo will be provided. 
Hazard ratios for the estimation of treatment effect of each sarilumab dose compared to placebo 
will be provided using Cox proportional hazards model stratified by the randomization stratum 
with treatment as a covariate, along with 2-sided confidence intervals. Kaplan-Meier (KM) plot 
and the median time-to-improvement of 2 points will also be provided by treatment groups. 
Superiority of sarilumab over placebo will be declared if the null hypothesis is rejected at the 5% 
(2-sided) significance level following the multiplicity control procedure specified in  
Section 2.4.4.3. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 24 
Patients who have an improvement of 2-points in clinical assessment or discharge (other than 
death) will be considered as events, while patients who do not experience improvement of 
2-points will be censored at the last observation time point. Patients who take rescue medication 
in the study without improvement of 2-points before that will be censored at the date of rescue 
medication started. 
In addition, the proportion of patients with at least 2-point improvement from baseline at each day 
post-baseline will be provided using descriptive statistics. Graphical presentations (bar charts) will 
be used to examine trends over time. 
The analyses using the log-rank test and Cox PH model specified above will be repeated for the 
severe patients and critical patients at baseline as recorded on CRFs. 
Baseline clinical status is defined as the worse (lower) value of screening visit and Day 1 prior to 
dosing. If there is a tie, flag Day 1 as baseline. Baseline values are 2, 3, 4, 5, or 6.  Values 1 and 7 
do not apply (if 1 or 7 appear, then data query is needed.)   
Post-baseline clinical status values range from 1 through 7 on ordinal scale and data will be as 
recorded on the ordinal scale eCRF.   
Handling of death or discharge on clinical status assessment (post-baseline) 
For patients who die, the clinical status recorded on the day of death will be replaced with 
“1=Death” and this value will be carried forward for all subsequent study days until end of study 
(Day 60).  Death date may be obtained from Adverse Events or Disposition CRFs or phone call at 
Day 60 (end of study).   
For patients who discharge early (other than death), the clinical status recorded on the earliest 
hospital discharge date will be replaced with 7 (not hospitalized), and this value will be carried 
forward for all subsequent study days until end of study (Day 60). Hospital discharge information 
(discharge date and discharge reason) may be obtained from the Discharge Reason eCRF.  If there 
is subsequent hospitalization, the clinical status will not be replaced by 7 after the second 
hospitalization. 
Handling of missing data on clinical status assessment (post-baseline) 
For patients who are alive and not discharged (ie, still hospitalized), missing clinical status value 
(ordinal scale) on a given study day will be imputed using data on the type of oxygen delivery 
device used by the patient on that day (last type of device used if multiple types were used in a 
day).  
Clinical status = 2 (if using invasive mechanical ventilation or ECMO), or  
                        = 3 (if using non-invasive mechanical ventilation or high-flow nasal cannula), or  
                        = 4 (if using nasal cannula, simple face mask, or non-rebreather face mask) or  
                        = 5 (if not using supplemental oxygen) 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 25 
Sensitivity analysis 
The PPS and ITT will be used for sensitivity analysis of the primary efficacy endpoint, as 
described above. 
Subgroup analyses 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment effect 
of each sarilumab dose versus placebo by the following variables: 
• 
Age (<median, >=median) 
• 
Age group (≥18 and <64, ≥65 and <84, ≥85 years) 
• 
Sex (Male, Female) 
• 
Race (White, Black or African American, Asian, Other). Note: Japanese will be grouped 
with Asian, a group with less than 5 patients in any treatment may be grouped with ‘Other’ 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• 
Severity of illness (per IRT) (Severe, Critical)  
• 
Severity of illness (as recorded on CRFs) (Severe, Critical)  
• 
Systemic corticosteroids use (per IRT) (Yes, No) 
• 
Systemic corticosteroids use (as recorded on CRFs) (Yes, No) 
• 
Fever status at baseline (Yes, No) 
• 
Pneumonia present based on historical chest X-Ray, CT scan or MRI or lung auscultation 
(Yes, No) 
• 
Any symptom of Fever, Cough, or Dyspnea (Yes, No) 
• 
Time from dyspnea onset to baseline (<=5 days, >5 days). Note: patients with no dyspnea 
will be classified as <=5 days 
• 
SpO2/FiO2 ratio (<median, >=median) 
• 
CRP level (<median, >=median) 
• 
Duration of hospitalization prior to first dose (<7 days, >=7 days);  
• 
Number of study drug administration (1, 2) 
Additional subgroups may be added as needed. The treatment effects will be estimated using 
hazard ratio (sarilumab compared to placebo) in the subgroups using the same analysis model as 
for the primary efficacy endpoint as described previously (without stratification factor for the 
stratification-related subgroups). In addition, p-value for the interaction of treatment by subgroup 
effect will be provided. Graphical presentation of the results (ie, forest plot) for each sarilumab 
dose versus placebo will also be provided.  
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 26 
2.4.4.2 Analyses of secondary efficacy endpoints  
Key secondary endpoint 
The percentage of patients alive at Day 29 will be analyzed using Cochran-Mantel-Haenszel 
(CMH) test stratified by randomization strata of severity of illness and corticosteroid use in the 
mITT population. The difference in proportions of patients for each Sarilumab dose compared to 
placebo (sarilumab - placebo), along with associated 2-sided 95% confidence levels, and p-value 
will be provided.  
Superiority of sarilumab over placebo will be declared if the null hypothesis is rejected at the 5% 
(2-sided) significance level following the multiplicity control procedure specified in  
Section 2.4.4.3. 
In addition, bar plot for the proportion of patients alive at Day 29, KM curves for the overall 
survival will be provided by treatment group. Hazard ratios for the estimation of treatment effect 
of each sarilumab dose compared to placebo will be provided using Cox proportional hazards 
model stratified by the randomization stratum with treatment as a covariate, along with 2-sided 
confidence intervals. 
These analyses will be repeated for the severe patients and critical patients at baseline as recorded 
on CRFs. 
Other secondary endpoints 
Details for analyses and derivation of the variables associated with the other secondary endpoints 
specified in Section 2.1.3.2 are detailed below. 
7-point ordinal scale 
The percent of patients with each category of the 7-point ordinal scale observed value at each day 
will be summarized using descriptive statistics. Graphical presentations (stacked bar charts) will 
also be used to examine trends over time. 
Analysis of endpoint #1: proportion of patients with one-point improvement from baseline  
Proportion of patients with at least 1-point improvement from baseline at Day 4, 7, 15, 21, and 29 
will be analyzed using the same analysis model as for the key secondary endpoint as described 
previously. Graphical presentations (bar charts) will be used to examine trends over time. 
Analysis of endpoint #2: Mean change in 7-point ordinal scale from baseline 
Changes from baseline in the 7-point ordinal scale for Day 4, 7, 15,21, 29 (or until discharge) will 
be analyzed using an ANCOVA model with treatment group and randomization strata as fixed 
effects and baseline value as a covariate. The least squares (LS) treatment mean difference from 
placebo with standard error, along with corresponding 95 % confidence interval and p-value will 
be provided.  Graphical presentations (line plot with mean and error bar) will also be used to 
examine trends over time using mean values (±SE) and mean changes from baseline (±SE).  
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 27 
The 7-point ordinal scale at each day and their changes from baseline will also be summarized for 
each treatment group through descriptive statistics including mean, median, standard deviation, 
minimum and maximum.  
Fever 
Body temperature is collected using varying methods (the routes in eCRF are axillary, auricular, 
oral, rectal) at multiple timepoints each day.  
Baseline body temperature is defined as the highest temperature at any time prior to first dose. 
Post-baseline body temperature is defined as the highest temperature from each day among all 
temperatures from different timepoints (morning, evening, etc).  
Patients body temperature and its change from baseline will be summarized at each day by 
treatment group by timepoint over the study period. Graphical presentations (line plot with mean 
and error bar) will also be used to examine trends over time using mean values (±SE) and mean 
changes from baseline (±SE). 
All temperatures will be converted to oral values as following: 
• 
Rectal/Auricular subtract 0.6 deg C = Oral deg C 
• 
Axillary add 0.6 deg C = Oral deg C 
Analysis of endpoint #3: time to resolution of fever 
Resolution of fever is defined as body temperature (≤36.6°C [axilla], or ≤37.2 °C [oral], or 
≤37.8°C [rectal or auricular]) for at least 2 consecutive days without antipyretics or until 
discharge, whichever is sooner.  
The analysis will be performed similarly to the primary endpoint.  
Patients who achieved resolution of fever or discharge (other than death) will be considered as 
events, while patients who do not experience resolution of fever will be censored at the end of 
study. Patients who started rescue therapy or died in the study will not be considered as having an 
endpoint event and will be censored at the earlier date of death or rescue therapy start date. 
Patients who do not have fever at baseline will be censored at the first dose date.  
Analysis of endpoint #5: the number of days with fever 
Fever is defined as body temperature >37.4°C (axillary), or >38°C(oral), or >38.4°C (rectal or 
auricular). 
The number of days with fever will be analyzed using the ANCOVA model with treatment group 
and randomization strata as fixed effects for patients alive by Day 29. The LS treatment mean 
difference from placebo with standard error, along with corresponding 95 % confidence interval 
and p-value will be provided.   
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 28 
Summary statistics with mean, median, standard deviation, minimum and maximum will be 
provided. Histogram will be provided to illustrate the distribution of days with fever. 
In addition, the percent of days with fever (100*number of days with fever divided by number of 
days of follow-up, defined as the earlier date of death or discharge or last visit up to Day 29) for 
all patients, will be analyzed using the ANCOVA model with treatment group and randomization 
strata as fixed effects. 
Improvement in Oxygenation 
Improvement in oxygenation is defined as increasing in SpO2/FiO2 of 50 or greater compared to 
the nadir SpO2/FiO2. Nadir SpO2/FiO2 is the nadir (lowest value) at any point in the study, and 
looking forward, an improvement in oxygenation is increase of 50 or greater from nadir value for 
at least 48 hours. If nadir is observed on 2 or more different days post baseline, the day of the first 
occurrence of nadir will be used.  
Baseline SpO2/FiO2 ratio is defined as the last available ratio prior to first dose. 
Post-Baseline SpO2/FiO2 ratio is defined as the worst (minimum) value in each day. 
For derivation of FiO2, please see conversion table in Section 2.5.2. 
Analyses of endpoint #4: time to resolution of fever and improvement in oxygenation, 
                                   #9: time to improvement in oxygenation, and  
                                   #14: time to saturation >=94% on room air 
The analysis of these endpoints will be performed similarly to the primary endpoint.  
Patients who do not experience the event under analysis will be censored at the last observation 
time point. Patients who die or take rescue medication in the study without experiencing the event 
will be censored at the earlier date of death or rescue medication started. 
Analyses of endpoint #11: days of hypoxemia,  
                                   #12: days with supplemental oxygen use,  
                                   #13: days of resting respiratory rate >24 breaths/min, and  
                                   #15: ventilator free days in the first 28 days 
The analysis of these endpoints will be performed using the ANCOVA model with treatment 
group and randomization strata as fixed effects for patients alive by Day 29. The LS treatment 
mean difference from placebo with standard error, along with corresponding 95 % confidence 
interval and p-value will be provided. Patient discharged early will be considered as ventilator free 
until the next hospitalization (if applicable). 
Summary statistics with mean, median, standard deviation, minimum and maximum will be 
provided. Histogram will be provided to illustrate the distribution. 
In addition, the percent of days with each endpoint (100*number of days with the endpoint 
divided by number of days of follow up, defined as the earlier date of death or discharge or last 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 29 
visit up to Day 29) for all patients, will be analyzed using the ANCOVA model with treatment 
group and randomization strata as fixed effects. 
Analyses of endpoint #10: % of patients alive off oxygenation at Day 29, and  
                                    #16: % of patients with initiation of mechanical ventilation, non-invasive 
ventilation, or use of high flow nasal cannula, and 
These endpoints will be analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by 
randomization strata. The difference in proportions of patients for each Sarilumab dose compared 
to placebo (sarilumab - placebo), along with associated 2-sided 95% confidence levels, and 
p-value will be provided.  
Bar plots will also be provided to illustrate the difference among treatments. 
NEWS2 
Please find NEWS2 score calculation and details in Section 2.5.2. 
Analyses of endpoint #6: Time to change in National Early Waring Score 2 (NEWS2) from 
baseline, and  
                                   #7: Time to NEWS2 of <2 and maintained for 24 hours 
The analysis for time to change in NEWS2 from baseline will be performed by evaluating the 
proportion of patients with clinical risk over time in each category (Low: 0-4; Low-medium: 3 in 
any individual parameter; Medium: 5-6; High: ≥7). The pattern of patients in the categories 
shifting from baseline and over time will be examined with no formal testing. 
The time to NEWS2 < 2 and maintained for 24 hours endpoint will be analyzed similarly to the 
primary endpoint. 
Patients who do not experience endpoint event under analysis will be censored at the last 
observation time point. Patients who die or take rescue medication in the study without 
experiencing the event will be censored at the earlier date of death or rescue medication started.  
Analyses of endpoint #8: Mean change from baseline to Day 4, 7, 15, 21, 29 in NEWS2 
Change from baseline in NEWS2 score at Day 4, 7, 15, 21, and 29 will be analyzed using an 
ANCOVA model with treatment group and randomization strata as fixed effects, and baseline 
value as a covariate. The least squares (LS) treatment mean difference from placebo with standard 
error, along with corresponding 95 % confidence interval and p-value will be provided.  Graphical 
presentations (line plot with mean and error bar) will also be used to examine trends over time 
using mean values (±SE) and mean changes from baseline (±SE).  
NEWS2 score at each day and their changes from baseline will be summarized for each treatment 
group through descriptive statistics including mean, median, standard deviation, minimum and 
maximum.  
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 30 
ICU use, rescue medication, hospitalization and other 
Analyses of endpoint #17: % of patients requiring rescue medication during the 28-day period, 
                                   #18: % of patients with ICU use (among those not in an ICU at baseline) 
These endpoints will be analyzed using a CMH method stratified by randomization strata. The 
difference in proportions of patients for each Sarilumab dose compared to placebo (sarilumab - 
placebo), along with associated 2-sided 95% confidence levels, and p-value will be provided.  
Bar plots will be provided to illustrate the difference among treatments. Summary of 
immunosuppressive medications used as rescue therapy over time will also be provided. 
Analyses of endpoint #19: Days of hospitalization among survivors 
Analysis of days of hospitalization among survivors will be performed using the ANCOVA model 
with treatment group and randomization strata as fixed effects. The LS treatment mean difference 
from placebo with standard error, along with corresponding 95 % confidence interval and p-value 
will be provided.   
Summary statistics with mean, median, standard deviation, minimum and maximum will be 
provided. Histogram will be provided to illustrate the distribution. 
In addition, the percent of patients died or “on a ventilator”, off oxygenation, and discharged will 
be summarized by treatment overtime, respectively. The time from first dose to discharge will 
also be summarized. 
2.4.4.3 Multiplicity issues  
Multiplicity will be controlled for the primary analysis (ie, Day 29). Final analysis (ie, Day 60) 
will be supportive. 
For the primary and key secondary endpoints, multiplicity will be controlled via a hierarchical 
testing procedure in the following order:  
1. Primary endpoint sarilumab 400 mg versus placebo 
2. Key secondary endpoint sarilumab 400 mg versus placebo 
3. Primary endpoint sarilumab 200 mg versus placebo 
4. Key secondary endpoint sarilumab 200 mg versus placebo 
If one sarilumab dose is discontinued for safety reasons, then all comparisons versus placebo for 
that dose will be removed and the remaining comparisons will be tested in the order specified 
above.  
2.4.5 Analyses of safety data  
The summary of safety results will be presented by treatment group. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 31 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
The baseline value 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 (see Appendix A) 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event 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. 
• 
Selected safety analyses will be summarized by age group, gender, racial subgroups, and 
any pertinent subgroups as appropriate (eg, number of doses administered). 
2.4.5.1 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pretreatment and posttreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or posttreatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or posttreatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will be sorted by SOC internationally agreed order and HLGT, 
HLT, PT by alphabetic order. For adverse event incidence tables presented by SOC and PT, they 
will be sorted by the internationally agreed SOC order and by decreasing incidence of PTs based 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 32 
on the Sarilumab 400 mg IV group within each SOC, for the number (n) and percentage (%) of 
patients experiencing an adverse event.  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. 
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• 
Overview of treatment-emergent adverse events, summarizing total number or number (%) 
of patients with any 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
- 
Severe treatment-emergent adverse event 
- 
AESI 
- 
Treatment-emergent adverse event leading to death 
- 
TEAE leading to study drug interruption or discontinuation  
• 
All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing the 
number (%) of patients with at least 1 treatment-emergent adverse event. 
• 
All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event. 
• 
All treatment-emergent adverse events by primary SOC, PT and CTC grade, showing the 
number (%) of patients with at least 1 treatment-emergent adverse event. 
• 
All treatment-emergent adverse events regardless of relationship and related by primary 
SOC and PT, showing the number (%) of patients with at least 1 treatment-emergent 
adverse event. 
• 
All treatment-emergent adverse events leading to study drug interruption or 
discontinuation by Primary SOC and PT, showing the number (%) of patients with at least 
1 treatment-emergent adverse event. 
Analysis of all treatment emergent serious adverse event(s) 
• 
All treatment-emergent serious adverse events by primary SOC and PT showing the 
number (%) of patients with at least 1 serious treatment-emergent adverse event. 
• 
All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, and PT, showing the number (%) of patients with at least 1 
treatment-emergent serious adverse event.   
Analysis adverse event of special interest 
Unless otherwise specified, AESI will be summarized during the TEAE period by prespecified- 
grouping (AE category of interest), showing the number (%) of participants, sorted by decreasing 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 33 
frequency of PT. In addition, summary of TEAE of infusion reactions, ALT increase, and 
infection events will be provided. 
Listings of all adverse events, serious adverse events and AESIs during the study will be 
provided. 
2.4.5.2 Deaths  
The following summaries of deaths will be generated for the safety population. 
• 
Number (%) of patients who died during the study 
• 
Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC and PT. 
Listing will be provided for all deaths with flags indicating TEAE period or post-treatment period 
status.  
2.4.5.3 Analyses of laboratory variables  
Hematology, blood chemistry and urinalysis are performed in local laboratories in this study. 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
laboratory variables (laboratory values and changes from baseline) will be calculated for each visit 
or study assessment (baseline, each post baseline time point, endpoint) by treatment group.  This 
section will be organized by biological function as specified in Section 2.1.4.3. 
The incidence of PCSAs (list provided in Appendix A) at any time during the treatment-emergent 
adverse event 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 
The incidence of abnormal laboratory values at any time during the TEAE period will be 
summarized in shift tables by biological function and treatment group whatever the baseline level 
and/or according to the following baseline status categories:  
• 
Normal/Missing 
• 
Abnormal high according to the normal range 
• 
Abnormal low according to the normal range 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
For bacterial infection testing, results will be summarized as number of patients (counts and 
percent) with negative and positive levels by treatment group. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 34 
2.4.5.4 Analyses of vital sign variables  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital sign variables (vital signs values and changes from baseline) will be 
calculated for each visit or study assessment (daily from baseline to Day 29) by treatment group.   
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment group irrespective of 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 for patients with at least one post-baseline PCSA values. 
2.4.5.5 Analyses of physical examination  
Physical examination data which is only collected at screening will not be summarized. 
2.4.5.6 Analyses of electrocardiogram variables  
Listing of patient ECG variables at screening will be provided. 
2.4.5.7 Analyses of anti-sarilumab antibodies  
The following summary will be provided separately for ADA positive patient, ADA negative 
patient. 
ADA prevalence and titer 
The following summary will be provided based on the ADA population: 
• Number (%) of patients with an ADA positive sample at baseline 
o 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 population during TEAE period: 
• 
Number (%) of ADA-negative patients 
• 
Number (%) of ADA-positive patients 
- 
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. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 35 
- 
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 treatment-boosted ADA positive patients.  
- 
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.  
Plot of percentage of patients with treatment-emergent ADA positive response at each visit will be 
provided by treatment group. 
Listing for ADA status will also be provided.  
ADA and PK 
Descriptive summary of sarilumab concentrations in serum will be provided by ADA patient 
classifications (positive or negative) over time for the sarilumab treatment group by number of 
sarilumab doses. 
ADA and clinical efficacy 
The primary and key secondary efficacy endpoints will be analyzed by ADA patient 
classifications (positive or negative).   
ADA and clinical safety 
The safety assessment will focus on the following events: 
• 
Hypersensitivity (standardized MedDRA query (SMQ): Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
• 
IV infusion reaction (HLT: IV infusion reaction) 
• 
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.  
2.4.6 Analysis of pharmacokinetics  
Analysis of drug concentration data:  
The concentrations of sarilumab over time and pharmacokinetic parameters, as appropriate, will 
be summarized using descriptive statistics by treatment group and number of sarilumab doses 
using the PK population.  
No formal statistical hypothesis testing will be performed. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 36 
2.4.7 Analysis of Pharmacodynamic and Exploratory Biomarker Data:  
The concentrations of CRP, IL-6, and sIL-6R over time will be summarized using descriptive 
statistics by treatment group using the safety population. The analysis will include: 
• 
Observed value, change from baseline and percent change from baseline by each sampling 
point through Day 29 /EoS. 
• 
The figures of mean ± standard error (SE) versus scheduled sampling time points. 
In addition, ANC will be analyzed similarly.  
As an exploratory analysis, the percentage of patients with SARS-CoV-2 positive (either 
nasopharyngeal swab or PCR) over time will be summarized using the safety population.   
The relationship between d-dimer, ferritin, LDH, IL-6, neutrophil:lymphocyte ratio and the 
clinical assessment using the 7-point ordinal scale will be explored. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computations of parameters. 
Demographic formulas: 
Age at baseline is calculated as follows: 
Age = (informed consent date – birth date)/365.25 
BMI is calculated as follows: 
BMI = Weight in kg/(height2 in meters). 
2.5.2 Data handling conventions for secondary efficacy variables  
SpO2 
If SpO2 is missing, then that value will be imputed using last observation carried forward. 
FiO2 
FiO2 will be derived as following. 
• 
For high flow nasal cannula, non-invasive ventilation, invasive ventilation, use FiO2 as 
reported on eCRF. 
• 
For Nasal cannula, simple face mask, non-rebreather face mask, FiO2 will be converted based 
on below table.  
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 37 
 
Method 
Oxygen flow rate 
O2 flow (l/min) 
Fraction of Inspired Oxygen [FiO2] (%) 
Nasal cannula 
1 
24 
 
2 
28 
 
3 
32 
 
4 
36 
 
5 
40 
 
6 
44 
 
>=7 
(O2*4) + 20.  Maximum will be 100 
Simple face mask 
5 
40 
 
6 
50 
 
7 
55 
 
8 
60 
 
9 
65 
 
>=10 
70 
Non-rebreather face 
mask 
<6 
60 
 
6 
60 
 
7 
70 
 
8 
80 
 
9 
90 
 
10 
95 
 
>=10 
95 
Note: If FiO2 data is entered in the CRF for above devices, ignore value and derive as 
above. Some values for FiO2 (not in the source table) are imputed according to a trend. 
• 
If ‘Other’ oxygen device, use FiO2 value if reported on eCRF. Otherwise, keep missing.  
• 
If patient receives ECMO, alone or in combination with any other oxygen supplementation, 
use FiO2 for ECMO only reported on eCRF.   
• 
If patient is not on supplemental oxygen, impute with FiO2=21%.   
NEWS2 
NEWS2 consists of 6 physiological parameters collected in various eCRF forms:  
• Consciousness  
• Respiratory rate  
• Oxygen saturation (SpO2)  
• Pulse rate  
• Systolic blood pressure  
• Temperature  
In addition, information on whether patients require supplemental oxygen and whether patient 
experienced chronic hypercapnic respiratory failure (collected in Pneumonia Status at Screening 
form) are required in the calculation of the NEWS2 score. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 38 
Calculation of NEWS2 score 
NEWS2 score is calculated according to below chart. 
• For patients with a history of or current chronic hypercapnic respiratory failure, use the 
dedicated section (SpO2 Scale 2) in the chart.  
• For patients who received oxygen supplementation, the score is uplifted by 2 points. 
 
NEWS2 thresholds and triggers 
 
Imputation for NEWS2 component 
If any component (physiological parameter) is missing, then that value will be imputed using last 
observation carried forward. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 39 
2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of 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, concomitant, and posttreatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
treatment or after the treatment-emergent adverse event period, the adverse event will be 
classified as treatment-emergent.  No imputation of adverse event 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 adverse event resolution. 
Handling of adverse events 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 adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events.  
The exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of missing assessment of 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 adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
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 potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 40 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
Handling of missing discharge date 
If a patient was discharged but the discharge date was missing, impute with last visit date. 
2.5.4 Windows for time points  
Visit windows based on days relative to the first IMP dose will be used to map the lab 
measurements to each scheduled visit (see Appendix B). The following rule will be applied when 
mapping the measurements to the visit: 
1. For the same laboratory parameter, 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).  
2. When a patient has more than one measurement on the same lab parameter (or vital sign) 
on the same date, then the one with the later/largest sample ID will be used. 
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data and vital signs will be used in PCSA analysis, 
computation of baseline, and will also be assigned to the appropriate visit window for the by-visit 
summaries. 
2.5.6 Pooling of centers for statistical analyses  
Not applicable. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 41 
3 
INTERIM ANALYSIS  
An interim analysis is planned to be performed when approximately 50% of total planned number 
of patients (~200) are randomized. The efficacy endpoints will be analyzed using the same 
methods described in the efficacy analyses section (Section 2.1.3). The key secondary endpoint 
will be modified to be the percent of patients alive at Day 15. 
The purpose of the interim analyses is to obtain an understanding of the possible drug effect in the 
population under study.  An administrative alpha of 0.001 will be spent at interim analysis. Due to 
the conservative amount of alpha spent at interim, no alpha adjustment will be made for the 
primary analysis when the last patient randomized of the whole study reaches Day 29 (or planned 
Day 29 if the patient is discharged or leaves the study early), or the supportive final analysis at 
Day 60. 
The interim analyses will be performed by an external statistical analysis center which is separate 
from personnel involved in the trial conduct. The unblinded results can only be viewed by a small 
group of senior sponsor individuals, who are separate from sponsor personnel involved in the 
conduct of the study. People involved in the conduct of the study (Patients, Investigators, Study 
Team, and Project Team) will have no access to the interim analysis results. Sponsor may decide 
to make changes to the dose and/or alter disease category based on the interim results. 
The interim analysis is planned to mainly include the following: 
• Demographics and baseline characteristics  
• 7-point ordinal scale (observed value and change from baseline category, time to 
improvement of at least two points, proportion of patients with at least 2-point 
improvement)  
• Patient survival status 
• Overview of TEAE 
• Number of patients with SAE  
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 42 
4 
DATABASE LOCK  
The primary analysis is planned when the last patient randomized reaches Day 29 (or planned 
Day 29 if the patient is discharged or leaves the study early). Final analysis will be performed at 
study end (ie, Day 60). 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 43 
5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 44 
6 
REFERENCES  
Not applicable. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 45 
7 
LIST OF APPENDICES  
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
Visit Windows based on day ranges 
Appendix C: 
AESI and search criteria 
 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 46 
Appendix A 
Potentially clinically significant abnormalities 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. 
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. 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 47 
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 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
 
Additional analysis*: 
>1.5 ULN 
>2 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
PCSA to be retrieved manually 
Unconjugated bilirubin 
Additional analysis*: 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
CPK** 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 48 
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 
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 
 
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 
 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 49 
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 
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. 
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) 
 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 50 
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 
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. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 51 
Appendix B 
Visit windows based on day ranges  
Table 4 – Time window for lab summaries  
Visit Label 
Target Day 
Hematology, Chemistry 
Bacterial infection testing 
Daily follow-up until hospital discharge or Day 29 
 
Baseline 
1 
≤1 
 
Day 4  
4 
2-5 
 
Day 7 
7 
6-10 
2-10 
Day 15 
15 
11-17 
≥11 
Day 21 
21 
18-24 
 
Day 29 
29 
≥25 
 
 
 
 
 
 
VV-CLIN-0581573 3.0


Statistical Analysis Plan  
05-May-2020 
SAR153191-EFC16844 - sarilumab 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 52 
Appendix C 
AESIs and search criteria  
Table 5 – AESIs and search criteria  
AESI flag 
Searcha criteria 
Grade ≥2 infusion related reactions 
Any Grade ≥2 (moderate) TEAE of infusion related reactions within 24 hours 
from the start of study drug infusion based upon CRF checkbox: Infusion 
Reaction and Yes to AESI event and Severity Grade ≥2. 
Grade ≥2 hypersensitivity reactions 
SMQ: Anaphylactic reaction, Hypersensitivity or Angioedema and Grade ≥2 
(moderate) 
Grade 4 neutropenia 
ANC <500/mm3 and CRF checkbox: Yes to AESI event 
Grade 4 neutropenia with concurrent 
invasive infectionb 
ANC <500/mm3 and Primary SOC: Infections and infestations within 1 week of 
ANC <500/mm3 
Invasive bacterial or fungal infectionc 
Primary SOC: Infections and infestations 
Alanine transaminase (ALT) increase 
CRF checkbox: ALT Increase and Yes to AESI event 
Overdosed 
CRF checkbox:  Symptomatic overdose 
TEAE: Treatment-emergent adverse event 
a All SMQs are narrow search 
b Patients having both a Grade 4 Neutropenia and a concurrent infection event will be further reviewed by the medical team to confirm that 
the infection event is invasive. 
c Patients identified as having an infection event will be further reviewed by the medical team to confirm that the infection is invasive. 
d Standard AESI applies to all Sanofi studies 
 
VV-CLIN-0581573 3.0


Signature Page for VV-CLIN-0581573 v3.0
efc16844-16-1-9-sap
Approve & eSign
Clinical
Approve & eSign
VV-CLIN-0581573 3.0