Clinical trial NCT04380961
Conditions: Critical Confirmed Coronavirus Disease (COVID)-19
Sponsor: Janssen Pharmaceutica N.V., Belgium
Start date: 2020-04-24; Completion date: 2021-06-24
Enrollment: 212 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the clinical response of sirukumab (administered as a single intravenous dose) plus standard of care (SOC) compared to placebo plus SOC in COVID-19.

Detailed description:
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is an enveloped, positive-sense, single-stranded ribonucleic acid (RNA) betacoronavirus. Symptoms of COVID-19 infection may appear from 2 to 14 days following exposure, with the spectrum of illnesses ranging from mild symptoms to severe illness or death. The identification of SARS-CoV-2 follows the emergence of 2 other novel betacoronaviruses: SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. While an understanding of the epidemiology and clinical spectrum of COVID-19 is still evolving during the ongoing pandemic, the current knowledge of the disease burden highlights the urgent medical need to develop a treatment. Sirukumab (also known as CNTO136) is a human anti-interleukin (IL)-6 immunoglobulin G1 kappa (IgG1k) monoclonal antibody (mAb). Sirukumab binds with high affinity and specificity to human IL-6 and as a result inhibits IL-6-mediated signaling and the biological effects of IL-6. The study will include a Screening Phase (up to 1 Day), a Treatment Phase (Day 1 to Day 28) and a Follow-up Phase (post Day 28, follow-up phone calls on Week 8, Week 12 and Week 16). Safety evaluations will include monitoring of adverse events and serious adverse events, physical examinations, vital sign measurements, electrocardiograms, clinical laboratory tests, pregnancy testing, and checking of vital status. The entire study duration for each participant will be 16 weeks.

Arms: arm 1: Participants will receive single intravenously (IV) dose infusion of sirukumab on Day 1 along with standard of care treatment. arm 2: Participants will receive IV single dose infusion of placebo on Day 1 along with standard of care treatment.
Interventions: intervention 1: Sirukumab intervention 2: Placebo intervention 3: Standard of Care (SOC)
Intervention descriptions: intervention 1: Participants will receive single dose infusion of sirukumab on Day 1. intervention 2: Participants will receive placebo IV single dose infusion on Day 1. intervention 3: SOC treatment will be determined by the investigator based on local practice and consists of supportive care.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 17 February 2021
Janssen Research & Development *
Clinical Protocol
Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and 
Safety of Sirukumab in Confirmed Severe or Critical COVID-19 Disease
Protocol CNTO136COV2001; Phase 2
AMENDMENT 5
CNTO136  (sirukumab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, 
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used 
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact 
Information page that accompanies the protocol.  
EudraCT NUMBER:         2020-003056-32
Status:
Approved
Date:
17 February 2021
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
EDMS number:
EDMS-ERI-207794964, 13.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04380961


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 17 February 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 5
This document
Amendment 4
15 September 2020
Amendment 3
23 July 2020
Amendment 2
17 June 2020
Amendment 1
24 April 2020
Original Protocol
14 April 2020
Amendment 5 (This document)
Overall Rationale for the Amendment: The protocol has been amended to limit the study population to 
a subset of the currently eligible population, ie, those with confirmed critical COVID-19 disease.
Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
1.1 Synopsis
1.2 Schema
3 OBJECTIVES AND ENDPOINTS
4.1 Overall Design
4.2 Scientific Rationale for Study 
Design
5.1 Inclusion Criteria
8.1.1 Six-point Ordinal Clinical 
Recovery Scale
9.1 Statistical Hypotheses
9.2 Sample Size Determination
9.3 Populations for Analysis Sets
9.4.4 Other Secondary Endpoints
9.5 Interim Analysis
10.4.6 Committees Structure
The participants with confirmed severe 
COVID-19 disease will no longer be 
eligible for this study as the study 
population will be limited to participants 
with confirmed critical COVID-19 disease.
Definition of critical COVID-19 is more 
clearly defined under Sections 5.1 and 
8.1.1.
The primary objective of this study will
evaluate the clinical response of sirukumab 
(administered as a single IV dose) + SOC 
compared to placebo + SOC in confirmed 
critical COVID-19 disease.
Sample size and population in scope for the 
primary and the key secondary objectives
have been modified accordingly. Former 
primary and key secondary objective in 
confirmed severe or critical COVID-19 
disease become additional secondary 
objectives. All other secondary objectives
will be analyzed in the confirmed (a) 
critical
and 
(b) 
severe 
or 
critical 
COVID-19 disease.
Based on the rapidly evolving 
space of COVID-19 therapeutics 
focusing on the highly impacted 
population of critical patients 
together with the results from the 
interim 
analysis, 
the 
study 
population will be limited to a 
subset of the currently eligible 
population, 
ie, 
those 
with 
confirmed critical COVID-19 
disease. 
1.1 Synopsis
9.4.6 Safety Analyses
9.4.7 Other Analyses
10.1 Appendix 1: Abbreviations and 
Definitions
The increase of ALT or AST combined 
with 
increase
of
bilirubin 
will 
be 
investigated by means of evaluation of 
drug-induced 
serious 
hepatotoxicity 
(eDISH) plots.
Alignment with Statistical 
Analysis Plan.
Update on tables to be generated for the 
clinical laboratory tests.
Removal
of analysis of the physical 
examination.
The coefficient of variation (CV) will not 
be analyzed for the biomarker analysis.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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3
Status: Approved, Date: 17 February 2021
Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
1.2 Schema
1.3 Schedule of Activities (SoA)
5 STUDY POPULATION
8 STUDY ASSESSMENTS AND 
PROCEDURES
10.3 Appendix 3: Clinical and 
Laboratory Assessments Described per 
Day
The ECG assessment has been added in the 
protocol text for clarification. 
Minor update to allow more 
flexibility to assess eligibility, 
based on local standard of care 
practices.
Footnote 
g 
was 
added 
to 
the 
screening/baseline ECG assessment. 
5.2 Exclusion Criteria
Exclusion criteria based on medical history 
or 
on 
past/current 
medications 
are 
pragmatic 
criteria. 
Deviation 
post 
randomization from these criteria due to 
late awareness of medical history and/or 
comedications are not intended to be 
qualified as major protocol deviations.
Clarification.
6.1 Study Intervention(s)
Administered
Clarify that placebo is to be provided 
locally and not centrally.
Clarification since the study is 
not intended to be performed 
outside of the United States of 
America. 
6.2
Preparation/Handling/Storage/Account
ability
To remove details on the preparation, 
handling, and storage
of the study 
intervention.
To 
avoid 
errors 
on 
the 
preparation, 
handling, 
and 
storage of the study intervention, 
reference is made to the IPPI
only. 
6.8 Prestudy and Concomitant Therapy The use of bamlanivimab, and casirivimab 
plus imdevimab is disallowed during the 
study.
Per CDC guidelines, monoclonal 
antibodies are not considered to 
be 
standard
of
care 
for 
COVID-19. 
Administration of a COVID-19 vaccine 
during the study is not allowed at any time 
between screening and the discharge visit.
Per CDC guidelines, vaccination 
of persons with known current 
SARS-COV-2 infection should 
be deferred until the person has 
recovered from the acute illness.
For the purpose of this study, 
recovered from acute illness is 
considered 
as 
ready 
for 
discharge.
7.3 Lost to Follow-up
Clarify that publicly available vital status 
information is not to be documented when 
a participant has withdrawn consent. This 
participant will be considered lost to 
follow-up.
Clarification on the rules of data 
handling consistent with GCP.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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4
Status: Approved, Date: 17 February 2021
Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
8.1.1 Six-point Ordinal Clinical 
Recovery Scale
Edits are made to the 6-point ordinal 
clinical recovery scale to clarify that:
For 
participants
not 
hospitalized 
(category 1), a distinction will be 
made between participants 
discharged and in need of (score 1.2) or 
not 
in 
need of (score 1.1) oxygen 
supplementation as indicated by the 
investigator 
on 
the 
discharge 
questionnaire.
Regardless of the device used: 
Hospitalized participants with a FiO2
below 50% corresponds to a category 
3.
Hospitalized participants with a FiO2
of 50% or higher corresponds to a 
category 4.
Clarification on category 1.
Clarifications on categories 3 and 
4 to make category 3 fully 
consistent with category 4, which 
is using the FiO2 as a threshold 
and making the allocation to 
category 3 or 4 independent of 
the device used.
8.1.4 Supplemental Oxygen Use
Clarify that the use of CPAP at home for 
obstructive sleep apnea syndrome will not 
be reported as a need for supplemental 
oxygen information.
Clarification.
10.1 Appendix 1: Abbreviations and 
Definitions
Definitions 
of 
critical 
and 
severe 
COVID-19 disease have been added to the 
definitions of terms.
Clarification.
1.1 Synopsis
1.3 Schedule of Activities (SoA)
4.1 Overall Design
10.2 Appendix 2: Clinical Laboratory 
Tests
10.3 Appendix 3: Clinical and 
Laboratory Assessments Described per 
Day
Minor rewording.
Corrections for respiratory and vital signs 
assessments to be performed once weekly 
after Day 28 if still hospitalized.
Clarification. 
Throughout the protocol
Minor formatting and minor updates made. Minor errors were noted.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 17 February 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 7
1.
PROTOCOL SUMMARY ..................................................................................................................... 8
1.1.
Synopsis........................................................................................................................................... 8
1.2.
Schema .......................................................................................................................................... 17
1.3.
Schedule of Activities (SoA)........................................................................................................... 18
2.
INTRODUCTION................................................................................................................................ 25
2.1.
Study Rationale.............................................................................................................................. 25
2.1.1.
Background................................................................................................................................. 25
2.2.
Dose Rationale............................................................................................................................... 37
2.3.
Benefit-Risk Assessment ............................................................................................................... 38
2.3.1.
Risks for Study Participation....................................................................................................... 38
2.3.2.
Benefits for Study Participation .................................................................................................. 38
2.3.3.
Benefit-Risk Assessment for Study Participation ....................................................................... 39
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 40
4.
STUDY DESIGN ................................................................................................................................ 42
4.1.
Overall Design................................................................................................................................ 42
4.2.
Scientific Rationale for Study Design............................................................................................. 43
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 45
4.3.
Justification for Dose...................................................................................................................... 46
4.4.
End of Study Definition................................................................................................................... 46
5.
STUDY POPULATION ...................................................................................................................... 46
5.1.
Inclusion Criteria ............................................................................................................................ 47
5.2.
Exclusion Criteria ........................................................................................................................... 48
5.3.
Lifestyle Considerations................................................................................................................. 52
5.4.
Screen Failures .............................................................................................................................. 52
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 53
6.1.
Study Intervention(s) Administered................................................................................................ 53
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 54
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 55
6.4.
Study Intervention Compliance...................................................................................................... 56
6.5.
Dose Modification........................................................................................................................... 56
6.6.
Continued Access to Study Intervention After the End of the Study ............................................. 56
6.7.
Treatment of Overdose .................................................................................................................. 56
6.8.
Prestudy and Concomitant Therapy .............................................................................................. 56
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 59
7.1.
Discontinuation of Study Intervention ............................................................................................ 59
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 60
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 60
7.3.
Lost to Follow-up............................................................................................................................ 61
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 61
8.1.
Efficacy Assessments .................................................................................................................... 63
8.1.1.
Six-point Ordinal Clinical Recovery Scale .................................................................................. 63
8.1.2.
Level of Consciousness.............................................................................................................. 64
8.1.3.
Virology Assessments ................................................................................................................ 65


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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Status: Approved, Date: 17 February 2021
8.1.4.
Supplemental Oxygen Use......................................................................................................... 66
8.1.5.
Resting SpO2 .............................................................................................................................. 66
8.1.6.
Arterial Blood Gas Test............................................................................................................... 67
8.2.
Safety Assessments....................................................................................................................... 67
8.2.1.
Physical Examinations................................................................................................................ 67
8.2.2.
Vital Signs................................................................................................................................... 68
8.2.3.
Electrocardiograms..................................................................................................................... 68
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 69
8.2.5.
Pregnancy Testing...................................................................................................................... 69
8.2.6.
Vital Status.................................................................................................................................. 69
8.2.7.
Self-reported Oxygen Need........................................................................................................ 69
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 69
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 70
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 70
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 71
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 71
8.3.5.
Pregnancy................................................................................................................................... 71
8.3.6.
Adverse Events of Special Interest............................................................................................. 72
8.4.
Pharmacokinetics and Immunogenicity ......................................................................................... 73
8.4.1.
Evaluations ................................................................................................................................. 73
8.4.2.
Analytical Procedures................................................................................................................. 74
8.4.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 74
8.4.4.
Immunogenicity Assessments .................................................................................................... 74
8.5.
Genetics and Pharmacogenomics................................................................................................. 74
8.6.
Biomarkers ..................................................................................................................................... 74
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 75
9.1.
Statistical Hypotheses.................................................................................................................... 75
9.2.
Sample Size Determination ........................................................................................................... 75
9.3.
Populations for Analysis Sets ........................................................................................................ 76
9.4.
Statistical Analyses ........................................................................................................................ 76
9.4.1.
General Considerations.............................................................................................................. 77
9.4.2.
Primary Endpoint ........................................................................................................................ 77
9.4.3.
Secondary Endpoints.................................................................................................................. 78
9.4.3.1.
Key Secondary Endpoints ....................................................................................................... 78
9.4.4.
Other Secondary Endpoints ....................................................................................................... 78
9.4.5.
Exploratory Endpoint(s) .............................................................................................................. 79
9.4.6.
Safety Analyses .......................................................................................................................... 79
9.4.7.
Other Analyses ........................................................................................................................... 80
9.5.
Interim Analysis.............................................................................................................................. 81
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 83
10.1.
Appendix 1: Abbreviations and Definitions .................................................................................... 83
10.2.
Appendix 2: Clinical Laboratory Tests ........................................................................................... 86
10.3.
Appendix 3: Clinical and Laboratory Assessments Described per Day......................................... 88
10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations....................................... 101
10.4.1.
Regulatory and Ethical Considerations .................................................................................... 101
10.4.2.
Financial Disclosure.................................................................................................................. 104
10.4.3.
Informed Consent Process ....................................................................................................... 104
10.4.4.
Data Protection ......................................................................................................................... 105
10.4.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 106
10.4.6.
Committees Structure............................................................................................................... 106
10.4.7.
Publication Policy/Dissemination of Clinical Study Data .......................................................... 107
10.4.8.
Data Quality Assurance............................................................................................................ 108
10.4.9.
Case Report Form Completion................................................................................................. 109
10.4.10.
Source Documents ................................................................................................................... 109
10.4.11.
Monitoring ................................................................................................................................. 110


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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Status: Approved, Date: 17 February 2021
10.4.12.
Audits........................................................................................................................................ 111
10.4.13.
Record Retention...................................................................................................................... 111
10.4.14.
Study and Site Start and Closure ............................................................................................. 112
10.5.
Appendix 5 : Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting............................................................................................................................... 113
10.5.1.
Adverse Event Definitions and Classifications ......................................................................... 113
10.5.2.
Attribution Definitions................................................................................................................ 114
10.5.3.
Severity Criteria ........................................................................................................................ 114
10.5.4.
Special Reporting Situations .................................................................................................... 114
10.5.5.
Procedures ............................................................................................................................... 115
10.5.6.
Product Quality Complaint Handling......................................................................................... 116
10.5.7.
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 116
10.6.
Appendix 6 : Contraceptive and Barrier Guidance ...................................................................... 117
10.7.
Appendix 7: Risks Associated with Sirukumab............................................................................ 119
10.8.
Appendix 8: DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) 
ADULT TOXICITY TABLE45 – NOVEMBER 2007....................................................................... 121
10.9.
Appendix 9: The New York Heart Association Classification System ......................................... 130
10.10.
Appendix 10: General Guidelines for Measuring Vital Signs and SpO2 ...................................... 131
10.11.
Appendix 11: Protocol Amendment History ................................................................................. 133
11.
REFERENCES................................................................................................................................. 143
INVESTIGATOR AGREEMENT ............................................................................................................... 148
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Treatment Half-life and 5 Half-lives .......................................................................................... 57
Table 2:
Events of Interest for a Single IV Dose of Interest.................................................................... 72
FIGURES
Figure 1:
Schematic Overview of the Study up to Protocol Amendment 4.............................................. 17
Figure 2:
Schematic Overview of the Study as of Protocol Amendment 5 .............................................. 17
Figure 3
IL-6 signaling............................................................................................................................. 28


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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Status: Approved, Date: 17 February 2021
1.
PROTOCOL SUMMARY
1.1. Synopsis
Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of 
Sirukumab in Confirmed Severe or Critical COVID-19 Disease
Sirukumab (also known as CNTO136) is a human anti- IL-6 immunoglobulin G1 kappa (IgG1κ) 
monoclonal antibody (mAb). Sirukumab binds with high affinity and specificity to human IL-6 and as a 
result inhibits IL-6-mediated signaling and the biological effects of IL-6.
OBJECTIVES AND ENDPOINTS
The primary and secondary objectives and endpoints are listed below. For the full list of objectives 
and endpoints see Section 3 OBJECTIVES AND ENDPOINTS.
Objectives
Endpoints
Primary
To evaluate the clinical response of 
sirukumab (administered as a single IV 
dose) + SOC compared to placebo + 
SOC in confirmed critical COVID-19 
disease

Time to improvementa of at least 2 categories relative to 
Baseline on the 6-point ordinal clinical recovery scale 
(up to Day 28)
Key Secondary
To evaluate the clinical response of 
sirukumab + SOC compared to placebo 
+ SOC in confirmed critical COVID-19 
disease

Proportion of participants with an improvement on Day 
28 of at least 2 categories relative to Baseline on the 6-
point ordinal clinical recovery scale 

Incidence of all-cause mortality (up to Day 28)
Other Secondary
To evaluate the clinical response of 
sirukumab (administered as a single IV 
dose) + SOC compared to placebo + 
SOC in confirmed severe or critical 
COVID-19 disease

Time to improvementa of at least 2 categories relative to 
Baseline on the 6-point ordinal clinical recovery scale 
(up to Day 28)
To evaluate the clinical response of 
sirukumab + SOC compared to placebo 
+ SOC in confirmed severe or critical 
COVID-19 disease

Proportion of participants with an improvement on Day 
28 of at least 2 categories relative to Baseline on the 6-
point ordinal clinical recovery scale 

Incidence of all-cause mortality (up to Day 28)
To evaluate the safety of sirukumab + 
SOC compared to placebo + SOC in 
confirmed (a) critical and (b) severe or 
critical COVID-19 disease

Incidence of SAEs (up to Day 28)

Incidence of related AEs (up to Day 28)

Proportion of participants with severe or life-
threatening bacterial, invasive fungal, viral or 
opportunistic infections (other than SARS-CoV-2) (up 
to Day 28).
                                                
a The improvement should be sustained until Day 28 (or discharge/discontinuation). 


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
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Status: Approved, Date: 17 February 2021
Objectives
Endpoints

Incidence of grade 3 and 4 neutropenia and 
lymphocytopenia (up to Day 28)

Incidence of increased ALT ≥3xULN combined with 
increased bilirubin >2xULN (up to Day 28)
To evaluate the clinical response of 
sirukumab + SOC compared to placebo 
+ SOC in confirmed (a) critical and (b) 
severe or critical COVID-19 disease

Time to improvementa of at least 1 category relative to 
Baseline on the 6-point ordinal clinical recovery scale 
(up to Day 28)

Proportion of participants with an improvement on 
Day 28 of at least 1 category relative to Baseline on the 
6-point ordinal clinical recovery scale 

Time from study intervention to end of oxygen 
supplementation (up to Day 28)

Time from study intervention to hospital discharge 
among the surviving participants (up to Day 28)

Total length of hospitalization among the surviving 
participants (up to Day 28)

Number of ventilation free days (up to Day 28)

Participant’s clinical status at Day 7, 14, 21, 28 (6-point 
ordinal clinical recovery scale)

Total time on invasive mechanical ventilation

Proportion of participants with a worseb category 
relative to Baseline on the 6-point ordinal clinical 
recovery scale (up to Day 28)

Proportion of participants on extracorporeal membrane 
oxygenation (ECMO) over time 

Total time on ECMO 
To evaluate the safety during follow-up
for (a) critical and (b) severe or critical 
COVID-19 disease

Proportion of alive participants at Day 28, Week 8, and
Week 16

Proportion 
of 
alive 
participants 
that 
required 
readmission at Week 8 and Week 16 (if previously 
discharged) 

Incidence of SAEs up to Week 16
                                                
a The improvement should be sustained until Day 28 (or discharge/discontinuation).
b Clinical recovery scale score worsened with at least 1 category between Day 5 and Day 28.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
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Status: Approved, Date: 17 February 2021
Hypothesis
The primary hypothesis of this study is that sirukumab in combination with SOC results in a statistically 
significant shorter time to improvement (defined as an improvement of at least 2 categories relative to 
Baseline on the 6-point ordinal clinical recovery scale) versus placebo in combination with SOC, in 
confirmed critical COVID-19 disease. 
OVERALL DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter, interventional Phase 2 study in 
hospitalized participants with confirmed COVID-19 disease, at risk for progressing to severe ARDS. 
Up to protocol amendment 4, a target of approximately 270 participants with confirmed severe or critical 
COVID-19 disease was to be randomly assigned in a 2:1 ratio to receive 1 of the following 2 treatments: 

Treatment Arm: sirukumab 5 mg/kg IV single dose infusion on Day 1 + SOC treatment 

Control Arm: placebo IV single dose infusion on Day 1 + SOC treatment. 
As of protocol amendment 5, the study aims to enroll approximately 111 participants with confirmed critical 
COVID-19 disease overall in the study. The primary and key secondary analyses will be tested on the 
participants with confirmed critical COVID-19 disease. 
At the time of release of protocol amendment 5, approximately 100 participants with confirmed severe 
COVID-19 disease had been enrolled. The overall population of participants with confirmed severe or 
critical COVID-19 disease will be analyzed as part of secondary objectives of the study.
Randomization is stratified by age (<65 and ≥65 years of age) and by use of invasive mechanical ventilation 
(yes/no) at the time of randomization.
The study will include a Screening Phase, a ‘Day 1 to Day 28’ Phase and Post Day 28 Follow-up Phase 
(phone calls on Week 8, Week 12 and Week 16). The entire study duration for each participant will be 
16 weeks with daily study assessments up to Day 28 or day of discharge (whichever comes first), and phone 
call assessments thereafter, ie, at Day 28 in case of discharge prior to Day 28, at Week 8, 12 and 16. The 
assessment schedule will be on a weekly basis for participants still hospitalized after Day 28. The study is 
considered completed with the completion of the last study assessment (phone call assessment at Week 16) 
for the last participant in the study or the discontinuation of the last participant in the study, whichever 
comes last.
NUMBER OF PARTICIPANTS
A target of approximately 111 participants with confirmed critical COVID-19 disease will be randomized.
At the time of release of protocol amendment 5, approximately 100 participants with confirmed severe 
COVID-19 disease had been enrolled. 


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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11
Status: Approved, Date: 17 February 2021
INTERVENTION GROUPS AND DURATION
Description of Interventions
Intervention Name
Sirukumab (CNTO136)
Type
Drug
Dose Formulation 
Solution for infusion
Unit Dose Strength(s)
Sirukumab: 100 mg/mL 
Dosage Level(s)
Sirukumab: 5 mg/kg single dose
Route of Administration
IV infusion
Use 
Intervention  
Investigational Medicinal Product (IMP)
Yes
Non-Investigational Medicinal Product/Auxiliary Medicinal 
Product (NIMP/AxMP)
No
Sourcing
Provided centrally by the sponsor
Packaging and Labeling
(Labels will contain information to meet the applicable regulatory 
requirements.)
Each unit will be labeled with unique 
medication ID number.
Not in child resistant packaging
Delivery Instructions
Refer to IPPI for instructions on IV infusion
Food/Fasting Requirement
Regardless of food intake 
EFFICACY EVALUATIONS
Efficacy assessments will include 6-point ordinal clinical recovery scale, level of consciousness (Glasgow 
coma scale), virology assessment, supplemental oxygen use, resting SpO2, arterial blood gas results, and 
pulmonary imaging. 
SAFETY EVALUATIONS
Safety evaluations will include monitoring of adverse events and serious adverse events, physical 
examinations, vital sign measurements, electrocardiograms, clinical laboratory tests, pregnancy testing, and 
checking of vital status.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Serum samples will be used to evaluate the pharmacokinetics of sirukumab, IL-6, as well as antibodies to 
sirukumab. Serum collected for pharmacokinetic and immunogenicity analyses may additionally be used 
to evaluate biomarkers, safety or efficacy aspects that address scientific questions relating to sirukumab or 
SARS-CoV-2 infection. 
GENETICS AND PHARMACOGENOMICS
An optional pharmacogenomic (host DNA) blood sample may be collected (preferably at baseline) from 
those participants who gave consent to allow for host pharmacogenomic research, where local regulations 
permit. Pharmacogenomic research may include expression quantitative trait locus (eQTL) mapping, 
single-nucleotide polymorphisms (SNPs) mapping and whole genome sequencing that is related to the IL-6 
gene, study intervention, and/or SARS-CoV-2 infection.
BIOMARKER EVALUATIONS 
Blood samples will be collected to evaluate biomarkers that may be associated with the safety, efficacy and 
PK of sirukumab and/or with the SARS-CoV-2 infection. Evaluations may include, but are not limited to, 
IL-6, procalcitonin, CRP, ferritin, LDH, and D-dimer concentrations. In addition, humoral immunity to 
SARS-CoV-2 will be evaluated by measuring SARS-CoV-2 specific antibodies.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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Status: Approved, Date: 17 February 2021
The study also includes collection of blood samples for exploratory analysis of host biomarkers at the host 
RNA, protein and cell level. Samples may be analyzed under the supervision of the sponsor and results 
might be reported separately.
STATISTICAL METHODS
The primary analysis will be done when all participants reached Day 28 or discontinued earlier.
The final analysis will be done when all participants completed the study. 
A hierarchical testing strategy will be used for the primary and key secondary endpoints. 
First, the primary endpoint will be tested for superiority of sirukumab over placebo at the 2-sided 5% 
significance level. If superiority is shown on the primary endpoint, then the proportion of participants with 
a clinical improvement of at least 2 categories at Day 28 will be tested at the 1-sided 5% significance level. 
If superiority on this endpoint is shown, the mortality by Day 28 will be tested, again at the 1-sided 5%
significance level.
The inclusion of a Data Monitoring Committee (DMC) consisting of internal and external members will 
ensure oversight of patient safety. The DMC will regularly evaluate the cumulative safety data of all 
participants in the study. As soon as the first 30 participants with confirmed severe or critical COVID-19 
disease had received study intervention and had at least 7 days of follow-up after study intervention, the 
DMC performed an interim data review focused on safety. All data available at the time of the interim data 
review were included. During this data review enrollment was continued, however, recruitment would have 
been halted should 60 patients had been enrolled before the outcome of the data review was known. In case 
recruitment was halted, it would have been resumed upon a positive assessment of results of these interim 
data by the DMC.
While futility or stopping of the study is to be based on totality of emerging safety data, the DMC has to
consider either of the following non-binding futility criteria as recommendation for stopping the study: 
-
Excess mortality in the treatment arm, beyond the realm of chance (Fisher’s Exact test at a 1-sided 
significance level of 10%).
-
Excess in “Worsening by at least 1 category” in the treatment arm, beyond the realm of chance 
(Fisher’s exact test at a 1-sided significance level of 10%).
In addition, an IA was performed by the sponsor on the primary endpoint when approximately 20% of the 
planned number of participants with confirmed severe and critical COVID-19 disease had reached Day 28 
or discontinued earlier (see Synopsis subsection Interim Analysis for more details). Results have been
discussed with the DMC.
The above DMC set-up and non-binding futility criteria have been implemented in the study for the 
participants with confirmed severe or critical COVID-19 disease. No additional non-binding futility 
analyses are planned for the participants with confirmed critical COVID-19 disease in the study.
The efficacy endpoints will be analyzed on the Intent-to-Treat- (ITT) and by randomized treatment. The 
ITT set consists of all participants who were randomized and treated. These analyses will be performed in 
the participants with confirmed (a) critical and (b) severe and critical COVID-19 disease.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 17 February 2021
All safety analyses will be made on the Safety Population. The safety population, consisting of all 
participants who received study drug, will be analyzed by actual treatment. These analyses will be 
performed in the participants with confirmed (a) critical and (b) severe and critical COVID-19 disease.
For all participants who receive study drug descriptive statistics will be provided. All demographic 
characteristics (eg, age, race, ethnicity, height, body weight, body mass index) and other initial participant 
characteristics (eg, medical and surgical history, concomitant diseases) will be tabulated and analyzed 
descriptively.
Subgroup analyses will be performed based on the stratification factors (age [<65 and ≥65 years of age] 
and use of invasive mechanical ventilation [yes/no]) and a selection of the major baseline parameters.
Sample Size Determination
The study was targeted to enroll 270 participants with confirmed severe or critical COVID-19 disease in a 
2:1 manner, with approximately 180 participants in the sirukumab treatment arm and approximately 
90 participants in the control arm. However, based on the rapidly evolving space of COVID-19 therapeutics 
focusing on the highly impacted population of critical patients together with the results from the interim 
analysis, the study population is being limited with protocol amendment 5 to a subset of the currently 
eligible population, ie, those with confirmed critical COVID-19 disease.
At the time of release of protocol amendment 5 approximately 100 participants with confirmed severe 
COVID-19 disease had been enrolled.
The study aims to enroll approximately 111 participants with confirmed critical COVID-19 disease overall 
in the study, with approximately 74 participants in the sirukumab treatment arm and approximately 
37 participants in the control arm. 
The primary endpoint in this study is the time to improvement of at least 2 categories relative to Baseline
on a 6-point ordinal clinical recovery scale, with participants who die prior to Day 28 treated as right 
censored at Day 28. For the sample size calculation on the primary endpoint, the following assumptions are 
used for survivors and participants who die prior to Day 28:

For survivors in the control arm, it is assumed that the log transformed time to improvement (days) 
follows a normal distribution with mean of log 28 and a standard deviation 0.9. Sirukumab is assumed 
to reduce the median time to clinical improvement from 28 days to 16.8 days (40% reduction) in the 
surviving participants, and is assumed to have the same standard deviation of 0.9.

For the mortality in the control arm, 40% by Day 28 is assumed. Sirukumab is assumed to reduce the 
mortality with an absolute difference of 20%: from a mortality rate of 40% in the control arm to 20% 
in the sirukumab arm (50% relative reduction).
Under these assumptions, at least 111 participants with confirmed critical COVID-19 disease are required 
to have at least 80% power to demonstrate a difference with the log-rank test, at a significance level of 5% 
two-sided. 
The proportion of participants with a clinical improvement of at least 2 categories at Day 28 is a key 
secondary endpoint. Based on simulations using the above assumptions, the rate with clinical improvement 
at Day 28 in the control arm is expected to be 30%. The targeted treatment effect is an absolute increase of 
25% (from 30% in the control arm to 55% in the sirukumab arm) on this key secondary endpoint. The 
mortality by Day 28 is considered another key secondary endpoint. The targeted treatment effect is an 
absolute reduction in mortality by 25% (from 40% in the control arm to 15% in the sirukumab arm). Under 


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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Status: Approved, Date: 17 February 2021
the aforementioned assumptions and with a sample size of 111 participants, at least 80% power is obtained 
for both key secondary endpoints a 1-sided significance level of 5%.
Analysis of the Primary Endpoint
The primary efficacy analysis will be based on the ITT analysis set restricted to participants with confirmed 
critical COVID-19 disease and the primary efficacy endpoint is the ‘time to improvement of at least 2 
categories relative to Baseline on a 6-point ordinal clinical recovery scale’. The improvement should be 
sustained until Day 28 (or discharge/discontinuation). Time to clinical improvement will be assessed during 
the 28-day period after study drug administration, with failure to reach clinical improvement or death before 
Day 28 considered as right-censored at Day 28. 
This primary parameter will be analyzed by a stratified log-rank test (using the stratification factors). 
Kaplan-Meier curves, overall and by stratum will be used to graphically present the primary parameter. The
sensitivity analyses will be defined in the statistical analysis plan (SAP).
Analysis of Secondary Endpoints
If superiority is shown on the primary endpoint, then the proportion of participants with a clinical 
improvement of at least 2 categories at Day 28 will be tested at the 1-sided 5% significance level. If 
superiority on this endpoint is shown, the mortality by Day 28 will be tested, again at the 1-sided 5%
significance level. 
The key secondary endpoints will be analyzed using the Cochrane-Mantel-Haenszel (CMH) test for 
difference in proportions.
Key and other secondary endpoints will be analyzed graphically and descriptively as described in the SAP. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, maximum, and 95% 
confidence intervals [CIs]) will be calculated. For categorical variables, frequency tables and corresponding 
95% CIs will be presented.
The primary and secondary endpoint evaluation will be conducted on the ITT population and on the ITT 
population restricted to the population with confirmed critical COVID-19 disease. Analyses of qualitative 
comparison between pre-interim analysis and post-interim analysis for treatment effect in the population 
with confirmed critical COVID-19 disease will be conducted to check the consistency in the study. This 
qualitative assessment will be limited to primary and key secondary endpoints only.
Safety analyses
All safety analyses will be made on the Safety Population and on participants with confirmed (a) critical 
and (b) severe or critical COVID-19 disease.
All reported AEs will be included in the analysis. For each AE, the percentage of participants who 
experience at least 1 occurrence of the given event will be summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an AE, or who experience a grade 3 or 4 AE, a 
serious AE, or an adverse event of special interest (AEOI).
The incidence of participants with SAEs, the incidence of participants with grade 3 or 4 AEs, the incidence
of participants with severe or life-threatening, bacterial, invasive fungal, viral or opportunistic infections 
(other than SARS-CoV-2), the incidence of grade 3 and 4 neutropenia and lymphocytopenia, and the 
incidence of increased ALT ≥3xULN combined with increased bilirubin >2xULN will be reported. Increase 


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 17 February 2021
of ALT or AST combined with increase of bilirubin will be investigated by means of evaluation of drug-
induced serious hepatotoxicity (eDISH) plots.
Descriptive statistics will be calculated for clinical laboratory parameters, ECG parameters, and vital signs 
parameters.
Statistical testing might be applied to the secondary endpoints.
Interim Analysis
A non-binding unblinded IA for futility was performed by the sponsor on the primary endpoint when 
approximately 20% of the planned number of participants with confirmed severe and critical COVID-19 
disease had reached Day 28 or discontinued earlier.
The randomization codes and the translation of randomization codes into treatment and control groups was
disclosed to those authorized and only for those participants included in the IA. The following 
implementation was followed for the non-binding IA for futility while considering the participants with 
confirmed severe and critical COVID-19 disease in the study. 
The futility criterion was based on the conditional power approach for the primary endpoint. The 
conditional power was calculated for the primary hypothesis using the observed data and assuming a 
mortality rate of 30% in the control arm versus 21% in the sirukumab arm in the remainder of the study. 
The effect size and outcomes for the primary endpoint in the survivors was simulated as used for the study 
sample size calculation. A non-binding futility stopping boundary of 80% for the conditional power was
used. Assuming the outcome for the primary endpoint as used for the sample size calculations was true, 
with a 30% mortality rate in the control arm, the chance of stopping for futility at the time of the IA was
2.5%. Otherwise, if the null hypothesis was true and again with a 30% mortality rate in the control arm, the 
chance of stopping for futility was 60%. If, at the time of the IA, the probability of a successful study was 
lower than the futility boundary, the sponsor could have taken the decision to stop for futility after 
evaluation of all available data. In addition to the conditional power calculations, descriptive analyses of 
the primary and key secondary endpoints were performed on the available data. The safety outputs planned 
for the regular DMC safety reviews will be provided too.
No additional non-binding IA for futility is planned for the critical participants to be enrolled in the 
remainder of the study.
Other Analyses
-
SARS-CoV-2 viral load in NP swabs and in endotracheal, blood, and stool samples will be 
measured by a qRT-PCR assay. These data will be analyzed graphically and descriptively as 
described in the statistical analysis plan. 
-
Serum sirukumab concentrations will be summarized using descriptive statistics. The 
concentrations below the lowest quantifiable sample concentration of the assay will be treated as 
zero in the summary statistics. All concentrations below the lowest quantifiable sample 
concentration of the assay or missing data will be labeled as such in the concentration data listing 
or statistical analysis dataset. 
-
The incidence of antibodies to sirukumab will be summarized for all participants in the ITT 
population with appropriate samples for detection of antibodies to sirukumab (ie, participants with 
at least predose and the Day 28 sample obtained). 


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
16
Status: Approved, Date: 17 February 2021
-
Analysis of the relationship between various blood biomarkers, such as cytokines, and viral 
parameters, immunogenicity, safety and clinical outcome may be conducted. Descriptive statistics 
for actual values and (relative) changes from baseline for the different blood biomarkers assessed, 
will be tabulated for each biomarker
-
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary 
and depend on the different data types of the applied technology platforms, as well as on the extent 
of observed differences between participants.
-
Associations between baseline levels of biomarkers, immunogenicity tests, PK parameters and 
clinical response (primary endpoint and a selection of secondary endpoints) will be explored.
-
DNA samples will be analyzed if it is hypothesized that this may help resolve issues with the 
clinical data. 
-
DNA samples will be used for research related to sirukumab or COVID-19. Pharmacogenomic 
research may consist of the analysis of one or more candidate genes, of the analysis of genetic 
markers throughout the genome, or the analysis of the entire genome (as appropriate) to evaluate 
potential genetic associations with prognosis of clinical outcomes in patients and prediction of 
responsiveness to active treatment.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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Status: Approved, Date: 17 February 2021
1.2. Schema
Figure 1:
Schematic Overview of the Study up to Protocol Amendment 4
COVID-19: coronavirus disease 2019; DMC: Data Monitoring Committee, EOT: end of trial, ICU: intensive care unit, IV: intravenous, PBO: 
placebo, SOC: standard of care
*
Randomization will be stratified by age (<65 and ≥65 years of age) and by use of invasive mechanical ventilation (yes/no) at the time of 
randomization.
#
Up to Day 28 or until hospital discharge or study discontinuation, whichever comes first. If a participant is discharged before Day 28, a phone 
call visit will be performed at Day 28.
§
SOC treatment (during study treatment and follow-phase) is determined by the investigator based on local practice and consists of supportive 
care. 
SARS-CoV-2 PCR positivity at any time before screening will be accepted. Results from local laboratory, ECG, and pulmonary imaging 
assessments taken up to 2 days prior to screening will be accepted for screening assessments. 
Screeninga assessments start after signing of the ICF and can continue on the next calendar day, if needed. All screening and baseline assessments 
may also take place on the same day.  
Participants need to receive study intervention preferably within 4 hours but no later than 6 hours after randomization.
a
If the participant is on invasive mechanical ventilation or veno-venous ECMO, duration may not be >48 hours at time of screening.
During the period covered up to and including protocol amendment 4: 

The DMC reviewed the interim data as soon as the first 30 participants with confirmed severe or critical COVID-19 disease had been dosed 
and had had at least 7 days of follow-up after study intervention.

An IA for futility was performed when approximately 20% of the planned number of participants with confirmed severe or critical COVID-
19 disease have reached Day 28 or discontinued earlier.
Figure 2:
Schematic Overview of the Study as of Protocol Amendment 5
As of protocol amendment 5, participants with confirmed severe COVID-19 disease are no longer enrolled in the study and the 
study aims to enroll approximately 111 participants with critical COVID-19 overall in the study. At the time of release of protocol 
amendment 5, approximately 100 participants with confirmed severe COVID-19 disease had been enrolled.
Footnotes: see Figure 1.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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18
Status: Approved, Date: 17 February 2021
1.3. Schedule of Activities (SoA)
Safety laboratory testing (hematology, chemistry, and coagulation tests) will routinely be performed by local laboratories (refer to Section
10.2 Appendix 2: Clinical Laboratory Tests and Section 10.3 Appendix 3: Clinical and Laboratory Assessments Described per Day).
Screening
Phasea
Phase Day 1 to Day 28 
Post Day 28 
Follow-up Phone 
Calls
Day Screening
Baselinea
Day 1
Day 2 to Day 28b                                            
or day of discharge from hospitalaa,
or study discontinuation, whichever comes first
Day 28 Visit 
if discharged 
earlier
(Phone Call) 
Day 28
±3 days
Day 56, Day 84, 
Day 112 
±7 days
Week
Week 1
Week 1 (Day 2) to Week 4
Week 4
Week 8, 12, 16
General Screening/Baseline assessments
ICFc
X
Inclusion/exclusion criteria
X
Xd
Demographics, medical historye
X
Targeted physical examh
X
Any clinically significant findings to be reported
Treatment administration
Randomizationi
X
Administration of study 
interventioni
X
Concomitant medication
Concomitant medication recording
X
X
Throughout the study
Xn
Xn
Respiratory function related assessments
Type of supplemental oxygen
X
X
Once per day
Resting SpO2, FiO2 (if any)j
X
X
Minimum 4 times per day
Arterial pH, PaO2, PaCO2j
As available
Level of consciousness (Glasgow 
coma scale score)k
X
X
Once per day while in the ICU
Pulmonary X-ray (or CT imaging 
or lung ultrasound if X-ray not 
available) 
Xg,bb
As per SOC, report upon worsening and last available


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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Status: Approved, Date: 17 February 2021
Screening
Phasea
Phase Day 1 to Day 28 
Post Day 28 
Follow-up Phone 
Calls
Day Screening
Baselinea
Day 1
Day 2 to Day 28b                                            
or day of discharge from hospitalaa,
or study discontinuation, whichever comes first
Day 28 Visit 
if discharged 
earlier
(Phone Call) 
Day 28
±3 days
Day 56, Day 84, 
Day 112 
±7 days
Week
Week 1
Week 1 (Day 2) to Week 4
Week 4
Week 8, 12, 16
General safety related assessments
Standard 12-lead ECG
Xg,bb
one ECG is to be taken between Day 4 and Day 8
Vital signs (body temperature, 
pulse, SBP/DBP, respiratory rate)
X
X
As per SOC, minimum 4 times per day while in the ICU, afterwards 
once per day
Any AE
X
X
Throughout the study
Xn
Xn
Record discharge from ICU, 
discharge from hospital
As applicable
Safety laboratory assessmentsdd
Hematologyl,
Xg
X
Day 3, Day 7, Day 14, Day 21, Day 28cc
Chemistryl general safety
Xg
X
Day 3, Day 7, Day 14, Day 21, Day 28cc
Chemistry- Total Cholesterol, 
LDL, HDL, Triglycerides
Xg
X
Day of discharge
Coagulation: PT/INR or aPPT,
fibrinogen
Xg,
X
Day of discharge
Urine Pregnancy assessmentf
Xg
X
Day 28 or at day of discharge 
Bacterial, fungal, viral infection 
testing (blood, other)m
As per local SOC, any new infection is to be reported as AESI


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
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Status: Approved, Date: 17 February 2021
Screening
Phasea
Phase Day 1 to Day 28 
Post Day 28 
Follow-up Phone 
Calls
Day Screening
Baselinea
Day 1
Day 2 to Day 28b                                            
or day of discharge from hospitalaa,
or study discontinuation, whichever comes first
Day 28 Visit 
if discharged 
earlier
(Phone Call) 
Day 28
±3 days
Day 56, Day 84, 
Day 112 
±7 days
Week
Week 1
Week 1 (Day 2) to Week 4
Week 4
Week 8, 12, 16
Virology Assessments
Nasopharyngeal swab for 
infections testing (PCR 
quantification of SARS-CoV-2 and 
multiplex PCR for detection of co-
infections)p,q
If participants are intubated, an 
endotracheal sample for 
quantification of SARS-CoV-2 is 
to be taken in addition to the NP 
swabt
Xr,q
Xs,●
Day 3, Day 7, Day 10, Day 14, Day 21, Day 28u,v,●
Optional: Day 4, Day 5, Day 8●
Xv,●
Stool sample (if feasible)●
Xbb           
Day 3, Day 7, Day 10, Day 14, Day 21, Day 28
Optional: Day 4, Day 5, Day 8
Blood sample for SARS-CoV-2 
viremia●
X
Day 7, Day 14, Day 28cc
Biomarker/Pharmacology Assessmentsdd
CRP, Ferritin, D-dimer,
Procalcitonin●
X
Day 3, Day 5, Day 7, Day 14, Day 21, Day 28cc
Blood samples for cytokines, 
chemokines●
X
Day 5, Day 14, Day 21, Day 28
Blood samples for various 
biomarkers,●
X
Day 5, Day 28
Blood sample for SARS-CoV-2 
specific antibodies●
X
Day 14, Day 28
Blood samples for 
pharmacologyw,●
X
Day 14, Day 21, Day 28
Blood samples for cellular 
profiling●
X
Day 5, Day 28


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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Status: Approved, Date: 17 February 2021
Screening
Phasea
Phase Day 1 to Day 28 
Post Day 28 
Follow-up Phone 
Calls
Day Screening
Baselinea
Day 1
Day 2 to Day 28b                                            
or day of discharge from hospitalaa,
or study discontinuation, whichever comes first
Day 28 Visit 
if discharged 
earlier
(Phone Call) 
Day 28
±3 days
Day 56, Day 84, 
Day 112 
±7 days
Week
Week 1
Week 1 (Day 2) to Week 4
Week 4
Week 8, 12, 16
Exploratory Biomarkers/Pharmacogenomics●,dd
PAXgene blood for RNA 
profilingx,●
X
Day 5, Day 28
Whole blood for DNA profiling
(optional)y,●
Xz
Phone call assessments
Record vital statuso
Xn
Xn
Self-reported oxygen needed 
(yes/no)
Xn
Xn
Self-reported pregnancy status
Xn
Xn
Record readmission(s) post 
discharge and reason
Xn
Xn
●
Laboratory testing to be performed centrally
Note: If multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence: ECG, oxygen saturation, 
vital signs, blood sampling.
Abbreviations: AE: adverse event, AESI: adverse event of special interest; aPPT: activated partial thromboplastin time; CRP: C-reactive protein; CT: computed 
tomography; DBP: diastolic blood pressure; FiO2: percentage of inspired oxygen; ECG: electrocardiogram; HDL: low-density lipoprotein; ICF: informed consent form; 
ICU: intensive care unit; INR: international normalized ratio; LDL: low-density lipoprotein; PaCO2: partial pressure of carbon dioxide in arterial blood; PaO2: partial 
pressures of oxygen in arterial blood; PCR: polymerase chain reaction; PT: prothrombin time; SAE: serious adverse event; SBP: systolic blood pressure; SOC: standard 
of care; SpO2: peripheral capillary oxygen saturation.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
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Status: Approved, Date: 17 February 2021
Footnotes:
a.
Screening assessments start after signing of the ICF and can continue on the next calendar 
day, if needed. All screening and baseline assessments may also take place on the same day. 
Screening/Baseline assessments required to verify study eligibility and data collection for 
assessment of the 6-point ordinal clinical recovery category should take place prior to 
randomization. All Screening/Baseline procedures should take place prior to study drug 
administration.
b.
The assessment schedule will be on a weekly basis for participants still hospitalized after Day 
28. For the required assessments, refer to Section 10.3, Appendix 3: Clinical and Laboratory 
Assessments Described per Day.
c.
Consent to be obtained before the first study-related activity. An exception is in the case of an 
emergency enrollment in which the informed consent can be obtained as soon as possible.
d.
If a participant's clinical status changes after screening but before randomization such that he 
or she no longer meets all eligibility criteria, then the participant should be excluded from 
participation in the study.
e.
Medical history should include collecting onset of COVID-19 symptoms, prior therapy, and 
date of SARS-CoV-2 diagnosis if available.
f.
A urine pregnancy test is to be performed in women of childbearing potential only.
g.
Results from the blood chemistry, hematology, and coagulation test, pregnancy test, ECG, and 
pulmonary imaging, completed as SOC, taken up to 2 days prior to screening will be accepted 
as screening assessments. 
h.
Targeted physical examination is to be performed as per local SOC and includes, if feasible, 
lung auscultation and any examination as indicated by the patient’s medical history. Height 
and body weight are only to be measured at screening if not already available in the 
participant’s chart and if practically feasible. If not feasible, weight for dose calculation can 
be verbally reported by the participant or a family member.
i.
Participants need to receive study intervention preferably within 4 hours but no later than 6 
hours after randomization.
j.
Supplemental oxygen/percentage of inspired oxygen (FiO2) use (if any) will be measured 
(simultaneously with SpO2, and at any time of arterial blood gas measurements) to monitor 
the patient’s status regarding gas exchange as applicable. The following will be recorded:
-
Oxygen delivery device (eg, nasal cannula, simple face mask, nonrebreather mask, high 
flow nasal cannula, non-invasive ventilation, invasive
mechanical ventilation, 
extracorporeal life support, etc).
-
Oxygen flow rate in liters/min.
-
Record FiO2 and SpO2 data 4 times per day, and at any time of arterial blood gas 
measurements. Record values that are sustained for at least 1 hour. 
-
If a patient is using more than one device (eg, extracorporeal life support and invasive 
ventilation), the worst value of FiO2 (and the corresponding SpO2 -and PaO2 if available-)
on the highest level of intervention will be recorded. The worst (highest) value of FiO2 (and 
the corresponding SpO2 -and PaO2 if available-) on each device will also be recorded 
separately.


CNTO136  (sirukumab)
Clinical Protocol CNTO136COV2001
AMENDMENT 5
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-
If a patient does not need oxygen supplementation, this should also be recorded.
k. The final worst score of the Glasgow Coma Scale of the day needs to be recorded in the eCRF. 
The level of sedation of the participant will be derived from the type of medication entered for 
indication sedation on the Concomitant Medication page of the eCRF.
l.
Laboratory testing to be performed includes:
-
Hematology: hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, RBC 
indices (mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], % 
reticulocytes), white blood cell (WBC) count with differential (neutrophils, lymphocytes, 
monocytes, basophils, eosinophils).
-
General safety chemistry: total protein, albumin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, glucose, sodium, 
potassium, calcium, phosphate, magnesium, chloride, bicarbonate, creatinine, blood urea 
nitrogen (BUN), creatine phosphokinase (CPK), lactate dehydrogenase (LDH), lactate, and 
troponin. If ALT or AST >3x ULN or 3x the entry level (if entry levels were >ULN), also 
provide conjugated bilirubin (direct), unconjugated bilirubin (indirect).
m. Culture results (bacterial, fungal, or viral) including site of infection and specimen source 
(bronchoalveolar lavage [BAL], tracheal aspirate, sputum, blood, urine, etc.), performed as 
part of patients’ workup for new infections, should be reported. Analyses will be performed 
by the local laboratory.
n.
For participants discharged or who discontinued the study prior to Day 28 and did not 
withdraw consent, phone calls will be conducted on Day 28 and during the post Day 28 
Follow-up Phase to record concomitant medication, the vital status, the occurrence of AEs, 
self-reported oxygen need, self-reported pregnancy status and the history of readmission since 
last contact.
o.
Whenever possible, vital status will be recorded if the patient is alive. If the participant is 
deceased, date and cause of mortality should be recorded in the eCRF. Death should be 
documented as SAE.
p.
NP swabs will be used to collect secretions from participants to explore quantification of viral 
load of SARS-CoV-2. For each participant, NP sampling should be done at approximately the 
same time (±4 hours) on each sampling day and from the same nostril.
q.
If an NP sample for detection of SARS-CoV-2 (local SOC) will be collected on the same day 
as the NP sample for quantification of SARS-CoV-2 (central lab), only one NP sample should 
be collected. The sample should be aliquoted and the remaining aliquots of the NP samples 
should be stored and sent to the central lab for quantification of SARS-CoV-2.
r.
SARS-CoV-2 positivity should be documented based on local testing on any specimen, by 
RT-PCR, any time before randomization. This might require a local test using an NP swab 
obtained at screening.
s.
After randomization, SARS-CoV-2 positivity will be confirmed in a central lab by quantitative 
RT-PCR. The baseline sample needs to be collected predose, as close as possible to dosing.
t.
If the participant is intubated, endotracheal samples need to be taken at the same time as the 
NP swab. If taking both NP and endotracheal samples is not feasible, the NP sample should 
be given priority.


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u.
Lab testing for detection of SARS-CoV-2 on the NP swab at day of hospital discharge. If 
SARS CoV-2 positive, an additional NP swab will be taken every 7 days, if feasible for the 
site and tested, until SARS-CoV-2 negative.
v.
If viral RNA is detected in NP samples at day of discharge, all possible efforts will be made 
to follow-up participants and collect samples every 7 days until viral RNA is negative, 
considering the current pandemic and related logistical challenges. If possible, home visits by 
a healthcare professional may be conducted to collect samples during the follow-up period.
w.
Includes serum samples for measurement of PK, antibodies to sirukumab, and IL-6. On Day 1, 
a predose and a postdose (within 30 minutes after the end of infusion) sample should be 
collected. The postdose sample should be collected from the arm contralateral to that used for 
IV infusion. On Day 1 (predose) and Day 28 the PK, antibodies to sirukumab, and IL-6 will 
be evaluated. On Day 1 (postdose), Day 14, and Day 21 the PK and IL-6 will be evaluated.
x.
PAXgene RNA tubes should always be used last for any blood draw.
y.
An optional pharmacogenetics blood sample (DNA) will be obtained from those participants 
who gave consent (where local regulations permit).
z.
Sample can be also taken at any other time point after study drug intervention on Day 1.
aa. For those participants discharged prior to Day 28, all Day 28 assessments should be done at 
day of discharge. Laboratory, virology, relevant respiratory function related assessments, and 
biomarker/pharmacology assessments completed maximum 1 day before discharge do not 
need to be repeated on the day of discharge provided that no clinically relevant changes were 
noted in the results and the participant was declared ‘ready to be discharged’ on the day before 
discharge.
bb. Assessments done at screening do not need to be repeated at baseline.
cc. For participants still hospitalized post Day 28, additional blood sampling should be done every 
7 days (±1 day) and at day of discharge.
dd. For all laboratory tests done on Day 21, Day 28, and every week thereafter as needed, a 
window of ±1 day for all sampling is allowed.


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2.
INTRODUCTION
Sirukumab (also known as CNTO136) is a human anti- IL-6 immunoglobulin G1 kappa (IgG1κ) 
monoclonal antibody (mAb). Sirukumab binds with high affinity and specificity to human IL-6 
and as a result inhibits IL-6-mediated signaling and the biological effects of IL-6.
For the most comprehensive nonclinical and clinical information regarding sirukumab, refer to the 
latest version of the Investigator's Brochure (IB) for sirukumab.29
The term “study intervention” throughout the protocol, refers to sirukumab or placebo as defined 
in Section 6.1, Study Interventions Administered. 
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
2.1. Study Rationale
Current management of COVID-19 is supportive, and respiratory failure from acute respiratory 
distress syndrome (ARDS) is the leading cause of mortality.53 Currently, no treatment of 
COVID-19 has been established. Many trials (eg, with antivirals) are currently ongoing. While an
understanding of the epidemiology and clinical spectrum of COVID-19 is still evolving during the 
ongoing pandemic, the current knowledge of the disease burden highlights the urgent medical need 
to develop a treatment. Learnings from SARS-CoV, initial COVID-19 data17,51 and preclinical 
mouse model data indicate that IL-6 might be a key driver of the acute lung injury (ALI) and 
ARDS observed in COVID-19. More severe COVID-19 patients from an initial study in China 
had elevated levels of IL-6.67 Tocilizumab (Actemra/roActemra®) is a human mAb that binds the 
IL-6 receptor (IL-6R) and blocks the IL-6 pathway.1,52 It is approved to treat cytokine release 
syndrome (CRS) due to chimeric antigen receptor T (CAR-T) cell therapy and has shown 
anecdotal preliminary benefit in treating ARDS in patients with COVID-19. Noncontrolled, 
interim data from patients being treated with sarilumab (Kevzara®, another mAb that binds to 
IL-6R)35 also provide some early reports of possible benefit to patients. Sirukumab blocks the IL-6 
signaling pathway by binding and neutralizing IL-6, which warrants a study to assess its utility as 
an additional treatment option for patients with COVID-19-associated ARDS. 
2.1.1.
Background
SARS-CoV-2 Virology and COVID-19 Disease Burden
SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), is an enveloped, 
positive-sense, single -stranded RNA betacoronavirus.18,75 It was first identified following reports 
of a cluster of acute respiratory illness cases in Wuhan, Hubei Province, China in December 
2019.39 Epidemiological investigations indicated that the majority of early cases were linked to a 
seafood market, with patients infected through zoonotic or environmental exposure, followed by 
the subsequent spread of infection by human-to-human transmission among close contacts.39
Genomic sequencing was performed on bronchoalveolar lavage fluid samples collected from 


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patients with viral pneumonia admitted to hospitals in Wuhan, which identified a novel RNA virus 
from the family Coronaviridae.43,75 Phylogenetic analysis of the complete viral genome revealed 
that the virus, SARS-CoV-2, is part of the subgenus Sarbecovirus of the genus Betacoronavirus, 
and is most closely related (approximately 88% identity) to a group of SARS-like coronaviruses 
previously sampled from bats in China.43
SARS-CoV-2 has spread rapidly and globally since its emergence.15,18,23,39,43,75 The World Health 
Organization (WHO) declared that the outbreak constituted a public health emergency of 
international concern on January 30, 2020, and declared the outbreak to be a pandemic on 
March 11, 2020.70,72,73,74 As of April 4, 2020, this pandemic has infected over 1,289,380 people 
with over 70,590 associated deaths worldwide.34
Symptoms of infection may appear from 2 to 14 days following exposure, with the spectrum of 
illnesses ranging from mild symptoms to severe illness or death.8 Severe clinical presentations 
have been reported for as many as 20–25% of laboratory-confirmed cases.25 In a study of 
99 patients in a single center in Wuhan with SARS-CoV-2 infection confirmed by real-time 
reverse-transcriptase polymerase chain reaction (RT-PCR), the most commonly reported clinical 
manifestations were fever (83%), cough (82%), shortness of breath (31%), and muscle ache 
(11%).15 In chest x-rays and CT scans, 75% of patients showed bilateral pneumonia and 14% of 
patients showed multiple mottling and ground-glass opacities. In a further study of 138 patients 
with novel coronavirus-induced pneumonia in a single center in Wuhan, common symptoms 
included fever (98.6%), fatigue (69.6%), and dry cough (59.4%).66 Lymphopenia occurred in 
70.3% of patients, and chest CT scans showed bilateral patchy shadows or ground-glass opacities 
in the lungs of all patients. Thirty-six patients (26%) were transferred to the intensive care unit 
(ICU) because of complications, including ARDS, arrhythmia, and shock. Broadly, similar 
findings were noted in other case studies, eg, in the Seattle region in the US.6 At present, it appears 
that individuals aged 65 years or older, especially those with comorbid diseases, are subject to the 
highest incidence of morbidity and mortality.10 In contrast, a study of 2,143 children aged <18 
years in China with laboratory-confirmed (34.1% of cases) or suspected (65.9% of cases) COVID-
19 indicated that the clinical manifestations of the disease may be less severe in children than 
adults, with approximately 94% of cases being asymptomatic, mild, or moderate.23 However, 
young children, particularly infants, were susceptible to severe disease, with the highest proportion 
of severe and critical cases by age group reported for children aged <1 year (10.6% of cases) and 
1-5 years (7.3% of cases). Also, new evidence has emerged from China indicating that a large 
number of infections do not result in symptoms.20
The identification of SARS-CoV-2 follows the emergence of 2 other novel betacoronaviruses 
capable of causing severe human disease over the past 18 years: SARS-CoV and Middle East 
respiratory syndrome coronavirus (MERS-CoV), which have nucleotide sequence identity with 
SARS-CoV-2 of approximately 79% and 50%, respectively.43 The first known cases of SARS 
occurred in Southern China in November 2002.74 The etiological agent, SARS-CoV, is believed 
to be an animal virus that crossed the species barrier to humans followed by human-to-human 
transmission, leading to SARS cases in >25 countries. The MERS-CoV was isolated from a patient 
in Saudi Arabia who died of severe pneumonia and multi-organ failure in June 2012.82 MERS-CoV 


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is considered to be a zoonotic virus infecting bats and camels capable of non-sustained 
human-to-human transmission. Since 2012, sporadic cases and community and health-care-
associated clusters of infected individuals have been reported in the Middle East.
Patients with SARS or MERS present with various clinical features, ranging from asymptomatic 
or mild respiratory illness to fulminant severe acute respiratory disease with extrapulmonary 
manifestations.12,82
Both diseases have predominantly respiratory manifestations, but 
extrapulmonary features may occur in severe cases. By July 2003, the international spread of 
SARS-CoV resulted in 8,098 SARS cases and 774 deaths (case-fatality- rate: 10%) with 
substantial social, economic and health service disruption in some affected countries.12,74 The 
case-fatality rate of MERS-CoV infections is estimated to be 35%.12
Interleukin-6 as a Key Target of ARDS
IL-6, a biomarker for inflammation and a high-level immune response, is a pleiotropic cytokine 
that can have multi-faceted effects on multiple cell types and organs.61,68 There can be both 
systemic (acute phase response) and local effects in activating and amplifying the immune 
response. Published studies have demonstrated the involvement of IL-6 in various inflammatory 
disease processes including asthma, lupus erythematosus, rheumatoid arthritis, anemia of chronic 
inflammation, insulin resistance, cancer, major depressive disorder, giant cell arteritis and 
virus-induced ARDS. In addition, IL-6 has been implicated as a central mediator of toxicity in 
cytokine release syndrome (CRS), a potentially life-threatening, systemic inflammatory response 
that can be triggered by a variety of factors including viral infections.  
IL-6 is a soluble, glycosylated protein expressed by a variety of immune (T-cells, B-cells, 
macrophages, and microglia) and nonimmune cell types (fibroblasts, endothelial cells, adipocytes, 
myocytes, and neurons). IL-6 facilitates diverse physiological processes such as T-cell- activation, 
induction of immunoglobulin secretion, initiation of hepatic acute-phase protein synthesis, and 
stimulation of hematopoiesis. IL-6 signals via a receptor complex comprising its specific receptor, 
the IL-6 receptor (IL6R) and glycoprotein (gp) 130, the signal transducing subunit. The IL-6Rα 
exists in 2 forms; a membrane-bound form and a soluble form. Once a monomer of IL-6 binds a 
monomer of either form of the IL-6Rα (termed “classic” signaling when using the membrane 
bound form and “trans” signaling when using the soluble form), the IL-6-IL-6Rα complex is 
engaged by a gp130 homodimer. While gp130 is present on most if not all cells of the body, the 
membrane-bound form of the IL-6R is only present on some cells, mainly hepatocytes and several 
leukocytes, such as monocytes, macrophages, B cells and subtypes of T cells. Cells, which only 
express gp130 are refractory to IL-6 signals. This facilitates the selective activation of target cells 
and differentiates between the two different signaling pathways.68 Activation of IL-6 signal 
transduction is initiated and mediated by gp130-associated Janus activated kinases (JAKs) and 
phosphorylation of signal transducer and activator of transcription 3 (STAT-3), resulting in 
subsequent intracellular signaling (Figure 3).


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Figure 3
IL-6 signaling
While the expression of IL-6 and other cytokines is a component of the normal immune response, 
excessive expression of cytokines such as IL-6 and the ensuing immune inflammation can lead to 
disease pathology. This excessive systemic release of proinflammatory cytokines, termed a 
“cytokine storm”, can occur in a number of non-infectious conditions such as graft-versus-host 
disease (GVHD), CAR-T cell therapy55, and ARDS as well as several infectious diseases such as 
sepsis, Ebola and other viral hemorrhagic fevers, avian influenza, and smallpox.48,59
Actemra/RoActemra®
(tocilizumab), an IgG1 mAb that binds to both soluble and 
membrane-bound IL-6 receptors blocking IL-6 mediated signaling, is indicated for the treatment 
of adults and children with severe or life-threatening CRS due to CAR-T cell therapy. Approval 
was based upon a retrospective analysis of pooled outcome data from clinical trials indicating that 
blocking the IL-6 pathway with tocilizumab resulted in resolution of severe or life-threatening 
CRS in patients receiving CAR-T cell therapies for hematological malignancies.1,52
Coronaviruses, Acute Respiratory Distress, and IL-6
Coronaviruses infect a variety of host species, including humans and several other animal species. 
In their natural hosts, these viruses predominantly cause respiratory and intestinal tract infections 
producing a wide range of clinical manifestations. Coronaviruses infecting the respiratory tract 
have long been recognized as significant pathogens in animals and as the cause of mild and severe 
respiratory illness in humans. Highly pathogenic human coronaviruses such as SARS-CoV and 


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MERS-CoV similarly cause a wide spectrum of clinical manifestations in humans. Typically, the 
majority of patients develop a short period of moderate clinical illness; however, a small but a 
substantial number of patients develop severe pneumonia often associated with rapid virus 
replication, 
massive 
inflammatory 
cell 
infiltration 
and 
elevated 
proinflammatory 
cytokine/chemokine responses resulting in ALI and ARDS.13
It has been well documented for many years that infection by several members of the 
Coronaviridae family both in vitro and in vivo in humans and animals is associated with increases 
in the production of IL-6.1,4,22,27,31,38,42,50,60,77,78,81 This induction of IL-6 expression can be caused 
by productive viral infection, non-productive infection, noninfectious virus-like particles5, and 
even individual coronavirus proteins such as the spike or nucleocapsid proteins.24,47,80,63,64
Elevated IL-6 levels in the fluid of the lungs have been associated with a poor prognosis for 
individuals with ARDS.7,65
In the case of SARS, increased levels of IL-6 have been reported to be a prognostic indicator 
associated with more severe pulmonary disease in both animal models14,19,30,56 as well as in 
individuals infected with SARS-CoV.3,32,37,62,69,79 Learnings from SARS-CoV, initial COVID-19 
data17,51 and preclinical mouse model data indicate that IL-6 might indeed be a key driver of the 
ALI and ARDS observed in COVID-19. More severe COVID-19 patients from an initial study in 
China had elevated levels of IL-6.67
Since blocking the IL-6 pathway in CAR-T induced CRS with tocilizumab is clinically beneficial, 
it is hypothesized that IL-6 might play a key role in the cytokine storm associated with serious 
adverse outcomes in COVID-19 patients, and that blocking IL-6 would be a suitable therapeutic 
target for these patients.54
Initial non-peer reviewed results from a single-arm, observational, non-controlled, 21-patient 
Chinese study showed that COVID-19 participants experienced rapidly reduced fevers and 75% 
of patients (15 out of 20) reduced their need for supplemental oxygen within days of receiving 
tocilizumab.76 The utility of blocking the IL-6 pathway using the IL-6R mAbs tocilizumab 
(Actemra/roActemra®)1 and sarilumab (Kevzara®)35 is now being investigated in an open-label 
clinical trial (ClinicalTrials.gov Identifier: NCT04322773). The primary outcome measure is the 
time to independence from supplementary oxygen therapy up to 30 days from enrollment. 
Secondary outcome measures (30 days from enrollment) include the number of deaths, number of 
days out of hospital and alive, number of ventilator free days alive and out of hospital, and CRP 
levels. 
Sirukumab is a human anti-IL-6 IgG1κ mAb that binds to human IL-6 with high affinity and 
specificity. The high affinity binding of sirukumab to IL-6 (equilibrium dissociation constant [Kd]
= 0.175 pM) prevents the association of IL-6 with the IL-6R, thereby blocking receptor signaling 
and biological activities attributed to IL-6 both in vitro and in vivo. In vitro bioassays show that 
sirukumab neutralizes both cis- and trans-signaling of human IL-6 (mediated via cell surface IL-6R 
and soluble IL-6R, respectively) in a concentration-dependent manner. Sirukumab also blocks 
human IL-6-induced expression of the acute phase proteins haptoglobin and serum amyloid A 


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(SAA) in mice; this effect is sirukumab-specific and dose-dependent. As such, treatment of 
patients with confirmed COVID-19 severe disease with sirukumab could reduce pulmonary and 
systemic levels of IL-6 resulting in a clinically meaningful benefit. 
Some studies allow for a second (and third) dose of the drug, in case of insufficient response (eg, 
NCT04320615, NCT04372186, NCT04335071, all with tocilizumab, an IL-6R blocking 
antibody). IL-6R blocking antibodies bind IL-6R (~2.5 nM for tocilizumab) with similar affinity 
as IL-6 (0.5-34 nM) and compete with IL-6 for IL-6R binding.45 At 5 mg/kg IV dose of sirukumab, 
serum Cmax is ~125 ug/mL and at Week 4, serum sirukumab concentration is ~10 ug/mL which is 
substantially higher than the serum IL-6 level in COVID-19 and ARDs patients. In combination 
with potent affinity of sirukumab for IL-6 (~0.175 pM), it is anticipated that sirukumab levels after 
a single dose will be sufficiently high to bind circulating IL-6 levels (pg/mL up to ng/mL in ARDS)
for at least 4 weeks, and that an additional dose will not be required to block the IL-6 pathway 
effectively.
Nonclinical Studies
No preclinical studies have been performed to assess the potential activity of sirukumab in 
SARS-CoV-2 infection.
Sirukumab does not neutralize guinea pig, beagle, rat, or murine-derived IL-6. As such, preclinical 
testing utilized an analogous mAb that was shown to bind and neutralize murine IL-6. Prophylactic 
treatment of New Zealand Black/W F1 lupus-prone mice with anti-murine IL-6 mAb reduced 
anti-dsDNA autoantibody production and suppressed renal damage in a murine model of systemic 
lupus.40 Treatment with the anti-murine IL-6 mAb was also effective in reducing the incidence and 
severity of arthritis and joint histopathology in a mouse model of collagen-induced arthritis.41
Pharmacologic Profile
Sirukumab is a human IgG1κ mAb monoclonal antibody with a molecular weight of approximately 
150,000 Daltons. Sirukumab binds to and neutralizes human IL-6 and subsequently attenuates IL-6 
signaling and the biological effects of IL-6. Sirukumab also binds to and neutralizes cynomolgus 
monkey IL-6. Because of this, the cynomolgus monkey was selected as a pharmacologically 
relevant species for the evaluation of the nonclinical pharmacokinetics (PK) and toxicology of 
sirukumab.
Toxicology
Toxicology results from the 3- and 6-month multiple IV and subcutaneous (SC) dose studies 
conducted in cynomolgus monkeys showed no adverse effects that were considered related to the 
administration of sirukumab in clinical signs and measurements and clinical/anatomic pathology 
parameters. The no-observed-adverse-effect-level (NOAEL) in the related toxicology studies was 
50 mg/kg weekly.
Standard genotoxicity studies are generally inappropriate for biotechnology-derived 
pharmaceuticals and therefore, mutagenesis and carcinogenesis studies have not been conducted. 
Evaluation of reproductive potential in sexually mature male cynomolgus monkeys by 


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measurement of testicular volume, sperm count, motility and morphology, and histopathology of 
male reproductive organs identified no adverse effects. Studies conducted in mice given an anti-
mouse IL-6 mAb showed no adverse effects on male or female fertility. 
Data from an embryo-fetal developmental toxicity study demonstrated that in the 50 mg/kg group
(IV once weekly for 98 days), the abortion/embryo-fetal death ratio was increased, and it was 
considered that the increased abortion/embryofetal death ratio in this group was possibly 
sirukumab-related. The NOAEL in dams and fetuses was 10 mg/kg once weekly for a total of 
15 administrations.
Pharmacokinetic and Immunogenicity Profile
The PK/toxicokinetics (TK) and immunogenicity of sirukumab have been investigated in 
cynomolgus monkeys following multiple IV administrations of sirukumab at doses of 10 and 
50 mg/kg, and multiple SC administrations of sirukumab at a dose of 50 mg/kg. Please refer to the 
IB for more information regarding the PK, TK, and immunogenicity of SC sirukumab.29
After IV administrations, systemic exposure of sirukumab increased in an approximately dose-
proportional manner over the dose range of 10 to 50 mg/kg. The mean terminal half-life (T1/2) of 
sirukumab ranged from 10 to 19 days across all IV dose groups. The mean accumulation ratios 
were 3.34 and 2.45 for once-weekly IV administrations at 10 and 50 mg/kg, respectively. All 
animals from all dosing groups tested negative for antibodies to sirukumab.
When administered to pregnant monkeys (IV 10 and 50 mg/kg/week), serum sirukumab 
concentrations in the maternal animals increased in an approximately dose-proportional 
manner and sirukumab was also detected in the fetal circulation on the day of cesarean section 
(during the third trimester). The mean ratios of the fetal to maternal serum sirukumab 
concentrations were 1.33 (10 mg/kg) and 1.36 (50 mg/kg). All dams who had milk samples 
collected (n=25) between lactation day (LD) 30 and LD 75 had non-detectable sirukumab 
concentration samples except 1 monkey in the 50 mg/kg IV group. Sirukumab was also detected 
in the infant at birth (LD 0-LD 3) with serum concentrations similar to those of the dams; these 
serum levels were still detected 3 to 6 months post-birth.
Clinical Studies
At time of writing the protocol, 14 interventional studies with administration of sirukumab for the 
treatment of systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus 
nephritis (LN), rheumatoid arthritis (RA), Major Depressive Disorder (MDD) and Giant-cell 
Arteritis (GCA) were completed. 
As of 23 October 2018, overall, 251 healthy participants and an estimated 5,044 participants with 
RA, 71 participants with lupus, 193 participants with MDD, and 161 participants with GCA have 
been exposed in the sirukumab clinical program; of these, 3,495 participants have received 
sirukumab (IV or SC) in company-sponsored interventional clinical trials (227 healthy 
participants, 3,120 participants with RA, 54 participants with lupus, and 94 participants with 
MDD) and 111 participants have received sirukumab in business partner-sponsored clinical trials. 


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Of the total 3,606 participants who have received sirukumab, 272 participants were in the Phase 1 
studies, 297 participants were in the Phase 2 studies, and 3,037 participants were in the Phase 3 
studies.
Of the participants included in the clinical program, a total of 107 participants received sirukumab 
IV. Of these, 55 received a dose that was higher than the dose of 5 mg/kg that will be administered 
in the current study. 
Relevant pharmacokinetic and immunogenicity results on IV administration of sirukumab in the 
clinical program are presented below. More detailed information of all clinical studies performed 
with sirukumab are described in the IB.29
Human Pharmacokinetics and Immunogenicity
The PK of sirukumab has been evaluated in healthy participants following a single IV 
administration (C0136T01). Sirukumab exhibited linear PK over a dose range of 0.3 to 10.0 mg/kg 
following a single IV administration to healthy participants. Following a single IV administration 
of sirukumab 0.3 to 10.0 mg/kg, the mean volume of distribution (Vz) ranged from 121 to 248 
mL/kg and the mean total systemic clearance (CL) appeared to be dose independent and ranged 
from 3.8 to 6.1 mL/day/kg. Mean T1/2 values in healthy participants were 15 to 32 days. The mean 
T1/2 at the dose level of 5 mg/kg was estimated to be about 21 days.
In participants with CLE or SLE, following 4 biweekly IV administration of 1, 4, or 10 mg/kg 
sirukumab, systemic exposure of sirukumab (Cmax and AUC0-14d) increased in an approximately 
dose-proportional manner (study C0136T03). Mean T1/2 values in participants with CLE or SLE 
were estimated to be 16 to 23 days. 
In participants with LN, following IV administration of sirukumab 10 mg/kg q4w, serum 
concentrations of sirukumab reached steady-state by Week 12 (study CNTO136LUN2001). The 
mean trough serum concentration of sirukumab was 20.63 μg/mL at Week 12 and was maintained 
through Week 24 (22.65 μg/mL). Mean Cmax and AUC0-28d values were 239.65 μg/mL and 
1421.26 μg*day/mL and 259.47 μg/mL and 1864.92 μg*day/mL following the first and last 
administrations of 10 mg/kg sirukumab, respectively. Mean accumulation ratios following IV 
administration of sirukumab 10 mg/kg q4w were 1.08 for Cmax and 1.24 for AUC0-28d, which 
indicated minimal drug accumulation. Mean values of CL and volume of distribution at 
steady-state (Vss) were 5.10 mL/day/kg and 87.03 mL/kg, respectively. Mean T1/2 values were 
comparable between healthy participants (19 to 30 days), and participants with CLE/SLE (16 to 
23 days) or participants with LN (16 days) following IV administration.
Immunogenicity of IV sirukumab has been evaluated in 2 Phase 1 and 1 Phase 2 studies as of 
16 August 2017, including: studies C0136T01, C0136T03, and CNTO136LUN2001. None of the 
participants with evaluable serum samples tested positive for antibodies to sirukumab in studies 
C0136T01 (0/31) and C0136T03 (0/32). In study CNTO136LUN2001, 1 (5.0%) of the 
20 sirukumab-treated participants with evaluable samples (5.0%) tested positive for antibodies to 
sirukumab.


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Clinical Efficacy
No efficacy data are available on the use of sirukumab to treat COVID-19 induced ARDS.
In 2016, the sponsor filed a Biologics License Application with the FDA seeking approval for the 
use of SC sirukumab in the treatment of RA based upon data from the RA clinical development 
program. During the review of the BLA, the FDA convened an Advisory Committee meeting, held 
in 2017. While the Advisory Committee felt that sirukumab convincingly demonstrated efficacy 
in RA, it could not definitely attribute the imbalance in overall mortality to chance or the study 
design, and given the availability of other drugs for RA, the Advisory Committee did not 
recommend approval of sirukumab for RA. As a result, the sponsor did not pursue further 
development of SC sirukumab in RA. Refer to latest version of the IB for a summary the efficacy 
results in RA and other indications.29
Clinical Safety
The clinical safety of sirukumab has been evaluated in 107 participants receiving IV administration 
(34 participants in C0136T01, 33 participants in C0136T03, 21 participants in 
CNTO136LUN2001, and 19 participants in CNTO136NAP1003 [Note: 1 participant discontinued 
participation]) as well as in 3,500 participants who have received sirukumab SC. 
Risks associated with sirukumab include infections, hypersensitivity reactions, gastrointestinal 
perforations, hematologic events such as neutropenia and thrombocytopenia, and changes in lipid 
profiles and elevations of liver enzymes. These risks are not dissimilar to those observed with other
biologics that target the IL-6 pathway such as tocilizumab1 and sarilumab35 which also include 
serious infections, gastrointestinal perforations, and changes in neutrophils, platelets, lipids, and 
liver function tests. In addition, tocilizumab and sarilumab both have black box warnings for risk 
of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, 
invasive fungal, viral, and other opportunistic infections. The utility of blocking the IL-6 pathway 
using the IL-6R mAbs tocilizumab and sarilumab (KEVZARA®) is now being investigated in 
several 
clinical 
trials 
(ClinicalTrials.gov 
Identifiers: 
NCT04317092, 
NCT04320615, 
NCT04310228, NCT04306705, NCT04315480, NCT04322773).
Relevant safety results on IV administration of sirukumab in the clinical program are presented 
below. More detailed information of all clinical studies performed with sirukumab are described 
in the IB.29
Safety in 3 Phase I studies with IV administration
Study C0136T01 was a Phase 1, double-blind, placebo-controlled, ascending single-dose study 
evaluating the safety, PK, and immunogenicity of IV administered sirukumab in healthy 
participants. A total of 34 participants received a single dose of either 0.3, 1.0, 3.0, 6.0, or 10.0 
mg/kg IV sirukumab and 11 participants received placebo. 
Sirukumab was generally well tolerated in the 34 healthy participants who received single IV 
infusions of sirukumab. The most common AE across all sirukumab treatment groups was 


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pharyngolaryngeal pain (5/34, 14.7%). There was 1 SAE not related to study agent. Thirteen of 
34 (38.2%), sirukumab-treated participants had 1 or more AEs considered related to study agent 
by the investigator. The most common drug-related AE was pharyngolaryngeal pain. No deaths 
were reported in the study. Overall, there were no dose-related safety concerns.
There were no noteworthy differences among cohorts in mean neutrophils values over time, and 
the mean values remained within the normal range. However, there was a dose-dependent decrease 
in median change from baseline in neutrophils in CNTO136-treated participants compared to 
placebo, with a nadir at Week 4. At Week 4, Cohort 6 (10.0 mg/kg) had the largest decrease from 
baseline, with a median of –1.8 x109 (approximately -28%). 
Of the CNTO136-treated participants, 4 (2 in the 3 mg/kg and 2 in the 6 mg/kg group) had 
abnormally low lymphocyte values vs one participant in the placebo group. Three treated 
participants (one each in the 1, 3, and 6 mg/kg group) had abnormally low neutrophil values. These 
episodes were generally isolated and transient in duration and none were considered by the 
investigator to be of clinical significance, or were reported as AEs. The participant in the 6.0 mg/kg 
group, had a low neutrophils count (1.69 x 109/L [LLN 1.5 x 109/L]) Day –1 prior to dosing. He 
experienced a marked abnormally low lymphocyte count of 0.81 x 109/L at Week 12, which 
returned to within normal range by Week 16 (2.28 x 109/L).
Study C0136T03 was a 2-part Phase 1 study. Part A was a multicenter/multinational, randomized, 
double-blind, placebo-controlled, staggered-parallel, 3 ascending-dose cohort study of multiple IV 
administrations of sirukumab in which 23/31 participants with CLE received either 1, 4, or 10 
mg/kg IV sirukumab biweekly over 6 weeks (8/31 participants received placebo). Part B was a 
multicenter/ multinational, randomized, double-blind, placebo-controlled, single-dose level cohort 
study of multiple IV administrations of sirukumab in which 10/15 participants with SLE received 
10 mg/kg IV sirukumab biweekly (5/15 participants received placebo).
Six SAEs were reported in Part A and 3 SAEs were reported in Part B. The single death in this 
study, due to a car accident, was considered to be not related to the administration of sirukumab. 
Two SAEs of infection were reported: pneumonia that was considered to be probably related to 
sirukumab administration and a bacterial infection of an iatrogenic wound that was considered to 
be unlikely related to sirukumab administration. Neutropenia and thrombocytopenia were reported 
more frequently in participants in the sirukumab groups than in the placebo groups in both lupus 
populations. Compared with the placebo group, participants with CLE in the 1 and 4 mg/kg 
sirukumab groups reported a relatively higher number of skin-related AEs that were considered to 
be reasonably related to sirukumab, whereas the 10 mg/kg group did not report any reasonably 
related skin events. 
Participants who received sirukumab showed immediate stable and sustained decreases in WBC, 
ANC, and platelets at all individual dose levels, while participants in the placebo group showed 
no change in results. The decreases were not dose dependent. There was little to no clear temporal 
association between low neutrophil counts and the occurrence of infections. Two participants in 
the Part B SLE cohort were discontinued from administration because of low ANC and platelet 
counts, but no immediate apparent clinical symptoms were associated with these low values. 


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Fasting lipids showed minor elevations of total cholesterol in the cohorts that received sirukumab. 
Complement C3 and C4 decreased in both CLE and SLE participants in all sirukumab groups, but 
not in the placebo group. In Part A, WBC, ANC, and platelets showed decreases compared with 
baseline for the CNTO 136 combined group and at all individual dose levels. Participants in the 
placebo group showed no changed results for all 3 parameters. For WBC and ANC, some (but not 
complete) recovery was observed at the Week 22 follow-up visit. For platelets, recovery at the 
Week 22 follow-up visit was less clear. The decreases were not dose dependent. The effect on 
platelets and ANC was already seen at Week 2 and the decreases observed during subsequent visits 
remained of the same order of magnitude. In Part B, median values for WBC, ANC, and platelets 
showed decreases from baseline for the CNTO 136 group compared with the placebo group. For 
all 3 parameters, median values reached stable levels upon continued dosing, and there was no 
clear recovery to baseline values at the Week 22 follow-up visit. The decrease in ANC was 
observed for most participants after the initial dose administration.
CNTO136NAP1003 was a Phase 1, randomized, open-label, parallel-design study to assess 
absolute bioavailability and single-dose PK following SC administration of sirukumab delivered 
by a pre-filled syringe fitted with UltraSafe Passive™ Delivery System (PFS-U) or a SmartJect™ 
Autoinjector (PFS-AI) in healthy male participants. As a comparator arm, 19/144 participants 
received a single IV administration of 100 mg sirukumab. Note that 1 of the 19 participants who 
received IV sirukumab 100 mg terminated study participation early (due to lost to follow-up).
Of the 144 participants who received sirukumab, 68 (47.2%) had at least 1 AE during the study.
The incidence of participants with AEs was higher in the IV 100 mg group (11 participants 
[57.9%]) as compared with the SC treatment groups (50 mg PFS-AI group: 6 participants [31.6%], 
50 mg PFS-U group: 9 participants [47.4%], 100 mg PFS-AI group: 22 participants [51.2%], and 
100 mg PFS-U group: 20 participants [45.5%]). 
Of the 19 participants who received IV 100 mg sirukumab, 11 participants (57.9%) reported 1 or 
more AEs with no apparent pattern in any system-organ class. None of the participants who 
received IV 100 mg sirukumab had an SAE or discontinued due to an AE. No deaths occurred.
No infusion reaction AEs were reported after IV infusion of sirukumab 100 mg in any of the 
participants. 
Safety in a Phase II study with IV administration
Study CNTO136LUN2001 was a randomized, double-blind, placebo-controlled, parallel group, 
multicenter proof-of-concept study of sirukumab in 25 participants aged between 18 and 70 years 
(inclusive) with a diagnosis of SLE and a biopsy-proven ISN/RPS Class III or IV LN within 
approximately 14 months prior to randomization who were not on cyclophosphamide therapy 
within 3 months of randomization and who were receiving stable maintenance treatment with 
either mycophenolate mofetil or azathioprine, with or without corticosteroids. Of the 
25 participants, 21 participants received sirukumab 10 mg/kg IV and 4 participants received 
placebo IV. Study treatments were administered every 4 weeks (at Weeks 0, 4, 8, 12, 16, 20, and 
24).


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The most frequently reported AEs were observed in the System Organ Class of Infections and 
infestations (17 of 21 participants [81.0%] in the sirukumab group and 2 of 4 participants [50.0%] 
in the placebo group) and Gastrointestinal disorders (10 of 21 participants [47.6%] in the 
sirukumab group and 1 of 4 participants [25.0%] in the placebo group. The majority of AEs were 
mild to moderate in intensity. No participant reported severe AEs in the placebo group whereas, 
in the sirukumab group 7 participants reported severe AEs, of which 3 participants reported a 
severe AE of lupus nephritis.
Approximately half of the sirukumab–treated participants (10 of the 21 participants [47.6%]) 
reported at least 1 SAE. The most frequently reported SAE was lupus nephritis, followed by 
pneumonia (including pneumonia haemophilus), and cellulitis. No deaths were reported during the 
study.
No discontinuations due to AEs were reported in the placebo group whereas, 5 of 
21 participants (23.8%) in the sirukumab group discontinued due to AEs. The AEs that led to 
discontinuation were pneumonia haemophilus, hepatic enzyme increased, anaphylactic reaction, 
neutropenia, and lupus nephritis.
Eight of 21 participants (38.1%) from the sirukumab group and no participant from the placebo 
group reported treatment–emergent serious infections. All serious infections occurred after patients 
had received at least 4 doses of sirukumab at Week 12. The most frequently reported 
treatment-emergent serious infections were pneumonia (3 of 21 participants [14.3%] reported 
pneumonia and 1 of 21 participants [4.8%] reported pneumonia haemophilus), and cellulitis 
(2 of 21 participants [9.5%]). In addition, 1 participant had a severe infusion reaction (anaphylactic 
reaction) following the first administration of sirukumab.
A higher reduction in absolute neutrophils count and WBC count from baseline was observed in 
the CNTO136 group as compared with the placebo group over time. No noteworthy changes from 
baseline were observed in other hematology parameters. For neutrophils, there was a 24.88% 
decrease from baseline at Day 4 and a 27.67% decrease at Week 4. Further decrease varied during 
the study until Week 40 with a decrease of 31.56%. For neutrophils (decreased), there were no 
toxicities observed in the placebo group whereas, all toxicities grades were observed in the 
CNTO136 group: Grade 1 (4 of 21 participants [20.0%]), Grade 2 (8 of 21 participants [40.0%]), 
Grade 3, and Grade 4 (each observed in 1 of 21 participants [5.0%]). For WBC (decreased), no 
Grade 4 toxicity was observed in either of the treatment groups. A similar percentage of 
participants had Grade 1 toxicity (5 of 21 participants [25.0%] in the CNTO 136 group and 1 of 4 
participants [25.0%] in the placebo group). No Grade 2 or 3 toxicities were observed in the placebo 
group whereas, 10 of 21 participants (50.0%) had Grade 2, and 2 of 21 participants (10.0%) had 
Grade 3 toxicity in the CNTO 136 group. For lymphocytes (decreased), no Grade 4 toxicity was 
observed in the placebo group whereas, 1 of 21 participants (5.0%) had Grade 4 toxicity in the 
CNTO 136 group. A higher percentage of participants had Grade 2 and Grade 3 (each observed in 
6 of 21 participants [30.0%]) toxicities in the CNTO 136 group whereas, in the placebo group 1 of 
4 participants (25.0%) had Grade 2 toxicity and 2 of 4 participants (50.0%) had Grade 3 toxicity. 
There were few participants in the sirukumab group with elevated toxicity grades for liver function 


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tests (ALT, AST, and alkaline phosphatase) as compared with no participant with liver toxicity in 
the placebo group. No clinically relevant changes in vital signs and posttreatment ECGs were 
observed in the treatment groups during the study.
2.2. Dose Rationale
The sirukumab dose proposed to be evaluated in severely and critically ill participants with 
confirmed COVID-19 disease is 5 mg/kg administered as a single IV infusion. 
It has been demonstrated that a single IV dose of sirukumab at 0.3 to 10 mg/kg was generally well
tolerated in healthy participants (C0136T01) without showing evidence of safety concerns. In 
addition, multiple IV doses of sirukumab at 1, 4 or 10 mg/kg every 2 weeks (q2w) or every 4 weeks
(q4w) were investigated in participants with systemic lupus erythematosus or cutaneous lupus 
erythematosus (n=33, C0136T03), and in participants with lupus nephritis (n=21, 
CNTO136LUN2001). The proposed IV dose of 5 mg/kg is 2-fold lower than the highest dose (ie, 
10 mg/kg IV) evaluated in completed studies of sirukumab. Furthermore, the safety margins at 
5 mg/kg as a single-dose IV administration are sufficiently large (~20 based on Cmax and ~10 based 
on AUC) compared to the PK exposure at the IV NOAEL dose of 50 mg/kg/week in a 6-month 
GLP toxicology study in cynomolgus monkeys.
The affinity of sirukumab for IL-6 (0.175 pM) is >1,000-fold higher than that of IL-6R for IL-6 
(0.5-34 nM).6 At 5 mg/kg IV dose of sirukumab, serum Cmax is predicted to be ~125 µg/mL and at 
week 4, serum sirukumab concentration is predicted to be ~10 µg/mL, which is substantially higher 
than the serum IL-6 level in COVID-19 and ARDS patients (in pg/mL magnitude). Molar ratios 
(serum sirukumab:IL-6) will remain high for at least 4 weeks. In RA patients, a dose at or above 
25 mg every 4 weeks inhibited CRP levels for > 4 weeks. For a 70 kg subject, a 5 mg/kg sirukumab 
dose would translate to 350 mg, which is 14-fold higher than 25 mg (C1377T04). Therefore, even 
with increased IL-6 levels in COVID-19 as compared to RA, inhibition of IL-6R signaling (read-
out by drop in CRP levels) is expected to last at least 4 weeks.
Based on the preliminary findings reported, the baseline blood IL-6 level is significantly elevated 
to hundreds pg/mL magnitude in severely and critically ill COVID-19 patients16,76, which is much 
higher than the baseline IL-6 levels seen in RA participants.33 In addition, IL-6 levels in 
bronchoalveolar lavage fluid in patients at risk for ARDS and with established ARDS could raise 
to thousands pg/mL and remain above the normal range for up to 3 weeks in patients with persistent 
ARDS.49 Given the acute nature of the disease for COVID-19 patients, IV administration is 
considered necessary for sirukumab treatment to rapidly suppress the elevated IL-6 levels in these 
patients. Subcutaneous absorption of sirukumab would be significantly slower to reach Cmax
compared to IV administration. A 5 mg/kg IV dose of sirukumab is expected to provide sufficient 
exposure to bind IL-6 efficiently in patients with confirmed severe or critical COVID-19 disease 
who are at risk of ARDS. A physiologically based pharmacokinetics-pharmacodynamics 
(PBPK-PD) model predicted treatment with an IV dose of 5 mg/kg sirukumab would suppress 
elevated IL-6 levels to the normal range (ie, <10 pg/mL) in severely and critically ill COVID-19 
patients who are at risk of ARDS.


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In summary, sirukumab 5 mg/kg administered as a single IV infusion is expected to be effective 
with acceptable risks in rapidly suppressing the free IL-6 levels for at least 4 weeks in participants 
with confirmed severe and critical COVID-19 disease.
2.3. Benefit-Risk Assessment
2.3.1.
Risks for Study Participation 
Potential risks for participants treated with sirukumab single IV dose are the occurrence of infusion
reactions, 
hypersensitivity, 
serious
infections, 
liver 
enzymes 
increase, 
and 
neutropenia/thrombocytopenia (see Section 8.3.6). Of these the most significant risks relate to the 
complications associated with immunosuppression, essentially bacterial, fungal and viral 
infections.
The following risk mitigations are in place:

The study population will be under continuous monitoring in a hospital/intensive care setting. 

The protocol prevents patients with the most severe COVID-19 disease (eg, on invasive
mechanical ventilation or veno-venous ECMO for >48 hours) and pre-existing comorbidities 
(including non-COVID-19-related active infections, severe COPD, steroid dependency, being 
on renal replacement therapy, chronic liver disease, malignancy), patients 85 years of age,
from participating. 

To further protect the participants from the immunomodulatory effects of sirukumab that may 
predispose them to infections, the investigators are referred to the local guidelines for the 
concomitant use of antibacterials and/or agents that are intended to inhibit SARS-CoV-2 viral 
activity for management of community acquired pneumonia, COVID-19 pneumonia, or 
secondary infections. Open-label or off-label use of agents that are intended to inhibit 
SARS-CoV-2 viral activity, with demonstrated in-vitro effect, as mentioned in the CDC 
guidelines on Therapeutic Options for patients with COVID-19 are permitted in the study.6
The co-administration of convalescent plasma introduces an additional protein load of 2.4 to 
8 g/L.25,35 This may be a concern in patients with renal impairment, however it is noted that the
following risk mitigations are in place:

The exclusion criterion 10 prevents patients with an estimated glomerular filtration rate 
(eGFR) ≤30 mL/min/1.73 m2 or requiring renal replacement therapy from participating.

The study population will be under continuous monitoring in a hospital/intensive care 
setting.
The inclusion of a Data Monitoring Committee (DMC) will ensure oversight of patient safety (see 
Section 10.4.6, Committee Structure).
2.3.2.
Benefits for Study Participation
There are currently no established pharmacologic therapies that are effective in the treatment of 
COVID-19 infection or associated ARDS. The potential benefit of sirukumab is to fulfill an urgent 
medical need for patients by reducing progression of ARDS and associated mortality.


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Additionally, there are potential benefits to global public health in establishing effective therapies 
with expediency. Given the burden that the COVID-19 pandemic has placed on global health 
resources in terms of demand for healthcare professionals to treat those hospitalized with COVID-
19, the worldwide demand for ventilators, and the overall mortality in those with COVID-19
severe disease, particularly those who are older and have pre-existing comorbidities, sirukumab 
has the potential to have a positive impact on the COVID-19 pandemic and on the overwhelmed 
healthcare systems by, eg, reducing duration of mechanical ventilation and of length of stay in 
ICU/hospital ward. 
2.3.3.
Benefit-Risk Assessment for Study Participation
The sponsor is of the opinion that the potential benefits of treatment with sirukumab outweigh any 
associated risks of treatment. This is based upon the following:

There are no established treatments for COVID-19. The proposed target patient population 
consists of individuals who have hypoxemia and who are at risk of ARDS. These are the 
patients with the most urgent medical need who are at the greatest risk of dying. The current 
mortality due to COVID-19-associated pulmonary complications for hospitalized patients 
with hypoxemia and pulmonary involvement ranges from approximately 20-50% depending 
upon the age of the individual and pre-existing comorbidities.

Access of patients to investigational therapeutics to mitigate the disease is limited in this 
pandemic setting, and this study will offer the potential to access a therapeutic in the context 
of a clinical study.

The proposed dosing is a single IV administration of 5 mg/kg. During the clinical development 
program, study participants have received up to 10 mg/kg sirukumab IV q2w and no dose-
limiting toxicity has been observed. In addition, multiple IV doses of sirukumab at 1, 4 or 10 
mg/kg q2w or q4w were administered to lupus patients (C0136T03 and CNTO136LUN2001).
In the placebo-controlled trial CNTO136LUN2001, 21 participants (men or women) aged 
between 18 and 70 years (inclusive) with a diagnosis of SLE and a biopsy-proven LN received 
sirukumab up to 10 mg/kg IV q4w for 24 weeks. Eight of 21 participants (38.1%) from the 
sirukumab group and 0/4 participants from the placebo group reported treatment–emergent 
serious infections. All serious infections occurred after patients had received at least 4 doses of 
sirukumab at Week 12. In Part A of C0136T03, the first 2 cohorts (1 and 4 mg/kg) consisted 
of 8 participants each (6 receiving sirukumab and 2 receiving placebo) and the highest dose 
cohort (10 mg/kg) consisted of 10 participants (8 receiving sirukumab and 2 receiving 
placebo). A total of 4 doses were to be administered q2w over a 6-week period. In Part B, 15 
participants (10 receiving sirukumab and 5 receiving placebo) received 10 mg/kg biweekly 
over a 6-week period. Two SAEs of infection were reported: pneumonia that was considered 
to be probably related to sirukumab administration and a bacterial infection of an iatrogenic 
wound that was considered to be unlikely related to sirukumab administration.

The risks associated with sirukumab are largely based upon data from studies in immune-
mediated diseases which involved chronic repeat dosing over an extended period of time (eg, 
1 year).

The known risks associated with sirukumab are not dissimilar to those of other approved agents 
that target the IL-6 pathway. 


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
The study population will be under careful monitoring in the hospital setting with several risk 
mitigations strategies in place. 

The inclusion of a DMC will ensure oversight of patient safety.
More detailed information about the known and expected benefits and risks of sirukumab can be 
found in the IB.29
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the clinical response of 
sirukumab (administered as a single IV 
dose) + SOC compared to placebo + 
SOC in confirmed critical COVID-19 
disease

Time to improvementa of at least 2 categories relative to 
Baseline on the 6-point ordinal clinical recovery scale 
(up to Day 28)
Key secondary
To evaluate the clinical response of 
sirukumab + SOC compared to placebo 
+ SOC in confirmed critical COVID-19 
disease

Proportion of participants with an improvement on 
Day 28 of at least 2 categories relative to Baseline on 
the 6-point ordinal clinical recovery scale 

Incidence of all-cause mortality (up to Day 28)
Other Secondary
To evaluate the clinical response of 
sirukumab (administered as a single IV 
dose) + SOC compared to placebo + 
SOC in confirmed severe or critical 
COVID-19 disease

Time to improvementa of at least 2 categories relative to 
Baseline on the 6-point ordinal clinical recovery scale 
(up to Day 28)
To evaluate the clinical response of 
sirukumab + SOC compared to placebo 
+ SOC in confirmed severe or critical 
COVID-19 disease

Proportion of participants with an improvement on 
Day 28 of at least 2 categories relative to Baseline on 
the 6-point ordinal clinical recovery scale 

Incidence of all-cause mortality (up to Day 28)
To evaluate the safety of sirukumab + 
SOC compared to placebo + SOC in 
confirmed (a) critical and (b) severe or 
critical COVID-19 disease

Incidence of SAEs (up to Day 28)

Incidence of related AEs (up to Day 28)

Proportion of participants with severe or life-
threatening bacterial, invasive fungal, viral or 
opportunistic infections (other than SARS-CoV-2) (up 
to Day 28)

Incidence of grade 3 and 4 neutropenia and 
lymphocytopenia (up to Day 28)

Incidence of increased ALT ≥3xULN combined with 
increased bilirubin >2xULN (up to Day 28)
                                                
aThe improvement should be sustained until Day 28 (or discharge/discontinuation).


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Objectives
Endpoints
To evaluate the clinical response of 
sirukumab + SOC compared to placebo 
+ SOC in confirmed (a) critical and (b) 
severe or critical COVID-19 disease

Time to improvementa of at least 1 category relative to 
Baseline on the 6-point ordinal clinical recovery scale 
(up to Day 28)

Proportion of participants with an improvement on Day 
28 of at least 1 category relative to Baseline on the 6-
point ordinal clinical recovery scale 

Time from study intervention to end of oxygen 
supplementation (up to Day 28)

Time from study intervention to hospital discharge 
among the surviving participants (up to Day 28)

Total length of hospitalization among the surviving 
participants (up to Day 28)

Number of ventilation free days (up to Day 28)

Participant’s clinical status at Day 7, 14, 21, 28 (6-point 
ordinal clinical recovery scale)

Total time on invasive mechanical ventilation

Proportion of participants with a worseb category 
relative to Baseline on the 6-point ordinal clinical
recovery scale (up to Day 28)

Proportion of participants on extracorporeal membrane 
oxygenation (ECMO) over time 

Total time on ECMO
To evaluate the safety during follow-up
for (a) critical and (b) severe or critical
COVID-19 disease

Proportion of alive participants at Day 28, Week 8, and 
Week 16

Proportion 
of 
alive 
participants 
that 
required 
readmission at Week 8 and Week 16 (if previously 
discharged) 

Incidence of SAEs up to Week 16
Exploratory
To evaluate biomarkers that may be 
associated 
with 
response 
to 
or 
complications of sirukumab treatment
Evaluations may include, but are not limited to, IL-6, 
procalcitonin, C-Reactive protein (CRP), ferritin, LDH 
and D-dimer serum concentrations (through Day 28) 
To explore changes in SARS-CoV-2 
viral load and viral genome

Time to SARS-CoV-2 undetectable viral load by 
RT-PCR (up to Day 28)

SARS-CoV-2 viral load over time by RT-PCR (up to 
Day 28)
                                                
a The improvement should be sustained until Day 28 (or discharge/discontinuation).
b Clinical recovery scale score worsened with at least 1 category between Day 5 and Day 28.


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Objectives
Endpoints

Proportion of participants with undetectable viral load
(at multiple time points up to Day 28)

Development of SARS-CoV-2 variants
To 
evaluate 
the 
incidence 
of 
SARS-CoV-2 viremia

Proportion of participants with SARS-CoV-2 viremia 
(at multiple time points up to Day 28)
To evaluate pharmacokinetics following 
sirukumab 5 mg/kg treatment

Sirukumab serum concentrations 
To evaluate immunogenicity following 
sirukumab treatment

Proportion of participants with sirukumab antibodies 
(Day 28 or at discharge if discharged after Day 28)
To evaluate SARS-CoV-2 humoral 
immunity

Serum levels of SARS-CoV-2 specific antibodies 
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
At the time of data analysis, additional endpoints may be considered for analysis in function of the 
evolution in scientific knowledge on COVID-19.
HYPOTHESIS
The primary hypothesis of this study is that sirukumab in combination with SOC results in a 
statistically significant shorter time to improvement (defined as an improvement of at least 
2 categories relative to Baseline on the 6-point ordinal clinical recovery scale) versus placebo in 
combination with SOC, in participants with confirmed critical COVID-19 disease.
4.
STUDY DESIGN
4.1. Overall Design
This is a randomized, double-blind, placebo-controlled, multicenter, interventional Phase 2 study
in hospitalized participants with confirmed COVID-19 disease, at risk for progressing to severe 
ARDS. 
Up to protocol amendment 4, a target of approximately 270 participants with confirmed severe or 
critical COVID-19 disease was randomly assigned in a 2:1 ratio to receive 1 of the following 
2 treatments: 

Treatment Arm: sirukumab 5 mg/kg IV single dose infusion on Day 1 + SOC treatment

Control Arm: placebo IV single dose infusion on Day 1 + SOC treatment
More information on the SOC treatment is provided in Section 6.8 Prestudy and Concomitant 
Therapy.
As of protocol amendment 5, the study aims to enroll approximately 111 participants with 
confirmed critical COVID-19 disease overall in the study. The primary and key secondary analyses 
will be tested on the participants with confirmed critical COVID-19 disease. 


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At the time of release of protocol amendment 5, approximately 100 participants with confirmed 
severe COVID-19 disease had been enrolled. The overall population of participants with 
confirmed severe or critical COVID-19 disease will be analyzed as part of secondary objectives of 
the study.
Randomization is stratified by age (<65 and ≥65 years of age) and by use of invasive mechanical 
ventilation (yes/no) at the time of randomization.
The study will include a Screening Phase, a ‘Day 1 to Day 28’ Phase and Post Day 28 Follow-up 
Phase (phone calls on Week 8, Week 12 and Week 16). The entire study duration for each 
participant will be 16 weeks with daily study assessments up to Day 28 or day of discharge 
(whichever comes first), and phone call assessments thereafter, ie, at Day 28 in case of discharge 
prior to Day 28, at Week 8, 12 and 16. The assessment schedule will be on a weekly basis for 
participants still hospitalized after Day 28. The study is considered completed with the completion 
of the last study assessment (phone call assessment at Week 16) for the last participant in the study 
or the discontinuation of the last participant in the study, whichever comes last. For details, refer 
to the Schedule of Activities (SoA). 
The impact of a single dose treatment with sirukumab on Day 1 + SOC on confirmed critical
COVID-19 disease will be evaluated throughout the study. Refer to the Schedule of Activities 
(SoA) and Section 8, Study Assessments and Procedures for details. 
The primary endpoint is the time to improvement of at least 2 categories relative to Baseline on 
the 6-point ordinal clinical recovery scale (up to 28 days). The improvement should be sustained 
until Day 28 (or discharge/discontinuation). For details, refer to Section 8.1.1, Six-point Ordinal 
Clinical Recovery Scale. 
The primary analysis will be done when all participants reached Day 28 or discontinued earlier. 
The final analysis will be done when all participants completed the study. 
The DMC reviewed the interim data after the first 30 participants with confirmed severe or critical 
COVID-19 disease had been dosed and have had at least 7 days of follow-up after study 
intervention. Details regarding the DMC are provided in Committees Structure in Section 10.4.6.
A non-binding unblinded IA for futility was performed by the sponsor on the primary endpoint 
when approximately 20% of the planned number of participants with confirmed severe or critical 
COVID-19 disease had reached Day 28 or discontinued earlier. Additional IAs on participants 
with confirmed critical COVID-19 disease are not planned for the study.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. Scientific Rationale for Study Design
There is currently no treatment for COVID-19. Many drugs are currently under investigation, but 
none so far have proven efficacy. Current treatment is therefore only supportive, as per SOC. 


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Sirukumab will be administered on top of SOC, and placebo in combination with SOC will 
constitute the control group in this Phase 2 exploratory study. Concomitant medications for 
consideration as part of SOC are provided in Section 6.8, Prestudy and Concomitant Therapy.
Blinded, Controlled, Randomized Study 
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active intervention with sirukumab and to characterize 
the safety profile in this placebo group.
Randomization will be used to minimize bias in the assignment of participants to treatment arms, 
to increase the likelihood that known and unknown participant attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment arms, and to enhance the validity of 
statistical comparisons across treatment arms. 
Double blinded intervention will be used to reduce potential bias during data collection and 
evaluation of clinical endpoints.
Stratification will be done by age (<65 and ≥65 years of age) and by use of invasive mechanical 
ventilation (yes/no) at randomization. 
Study Population 
The goal is to identify a patient population with confirmed critical COVID-19 disease as defined 
in Inclusion Criterium 5 (see Section 5.1) who might benefit most from an anti-IL-6 intervention, 
ie, patients at risk of progressing to severe ARDS.
The initial study design included enrollment of participants with confirmed severe or critical 
COVID-19 disease. Based on the rapidly evolving space of COVID-19 therapeutics focusing on 
the highly impacted population of critical patients together with the results from the interim 
analysis, as of protocol amendment 5, the study population is being limited to a subset of the 
currently eligible population, ie, those with confirmed critical COVID-19 disease. 
At the time of release of protocol amendment 5, approximately 100 participants with confirmed 
severe COVID-19 disease had been enrolled. The overall population of participants with 
confirmed severe or critical COVID-19 disease will be analyzed as part of secondary objectives of 
the study.
DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in response to study intervention and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to an intervention. The goal of the pharmacogenomic component is to evaluate potential 
genetic associations with prognosis of clinical outcomes in patients and prediction of 
responsiveness to sirukumab treatment.


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Biomarker samples will be collected to evaluate the mechanism of action of sirukumab or to help 
explain interindividual variability in clinical outcomes, to potentially help identify population 
subgroups that respond differently to an intervention or to SARS-CoV-2 infection, and/or to 
characterize markers associated with SARS-CoV-2 infection. The goal of the biomarker analyses 
is to evaluate the PD of sirukumab and aid in evaluating the intervention-clinical response
relationship. 
Biomarker samples may be used to help address emerging issues and to enable the development 
of safer, more effective, and ultimately individualized therapies.
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants or (legally acceptable representatives) will be fully informed of the risks and 
requirements of the study and, during the study, participants (or legally acceptable representatives) 
will be given any new information that may affect their decision to continue participation. They will 
be told that their consent to participate in the study is voluntary and may be withdrawn at any time 
with no reason given and without penalty or loss of benefits to which they would otherwise be 
entitled. Participants (or legally acceptable representatives) who are fully able to understand the 
risks, benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled. 
In case of emergency situations due to COVID-19, when patients are incapable of giving their 
informed consent (eg, under intensive medical care) to enter the study, and the participant's legally 
acceptable representative is not available (eg, none is in place since the participant had been 
otherwise healthy before infection with SARS-CoV-2), deferred consent is permitted if in 
compliance with national law and local regulations. Enrollment procedures should be described in 
the protocol with documented approval/favorable opinion by the IEC/IRB to protect the rights, 
safety, and well-being of the participant and to ensure compliance with applicable regulatory 
requirements. The participant or legally acceptable representative should be informed about the 
study as soon as possible and give consent to continue. In the event the legally acceptable
representative is not available, a member of the family can take that role.  
Due to the COVID-19 pandemic, alternative procedures to obtain informed consent may be 
needed, as it is likely that the physical consent form cannot leave the isolation room and is not 
appropriate as study documentation. In that case, an alternative document (eg, photograph of the 
signature page) can be filed as a signed consent. For any informed consent that cannot be 
performed in person (eg, verbal consent by telephone), the process must be documented and 
confirmed by way of normal consent procedures at the earliest opportunity. An impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign a copy of the ICF (obtained and 
maintained outside the isolation room) after the oral consent of the participant is obtained. 
The primary ethical concerns are that sirukumab may not improve clinical outcomes of a 
participant with COVID-19 or may worsen clinical outcomes due to the immunosuppressant effect
of sirukumab. 


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The total blood volume to be collected of approximately 275 mL, including the optional sample for 
pharmacogenomic research, is considered to be an acceptable amount of blood to be collected over 
this time period from the population in this study based upon the standard of the American Red 
Cross standard blood donation.2
4.3. Justification for Dose
Refer to Section 2.2 Dose Rationale.
4.4. End of Study Definition
End of Study Definition
The end of study is considered as the last scheduled study assessment at Week 16 as shown in the 
Schedule of Activities for the last participant in the study or the discontinuation of the last 
participant, whichever comes last. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final participant assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed 
assessments at Week 16 or has experienced a clinical endpoint that precludes further continuation 
in the study (eg, early mortality).
5.
STUDY POPULATION
Screening assessments start after signing of the ICF and can continue on the next calendar day, if 
needed. All screening and baseline assessments may also take place on the same day. Results from 
the blood test, pregnancy test, ECG, and pulmonary imaging, completed as SOC, taken up to 
2 days prior to screening will be accepted as screening assessments. SARS-CoV-2 positivity, as 
determined locally by real time-PCR, in any specimen at any time prior to randomization is 
acceptable and this should not be repeated for inclusion in the study. If all eligibility criteria are 
met at screening then randomization may occur on that same day. 
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed. 
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
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5.1. Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. Male or female ≥18 and <85 years of age.
2. Hospitalized.
3. Criterion modified by Amendment 4
3.1 Has laboratory-confirmed SARS-CoV-2 infection as determined by real time-PCR at 
any time before randomization.
4. Criterion modified per Amendment 3
4.1 Evidence of infiltrates by chest X-ray, chest CT, lung ultrasound, or chest auscultation 
(rales, crackles).
5. Criterion modified per Amendment 2
5.1 Criterion modified per Amendment 3
5.2 Criterion modified per Amendment 5
5.3 Critical COVID-19 disease, defined as:
Critical disease: Requires supplemental oxygen delivered by nonrebreather mask 
or high-flow nasal cannula OR use of non-invasive or invasive ventilation OR 
requiring treatment in an ICU.
AND,
corresponding to category 4 on the 6-point ordinal recovery scale (see Section 8.1.1), 
ie, 
Requires one of the above modalities to sustain a SpO2 >93%, with an a FiO2 of 
50%a or higher. Note, the use of other devices may fit with category 4 if the FiO2 
is 50%a or higher.
OR, corresponding to category 5 on the 6-point ordinal recovery scale, ie,
PaO2/FiO2 ratio <300 mmHg while on invasive mechanical ventilation or veno-
venous ECMO for less than 48 hours prior to screening.
Note: as of protocol amendment 5, patients with confirmed severe COVID-19 disease 
are no longer eligible in the study. Severe COVID-19 is defined as requiring 
supplemental oxygen administration by nasal cannula, simple face mask, or other 
similar oxygen delivery device (ie, above pre-COVID baseline oxygen requirement, 
                                                
a The conversion between the oxygen flow expressed in L/min to the corresponding FiO2 value in % is the 
following: 
L/min
1
2
3
4
5
6
7
8
9
10
FiO2 %
24
28
32
36
40
44
48
52
56
60


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if any, by the participant) at a FiO2 less than 50%a. This corresponds to category 3 
on the 6-point ordinal scale (see Section 8.1.1).
6. Criterion modified per Amendment 1
6.1 Informed consent must be obtained from the participant (or their legally acceptable 
representative must sign based on local regulations) indicating that he or she
understands the purpose of, and procedures required for, the study and is willing to 
participate in the study.
Note: In case of emergencies, when participants and their legally acceptable
representative are incapable of giving their informed consent (eg, under intensive 
medical care) to enter the study, the sponsor will adhere to local regulations. Refer to 
Section 4.2.1 for more information.
For optional DNA research:
Separate informed consent must be obtained from the participant (or their legally acceptable 
representative) if he or she agrees to provide an optional DNA sample for research (where local 
regulations permit). The informed consent for the optional DNA research will be obtained in the 
main study informed consent form (ie, by a tick box).
Refusal to give consent for the optional DNA research sample does not exclude a participant from 
participation in the study.
5.2. Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1.
Criterion modified per Amendment 2
1.1 On invasive mechanical ventilation or on veno-venous ECMO for >48 hours at time
of screening.
2.
Meets local or global criteria to not receive mechanical ventilation or has designated 
themselves as DNR per a living will.
3.
Criterion modified per Amendment 2
3.1
Received an investigational intervention (including investigational vaccines) or used 
an invasive investigational medical device within 30 days before the planned dose of 
study intervention.
Note: the investigator must ensure that the participant is not enrolled in another 
COVID-19 study with an investigational intervention (apart from the exception 
specified below) prior to completion of Day 28 of the current study.


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Exceptions: Participation in a single arm study, a non-blinded controlled study, 
expanded access, compassionate use program or any other program that is not a 
blinded study is allowed if it is conducted with one of the following:
agents with demonstrated in vitro-effect against SARS-CoV-2, as mentioned in the 
CDC guidelines.6
convalescent plasma.
4.
Criterion modified per Amendment 2
4.1 Current confirmed or high suspicion for pulmonary embolus, hemodynamic significant 
pericardial effusion, myocarditis, or Class 3 or 4 congestive heart failure as defined by 
the New York Heart Association Functional Classification (Section 10.9, Appendix 9)
AND/OR
Current evidence of active cardiac ischemia.
5.
Criterion modified per Amendment 1
5.1 Criterion modified per Amendment 2
5.2 Currently active clinically significant (eg, causing hemodynamic instability and/or 
causing hypoxemia) and uncontrolled arrhythmia.
6.
Liver function impairment defined as Child Pugh Class B/C based on medical history.
7.
Has congenital bleeding diathesis based on medical history.
8.
Criterion modified per Amendment 2
8.1 Has a history of chronic respiratory condition (ie, asthma, chronic obstructive 
pulmonary disease [COPD], cystic fibrosis, fibrotic lung disease) that requires home 
oxygen supplementation, supportive non-invasive ventilation, or is status/post lung 
volume reduction surgery (LVRS)
Exception: Participants with sleep apnea using supportive non-invasive ventilation 
(continuous positive airway pressure [CPAP]) at screening may be included. 
9.
On renal replacement therapy (defined as peritoneal dialysis or hemodialysis)
10. Criterion modified per Amendment 1
10.1 Criterion modified per Amendment 2
10.2 Criterion modified per Amendment 3
10.3 Screening laboratory test result as follows:
-
Absolute neutrophil count (ANC) <1.0 × 103 cells/μL (SI: <1.0 × 109 cells/L) 
-
Platelet count <50 × 103 cells/μL (SI: <50 × 109 cells/L)


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-
Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2
-
Bilirubin >2xULN unless bilirubin rise is due to Gilbert’s syndrome or of non-
hepatic origin 
-
ALT >5xULN
-
Prothrombin time (PT)/international normalized ratio (INR) >1.5xULN or 
activated partial thromboplastin time (aPTT) >1.5xULN related to known 
coagulopathy or bleeding disorder (the participant can receive anticoagulant 
therapies for underlying conditions, or as systematic thromboprophylaxis due to 
COVID-19, or as part of the treatment of complications of COVID-19, but cannot 
participate in a clinical study with anticoagulants for COVID-19).
11. Criterion modified per Amendment 1
11.1 Pregnant or breastfeeding, unless in the opinion of the investigator, the benefit 
outweighs the risks. 
12. Has active hepatitis B or C infection, or has HIV/AIDS based on medical history and/or
concomitant medication.
13. Criterion modified per Amendment 4
13.1 Known active or latent TB, history of incompletely treated TB, suspected or known 
extrapulmonary TB based on medical history and/or concomitant medication.
14. Evidence of active bacterial (including but not limited to bacterial pneumonia), fungal, 
viral or opportunistic infection (other than SARS-CoV-2). 
15. Known allergies, hypersensitivity, or intolerance to sirukumab or its excipients or to other 
monoclonal antibodies (refer to the IB).29
16. Unlikely to be able to complete the study (including but not limited to: likely to be 
transferred to another hospital, surgery is anticipated to be necessary, in the opinion of the 
investigator unlikely to survive for >48 hours from screening)
17. Any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the participant (eg, compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments.
18. Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before the 
planned dose of study intervention. 
19. History of malignancy within 5 years before screening (exceptions are squamous and basal 
cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is 
considered cured with minimal risk of recurrence). 
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NOTE:

Exclusion criteria based on medical history or on past/current medications are pragmatic 
criteria. Deviation post randomization from these criteria due to late awareness of medical 
history and/or comedications are not intended to be qualified as major protocol deviations.

Investigators should ensure that all study enrollment criteria have been met at screening. 
Retesting of abnormal laboratory values that may lead to exclusion will be allowed once. If a 
participant's clinical status changes after screening but before randomization such that he or 
she no longer meets all eligibility criteria, then the participant should be excluded from 
participation in the study. The required source documentation to support meeting the 
enrollment criteria are noted in Section 10.4, Appendix 4 Regulatory, Ethical, and Study 
Oversight Considerations.


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5.3. Lifestyle Considerations
Potential participants must be able to adhere to the following lifestyle restrictions during the course 
of the study to be eligible for participation:
1.
Refer to Section 6.8, Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study.
2.
All requirements must be met during the study as noted in the Inclusion and Exclusion 
Criteria.
3.
Once dismissed from the hospital, female participants should avoid getting pregnant for 
a period of 4 months after the study intervention.
4.
Once dismissed from the hospital, a woman of childbearing potential must practice a 
highly effective, preferably user-independent method of contraception (failure rate of 
<1% per year when used consistently and correctly) and agree to remain on a highly 
effective method until 4 months after the study intervention or the end of relevant
systemic exposure. The investigator should evaluate the potential for contraceptive 
method failure (eg, noncompliance, recently initiated) in relationship to the dose of 
study intervention. Examples of highly effective methods of contraception are located
in Section 10.6, Appendix 6 Contraceptive and Barrier Guidance.
5.
A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the 
purposes of assisted reproduction for a period of 4 months after the administration of 
study intervention. 
6.
Once dismissed from the hospital, a male participant must wear a condom when 
engaging in any activity that allows for passage of ejaculate to another person until the 
end of the study. Male participants should also be advised of the benefit for a female 
partner to use a highly effective method of contraception as condom may break or leak.
7.
A male participant must agree not to donate sperm for the purpose of reproduction for
a period of 4 months after the administration of study intervention.
5.4. Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 


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identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, the date seen and age at initial informed consent will be used.
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. Study Intervention(s) Administered
Study intervention administration must be captured in the source documents and the electronic 
case report form (eCRF).
Sirukumab will be manufactured and provided under the responsibility of the sponsor. Refer to the 
IB for a list of excipients.29
Participants need to receive study intervention preferably within 4 hours but no later than 6 hours
after randomization.
Description of Interventions
The study intervention will be administered to the participant via an IV infusion using a 5% 
dextrosea IV bag with a total volume of 50 mL. 
Sirukumab will be injected into the bag for use in the treatment arm, the volume of the bag will be 
adjusted so that the total bag volume remains 50 mL. 
No substance will be injected in the bag for the placebo arm, and a 5% dextrosea 50 mL IV bag 
will be used as such.b
An unblinded pharmacist or qualified staff member will prepare the IV bags before distribution to 
the clinic. 
                                                
a Dextrose is also commonly known and referred to as glucose.
b Placebo will be provided locally by the study site.


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Intervention Name
Sirukumab (CNTO136)
Type
Drug
Dose Formulation 
Solution for infusion
Unit Dose Strength(s)
Sirukumab: 100 mg/mL 
Dosage Level(s)
Sirukumab: 5 mg/kg single dose
Route of Administration
IV infusion
Use
Intervention 
Investigational Medicinal Product (IMP)
Yes
Non-Investigational Medicinal Product/Auxiliary Medicinal 
Product (NIMP/AxMP)
No
Sourcing
Provided centrally by the sponsor
Packaging and Labeling
(Labels will contain information to meet the applicable regulatory 
requirements.)
Each unit will be labeled with unique 
medication ID number.
Not in child resistant packaging
Delivery Instructions
Refer to IPPI for instructions on IV infusion
Food/Fasting Requirement
Regardless of food intake 
6.2. Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Sirukumab must be stored at controlled temperatures ranging from 36°F to 46°F (2°C to 8°C) and 
protected from light.
Refer to the IPPI for additional guidance on study intervention preparation, handling, and storage. 
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. 
The study intervention administered to the participant must be documented on the intervention 
accountability form. All study intervention will be stored and disposed of according to the 
sponsor's instructions. Study-site personnel must not combine contents of the study intervention 
containers.
Study intervention must be handled in strict accordance with the protocol and the container label, 
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study intervention must be available for verification by the 
sponsor's study site monitor during monitoring visits. The return to the sponsor of unused study 
intervention will be documented on the intervention return form. When the study site is an 
authorized destruction unit and study intervention supplies are destroyed on-site, this must also be 
documented on the intervention return form.
Potentially hazardous materials containing hazardous liquids, such as used needles, syringes and 
vials, should be disposed of immediately in a safe manner and therefore will not be retained for 
intervention accountability purposes. 


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Study intervention should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be 
supplied only to participants participating in the study. Returned study intervention must not be 
dispensed again, even to the same participant. Study intervention may not be relabeled or 
reassigned for use by other participants. The investigator agrees neither to dispense the study 
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
6.3. Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 intervention groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. The randomization will be balanced 
by using randomly permuted blocks and will be stratified by age (<65 and ≥65 years of age) and 
invasive mechanical ventilation (yes/no) at randomization. The interactive web response system 
(IWRS) will assign a unique intervention code, which will dictate the intervention assignment and 
matching study intervention kit for the participants assigned to the active study treatment. The 
requestor must use his or her own user identification and personal identification number when 
contacting the IWRS, and will then give the relevant participant details to uniquely identify the 
participant.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
Data that may potentially unblind the intervention assignment (ie, preparation) will be handled 
with special care to ensure that the integrity of the blind is maintained and the potential for bias is 
minimized. 
The participants, study-site personnel, and investigators will be blinded to treatment allocation 
throughout the study, except for the designated pharmacist(s) or independent qualified staff 
member(s) with primary responsibility for study preparation. These unblinded members will not 
be part of the team performing the evaluations. The infusion administrator will be blinded and can 
perform other study evaluations. The sponsor study team will be blinded to study treatment 
allocation until the database release of the primary analysis.
Under normal circumstances, the blind should not be broken until the database for the primary 
analysis is locked. However, for the IA, the randomization codes and the translation of 
randomization codes into treatment and control groups will be disclosed to those authorized and 
only for those participants included in the IA. Details on the level of unblinding and the parties 


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authorized to be unblinded during the interim analysis will be specified in the SAP. Otherwise, the 
blind should be broken only if specific emergency treatment/course of action would be dictated by 
knowing the treatment status of the participant. In such cases, the investigator may in an emergency 
determine the identity of the intervention by contacting the IWRS. While the responsibility to 
break the intervention code in emergency situations resides solely with the investigator, it is 
recommended that the investigator contact the sponsor or its designee if possible to discuss the 
particular situation, before breaking the blind. Telephone contact with the sponsor or its designee 
will be available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor 
must be informed as soon as possible. The date and reason for the unblinding must be documented 
in IWRS, in the appropriate section of the eCRF and in the source document. The documentation 
received from the IWRS indicating the code break must be retained with the participant's source 
documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue the scheduled 
evaluations.
6.4. Study Intervention Compliance
Study intervention will be administered as an IV infusion by qualified study-site personnel and the 
details of each administration will be recorded in the source documentation and in the eCRF 
(including date, start and stop times of the IV infusion, and volume infused). 
6.5. Dose Modification
Not applicable.
6.6. Continued Access to Study Intervention After the End of the Study
No continued access will be proposed for this study as one single dose will be administered by 
study site personnel. 
6.7. Treatment of Overdose
There is no known specific antidote for sirukumab overdose. In the event of an overdose, the 
participant should be monitored for any signs or symptoms of adverse effects and institute 
appropriate symptomatic treatment immediately.
6.8. Prestudy and Concomitant Therapy
Sirukumab has immunomodulatory effects that may predispose participants to opportunistic 
infections. Therefore, all participants are to be managed according to local treatment guidelines, 
including the latest version of CDC Information for Clinicians on Therapeutic Options for Patients 
with COVID-19. Open-label or off-label use of agents that are intended to inhibit SARS-Cov-2 
viral activity are permitted in the study, but they must have demonstrated in-vitro effect as listed 
in the CDC guidelines on Therapeutic Options for patients with COVID-19.6


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Disallowed concomitant medications

Conventional synthetic disease-modifying anti-rheumatic drugs/ immunosuppressive 
agents:
o
Oral anti-rejection or immunomodulatory drugs (including tocilizumab) are disallowed 
from 6 months prior to randomization until the end of the study.
o
Treatment with other anti-IL-6, anti-IL6R antagonists, Janus kinase inhibitors, 
ustekinumab (anti IL-12/23), or anti IL-23 agents (guselkumab) is disallowed within 
5 half-lives (Table 1) or from 30 days prior to randomization (whichever is longer) until 
the end of the study.
Table 1:
Treatment Half-life and 5 Half-lives
Drug
Half-life
5 half-lives
tocilizumab IV
21.5 days
107.5 days
siltuximab IV
20.6 days
103 days
sarilumab IV 200 mg
10 days
50 days
sarilumab IV 150 mg
8 days
40 days
ustekinumab IV
19 days
95 days
guselkumab IV
15-18 days
75-90 days
ustekinumab SC
14.9-45.6 days
74.5-228 days
upadacitinib
8-14 hours
40-70 hours
baricitinib
12 hours
60 hours
tofacitinib XR
6-8 hours
30-40 hours
Source: Respective US Prescribing Informations
o
Systemic 
treatment 
with 
disease-modifying 
anti-rheumatic 
drugs
or 
immunosuppressive agents including methotrexate, bucillamine, azathioprine, oral 
cyclosporine A, tacrolimus, mycophenolate mofetil, oral or parenteral gold, and IL-1ra 
(anakinra) is disallowed from 2 weeks prior to randomization until the end of the study.
Exceptions: sulfasalazine, hydroxychloroquine and chloroquine
o
The use of cyclophosphamide is disallowed from 12 weeks prior to randomization until 
the end of the study.
o
Corticosteroids:

potential participants on chronic (for >3 months in duration) prednisone in a 
dose higher than 10 mg/day or other oral corticosteroids at an equivalent dose 
for any condition are not eligible for the study 
o
The use of leflunomide is disallowed from 8 weeks prior to randomization until the end 
of the study. Potential participants who have undergone standard cholestyramine 
washout may qualify if it is done at least 4 weeks before randomization: cholestyramine 


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at a dosage of 8 mg/3 times a day for at least 24 hours, or activated charcoal at a dosage 
of 50 mg/4 times a day for at least 24 hours.

The participants should not have received an investigational intervention (including 
investigational vaccines) or used an invasive investigational medical device within 30 days of 
the planned dose of study intervention and should not receive any investigational medication, 
other than sirukumab, prior to completion of Day 28. 
Note: the investigator must ensure that the participant is not enrolled in another COVID-19 
study with an investigational intervention (apart from the exception specified below) prior to 
completion of Day 28 of the current study.
Exceptions:

Participation in a single arm study, a non-blinded controlled study, an expanded access,
compassionate use program or any other program that is not a blinded study is allowed if 
it is conducted with one of the following: 
o
agents with demonstrated in vitro-effect against SARS-CoV-2, as mentioned in the
CDC guidelines.6
o
convalescent plasma.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Use of monoclonal antibodies
The use of bamlanivimab, and casirivimab plus imdevimab is disallowed during the study as they 
are not authorized in hospitalised participants or participants requiring oxygen. 
Participants who did receive bamlanivimab or casirivimab plus imdevimab prior to screening are 
still eligible for the study as long as the administration was stopped before first hospital admission 
and the participants fulfil all Inclusion/Exclusion criteria of the study.
Any co-administration through co-enrolment in a study investigating the effects of bamlanivimab, 
casirivimab, or imdevimab is not permitted. Similarly, co-enrolment in other clinical studies
investigating the effects of other monoclonal antibodies that are specifically directed against the 
spike protein of SARS-CoV-2 and designed to block the virus’ attachment and entry into human 
cells is not permitted per protocol.
Use of vaccines
Live vaccines should not be given during the study.
Administration of a COVID-19 vaccine during the study is not allowed at any time between 
screening and the discharge visit.
In case a participant was administered a COVID-19 vaccine outside the hospital prior to the study 
and becomes infected with COVID-19 the participant can be allowed in the study if all protocol 
eligibility criteria are fulfilled.


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Administration of a COVID-19 vaccine is allowed at the time of the discharge visit, provided there 
are no contraindications. The administration should be done after the very last blood samplings 
required per protocol at the discharge visit to avoid potential interference of the COVID-19 
vaccine.
Medications to be used with caution as their exposure could be modified by the study medication
Examples include but are not limited to warfarin, theophylline, digoxin, antiepileptics, 
antiarrhythmics.
Various in vitro studies have shown that cytokines such as IL-6 can affect the expression and 
activity of multiple cytochrome P450 (CYP) enzymes, such as CYP3A4, CYP2C9, CYP2C19, and 
CYP1A2. Sirukumab treatment may potentially reverse the effect of IL-6 on CYP enzyme 
activities in patients with elevated IL-6, which could lead to altered metabolism of drugs that are 
CYP substrates. The effect of sirukumab on the CYP enzymes may be clinically relevant for CYP 
substrates with a narrow therapeutic index, where the dose is individually adjusted. Therefore, it 
is recommended to use these types of drugs with caution until 12 weeks after sirukumab 
administration (3x half-life); therapeutic monitoring of effect (eg, warfarin) or drug concentration 
(eg, theophylline) should be performed and the individual dose of the drug adjusted as needed. 
Caution should be exercised when sirukumab is co-administered with CYP3A4 substrate drugs 
where a decrease in effectiveness would be undesirable (eg, oral contraceptives). The effect of 
sirukumab on CYP enzymes may persist for several weeks after stopping therapy. Therefore, 
female participants using oral contraceptives should use an additional contraceptive method above 
that required per the Section 5.3 Lifestyle Considerations.
Data collection of concomitant medications
To the extent possible, prestudy therapies administered up to 30 days before obtaining of informed 
consent must be recorded at screening.
As of obtaining informed consent, concomitant therapies must be recorded in the eCRF throughout 
the study till 16 weeks after the study intervention. Recorded information will include a description 
of the type of therapy, duration of use, dosing regimen, route of administration, and indication. 
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a participant into the study.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
As this is a single injection study, this section is not applicable.


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7.2. Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
When a participant withdraws before study completion, the reason for withdrawal is to be 
documented in the eCRF and in the source document. 
Withdrawal of Consent
Participants who withdraw consent will be offered an optional Safety Follow-up Visit (call), that 
will occur the day of consent withdrawal and will consist of the same assessments as at the Day 
28 (or day of discharge) visit.
7.2.1.
Withdrawal From the Use of Research Samples
A participant who withdraws from the study will have the following options regarding the optional 
research samples:

The collected samples will be retained and used in accordance with the participant's original 
separate informed consent for optional research samples.

The participant may withdraw consent for optional research samples, in which case the 
samples will be destroyed and no further testing will take place. To initiate the sample 
destruction process, the investigator must notify the sponsor study site contact of withdrawal 
of consent for the optional research samples and to request sample destruction. The sponsor 
study site contact will, in turn, contact the biomarker representative to execute sample 
destruction. If requested, the investigator will receive written confirmation from the sponsor 
that the samples have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for optional research samples while remaining in the study. 
In such a case, the optional research samples will be destroyed. The sample destruction process 
will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research (See Section 10.4.Regulatory, Ethical, and 
Study Oversight Considerations). In such a case, samples will be destroyed after they are no longer 
needed for the clinical study. Details of the sample retention for research are presented in the ICF,
including the separate consent for optional research samples.


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7.3. Lost to Follow-up
Lost to follow-up concerns the Phone Call Visits. A participant will be considered lost to follow-
up if he or she is unable to be contacted by the study site. A participant cannot be deemed lost to 
follow-up until all reasonable efforts made by the study-site personnel to contact the participant 
are deemed futile. The following actions must be taken:

Before a participant is deemed lost to follow up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, e-
mails, fax, 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 records.

Should participants continue to be unreachable, they will be considered to have withdrawn 
from the study and documented as ‘lost to follow-up’ in the eCRF.

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. If the participant withdrew consent, the 
vital status information available after consent withdrawal will not be collected in the eCRF 
and the participant will be considered to have discontinued from the study for consent 
withdrawal. Sponsor personnel will not be involved in any attempts to collect vital status 
information.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (SoA) summarizes the frequency and timing of respiratory function 
assessments, 
virology 
assessments, 
pharmacology 
assessments, 
exploratory 
biomarkers/pharmacogenomics, and safety measurements applicable to this study.
Screening assessments start after signing of the ICF and can continue on the next calendar day, if 
needed. All screening and baseline assessments may also take place on the same day.
Results from the blood test, pregnancy test, ECG, and pulmonary imaging, completed as SOC, 
taken up to 2 days prior to screening will be accepted for screening assessments. SARS-CoV-2 
positivity, as determined locally by real time-PCR in any specimen at any time prior to 
randomization is acceptable and this should not be repeated for inclusion in the study.
Screening/baseline assessments required to verify study eligibility criteria and data collection for 
assessment of the 6-point ordinal clinical recovery category should take place prior to 
randomization.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: ECG, oxygen saturation, vital signs, blood sampling. 
Blood collections for PK assessments should be kept as close to the specified time as possible. 


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Other measurements may be done earlier than specified timepoints if needed. Actual dates and 
times of assessments will be recorded in the source documentation and eCRF.
For those participants discharged prior to Day 28, all Day 28 assessments should be done at day 
of discharge. Laboratory, virology, relevant respiratory function related assessments, and 
biomarker/pharmacology assessments completed maximum 1 day before discharge do not need to 
be repeated on the day of discharge provided that no clinically relevant changes were noted in the 
results and the participant was declared ‘ready to be discharged’ on the day before discharge.
Leftover samples may be used for exploratory biomarker research.
For all laboratory tests done on Day 21, Day 28, and every week thereafter as needed, a window 
of ±1 day for all sampling is allowed.
For participants discharged after Day 28, additional assessments to be taken after Day 28 are listed 
in Schedule of Activities (SoA).
The amount of blood drawn from each participant in this study is approximately 275 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. 
Refer to the Schedule of Activities (SoA) for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
Study-Specific Materials
The investigator will be provided with the following supplies:

IB

Pharmacy Manual

Investigational Product Preparation Instructions

Laboratory Manual

IWRS Manual 

Sample ICF

Site Blinding Plan Template 


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
Contact Information Page(s)

eDC Manual
8.1. Efficacy Assessments
Efficacy assessments will be done per the Schedule of Activities (SoA) and will include all 
information necessary for the 6-point ordinal clinical recovery scale, level of consciousness 
(Glasgow coma scale [GCS]), virology assessment, supplemental oxygen use, resting SpO2, 
arterial blood gas results, and pulmonary imaging. Details for selected assessments are provided 
below.
8.1.1.
Six-point Ordinal Clinical Recovery Scale
The 6-point ordinal clinical recovery scale provides 6 mutually exclusive conditions ordered from 
best to worst, and the score reflects the participant’s worst situation on the day assessed. The 
sponsor will assign the ordinal scale category based on the assessment of the participant’s clinical 
status by the investigator. The ordinal clinical recovery scale categories are defined below.
Ordinal Clinical Recovery Scale (and Definitions)a
1. Not hospitalizedb
Any of the following:

Discharged from the hospital the day of assessment 

Hospitalized at the day of assessment but ready for discharge on the day of assessment, 
as judged by the investigator (eg, if still hospitalized in case of lack of bed availability in 
a skilled nursing facility, lack of social support at home).
2. Hospitalization, not requiring supplemental oxygen
                                                
a Alternate care settings delivering care which would normally be delivered in a hospital setting will be categorized 
as hospitalized.
If a participant was discharged from the hospital “Against Medical Advice” on the day prior to the day of 
assessment, the participant will be categorized per the definitions above in the category the participant was in at 
the moment of discharge “Against Medical Advice”. The hospital recovery scale category will be considered 
missing on subsequent days. 
If a participant declines medically-indicated mechanical ventilation, the participant will be categorized according 
to the care they would otherwise have received on that day.
b A distinction will be made between participants discharged and in need of (score 1.2) or not in need of (score 1.1) 
oxygen supplementation as indicated by the investigator on the discharge questionnaire. This distinction will not 
be made when calculating improvements on the CRS, for which score 1 will be used in both cases.


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3. Hospitalized, requiring low flow supplemental oxygen

Hospitalized on the day of assessment (including readmittance), and supplemental 
oxygen is required by the participant.
Requiring supplemental oxygen is defined by:

Receiving supplemental oxygen for instance through a face mask or nasal cannula, at a 
FiO2 < 50%,a and not being able to sustain a blood oxygen saturation of >93% when 
breathing room air. 
OR

Not receiving supplemental oxygen and having a blood oxygen saturation of 93% 
sustained for 5 minutes.
4. Hospitalized, on non-invasive ventilation, nonrebreather mask, or high flow oxygen 
device
−
On supplemental oxygen, on one of the above modalities, with a FiO2 (worst of the day) 
of 50%a or higher unless they satisfy a higher category (eg, on invasive mechanical 
ventilation). Note, the use of other devices may fit with category 4 if the FiO2 is 50%a or 
higher. 
5. Hospitalized, on invasive mechanical ventilation or ECMO

Any oxygen support requiring intubation or extracorporeal oxygenation.

Invasive mechanical ventilation is used at any time on the day of assessment.
6. Death

Participant died at any time on the day of assessment or earlier (all-cause mortality).
In addition, the site will be asked whether or not they are working under (a) restricted material 
resources for supplemental oxygenation/ventilation and/or (b) changes in hospital discharge 
policies.
8.1.2.
Level of Consciousness
The participant’s level of consciousness will be assessed using the GCS. The GCS is a neurological 
scale ranging from 3 (lowest, corresponds to deep coma or death) to 15 (highest, corresponds to a 
fully awake person) to assess the state of a person’s consciousness. The investigator should record
the worst total GCS score once a day in the eCRF, as long as the patient is in ICU.44
                                                
a The conversion between the oxygen flow expressed in L/min to the corresponding FiO2 value in % is the 
following:  
L/min
1
2
3
4
5
6
7
8
9
10
FiO2 %
24
28
32
36
40
44
48
52
56
60


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The level of sedation of the participant will be derived from the type of medication entered for 
indication sedation on the Concomitant Medication page of the eCRF.
The frequency and timing of the assessment can be found in the Schedule of Activities (SoA).
8.1.3.
Virology Assessments 
Respiratory tract samples
SARS-CoV-2 positivity should be documented based on local testing on any specimen, by 
RT-PCR any time before randomization. This might require a local test using a NP swab obtained 
at screening.
In addition, nasopharyngeal swabs will be collected for central testing. An NP swab will be used 
to collect secretions from patients to explore quantification of viral load of SARS-CoV-2 virus. At 
baseline, the presence of other respiratory pathogens, using multiplex PCR, will also be tested.
Furthermore, sequencing might be performed upon request of the virologist to determine mutations 
in the viral genome.
For participant who are intubated, endotracheal samples need to be taken at the same time as the 
NP swabs. If taking both samples is not feasible, the NP should be given priority. Collected 
samples need to be sent to the central lab to explore quantification of viral load. Sequencing might 
be performed upon request of the virologist to determine mutations in the viral genome.
Only one sample should be collected if the NP sample for detection and the NP sample for 
quantification are collected on the same day. This sample should be aliquoted and the remaining 
aliquots of the NP samples should be stored and sent to the central lab for quantification of 
SARS-CoV-2.
For each participant, NP sampling should be done at approximately the same time (± 4 hours) on 
each sampling day and from the same nostril. 
Leftover NP swabs and endotracheal samples may be used for exploratory biomarker analyses. 
If viral RNA is detected in nasopharyngeal samples at day of discharge, all possible efforts will be 
made to follow-up subjects and collect samples every 7 days until viral RNA is negative, 
considering the current pandemic and related logistical challenges. If possible, home visits by a 
healthcare professional may be conducted to collect samples during the follow-up period.
The frequency and timing of the assessments can be found in the Schedule of Activities (SoA). 
Details about sample collection, processing, and shipping will be provided in the laboratory 
manual. 
Blood samples
In addition to NP swabs, plasma samples will be collected to assess SARS-CoV-2 viremia.
Leftover serum samples may be used for exploratory biomarker analyses.


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The frequency and timing of the assessments can be found in the Schedule of Activities (SoA). 
Details about sample collection, processing, and shipping will be provided in the laboratory 
manual. 
Stool Samples (if feasible)
In addition to respiratory tract and plasma samples, stool samples will be collected to explore 
quantification of viral load of SARS-CoV-2 virus. The stool collections will only be collected if 
feasible for the site. 
Collected samples need to be sent to the central lab. Leftover stool samples may be used for 
exploratory biomarker analyses.
The frequency and timing of the assessments can be found in the Schedule of Activities (SoA). 
Details about sample collection, processing, and shipping will be provided in the laboratory 
manual.
8.1.4.
Supplemental Oxygen Use 
Supplemental oxygen/percentage of inspired oxygen (FiO2) use (if any) will be measured to 
monitor the patient’s status regarding gas exchange as applicable. The following will be recorded:

Oxygen delivery device (eg, nasal cannula, simple face mask, nonrebreather mask, high flow 
nasal cannula, non-invasive ventilation, invasive mechanical ventilation, extracorporeal life 
support, etc)

Oxygen flow rate in liters/min

Record FiO2 and SpO2 data 4 times per day, and at any time of arterial blood gas 
measurements. Record values that are sustained for at least 1 hour. 

If a patient is using more than one device (eg, extracorporeal life support and invasive 
ventilation), the worst value of FiO2 (and the corresponding SpO2 -and PaO2 if available-) on 
the highest level of intervention will be recorded. The worst (highest) value of FiO2 (and the 
corresponding SpO2 -and PaO2 if available-) on each device will also be recorded.

If a patient does not need oxygen supplementation, this should also be recorded.
The frequency and timing of the assessment can be found in the Schedule of Activities (SoA).
Note: The use of CPAP at home for obstructive sleep apnea syndrome will not be reported as a 
need of oxygen supplementation information. Only the information on oxygen supplementation 
that is COVID-19 related is to be reported.
8.1.5.
Resting SpO2
Resting SpO2 will be measured to assess arterial oxyhemoglobin saturation. SpO2 will be measured 
using a fingertip or similar non-invasive device, while patient is stable, following 5 minutes of rest 
(inactivity) in supine, semi-recumbent, or sitting position 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.


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For participants receiving invasive or non-invasive mechanical ventilation, peripheral oxygen 
saturation should be measured with the ventilatory support in place, and it should be recorded.
The frequency and timing of the assessment can be found in the Schedule of Activities (SoA).
General guidelines for measuring SpO2 are provided in Section 10.10 Appendix 10: General 
Guidelines for Measuring Vital Signs and SpO2. 
8.1.6.
Arterial Blood Gas Test
An arterial blood test will be conducted to assess the following parameters:

pH: acid-base balance of blood

PaO2: partial pressure of oxygen in arterial blood

PaCO2: partial pressure of carbon dioxide in arterial blood
Supplemental oxygen/FiO2 and resting SpO2 must be recorded at the same time as when an arterial 
blood gas is obtained. Results should be recorded in the eCRF. The frequency and timing of the 
assessment can be found in the Schedule of Activities (SoA).
8.2. Safety Assessments
Safety and tolerability will be evaluated throughout the study from obtaining informed consent
onwards until the last study-related activity. 
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Section 10.5, Appendix
5
Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other Safety 
Reporting: Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable condition is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities (SoA).
8.2.1.
Physical Examinations
A targeted physical examination will be performed as indicated in the Schedule of Activities 
(SoA). A targeted physical examination is to be performed as per local SOC and includes, if 
feasible, lung auscultation and any examination as indicated by the patient’s medical history. 
Height and body weight are only to be measured at screening if not already available in the 
participant’s chart and if practically feasible. If not feasible, weight for dose calculation can be 
verbally reported by the participant or a family member.


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Clinically significant findings should be documented as AE in the eCRF if they are serious, 
possibly related to the study drug or correspond to an adverse event of interest.
8.2.2.
Vital Signs
Temperature, pulse rate, respiratory rate, and blood pressure (SBP/DBP) will be assessed. The 
frequency and timing for each assessment can be found in the Schedule of Activities (SoA). 
Body temperature will be measured 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) and before taking antipyretics or more than 4 hours after the last dose of antipyretics.
Blood pressure and pulse/heart rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
Confirmatory vital signs measurements can be performed if inconsistent with a prior measurement.
Any clinically relevant abnormalities or changes in severity should be documented as AE in the 
eCRF if they are serious, possibly related to the study drug or correspond to an adverse event of 
interest.
General guidelines for measuring vital signs are provided in Section 10.10 Appendix 10: General 
Guidelines for Measuring Vital Signs and SpO2.
8.2.3.
Electrocardiograms
Participants should rest in a supine position for at least 5 minutes before ECG collection and should 
refrain from talking or moving arms or legs. If multiple assessments are scheduled for the same 
time point as ECG recording, the procedures should preferably be performed in the following 
order: ECG(s), oxygen saturation, vital signs, blood draw.
If an ECG is performed, the following parameters should be collected in the eCRF: Heart rate will 
be recorded from the ventricular rate and the PR, QRS, and QT (identify QT interval corrected for 
heart rate [QTc] using Bazett’s formula [QTcB] or QTc using Fridericia’s formula [QTcF]) 
intervals will be recorded in the eCRF. The ECG strips or reports will be retained with the source
and may be requested in case of documentation of a cardiovascular SAE.
The frequency and timing for each assessment can be found in the Schedule of Activities (SoA).
Any clinically relevant abnormalities or changes in severity should be documented as AE in the 
eCRF if they are serious, possibly related to the study drug or correspond to an adverse event of 
interest.


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8.2.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in Section 10.2, 
Appendix 2 Clinical Laboratory Tests. The investigator must review the laboratory results, 
document this review, and record any clinically relevant changes occurring during the study in the 
AE section of the eCRF. The laboratory reports must be filed with the source documents.
Any clinically relevant abnormalities or changes in severity should be documented as AE in the 
eCRF if they are serious, possibly related to the study drug or correspond to an adverse event of 
special interest (AESI).
8.2.5.
Pregnancy Testing
At screening, baseline, and Day 28 (or at discharge, whichever comes first), absence of pregnancy 
in women of childbearing potential should be confirmed by a urine rapid pregnancy test. The result 
of a prior serum pregnancy test that occurred within 2 calendar days (as part of SOC) before 
obtaining consent can be used in lieu of the screening requirement. Self-reported pregnancy status 
of female participants will be recorded during phone call visits on Day 28 (for participants 
discharged or who discontinued the study prior to Day 28 and did not withdraw consent) and during 
the post Day 28 follow-up phase phone call visits. Results should be recorded in the eCRF.
8.2.6.
Vital Status 
At Day 28 (if discharged before Day 28), and during the post Day 28 follow-up phase (phone call 
visits), vital status of study participants will be recorded, if the participant is alive. If the participant 
is deceased, date and cause of mortality should be recorded. Death should be documented as SAE 
in the eCRF. 
8.2.7.
Self-reported Oxygen Need
On the Day 28 phone call visit (if discharged before Day 28) and during the post Day 28 follow-up 
phase (phone call visits) participants will be asked whether they require supplemental oxygen (yes 
or no). The results should be documented in the eCRF. 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs, 
and product quality complaints (PQCs), from clinical studies are crucial for the protection of 
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. 
The sponsor has established Standard Operating Procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies 
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported as specified in Section 8.3.1 by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally acceptable representative) for the 
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Further details on AEs, SAEs, and PQCs can be found in Section 10.5, Appendix 5 Adverse 
Events, Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting: 
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until completion of the participant's last study-
related procedure, which may include phone call contact for follow-up of safety. 
Serious Adverse Events
All SAEs, as well as PQCs, occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator through the 
Week 16 phone call visit, must be reported using a Serious Adverse Event form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form and Safety Report Form of the eCRF, which must be completed and reviewed by a physician 
from the study site, and transmitted to the sponsor within 24 hours. The initial and follow-up 
reports of an SAE should be transmitted electronically. Telephone reporting should be the 
exception and the reporter should be asked to complete the appropriate form(s) first.
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about adverse event
occurrence. During the hospital stay, in case participants are non-responsive, investigators will 
report AEs as specified in Section 8.3.1. 
Solicited Adverse Events
Solicited adverse events are predefined local (at the injection site) and systemic events for which 
the participant is specifically questioned. 
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.


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8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or 
PQC as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in Section 
10.5, Appendix 5 Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute where 
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or 
sponsor where required) must report SUSARs to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities 
unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR summary, 
unless otherwise specified. 
8.3.5.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered serious adverse events and must be reported using a serious adverse event reporting 
form. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 


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8.3.6.
Adverse Events of Special Interest
Adverse events of special interest for the single IV administration of sirukumab (5 mg/kg) are
provided below. 
Table 2:
Events of Interest for a Single IV Dose of Interest
Potential Risks of Clinical 
Significance
Summary of Data/
Rationale for Risk
Mitigation Strategy
Serious infections
(Bacterial, fungal, and viral 
infection)
Interleukin-6 stimulates hepatic 
acute-phase proteins and Ig 
production and promotes the 
growth and differentiation of T 
cells, B cells, and tumor cells. 
Interleukin-6 is a mediator of 
inflammation and cellular immune 
responses in the defense against 
some intracellular pathogens. 
Interleukin-6 has been known to 
serve as a marker of disease 
severity for infections. Although 
IL-6 modulates certain physiologic 
acute-phase responses to infection, 
a complete lack of IL-6 has not 
been shown to alter mortality rates 
in IL-6 knockout mice. Blockage of 
IL-6 may blunt the acute-phase 
pyretic response and therefore, 
fever may be masked in participants 
receiving sirukumab. Serious, life-
threatening infections such as septic 
shock, some of which have been 
fatal, have occurred in participants 
receiving sirukumab.
Inclusion and exclusion criteria; 
hematologic monitoring; safety 
evaluation; and supportive 
treatment.
Hypersensitivity
Reactions observed in humans after 
IV or SC administration of mAbs 
include headache, fever, facial 
flushing, pruritus, urticaria, 
dermatitis, myalgia, nausea, chest 
tightness, laryngeal edema, 
dyspnea, vomiting, erythema, 
abdominal discomfort, diaphoresis, 
shivers, hypertension, Stevens-
Johnson syndrome, 
lightheadedness, hypotension, 
palpitations, and somnolence.
Inclusion and exclusion criteria; 
clinical monitoring; safety 
evaluation; and supportive 
treatment. 
Hematologic Events
Neutropenia and thrombocytopenia 
have occurred in sirukumab studies, 
including severe thrombocytopenia 
associated with bleeding. In the 
Phase 2 and Phase 3 RA studies, 
decreases in ANC and platelets 
occurred in all sirukumab treatment 
groups. Most patients who 
developed neutropenia while being 
treated with sirukumab did not 
Inclusion and exclusion criteria; 
clinical monitoring; safety 
evaluation; and supportive 
treatment. 


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develop infections, and most 
patients who developed 
thrombocytopenia did not report 
bleeding events. Changes were not 
observed in participants who 
received placebo, but did occur 
after participants crossed over to 
active treatment. No dose response 
was observed.
Liver enzymes
Increases (1 to 3 x ULN, sometimes 
>5 x ULN) in blood ALT and AST 
values were observed in 
participants in completed studies of 
sirukumab; the majority were 
transient, asymptomatic, and not 
associated with an increase in 
bilirubin
Monitoring of liver parameters
(ALT, AST, bilirubin [total, direct 
and indirect], coagulation factors, 
alkaline phosphatase)
For information on the adverse events of interest associated with chronic administration of 
Sirukumab in other disease conditions, such as rheumatoid arthritis, refer to Section 10.7, 
Appendix 7. 
8.4. Pharmacokinetics and Immunogenicity 
Serum samples will be used to evaluate the pharmacokinetics of sirukumab, IL-6, as well as 
antibodies to sirukumab. Serum collected for pharmacokinetic and immunogenicity analyses may 
additionally be used to evaluate biomarkers, safety or efficacy aspects that address scientific 
questions relating to sirukumab or SARS-CoV-2 infections. Genetic analyses will not be 
performed on these serum samples. Participant confidentiality will be maintained.
Details about sample collection, processing, and shipping will be provided in the laboratory 
manual. 
8.4.1.
Evaluations
At visits where PK, immunogenicity, and IL-6 will be evaluated (Day 1 predose, Day 28), one 
venous blood draw will be collected as specified in the Schedule of Activities (SoA). Serum 
samples will be obtained and split into 3 aliquots (one for sirukumab concentration, one for 
antibodies to sirukumab, and one for IL-6). 
At visits where PK and IL-6 will be evaluated (Day 1 postdose, Day 14, Day 21), one venous blood 
draw will be collected as specified in the Schedule of Activities (SoA). Serum samples will be 
obtained and split into 2 aliquots (one for sirukumab concentration and one for IL-6). 
Additional information about the collection, handling, and shipment of biological samples can be 
found in the Laboratory Manual.


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8.4.2.
Analytical Procedures 
Pharmacokinetics 
Serum samples will be analyzed to determine concentrations of sirukumab using a validated, 
specific, and sensitive immunoassay method by or under the supervision of the sponsor.
Immunogenicity
The detection and characterization of antibodies to sirukumab will be performed using a validated 
immunoassay method by or under the supervision of the sponsor. 
8.4.3.
Pharmacokinetic Parameters and Evaluations
If feasible, a population PK approach will be used to characterize the disposition characteristics of 
sirukumab. Total systemic clearance (CL) and volume of distribution (V) after IV administration
may be estimated from population PK modeling using nonlinear mixed effects model (NONMEM) 
approach.
8.4.4.
Immunogenicity Assessments
Antibodies to sirukumab will be evaluated in serum samples collected on Day 1 predose and on 
Day 28.
Serum samples will be screened for antibodies binding to sirukumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to sirukumab and/or further characterize the immunogenicity of sirukumab.
8.5. Genetics and Pharmacogenomics
An optional pharmacogenomic (host DNA) blood sample may be collected (preferably at baseline) 
from those participants who gave consent to allow for host pharmacogenomic research, where 
local regulations permit. Pharmacogenomic research may include expression quantitative trait 
locus (eQTL) mapping, single-nucleotide polymorphisms (SNPs) mapping and whole genome 
sequencing that is related to the IL-6 gene, study intervention, and/or SARS-CoV-2 infection.
Participant participation in pharmacogenomic research is optional.
8.6. Biomarkers
The frequency and timing of the assessment can be found in the Schedule of Activities (SoA).
Biomarkers for exploratory endpoint evaluation
Blood samples will be collected to evaluate biomarkers that may be associated with the safety, 
efficacy and PK of sirukumab and/or with SARS-CoV-2 infection. Evaluations may include, but 
are not limited to, IL-6, procalcitonin, CRP, ferritin, LDH, and D-dimer concentrations. In
addition, humoral immunity to SARS-CoV-2 will be evaluated by measuring SARS-CoV-2 
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Biomarker sample collection for research
The study includes collection of blood samples for exploratory analysis of host biomarkers at the 
host RNA, protein and cell level. Samples may be analyzed under the supervision of the sponsor 
and results might be reported separately.
Samples can only be used for research related to sirukumab or SARS-CoV-2 infection and/or to 
develop tests/assays related to sirukumab or SARS-CoV-2 infection. This may include target 
pathway of IL-6 inhibition, and the impact on pneumonia and respiratory illness associated with 
SARS-CoV-2 infection.
Analysis of exploratory biomarkers may be conducted at the sponsor’s discretion and results may 
be reported separately from this study. These samples may be stored for up to 15 years after the 
study completion.
9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
9.1. Statistical Hypotheses
The primary hypothesis of this study is that sirukumab in combination with SOC results in a 
statistically significant shorter time to improvement (defined as an improvement of at least 
2 categories relative to Baseline on the 6-point ordinal clinical recovery scale) versus placebo in 
combination with SOC, in participants with confirmed critical COVID-19 disease.
9.2. Sample Size Determination
The study was targeted to enroll 270 participants with confirmed severe or critical COVID-19 
disease in a 2:1 manner, with approximately 180 participants in the sirukumab treatment arm and 
approximately 90 participants in the control arm. However, based on the rapidly evolving space of 
COVID-19 therapeutics focusing on the highly impacted population of critical patients together 
with the results from the interim analysis, the study population is being limited with protocol 
amendment 5 to a subset of the currently eligible population, ie, those with confirmed critical 
COVID-19 disease.
At the time of release of protocol amendment 5, approximately 100 participants with confirmed 
severe COVID-19 had been enrolled.
The study aims to enroll approximately 111 participants with confirmed critical COVID-19 disease
overall in the study, with approximately 74 participants in the sirukumab treatment arm and 
approximately 37 participants in the control arm. 
The primary endpoint in this study is the time to improvement of at least 2 categories relative to 
Baseline on the 6-point ordinal clinical recovery scale, with participants who die prior to Day 28 


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treated as right censored at Day 28. For the sample size calculation on the primary endpoint, the 
following assumptions are used for survivors and participants who die prior to Day 28:

For survivors in the control arm, it is assumed that the log transformed time to improvement 
(days) follows a normal distribution with mean of log 28 and a standard deviation 0.9. 
Sirukumab is assumed to reduce the median time to clinical improvement from 28 days to 
16.8 days (40% reduction) in the surviving participants and is assumed to have the same 
standard deviation of 0.9.

For the mortality rate in the control arm, 40% by Day 28 is assumed. Sirukumab is assumed 
to reduce the mortality with an absolute difference of 20%: from a mortality rate of 40% in 
the control arm to 20% (50% relative reduction).
Under these assumptions, at least 111 participants with confirmed critical COVID-19 disease are 
required to have at least 80% power to demonstrate a difference with the log-rank test, at a 
significance level of 5% two-sided. 
The proportion of participants with a clinical improvement of at least 2 categories at Day 28 is a 
key secondary endpoint. Based on simulations using the above assumptions, the rate with clinical 
improvement at Day 28 in the control arm is expected to be 30%. The targeted treatment effect is 
an absolute increase of 25% (from 30% in the control arm to 55% in the sirukumab arm) on this 
key secondary endpoint. The mortality by Day 28 is considered another key secondary endpoint.
The targeted treatment effect is an absolute reduction in mortality by 25% (from 40% in the control 
arm to 15% in the sirukumab arm). Under the aforementioned assumptions and with a sample size 
of 111, at least 80% power is obtained for both key secondary endpoints a 1-sided significance 
level of 5%.
9.3. Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
The efficacy endpoints will be analyzed on the Intent-to-Treat (ITT) and by randomized treatment. 
The ITT set consists of all participants who were randomized and treated.
The primary and key secondary analyses will be tested on the participants with confirmed critical 
COVID-19 disease. 
All safety endpoints will be evaluated on the Safety Population which consists of all randomized 
participants who received study intervention and will be analyzed by actual treatment.
Pharmacokinetic data will be evaluated on participants in the ITT set who received sirukumab.
9.4. Statistical Analyses
The statistical analysis plan will be finalized prior to database lock of the primary 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.


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An IA was performed when approximately 20% of the planned number of participants with 
confirmed severe and critical COVID-19 disease have reached Day 28, or discontinued earlier 
from the study (refer to Section.9.5).
The primary analysis will be done when all participants reached Day 28 or discontinued earlier. 
The final analysis will be done when all participants completed the study. 
A hierarchical testing strategy will be used for the primary and key secondary endpoints. 
First, the primary endpoint will be tested for superiority of sirukumab over placebo at the 2-sided 
5% significance level. If superiority is shown on the primary endpoint, then the proportion of 
participants with a clinical improvement of at least 2 categories at Day 28 will be tested at the 
1-sided 5% significance level. If superiority on this endpoint is shown, the mortality by Day 28 
will be tested, again at the 1-sided 5% significance level.
9.4.1.
General Considerations
For all participants who receive study drug descriptive statistics will be provided. All demographic 
characteristics (eg, age, race, ethnicity, height, body weight, body mass index) and other initial 
participant characteristics (eg, medical and surgical history, concomitant diseases) will be 
tabulated and analyzed descriptively.
Subgroup analyses will be performed based on the stratification factors (age [<65 and ≥65 years 
of age] and use of invasive mechanical ventilation [yes/no]) and a selection of the major baseline 
parameters.
A DMC will be established as noted in Committees Structure in Section 10.4.6 Committees 
Structure.
9.4.2.
Primary Endpoint
The primary efficacy analysis will be based on the ITT analysis set restricted to participants with 
confirmed critical COVID-19 disease and the primary efficacy endpoint is the ‘time to 
improvement of at least 2 categories relative to Baseline on a 6-point ordinal clinical recovery 
scale’. The improvement should be sustained until Day 28 (or discharge/discontinuation). Time to 
clinical improvement will be assessed during the 28-day period after study drug administration, 
with failure to reach clinical improvement or death before Day 28 considered as right-censored at 
Day 28. 
This primary parameter will be analyzed by a stratified log-rank test (using the stratification 
factors). Kaplan-Meier curves, overall and by stratum will be used to graphically present the 
primary parameter. The sensitivity analyses will be defined in the statistical analysis plan. 
First, the primary endpoint will be tested for superiority of sirukumab over placebo at the 2-sided 
5% significance level. If superiority is shown on the primary endpoint, then the key secondary 
endpoints will be tested at the 1-sided 5% significance level. 


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9.4.3.
Secondary Endpoints
Key and other secondary endpoints will be analyzed graphically and descriptively as described in 
the statistical analysis plan. For continuous variables, descriptive statistics (n, mean, SD, median, 
minimum, maximum, and 95% confidence intervals [CIs]) will be calculated. For categorical 
variables, frequency tables and corresponding 95% CIs will be presented. 
9.4.3.1.
Key Secondary Endpoints
The key secondary endpoints will be analyzed using the Cochrane-Mantel-Haenszel (CMH) test 
for difference in proportions.
9.4.4.
Other Secondary Endpoints
To compare the proportion of participants with an improvement of at least 1 category relative to 
Baseline on the 6-point ordinal clinical recovery scale relative to Baseline, the proportion of 
participants with a worse score relative to Baseline on the 6-point ordinal clinical recovery scale,
the proportion of participants who progress to mechanical ventilation (for participants not on 
mechanical ventilation at baseline), and the mortality rates defined as category 6 on the 6-point 
ordinal clinical recovery scale, the difference in cumulative incidence at Day 28 will be estimated 
using the same techniques as for the key secondary endpoints.
Total length of hospitalization, total time on invasive mechanical ventilation, number of ventilation 
free days, and total time on ECMO will be analyzed by the stratified Wilcoxon Rank-Sum test and 
using the stratification factors. Corresponding 95% CIs will be derived using the Hodges-Lehmann 
approach. 
Time to improvement of at least 1 category and other ‘time to event’ parameters will be analyzed 
using the stratified log-rank test.
The distribution of outcomes on the 6-point ordinal clinical recovery scale will be described via 
plots (eg, stacked bar plots representing the proportion of participants in each category, by 
treatment arm and over time).
A proportional odds model will be used to analyze the 6-point ordinal clinical recovery scale of 
the clinical status at Days 7, 14, 21 and 28. 
Drugs used in the SOC at baseline and changes in the SOC after treatment administration will be
tabulated by treatment group.
The primary and secondary endpoint evaluation will be conducted on the ITT population and on 
the ITT population restricted to the population with confirmed critical COVID-19 disease. 
Analyses of qualitative comparison between pre-interim analysis and post-interim analysis for 
treatment effect in the population with confirmed critical COVID-19 disease will be conducted to 
check the consistency in the study. This qualitative assessment will be limited to primary and key 
secondary endpoints only.
Other secondary parameters might be added in the SAP.


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9.4.5.
Exploratory Endpoint(s) 
Time to viral negativity will be analyzed analogously to that of the primary efficacy parameter.
SARS-CoV-2 viral load in NP swabs and in endotracheal, blood, and stool samples will be 
measured by a qRT-PCR assay. These data will be analyzed graphically and descriptively as 
described in the statistical analysis plan. 
Other exploratory parameters might be added in the SAP.
9.4.6.
Safety Analyses
All safety analyses will be made on the Safety Population and on participants with confirmed 
(a) critical and (b) severe or critical COVID-19 disease.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after 
the initial administration of study intervention is considered to be treatment-emergent. All reported
AEs will be included in the analysis. For each AE, the percentage of participants who experience 
at least 1 occurrence of the given event will be summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an AE, or who experience a grade 3 or 
4 AE, a serious AE, or an adverse event of special interest (AEOI).
The incidence of participants with SAEs, the incidence of participants with grade 3 or 4 AEs, the 
incidence of participants with severe or life-threatening, bacterial, invasive fungal, viral or 
opportunistic infections (other than SARS-CoV-2), the incidence of grade 3 and 4 neutropenia and 
lymphocytopenia, and the incidence of increased ALT ≥3xULN combined with increased bilirubin 
>2xULN will be reported. Increase of ALT or AST combined with increase of bilirubin will be 
investigated by means of evaluation of drug-induced serious hepatotoxicity (eDISH) plots.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. The laboratory abnormalities will 
be determined per the criteria specified in the DMID Adult Toxicity Table (Section 10.8, Appendix
8) and in accordance with the normal ranges of the clinical laboratory if no gradings are available. 
Tables showing n and percent of participants with treatment-emergent worst toxicity grades (for 
tests with defined toxicity grades) and treatment-emergent worst abnormalities (for tests without 
defined toxicity grades) during treatment phase will be generated. A listing of participants with 
any laboratory results outside the reference ranges will be provided. A listing of participants with 
any markedly abnormal laboratory results will also be provided.


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Electrocardiogram
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made.
Vital Signs
Vital signs including temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic 
and diastolic) will be summarized over time, using descriptive statistics and/or graphically. The 
percentage of participants with values beyond clinically important limits will be summarized.
9.4.7.
Other Analyses
Pharmacokinetic Analyses 
Serum sirukumab concentrations will be summarized using descriptive statistics. The 
concentrations below the lowest quantifiable sample concentration of the assay will be treated as 
zero in the summary statistics. All concentrations below the lowest quantifiable sample 
concentration of the assay or missing data will be labeled as such in the concentration data listing 
or statistical analysis dataset. 
If feasible, population PK analysis of serum concentration-time data of sirukumab may be 
performed using nonlinear mixed-effects modeling. Data may be combined with other selected 
studies to support a relevant structural model. Available baseline participant characteristics (eg, 
demographics, laboratory variables) may be tested as potential covariates affecting PK parameters. 
The results of the population PK analysis will be presented in a separate report. 
Biomarkers Analyses 
Analysis of the relationship between various blood biomarkers, such as cytokines, and viral 
parameters, immunogenicity, safety and clinical outcome may be conducted.
Descriptive statistics for actual values and (relative) changes from baseline for the different blood 
biomarkers assessed, will be tabulated for each biomarker at each applicable time point specified 
in the Schedule of Activities (SoA). Statistics include n, mean, SD, geometric mean, median, 
minimum, and maximum.
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary 
and depend on the different data types of the applied technology platforms, as well as on the extent 
of observed differences between participants. Analyses will be conducted at the sponsor’s 
discretion and may be reported separately from this study. 
Immunogenicity Analyses
The incidence of antibodies to sirukumab will be summarized for all participants in the ITT 
population with appropriate samples for detection of antibodies to sirukumab (ie, participants with 
at least predose and the Day 28 sample obtained). 


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Virology Analyses 
SARS-CoV-2 viral load summaries will be presented with descriptive statistics by intervention 
arm. If the virology endpoint is continuous, the descriptive statistics will include the number of 
participants, mean, standard deviation (SD), median, and range. If the virology endpoint is binary 
or categorical, the frequency distribution with the number and percentage of participants in each 
category will be calculated. For time-to-event variables, a summary table including number of 
participants included in the analysis, number of participants censored, 25th and 75th percentiles and 
median time-to event will be shown by intervention arm. Graphic displays will also be used to 
summarize the data. Comparison between viral load in NP, endotracheal, blood and stool samples 
might be performed.
Amino acid and/or nucleic acid substitutions in the SARS-CoV-2 genome will be tabulated and 
described.
Additional exploratory characterization may be performed and reported separately.
Pharmacodynamic Analyses 
Associations between baseline levels of biomarkers, immunogenicity tests, PK parameters and 
clinical response (primary endpoint and a selection of secondary endpoints) will be explored. 
More details will be provided in the statistical analysis plan.
Pharmacogenomic Analyses 
DNA samples will be analyzed if it is hypothesized that this may help resolve issues with the 
clinical data. 
DNA samples will be used for research related to the IL-6 gene, sirukumab, or SARS-CoV-2 
infection. Pharmacogenomic research may consist of the analysis of one or more candidate genes,
of the analysis of genetic markers throughout the genome, or the analysis of the entire genome (as 
appropriate) to evaluate potential genetic associations with prognosis of clinical outcomes in 
patients and prediction of responsiveness to active treatment.
Results will be presented in a separate report.
9.5. Interim Analysis
A non-binding unblinded IA for futility was performed by the sponsor on the primary endpoint 
when approximately 20% of the planned number of participants with confirmed severe and critical 
COVID-19 disease had reached Day 28 or discontinued earlier.
The randomization codes and the translation of randomization codes into treatment and control 
groups was disclosed to those authorized and only for those participants included in the IA. The 
following implementation was followed for the non-binding IA for futility while considering the 
severe and critical participants in the study.


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The futility criterion was based on the conditional power approach for the primary endpoint. The 
conditional power was calculated for the primary hypothesis using the observed data and assuming 
a mortality rate of 30% in the control arm versus 21% in the sirukumab arm in the remainder of 
the study. The effect size and outcomes for the primary endpoint in the survivors was simulated as 
used for the study sample size calculation. A non-binding futility stopping boundary of 80% for 
the conditional power was used. Assuming the outcome for the primary endpoint as used for the 
sample size calculations was true, with a 30% mortality rate in the control arm, the chance of 
stopping for futility at the time of the IA was 2.5%. Otherwise, if the null hypothesis was true and 
again with a 30% mortality rate in the control arm, the chance of stopping for futility was 60%. If, 
at the time of the IA, the probability of a successful study was lower than the futility boundary, the 
sponsor could have taken the decision to stop for futility after evaluation of all available data. In 
addition to the conditional power calculations, descriptive analyses of the primary and key 
secondary endpoints were performed on the available data. The safety outputs planned for the 
regular DMC safety reviews will be provided too.
No additional non-binding IA for futility is planned for the critical participants to be enrolled in 
the remainder of the study.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.Appendix 1: Abbreviations and Definitions
AE
adverse event
AEOI
adverse event of interest
AESI
adverse event of special interest
ALI
acute lung injury
ALP
Alkaline phosphatase
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
AxMP
Auxiliary Medicinal Product (also known as NIMP)
BAL
bronchoalveolar lavage
BIPAP
bilevel positive airway pressure
BUN
blood urea nitrogen
CAR
chimeric antigen receptor
CDC
Center of Disease Control and Prevention
CI
confidence interval
CMH
Cochrane-Mantel-Haenszel
COVID-19
coronavirus disease 2019
CPAP
continuous positive airway pressure
CPK
creatine phosphokinase
CRF
case report form(s) (paper or electronic as appropriate for this study)
CRP 
C-reactive protein
CRS
cytokine release syndrome
CRS
cytokine release syndrome
CT
computerized tomography
D
day
DBP
diastolic blood pressure
DMC
data monitoring committee
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic case report form
eDC
electronic data capture
eDISH
evaluation of drug-induced serious hepatotoxicity
EOT
end of trial
eQTL
expression quantitative trait locus
FiO2
percentage of inspired oxygen
FOIA
Freedom of Information Act
GCP
Good Clinical Practice
GCS
Glasgow coma scale
gG1κ
Immunoglobulin G1 kappa 
GGT
gamma-glutamyltransferase
gp
glycoprotein
GVHD
graft-versus-host disease
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
IB
Investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ICU
intensive care unit
IEC
Independent Ethics Committee
IL
interleukin
IL6R
IL-6 receptor 
IMP
Investigational Medicinal Product
IND
Investigational New Drug


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INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
JAK
Janus activated kinase
Kd
equilibrium dissociation constant
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MERS-CoV
Middle East respiratory syndrome coronavirus
MT
mid-turbinate
NIMP
Non-Investigational Medicinal Product
NP
nasopharyngeal
PaCO2
partial pressure of carbon dioxide in arterial blood
PaO2
partial pressure of oxygen in arterial blood
PBO
placebo
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PT
prothrombin time
PTT
partial thromboplastin time
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
red blood cell
RT-PCR
reverse-transcriptase polymerase chain reaction
SAA
serum amyloid A
SAE
serious adverse event
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SARS-CoV(-2)
severe acute respiratory syndrome coronavirus (2)
SBP
systolic blood pressure
sIL-6R
soluble form of IL-6 receptor 
SNP
single-nucleotide polymorphisms
SoA
Schedule of Activities
SOC
standard of care
SpO2
peripheral capillary oxygen saturation
STAT-3
signal transducer and activator of transcription 3
SUSAR
suspected unexpected serious adverse reaction
US
United States
W
week
WBC
white blood cell


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Definitions of Terms
Critical COVID-19 disease
Requires supplemental oxygen delivered by nonrebreather mask or high-flow nasal 
cannula OR use of non-invasive or invasive ventilation OR requiring treatment in an 
ICU.
Severe COVID-19 disease
Requires supplemental oxygen administration by nasal cannula, simple face mask, 
or other similar oxygen delivery device (ie, above pre-COVID baseline oxygen 
requirement, if any, by the participant).
Study Interventions
Sirukumab (CNTO136)
Sirukumab solution for infusion (100 mg/mL) at a dose of 5 mg/kg injected into a 
50 mL dextrosea bag (5% dextrose) with the total volume of the bag adjusted to 
50 mL. 
placebo
50 mL dextrosei bag (5% dextrose) without any substance injected in the bag.
                                                
a Dextrose is also commonly known and referred to as glucose.


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10.2.Appendix 2: Clinical Laboratory Tests
The following tests will be performed according to the Schedule of Activities by local laboratories
unless specified otherwise.
Protocol-Required Laboratory Assessments
Laboratory 
Assessments
Parameters
Tests to be done by a
Local 
laboratory
Central 
laboratory
Safety 
assessments
Hematology
Platelet count
Red blood cell 
count
Hemoglobin
Hematocrit
RBC Indices:
MCV
MCH
% 
Reticulocytes
White Blood Cell 
(WBC) count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
All tests
Note: A WBC evaluation may include any abnormal cells, 
which will then be reported by the laboratory. A RBC 
evaluation may include abnormalities in the RBC count, 
RBC parameters, or RBC morphology, which will then be 
reported by the laboratory. In addition, any other abnormal 
cells in a blood smear will also be reported.
Blood
Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Phosphate
Magnesium
Blood urea nitrogen (BUN)
Creatinine
Aspartate aminotransferase 
(AST)/Serum glutamic-
oxaloacetic transaminase
Alanine aminotransferase 
(ALT)/Serum glutamic-
oxaloacetic pyruvic 
transaminase
Alkaline phosphatase (ALP)
Total bilirubin
Conjugated bilirubin (direct)b
Unconjugated bilirubin 
(indirect) b
Creatine phosphokinase 
(CPK)
Lactic acid 
dehydrogenase (LDH)
Lactate
Albumin
Total protein
Glucose
Troponin I or T
Total cholesterol
LDL
HDL
Triglycerides
All tests
Coagulation 
tests
Prothrombin time (PT) and international normalized ratio 
(INR) or, activated partial thromboplastin time (aPTT), 
fibrinogen
All tests
Arterial 
blood gases
pH, PaO2, PaCO2 (as per local SOC, collect if available)
All tests


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Laboratory 
Assessments
Parameters
Tests to be done by a
Local 
laboratory
Central 
laboratory
Other Tests

Urine pregnancy testing for all women of childbearing 
potential (at screening, baseline, and Day 28 or at day 
of discharge).
All tests

Bacterial, fungal, or viral infection testing (as per local 
SOC).
All tests

NP swabs to determine SARS-CoV-2 positivity, refer 
to the Schedule of Activities (SoA) for more detailsa.
Any 
time 
before 
randomizat
ion

NP swabs for infections testing (PCR quantification 
of SARS-CoV-2 and multiplex PCR for detection of 
co-infections).
All 
time
points
as 
from Day 1

Endotracheal aspirate (only if intubated) for virology 
testing (PCR SARS-CoV-2).
Any 
time 
before 
randomizat
ion
All 
time
points
as 
from Day 1

Stool sample (if feasible) for virology.

Blood samples for SARS-CoV-2 viremia.

Blood samples for cellular profiling.

Blood samples for RNA profiling.

Whole blood for DNA profiling (optional).

Pharmacology samples (including testing for IL-6 and 
antibodies to sirukumab).

Blood samples to evaluate biomarkers.

Blood samples for SARS-CoV-2 specific antibodies.

CRP, Ferritin, D-dimer, Procalcitonin.
All 
time
points
a.
SARS-CoV-2 positivity should be documented based on local testing on any specimen, by RT-PCR any time 
before randomization. This might require a local test using a NP swab obtained at screening.
b.
Only if ALT or AST >3x ULN or if 3x the entry level (if these were >ULN).


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10.3.Appendix 3: Clinical and Laboratory Assessments Described per Day
From Screening to Baseline
Screening 
Phasea
Day
Screening
1 (Baseline)
General Screening/Baseline assessments
ICFc
X
Inclusion/Exclusion criteria
X
Xd
Demographics, medical historye
X
Targeted physical examh
X
Treatment administration
Randomizationi
X
Administration of study interventioni
X
Concomitant medication
Concomitant medication recording
X
X
Respiratory function related assessments
Type of supplemental oxygen
X
X
Resting SpO2, FiO2 (if any)j
X
X
Arterial pH, PaO2, PaCO2j
As available per day
Level of consciousness (Glasgow coma scale score)k
X
X
Pulmonary X-ray (or CT imaging or lung ultrasound if X-ray not available)
Xg,bb
General safety related assessments
Standard 12-lead ECG
Xg bb
Vital signs (body temperature, pulse, SBP/DBP, respiratory rate)
X
X
Any AE
X
X
Safety laboratory assessmentsdd
Hematologyl
Xg
X
Chemistry: General Safetyl
Xg
X
Chemistry: Total Cholesterol, LDL, HDL, Triglycerides
Xg
X
Coagulation: PTT/INR or aPTT, fibrinogen
Xg
X
Pregnancy assessment urinef
Xg
X
Bacterial, fungal, viral infection testing (blood, other)m
Per SOC, any infection to be reported as 
AESI


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Screening 
Phasea
Day
Screening
1 (Baseline)
Virology Assessments
Blood sample for SARS-CoV-2 viremia
X●
Nasopharyngeal swab for infections testing (PCR quantification of SARS-CoV-2 and multiplex PCR for 
detection of co-infections)p,q
Xq,r
X●,s
If participants are intubated, an endotracheal sample for quantification of SARS-CoV-2 is to be taken in addition 
to the NP swabt
Xq,r
X●,s
Stool sample (if feasible) 
X●,bb
Biomarker/Pharmacology Assessmentsdd
CRP, Ferritin, D-dimer, Procalcitonin
X●
Blood samples for cytokines, chemokines
X●
Blood samples for various biomarkers
X●
Blood sample for SARS-CoV-2 specific antibodies
X●
Blood samples for pharmacologyw
X●predose   / X●postdose
Blood samples for cellular profiling
X
Exploratory Biomarkers/Pharmacogenomicsdd
PAXgene blood for RNA profilingx
X●
Whole blood for DNA profiling (optional)y
X●,z
●
Laboratory testing to be performed centrally.
Note: If multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence: ECG, oxygen 
saturation, vital signs, blood sampling.


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Hospitalization Follow-Up Day 2 until Day 14
Hospital Follow-Up (Day)
Day
2
3
4
5
6
7
8
9
10
11
12
13
14
Week
1
2
General Screening/Baseline assessments
Targeted physical examh
X
X
X
X
X
X
X
X
X
X
X
X
X
Any clinically significant findings to be reported
Concomitant medication
Concomitant medication recording
X
X
X
X
X
X
X
X
X
X
X
X
X
Respiratory function related assessments
Type of supplemental oxygen
X
X
X
X
X
X
X
X
X
X
X
X
X
1x per day
Resting SpO2, FiO2 (if any)j
X
X
X
X
X
X
X
X
X
X
X
X
X
Minimum 4x per day
Arterial pH, PaO2, PaCO2j
X
X
X
X
X
X
X
X
X
X
X
X
X
As available per day
Level of consciousness 
(Glasgow coma scale score)k
X
X
X
X
X
X
X
X
X
X
X
X
X
1x per day in ICU
Pulmonary X-ray (or CT imaging or lung 
ultrasound if X-ray not available)
X
X
X
X
X
X
X
X
X
X
X
X
X
Per SOC, report upon worsening and last available
General safety related assessments
Standard 12-lead ECG
Once between Day 4 and Day 8
Vital signs (body temperature, pulse, 
SBP/DBP, respiratory rate)
X
X
X
X
X
X
X
X
X
X
X
X
X
Per SOC, minimum 4x per day in ICU/ 1x per day non-ICU
Any AE
X
X
X
X
X
X
X
X
X
X
X
X
X
Record discharge from ICU, discharge 
from hospital
X
X
X
X
X
X
X
X
X
X
X
X
X
As applicable
Safety laboratory assessmentsdd
Hematologyl
X
X
X
Chemistry general safetyl
X
X
X
Bacterial, fungal, viral infection testing 
(blood, other)m
X
X
X
X
X
X
X
X
X
X
X
X
X
Per SOC, any infection to be reported as AESI


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Hospital Follow-Up (Day)
Day
2
3
4
5
6
7
8
9
10
11
12
13
14
Week
1
2
Virology Assessments
Blood sample for SARS-CoV-2 viremia
X●
X●
Nasopharyngeal swab for infections 
testing (PCR quantification of SARS-
CoV-2 and multiplex PCR for detection of 
co-infections)p,q
X●
(X●)
(X●)
X●
(X●)
X●
X●
If participants are intubated, an 
endotracheal sample for quantification of 
SARS-CoV-2 is to be taken in addition to 
the NP swabt
X●
(X●)
(X●)
X●
(X●)
X●
X●
Stool sample (if feasible)
X●
(X●)
(X●)
X●
(X●)
X●
X●
Biomarker/Pharmacology Assessmentsdd
CRP, Ferritin, D-dimer, Procalcitonin
X●
X●
X●
X●
Blood samples for cytokines, chemokines
X●
X●
Blood samples for various biomarkers
X●
Blood sample for SARS-CoV-2 specific 
antibodies
X●
Blood samples for pharmacologyw
X●
Blood samples for cellular profiling
X●
Exploratory Biomarkers/Pharmacogenomicsdd
PAXgene blood for RNA profilingx
X●
●
Laboratory testing to be performed centrally.
Note: If multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence: ECG, oxygen 
saturation, vital signs, blood sampling


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.Hospitalization Follow-Up Day 15 until Day 28
Hospital Follow-Up (Day)
Day
15
16
17
18
19
20
21
22
23
24
25
26
27
28b
Week
3
4
General Screening/Baseline assessments
Targeted physical examh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Any clinically significant findings to be reported
Concomitant medication
Concomitant medication recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Respiratory function related assessments
Type of supplemental oxygen
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1x per day
Resting SpO2, FiO2 (if any)j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Minimum 4x per day
Arterial pH, PaO2, PaCO2j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
As available per day
Level of consciousness 
(Glasgow coma scale score)k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1x per day in ICU
Pulmonary X-ray (or CT imaging or 
lung ultrasound if X-ray not available)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Per SOC, report upon worsening and last available
General safety related assessments
Vital signs (body temperature, pulse, 
SBP/DBP, respiratory rate)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Per SOC, minimum 4x per day in ICU, 1x per day non-ICU
Any AE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record discharge from ICU, discharge 
from hospital
X
X
X
X
X
X
X
X
X
X
X
X
X
X
As applicable


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Hospital Follow-Up (Day)
Day
15
16
17
18
19
20
21
22
23
24
25
26
27
28b
Week
3
4
Safety laboratory assessmentsdd
Hematologyl
X
X
Chemistry general safetyl
X
X
Chemistry:Total Cholesterol, LDL, 
HDL, Triglycerides
Coagulation: PTT/INR or aPTT,
fibrinogen
Pregnancy assessment urinef
X
Bacterial, fungal, viral infection testing 
(blood, other)m
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Per SOC, any infection to be reported as AESI
Virology Assessments
Blood sample for SARS-CoV-2 viremia
X●
Nasopharyngeal swab for infections 
testing (PCR quantification of SARS-
CoV-2 and multiplex PCR for detection 
of co-infections)p,q
X●
X●,u,v
If participants are intubated, an 
endotracheal sample for quantification 
of SARS-CoV-2 is to be taken in 
addition to the NP swabt
X●
X●,u,v
Stool sample (if feasible)
X●
X●
Biomarker/Pharmacology Assessmentsdd
CRP, Ferritin, D-dimer, Procalcitonin
X●
X●
Blood samples for cytokines, 
chemokines
X●
X●
Blood samples for various biomarkers
X●
Blood sample for SARS-CoV-2 specific 
antibodies
X●
Blood samples for pharmacologyw
X●
X●
Blood samples for cellular profiling
X●


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Hospital Follow-Up (Day)
Day
15
16
17
18
19
20
21
22
23
24
25
26
27
28b
Week
3
4
Exploratory Biomarkers/Pharmacogenomicsdd
PAXgene blood for RNA profilingx
X●
●
Laboratory testing to be performed centrally.
Note: If multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence: ECG, oxygen saturation, 
vital signs, blood sampling.


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Hospitalization after Day 28, Discharge/Discontinuation Visit after Day 28, and Post-Hospitalization Follow-Up
Hospital 
Follow-Up
Discharge / Discontinuation Visit
Post-hospitalization Follow-Up Phone Call 
Day
After Day 28b
(if hospitalized)
Discharge 
up to Day 28aa
Discharge post 
Day 28aa
Day 28 if
discharged 
earlier (±3
days)
Day 56
(±7 days)
Day 84
(±7 days)
Day 112
(±7 days)
Week
Every Week
(Once on the day of 
assessment unless 
specified differently 
below)
Week 4
Week 8
Week 12
Week 16
General Screening/Baseline assessments
Targeted physical examh
X
X
X
Any clinically significant findings to be reported
Concomitant medication
Concomitant medication recording
X
X
X
Xn
Xn
Xn
Xn
Respiratory function related assessments
Type of supplemental oxygen
X
X
X
Resting SpO2, FiO2 (if any)j
X
X
X
Minimum 4x per day on the day of assessment
Arterial pH, PaO2, PaCO2j
X
X
X
As available per day
Level of consciousness (Glasgow 
coma scale score)k
X (if still in 
ICU)
Pulmonary X-ray (or CT imaging 
or lung ultrasound if X-ray not 
available)
X
X
X
per SOC, report upon worsening and last available
General safety related assessments
Vital signs (body temperature, 
pulse, SBP/DBP, respiratory rate)
X
X
X
Any AE
X
X
X
Xn
Xn
Xn
Xn
Record discharge from ICU, 
discharge from hospital
As applicable
As applicable
As applicable


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Hospital 
Follow-Up
Discharge / Discontinuation Visit
Post-hospitalization Follow-Up Phone Call 
Day
After Day 28b
(if hospitalized)
Discharge 
up to Day 28aa
Discharge post 
Day 28aa
Day 28 if
discharged 
earlier (±3
days)
Day 56
(±7 days)
Day 84
(±7 days)
Day 112
(±7 days)
Week
Every Week
(Once on the day of 
assessment unless 
specified differently 
below)
Week 4
Week 8
Week 12
Week 16
Safety laboratory assessmentsdd
Hematologyl
Xcc
X
X
Chemistry general safetyl
Xcc
X
X
Chemistryl: Total Cholesterol, 
LDL, HDL, Triglycerides
X
X
Coagulation: PTT/INR or aPTT,
fibrinogen
X
X
Pregnancy assessment urinef
X
Bacterial, fungal, viral infection 
testing (blood, other)m
X
X
X
per SOC, any infection to be reported as AESI
Virology Assessments
Blood sample for SARS-CoV-2 
viremia
X●
X●
X●
Nasopharyngeal swab for 
infections testing (PCR 
quantification of SARS-CoV-2 and 
multiplex PCR for detection of co-
infections)p,q
X●
X●,u,v
X●,u,v
X●,v
X●,v
X●,v
If participants are intubated, an 
endotracheal sample for 
quantification of SARS-CoV-2 is 
to be taken in addition to the NP 
swabt
X●
Stool sample (if feasible)
X●
X●
X●


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Hospital 
Follow-Up
Discharge / Discontinuation Visit
Post-hospitalization Follow-Up Phone Call 
Day
After Day 28b
(if hospitalized)
Discharge 
up to Day 28aa
Discharge post 
Day 28aa
Day 28 if
discharged 
earlier (±3
days)
Day 56
(±7 days)
Day 84
(±7 days)
Day 112
(±7 days)
Week
Every Week
(Once on the day of 
assessment unless 
specified differently 
below)
Week 4
Week 8
Week 12
Week 16
Biomarker/Pharmacology Assessmentsdd
CRP, Ferritin, D-diner, 
Procalcitonin
X●,cc
X●
X●
Blood samples for cytokines, 
chemokines
X●
Blood samples for various 
biomarkers
X●
Blood sample for SARS-CoV-2 
specific antibodies
X●
Blood samples for pharmacologyw
X●
Blood samples for cellular 
profiling
X●
Exploratory Biomarkers/Pharmacogenomicsdd
PAXgene blood for RNA 
profilingx
X●
Phone call assessments
Record vital statuso
Xn
Xn
Xn
Xn
Self-reported oxygen needed 
(yes/no)
Xn
Xn
Xn
Xn
Self-reported pregnancy status
Xn
Xn
Xn
Xn
Record readmission(s) post 
discharge and reason
Xn
Xn
Xn
Xn
●
Laboratory testing to be performed centrally.
Note: If multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence: ECG, oxygen 
saturation, vital signs, blood sampling.


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Abbreviations: AE: adverse event, AESI: adverse event of special interest; aPPT: activated partial thromboplastin 
time; CRP: C-reactive protein; CT: computed tomography; DBP: diastolic blood pressure; FiO2: percentage of 
inspired oxygen; ECG: electrocardiogram; HDL: low-density lipoprotein; ICF: informed consent form; ICU: intensive 
care unit; INR: international normalized ratio; LDL: low-density lipoprotein; PaCO2: partial pressure of carbon 
dioxide in arterial blood; PaO2: partial pressures of oxygen in arterial blood; PCR: polymerase chain reaction; PT: 
prothrombin time; SAE: serious adverse event; SBP: systolic blood pressure; SOC: standard of care; SpO2: peripheral 
capillary oxygen saturation.
Footnotes:
a.
Screening assessments start after signing of the ICF and can continue on the next calendar 
day, if needed. All screening and baseline assessments may also take place on the same day. 
Screening/Baseline assessments required to verify study eligibility and data collection for 
assessment of the 6-point ordinal clinical recovery category should take place prior to 
randomization. All Screening/Baseline procedures should take place prior to study drug 
administration.
b.
The assessment schedule will be on a weekly for participants still hospitalized after Day 28.
c.
Consent to be obtained before the first study-related activity. An exception is in the case of an 
emergency enrollment in which the informed consent can be obtained as soon as possible.
d.
If a participant's clinical status changes after screening but before randomization such that he 
or she no longer meets all eligibility criteria, then the participant should be excluded from 
participation in the study.
e.
Medical history should include collecting onset of COVID-19 symptoms, prior therapy, and 
date of SARS-CoV-2 diagnosis if available.
f.
A urine pregnancy test is to be performed in women of childbearing potential only.
g.
Results from the blood chemistry, hematology, and coagulation test, pregnancy test, ECG, and 
pulmonary imaging, completed as SOC, taken up to 2 days prior to screening will be accepted 
as screening assessments. 
h.
Targeted physical examination is to be performed as per local SOC and includes, if feasible, 
lung auscultation and any examination as indicated by the patient’s medical history. Height 
and body weight are only to be measured at screening if not already available in the 
participant’s chart and if practically feasible. If not feasible, weight for dose calculation can 
be verbally reported by the participant or a family member.
i.
Participants need to receive study intervention preferably within 4 hours but no later than 6 
hours after randomization.
j.
Supplemental oxygen/percentage of inspired oxygen (FiO2) use (if any) will be measured 
(simultaneously with SpO2, and at any time of arterial blood gas measurements) to monitor 
the patient’s status regarding gas exchange as applicable. The following will be recorded:
-
Oxygen delivery device (eg, nasal cannula, simple face mask, nonrebreather mask, high 
flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, 
extracorporeal life support, etc).
-
Oxygen flow rate in liters/min.
-
Record FiO2 and SpO2 data 4 times per day, and at any time of arterial blood gas 
measurements. Record values that are sustained for at least 1 hour. 


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-
If a patient is using more than one device (eg, extracorporeal life support and invasive 
ventilation), the worst value of FiO2 (and the corresponding SpO2 -and PaO2 if available-)
on the highest level of intervention will be recorded. The worst (highest) value of FiO2 (and 
the corresponding SpO2 -and PaO2 if available-) on each device will also be recorded 
separately.
-
If a patient does not need oxygen supplementation, this should also be recorded.
k. The final worst score of the Glasgow Coma Scale of the day needs to be recorded in the eCRF. 
The level of sedation of the participant will be derived from the type of medication entered for 
indication sedation on the Concomitant Medication page of the eCRF.
l.
Laboratory testing to be performed includes:
-
Hematology: hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, RBC 
indices (mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], % 
reticulocytes), white blood cell (WBC) count with differential (neutrophils, lymphocytes, 
monocytes, basophils, eosinophils).
-
General safety chemistry: total protein, albumin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, glucose, sodium, 
potassium, calcium, phosphate, magnesium, chloride, bicarbonate, creatinine, blood urea 
nitrogen (BUN), creatine phosphokinase (CPK), lactate dehydrogenase (LDH), lactate, and 
troponin. If ALT or AST >3x ULN or 3x the entry level (if entry levels were >ULN) also 
provide conjugated bilirubin (direct), unconjugated bilirubin (indirect).
m. Culture results (bacterial, fungal, or viral) including site of infection and specimen source 
(bronchoalveolar lavage [BAL], tracheal aspirate, sputum, blood, urine, etc.), performed as 
part of patients’ workup for new infections, should be reported. Analyses will be performed 
by the local laboratory.
n.
For participants discharged or who discontinued the study prior to Day 28 and did not 
withdraw consent, phone calls will be conducted on Day 28 and during the post Day 28 
Follow-up Phase to record concomitant medication, the vital status, the occurrence of AEs, 
self-reported oxygen need, self-reported pregnancy status and the history of readmission since 
last contact.
o.
Whenever possible, vital status will be recorded if the patient is alive. If the participant is 
deceased, date and cause of mortality should be recorded in the eCRF. Death should be 
documented as SAE.
p.
NP swabs will be used to collect secretions from participants to explore quantification of viral 
load of SARS-CoV-2. For each participant, NP sampling should be done at approximately the 
same time (±4 hours) on each sampling day and from the same nostril.
q.
If an NP sample for detection of SARS-CoV-2 (local SOC) will be collected on the same day 
as the NP sample for quantification of SARS-CoV-2 (central lab), only one NP sample should 
be collected. The sample should be aliquoted and the remaining aliquots of the NP samples 
should be stored and sent to the central lab for quantification of SARS-CoV-2.
r.
SARS-CoV-2 positivity should be documented based on local testing on any specimen, by 
RT-PCR any time before randomization. This might require a local test using an NP swab 
obtained at screening.


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s.
After randomization, SARS-CoV-2 positivity will be confirmed in a central lab by quantitative 
RT-PCR. The baseline sample needs to be collected predose, as close as possible to dosing.
t.
If the participant is intubated, endotracheal samples need to be taken at the same time as the 
NP swab. If taking both NP and endotracheal samples is not feasible, the NP sample should 
be given priority.
u.
Lab testing for detection of SARS-CoV-2 on the NP swab at day of hospital discharge. If 
SARS CoV-2 positive, an additional NP swab will be taken every 7 days, if feasible for the 
site and tested, until SARS-CoV-2 negative.
v.
If viral RNA is detected in NP samples at day of discharge, all possible efforts will be made 
to follow-up participants and collect samples every 7 days until viral RNA is negative, 
considering the current pandemic and related logistical challenges. If possible, home visits by 
a healthcare professional may be conducted to collect samples during the follow-up period.
w.
Includes serum samples for measurement of PK, antibodies to sirukumab, and IL-6. On Day 1, 
a predose and a postdose (within 30 minutes after the end of infusion) sample should be 
collected. The postdose sample should be collected from the arm contralateral to that used for 
IV infusion. On Day 1 (predose) and Day 28 the PK, antibodies to sirukumab, and IL-6 will 
be evaluated. On Day 1 (postdose), Day 14, and Day 21 the PK and IL-6 will be evaluated.
x.
PAXgene RNA tubes should always be used last for any blood draw.
y.
An optional pharmacogenetics blood sample (DNA) will be obtained from those participants 
who gave consent (where local regulations permit).
z.
Sample can be also taken at any other time point after study drug intervention on Day 1.
aa.
For those participants discharged prior to Day 28, all Day 28 assessments should be done at 
day of discharge. Laboratory, virology, relevant respiratory function related assessments, and 
biomarker/pharmacology assessments completed maximum 1 day before discharge do not 
need to be repeated on the day of discharge provided that no clinically relevant changes were 
noted in the results and the participant was declared ‘ready to be discharged’ on the day before 
discharge.
bb. Assessments done at screening do not need to be repeated at baseline.
cc.
For participants still hospitalized post Day 28, additional blood sampling should be done every 
7 days (±1 day) and at day of discharge.
dd. For all laboratory tests done on Day 21, Day 28, and every week thereafter as needed, a 
window of ±1 day for all sampling is allowed.


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10.4.Appendix 4: Regulatory, Ethical, and Study Oversight Considerations
10.4.1.
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 
situation and agree on an appropriate course of action. The data recorded in the eCRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.


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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
participant:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)


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
IB (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
intervention

New information that may adversely affect the safety of the participants or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the participants

Report of deaths of participants under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB


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For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.4.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations 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.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.
10.4.3.
Informed Consent Process 
Consent of each participant (or legally acceptable representative based on local regulations) must 
be obtained according to local requirements after the nature of the study has been fully explained. 
The informed consent (s) must be obtained before performance of any study-related activity. The 
ICF(s) that is/are used must be approved by both the sponsor and by the reviewing IEC/IRB and 
be in a language that the participant can read and understand. The informed consent should be in 
accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP 
guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants or their legally acceptable representative (based 
on local regulations) the aims, methods, reasonably anticipated benefits, and potential hazards of 
the study, and any discomfort participation in the study may entail. They will be informed that 
participation is voluntary and that they may withdraw consent to participate at any time. They will 
be informed that choosing not to participate will not affect the care the participant will receive for 
the treatment of his or her disease. Finally, they will be told that the investigator will maintain a 
participant identification register for the purposes of long-term follow up if needed and that their 
records may be accessed by health authorities and authorized sponsor personnel without violating 
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations. 
For more information on emergency situations due to COVID-19, see also Section 4.2.1.


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By obtaining the informed consent the participant or legally acceptable representative (based on 
local regulations) is authorizing such access, which includes permission to obtain information 
about his or her survival status. It also denotes that the participant agrees to allow his or her study 
physician to recontact the participant for the purpose of obtaining consent for additional safety 
evaluations, and subsequent disease-related treatments, if needed. 
The participant or legally acceptable representative (based on local regulations) will be given 
sufficient time to read the ICF and the opportunity to ask questions. After this explanation and
before entry into the study, consent should be appropriately recorded by means of either the 
participant's or his or her legally acceptable representative (based on local regulations) personally 
dated signature. After having obtained the consent, a copy of the ICF must be given to the 
participant.
Where local regulations require, separate consent needs to be obtained for the optional DNA 
component of the study.
If the participant or legally acceptable representative (based on local regulations) is unable to read 
or write, or consent is given verbally by phone, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the participant or legally 
acceptable representative (based on local regulations) is obtained.
When prior consent of the participant is not possible and the participant's legally acceptable 
representative (based on local regulations) is not available, enrollment procedures should be 
described in the protocol with documented approval/favorable opinion by the IEC/IRB to protect 
the rights, safety, and well-being of the participant and to ensure compliance with applicable 
regulatory requirements. The participant or legally acceptable representative (based on local 
regulations) must be informed about the study as soon as possible and give consent to continue.
10.4.4.
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant or his or her legally acceptable representative 
(based on local regulations) includes explicit consent for the processing of personal data and for 
the investigator/institution to allow direct access to his or her original medical records (source 


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data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. 
This consent also addresses the transfer of the data to other entities and to other countries.
The participant has the right to request through the investigator access to his or her personal data 
and the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory pharmacogenomic and biomarker research is not conducted under standards 
appropriate for the return of data to participants. In addition, the sponsor cannot make decisions as 
to the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to participants or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
10.4.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand sirukumab, to understand 
COVID-19, to understand differential intervention responders, and to develop tests/assays related 
to sirukumab and COVID-19. The research may begin at any time during the study or the 
post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
10.4.6.
Committees Structure
Data Monitoring Committee (DMC)
A DMC will be established to actively monitor interim data to review the ongoing safety of the 
participants in this study and to make recommendations about early study closure or changes to 
the conduct of the study. This committee will consist of sponsor personnel not directly involved 
in the conduct of the study and who have expertise in clinical study conduct, at least one medical 
expert in the relevant therapeutic area, at least one statistician and a safety expert. In addition, at 
least 2 external experts, are also included in this DMC. The committee will convene regularly at 
the discretion of the DMC chair during the study conduct, according to their charter, to evaluate 
the cumulative safety data of all participants in the study. The study responsible physician will 
inform the DMC of any AE of concern. 
As soon as the first 30 participants with confirmed severe and critical COVID-19 disease had 
received study intervention and had at least 7 days of follow-up after study intervention, the DMC 
performed an interim data review focused on safety. All data available at the time of the interim 
data review was included. During this data review enrollment was continued, however, recruitment 
would have been halted should 60 patients had been enrolled before the outcome of the data review 


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was known. In case recruitment was halted, it would have been resumed upon a positive 
assessment of results of these interim data by DMC.
While futility or stopping of the study will be based on totality of emerging safety data, the DMC 
will consider either of the following non-binding futility criteria as recommendation for stopping 
the study. 
-
Excess mortality in the treatment arm, beyond the realm of chance (Fisher’s Exact test at a 
1-sided significance level of 10%).
-
Excess in “Worsening by at least 1 category” in the treatment arm, beyond the realm of 
chance (Fisher’s exact test at a 1-sided significance level of 10%).
A non-binding unblinded IA for futility was performed by the sponsor on the primary endpoint 
when approximately 20% of the planned number of participants with confirmed severe and critical 
COVID-19 disease had reached Day 28 or discontinued earlier (see Interim Analysis Section 9.5).
Results have been discussed with the DMC.
The DMC is also instructed to use their assessment of individual cases to evaluate even if data do 
not meet the criteria.
10.4.7.
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding sirukumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory biomarker 
research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and use 
this information only to accomplish this study and will not use it for other purposes without the 
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of sirukumab, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of PK, 
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report 
has been issued will be reported in a separate report and will not require a revision of the Clinical 
Study Report. 


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Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not 
be published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
10.4.8.
Data Quality Assurance
Data Quality Assurance/Quality Control
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These pre-defined parameters will be 
monitored during the study and important deviations from the QTLs and remedial actions taken 
will be summarized in the clinical study report.


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Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. 
The sponsor will review eCRF for accuracy and completeness during monitoring visits and after 
transmission to the sponsor; any discrepancies will be resolved with the investigator or designee, 
as appropriate. After upload of the data into the study database they will be verified for accuracy 
and consistency with the data sources.
10.4.9.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the eCRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into 
the eCRF in English. The eCRF must be completed as soon as possible after a participant visit and 
the forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after 
the initial entry into the eCRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
10.4.10.
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
intervention receipt/dispensing/return records; study intervention administration information; and 


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date of study completion and reason for early discontinuation of study intervention or withdrawal 
from the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The following data may be recorded directly into the eCRF and may be considered source data:

Race

History of all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of e-
cigarettes), cigars, chewing tobacco, patch, gum

Blood pressure and pulse/heart rate

Height and weight

Details of physical examination

Investigator-completed scales and assessments
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history may include:

Referral letter from treating physician 

Complete history of medical notes at the site

Discharge summaries

Hospital admission records
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
eCRF.
10.4.11.
Monitoring
The sponsor will use a combination of monitoring techniques, ie central, remote, and/or on-site 
monitoring to monitor this study.


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The sponsor will conduct monitoring activities as frequently as necessary. The first post-initiation 
visit will be made as soon as feasible. At these visits, the monitor will compare the data entered 
into the eCRF with the source documents (eg, hospital/clinic/physician’s office medical records), 
if possible. The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the eCRF are known to the sponsor and study-site 
personnel. If electronic records are maintained at the study site, the method of verification must be 
discussed with the study-site personnel. 
If possible, given the current pandemic, direct access to source documents (medical records) must 
be allowed for the purpose of verifying that the recorded data are consistent with the original source 
data. Findings from this review will be discussed with the study-site personnel. The sponsor 
expects that, during monitoring visits, the relevant study-site personnel will be available, the 
source documents will be accessible, and a suitable environment will be provided for review of 
study-related documents. The monitor will meet with the investigator on a regular basis during the 
study to provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site. 
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.4.12.
Audits
Representatives of the sponsor's clinical quality assurance department may conduct an audit 
remote and/or on-site (when feasible) at any time during or after completion of the study in 
compliance with regulatory guidelines and company policy. These audits will require access to all 
study records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and available 
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its 
designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
10.4.13.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.


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Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
10.4.14.
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site Termination
The sponsor 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 the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development


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10.5.Appendix 5 : Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.5.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a pharmaceutical (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the intervention. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational or non-investigational) product, whether or 
not related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH]28)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events as of time of obtaining consent, as specified in 
Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information.
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also 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 intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.


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If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study intervention and the event (eg, death from anaphylaxis), the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a component 
of the study endpoint.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For sirukumab, the expectedness of an adverse event will be 
determined by whether or not it is listed in the IB. For SOC treatment with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not it is listed 
in the local product information.
10.5.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following 
selection should be used to assess all adverse events (AE).
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the 
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.5.3.
Severity Criteria
An assessment of severity grade will be made by the investigator using the general categorical 
descriptors outlined in the Microbiology and Infectious Diseases (DMID) toxicity table (see 
Section 10.8, Appendix 8 DMID Table).
10.5.4.
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention

Medication error, intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson & 
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted 
prescribing or dispensing errors)


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
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
10.5.5.
Procedures
All Adverse Events
Adverse events, collected as specified in Section 8.3.1, must be recorded using medical 
terminology in the source document and the eCRF. Whenever possible, diagnoses should be given 
when signs and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore 
throat, and head congestion should be reported as "upper respiratory infection"). Investigators must 
record in the eCRF their opinion concerning the relationship of the adverse event to study therapy. 
All measures required for adverse event management must be recorded in the source document 
and reported according to sponsor instructions.
The participant, once discharged, will be provided with a "wallet (study) card" and instructed to 
carry this card with them for the duration of the study indicating the following: 

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical personnel only)

Site number

Participant number

Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon the participant's discontinuation from the study, must be followed until any of the following 
occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study intervention or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
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Any event requiring hospitalization (or prolongation of hospitalization) that occurs during 
participation in the study must be reported as a serious adverse event.
The cause of death of a participant in a study, whether or not the event is expected or associated 
with the study intervention, is considered a serious adverse event.
Information regarding serious adverse events will be transmitted to the sponsor using a serious 
adverse event reporting form and safety report form of the eCRF, which must be completed and 
reviewed by a physician from the study site, and transmitted in a secure manner to the sponsor 
within 24 hours. The initial and follow-up reports of a serious adverse event should be transmitted 
in a secure manner electronically. Telephone reporting should be the exception and the reporter 
should be asked to complete the appropriate form(s) first.
10.5.6.
Product Quality Complaint Handling
Definition
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, reliability, or performance of a distributed product, including its labeling, drug delivery 
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
10.5.7.
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.


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10.6.Appendix 6 : Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria 5.3, 
Lifestyle Considerations. Pregnancy information will be collected and reported as noted in 
Section 8.3.5, Pregnancy and Section 10.5, Appendix 5 Adverse Events, Serious Adverse Events, 
Product Quality Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 

permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the lifestyle considerations.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT (preferable)
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion


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
Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of 1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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10.7.Appendix 7: Risks Associated with Sirukumab 
Note: the below listed risks associated with sirukumab are largely based upon data from studies in 
immune-mediated diseases which involved chronic subcutaneous repeat dosing over an extended 
period of time (eg, 1 year).
Potential Risks of Clinical Significance
Summary of Data/
Rationale for Risk
Serious infections
Interleukin-6 stimulates hepatic acute-phase proteins 
and Ig production and promotes the growth and 
differentiation of T cells, B cells, and tumor cells. 
Interleukin-6 is a mediator of inflammation and 
cellular immune responses in the defense against some 
intracellular pathogens. Interleukin-6 has been known 
to serve as a marker of disease severity for infections. 
Although IL-6 modulates certain physiologic acute-
phase responses to infection, a complete lack of IL-6 
has not been shown to alter mortality rates in IL-6 
knockout mice. Blockage of IL-6 may blunt the acute-
phase pyretic response and therefore, fever may be 
masked in participants receiving sirukumab. Serious, 
life-threatening infections such as septic shock, some 
of which have been fatal, have occurred in participants 
receiving sirukumab.
Hypersensitivity
Reactions observed in humans after IV or SC 
administration of mAbs include headache, fever, facial 
flushing, pruritus, urticaria, dermatitis, myalgia, 
nausea, chest tightness, laryngeal edema, dyspnea, 
vomiting, erythema, abdominal discomfort, 
diaphoresis, shivers, hypertension, Stevens-Johnson 
syndrome, lightheadedness, hypotension, palpitations, 
and somnolence.
Gastrointestinal Perforation
Events of gastrointestinal (GI) perforation have been 
reported in clinical studies with sirukumab, primarily 
as a complication of peptic ulcer disease or 
diverticulitis in RA patients. Most patients who 
developed gastrointestinal perforations were taking 
concomitant nonsteroidal anti-inflammatory drugs, 
corticosteroids, and/or MTX. The relative contribution 
of these concomitant medications versus sirukumab to 
the development of GI perforations is not known.
Hematologic Events
Neutropenia and thrombocytopenia have occurred in 
sirukumab studies, including severe thrombocytopenia 
associated with bleeding. In the Phase 2 and Phase 3 
RA studies, decreases in ANC and platelets occurred in 
all sirukumab treatment groups. Most patients who 
developed neutropenia while being treated with 
sirukumab did not develop infections, and most 
patients who developed thrombocytopenia did not 
report bleeding events. Changes were not observed in 
participants who received placebo, but did occur after 
participants crossed over to active treatment. No dose 
response was observed.
Lipids
Increases in blood total cholesterol, LDL, HDL, and 
triglycerides have occurred in sirukumab treated 
participants. No dose response was observed.


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Potential Risks of Clinical Significance
Summary of Data/
Rationale for Risk
Liver enzymes
Increases (1 to 3 x ULN, sometimes >5 x ULN) in 
blood ALT and AST values were observed in 
participants in completed and ongoing studies of 
sirukumab; the majority were transient, asymptomatic, 
and not associated with an increase in bilirubin
Drug-drug interactions
Inflammatory cytokines, including IL-6, are known to 
down-regulate activity and expression of multiple CYP 
enzymes. Hypothetically, IL-6 inhibition in a patient 
with an inflammatory condition will restore the CYP 
enzyme activity, and, in turn, increase the hepatic 
metabolism and clearance of drugs that are substrates 
for those enzymes.
Geriatric patients (>65 years of age)
Of the 2,926 participants treated with sirukumab in RA 
studies, 498 were 65 years and older. The incidence of 
serious infections among elderly participants (65 years 
and older) treated with sirukumab was higher than 
participants younger than 65 years.
Pediatric patients (<18 years of age)
The safety of sirukumab in children has not been 
studied.
Renal impairment/hepatic dysfunction/failure
There is no experience with the use of sirukumab in 
patients with hepatic insufficiency.
Pregnancy
It is not known whether sirukumab can cause fetal 
harm when administered to a pregnant woman or affect 
reproductive capacity.
Nursing
Sirukumab was not detectable in most cynomolgus 
monkey milk samples. It is not known whether 
sirukumab is excreted in human milk.
Acute and subacute toxicity
No information is available on acute and subchronic 
toxicity in humans.


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10.8. Appendix 8: DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES 
(DMID) ADULT TOXICITY TABLE45 – NOVEMBER 2007
ABBREVIATIONS: Abbreviations utilized in the Table:
ULN = Upper Limit of Normal
LLN = Lower Limit of Normal 
Rx = Therapy
Req = Required
Mod = Moderate
IV = Intravenous
ADL = Activities of Daily Living
Dec = Decreased
ESTIMATING SEVERITY GRADE
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity:
GRADE 1
Mild Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required
GRADE 2
Moderate Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required
GRADE 3
Severe Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible
GRADE 4
Life-threatening Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable
SERIOUS OR LIFE-THREATENING AEs
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression.
COMMENTS REGARDING THE USE OF THESE TABLES

Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization [WHO]) have been adapted for 
use by the Division of Microbiology and Infectious Diseases (DMID) and modified to 
better meet the needs of participants in DMID trials.

For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade” located above.

Criteria are generally grouped by body system.

Some protocols may have additional protocol-specific grading criteria, which will 
supersede the use of these tables for specified criteria.


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5 - 10.5 gm/dL
8.0 - 9.4gm/dL
6.5 - 7.9 gm/dL
< 6.5 gm/dL
Absolute Neutrophil Count
1,000-1,500/ mm3
750-999/ mm3
500-749/ mm3
<500/ mm3
Absolute Lymphocyte 
Count, Lowa
aged >5 years 
(not HIV-infected) 
600 to <650 / mm3
0.600×109 to 
<0.650×109
500 to <600 / mm3
0.500×109 to 
<0.600×109
350 to <500 / mm3
0.350×109 to 
<0.500×109
<350 / mm3
<0.350×109
Platelets
75,000-
99,999/ mm3
50,000-
74,999/ mm3
20,000-49,999/ mm3
<20,000/ mm3
WBCs
11,000-13,000/
mm3
13,000-
15,000 / mm3
15,000-
30,000/ mm3
>30,000 or
<1,000 / mm3
% Polymorphonuclear
Leucocytes + Band Cells
> 80%
90 – 95%
>95%
----------
Abnormal Fibrinogen
Low:
100-200 mg/dL
High:
400-600 mg/dL
Low:
<100 mg/dL
High:
>600 mg/dL
Low:
< 50 mg/dL
----------
Fibrinogen
associated with gross 
bleeding or with 
disseminated 
coagulation
Fibrin Split Product
20-40 mcg/ mL
41-50 mcg/ mL
51-60 mcg/ mL
> 60 mcg/ mL
Prothrombin Time (PT)
1.01 - 1.25 x ULN
1.26-1.5 x ULN
1.51 -3.0 x ULN
>3 x ULN
Activated Partial 
Thromboplastin (APPT)
1.01 -1.66 x ULN
1.67 - 2.33 x ULN
2.34 - 3 x ULN
> 3 x ULN
Methemoglobin
5.0 - 9.9 %
10.0 - 14.9 %
15.0 - 19.9%
> 20.0 %
a
Added by the sponsor, based on Division of AIDS (DAIDS) table for grading the severity of adult and
pediatric adverse events, version 2.1, July 2017.21


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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130-135 mEq/ L
123-129 mEq/ L
116-122 mEq/ L
< 116 mEq/ L or abnormal sodium 
with mental
status changes or seizures
Hypernatremia
146-150 mEq/ L
151-157 mEq/ L
158-165 mEq/ L
> 165 mEq/ L or abnormal sodium 
with mental
status changes or seizures
Hypokalemia
3.0 - 3.4 mEq/ L
2.5 - 2.9 mEq/ L
2.0 - 2.4 mEq/ L or 
intensive replacement 
therapy or 
hospitalization 
required
< 2.0 mEq/ L or abnormal 
potassium with
paresis, ileus or life-threatening 
arrhythmia
Hyperkalemia
5.6 - 6.0 mEq/ L
6.1 - 6.5 mEq/ L
6.6 - 7.0 mEq/l
> 7.0 mEq/ L or abnormal
potassium with life-threatening 
arrhythmia
Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
<30 mg/dL or abnormal glucose 
with mental
status changes or coma
Hyperglycemia
(nonfasting and no 
prior diabetes)
116 - 160 mg/dL 161- 250 mg/d L
251 - 500 mg/dL
> 500 mg/dL or abnormal glucose 
with ketoacidosis or seizures
Hypocalcemia
(corrected for 
albumin)
8.4 - 7.8 mg/dL
7.7 - 7.0 mg/dL
6.9 - 6.1 mg/dL
< 6.1 mg/dL or abnormal
calcium with life-threatening 
arrhythmia or tetany


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CHEMISTRIES (continued)
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (correct for 
albumin)
10.6 - 11.5 mg/dL
11.6 - 12.5
mg/d L
12.6 - 13.5 mg/dL
> 13.5 mg/dL or abnormal 
calcium with life-
threatening arrhythmia
Hypomagnesemia
1.4 - 1.2 mEq/ L
1.1 - 0.9 mEq/ L
0.8 - 0.6 mEq/ L
< 0.6 mEq/ L or abnormal 
magnesium with life-
threatening arrhythmia
Hypophosphatemia
2.0 - 2.4 mg/dL
1.5 -1.9 mg/dL or
replacement Rx 
required
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required
< 1.0 mg/dL or abnormal
phosphate with life-
threatening arrhythmia
Hyperbilirubinemia (when 
accompanied by any 
increase in other liver 
function test)
1.1 - <1.25 x ULN
1.25 - <1.5 x 
ULN
1.5 – 1.75 x ULN
> 1.75 x ULN
Hyperbilirubinemia (when 
other liver function are in 
the normal range)
1.1 - <1.5 x ULN
1.5 - <2.0 x ULN
2.0 – 3.0 x ULN
> 3.0 x ULN
BUN
1.25 - 2.5 x ULN
2.6 - 5 x ULN
5.1 - 10 x ULN
> 10 x ULN
Hyperuricemia (uric acid)
7.5 – 10.0 mg/dL
10.1 – 12.0 
mg/dL
12.1 – 15.0 mg/d L
>15.0 mg/d L
Creatinine
1.1 - 1.5 x ULN
1.6 - 3.0 x ULN
3.1 - 6 x ULN
>6 x ULN or dialysis 
required
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT)
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
ALT (SGPT)
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
GGT
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
Alkaline Phosphatase
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
Amylase
1.1 - 1.5 x ULN
1.6 - 2.0 x ULN
2.1 - 5.0 x ULN
> 5.1 x ULN
Lipase
1.1 - 1.5 x ULN
1.6 - 2.0 x ULN
2.1 - 5.0 x ULN
> 5.1 x ULN


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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+
or
200 mg - 1 gm 
loss/day
2-3+
or
1- 2 gm loss/day
4+
or
2-3.5 gm loss/day
nephrotic syndrome
or
>3.5 gm loss/day
Hematuria
microscopic only
<10 rbc/hpf
gross, no clots
>10 rbc/hpf
gross, with or without 
clots, OR RBC casts
obstructive or 
required
transfusion
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Rhythm
asymptomatic, 
transient signs, no
Rx required
recurrent/persistent; 
symptomatic Rx 
required
unstable dysrythmia;
hospitalization
and treatment 
required
Hypertension
transient increase
>20 mm/ Hg; no 
treatment
recurrent, chronic 
increase
> 20mm/ Hg
/treatment required
acute treatment 
required; outpatient 
treatment or 
hospitalization
possible
end organ damage or 
hospitalization 
required
Hypotension
transient orthostatic
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
No treatment 
required
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable with oral 
flu id treatment
requires IV fluids; no 
hospitalization 
required
mean arterial 
pressure
<60mm/ Hg or end 
organ damage or 
shock; requires 
hospitalization and 
vasopressor treatment
Pericarditis
minimal effusion
mild/ moderate 
asymptomatic 
effusion, no 
treatment
symptomatic 
effusion; pain; EKG 
changes
tamponade; 
pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
microscopic/occult
mild, no transfusion
gross blood loss;
1-2 units transfused
massive blood loss; 
>3 units transfused


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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
transient- no 
treatment
persistent cough; 
treatment responsive
Paroxysmal cough; 
uncontrolled with 
treatment
--------------------
Bronchospasm, Acute
transient; no 
treatment;
70% - 80% FEV1
of peak flow
requires
treatment; normalizes 
with bronchodilator; 
FEV1 50% -
70%
(of peak flow)
no normalization 
with bronchodilator; 
FEV1 25% - 50%
of peak flow; or
retractions present
cyanosis: FEV1
<25%
of peak flow or 
intubation necessary
Dyspnea
dyspnea on exertion dyspnea with normal 
activity
dyspnea at rest
dyspnea requiring 
oxygen therapy
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
mild or transient; 
maintains
reasonable intake
moderate discomfort; 
intake decreased
significantly; some 
activity limited
no significant intake; 
requires IV flu ids
hospitalization 
required;
Vomiting
1 episode in 24 hours
2-5 episodes in
24 hours
>6 episodes in 
24 hours or needing 
IV fluids
physiologic 
consequences 
requiring
hospitalization or 
requiring parenteral 
nutrition
Constipation
requiring stool
softener or dietary 
modification
requiring
laxatives
obstipation
requiring manual 
evacuation or enema
obstruction or
toxic megacolon
Diarrhea
mild or transient; 3-4 
loose
stools/day or mild
diarrhea last <1 week
moderate or 
persistent; 5-7 loose 
stools/day or diarrhea
lasting >1 week
>7 loose stools/day
or bloody diarrhea; or 
orthostatic 
hypotension or 
electrolyte imbalance 
or >2L IV fluids 
required
hypotensive shock or 
physiologic 
consequences 
requiring
hospitalization
Oral Discomfort/Dysphagia mild discomfort; no 
difficulty
swallowing
some limits on 
eating/drinking
eating/talking very 
limited; unable to 
swallow solid foods
unable to drink flu 
ids; requires IV fluids


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Neuro-Cerebellar
slight incoordination 
dysdiadochokinesis
intention tremor, 
dysmetria,
slurred speech; 
nystagmus
locomotor ataxia
incapacitated
Psychiatric
mild anxiety or 
depression
moderate anxiety or 
depression; therapy 
required; change in 
normal routine
severe mood changes 
requiring therapy; or 
suicidal ideation; or 
aggressive ideation
acute psychosis 
requiring 
hospitalization; or 
suicidal 
gesture/attempt or 
hallucinations
Muscle Strength
subjective weakness 
no objective
symptoms/ signs
mild objective
signs/symptoms no 
decrease in function
objective weakness 
function limited
paralysis
Paresthesia (burning, 
tingling, etc.)
mild discomfort; no 
treatment required
moderate discomfort;
non-narcotic 
analgesia required
severe discomfort; or 
narcotic analgesia 
required with 
symptomatic 
improvement
incapacitating; or not 
responsive to narcotic 
analgesia
Neuro-sensory
mild impairment in 
sensation
(decreased
sensation, eg, 
vibratory, pinprick, 
hot/cold in great toes) 
in focal area or 
symmetrical
distribution; or 
change in taste, 
smell, vision and/or 
hearing
moderate
impairment (mod 
decreased sensation, 
eg, vibratory, 
pinprick, hot/cold to 
ankles) and/or joint 
position or mild
impairment that is 
not
symmetrical
severe impairment 
(decreased or loss of 
sensation to knees or 
wrists) or loss of 
sensation of at least 
mod degree in 
multiple
different body areas 
(ie, upper and lower
extremities)
sensory loss involves 
limbs and trunk; 
paralysis; or seizures


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MUSCULOSKELATEL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia (joint pain)
mild pain not 
interfering with 
function
moderate pain, 
analgesics and/or pain 
interfering with 
function but not with 
activities of daily 
living
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living
disabling pain
Arthritis
mild pain with
inflammation,
erythema or joint
swelling – but not
interfering with
function
moderate pain with
inflammation,
erythema or joint 
swelling – interfering 
with function, but not 
with activities of
daily living
severe pain with
inflammation,
erythema or joint
swelling –and
interfering with
activities of daily
living
permanent and/or 
disabling joint
destruction
Myalgia
Myalgia with no 
limitation of activity
muscle
tenderness (at other 
than injection site) or 
with moderate
impairment of 
activity
severe muscle
tenderness with
marked impairment 
of activity
frank
myonecrosis
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
erythema; pruritus
diffuse, 
maculopapular rash, 
dry desquamation
vesiculation or
moist desquamation 
or ulceration
exfoliative
dermatitis, mucous 
membrane
involvement or 
erythema,
multiforme or 
suspected
Stevens-Johnson
or necrosis requiring 
surgery
Induration
<15mm
15-30 mm
>30mm
Erythema
<15mm
15-30 mm
>30mm
Edema
<15mm
15-30 mm
>30mm
Rash at Injection Site
<15mm
15-30 mm
>30mm
Pruritus
slight itching at 
injection site
moderate itching at 
injection extremity
itching over entire 
body


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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Allergic Reaction
pruritus without rash
localized urticaria
generalized urticaria; 
angioedema
anaphylaxis
Headache
mild, no treatment 
required
transient, moderate; 
treatment required
severe; responds to 
initial narcotic 
therapy
intractable; requires 
repeated narcotic 
therapy


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10.9.Appendix 9: The New York Heart Association Classification System
Class
New York Heart Association functional classification
I
Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnoea or anginal pain
II
Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea or anginal pain
III
Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at 
rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnoea or anginal pain
IV
Patients have cardiac disease resulting in inability to carry on any physical activity without discomfort. 
Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased


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10.10. Appendix 10: General Guidelines for Measuring Vital Signs and SpO2
Variability in the measurement of vital signs and SpO2 is to be expected due to a number of reasons; 
therefore, general guidelines for measuring vital signs and SpO2 have been developed to have a more 
consistent approach across sites and countries related to the methodology for measuring these clinical 
parameters. 
Parameter
General Instructions
Blood Pressure

While participant is hospitalized, if possible, use the same blood pressure 
measurement methodology for all patients enrolled at the site.

Prior to the measurement, participant needs to be rested for at least 5 minutes 
and preferably 10 minutes in a quiet setting without distractions.

Participant can be in either a sitting or supine position. In the sitting position, 
the participant should be comfortably seated, with the legs uncrossed. When 
measurements are taken in the supine position, the arm should be supported 
with a pillow.

Blood pressure measurements should preferentially be assessed with a 
completely automated device. Manual techniques will be used only if an 
automated device is not available.

If an automated device is not available, a properly maintained mercury 
sphygmomanometer 
is 
preferred 
over 
aneroid 
and 
hybrid 
sphygmomanometers. When using a mercury sphygmomanometer, the 
mercury column should be deflated at 2 to 3 mm/s, and the first and last 
audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mm Hg.

Preferentially, the standard location for blood pressure measurement is the 
upper arm, with the stethoscope at the elbow crease over the brachial artery 
(with manual technique). Clothing that covers the arm should be removed 
prior to the placement of the cuff.
Heart Rate

While participant is hospitalized, if possible, use the same heart rate 
measurement methodology for all patients enrolled at the site.

Prior to the measurement, participant needs to be rested for at least 5 minutes, 
and preferably 10 minutes in a quiet setting without distractions.

Participant can be in either a sitting or supine position.

Heart rate measurements should preferentially be assessed with a completely 
automated device.

Manual techniques will be used only if an automated device is not available.

If manual measurement, auscultation of the heart or pulse (radial, brachial) 
determination is considered acceptable.

If manual measurement, 30 seconds (minimum) or 1 minute (preferred) 
counts are considered acceptable.
Respiratory Rate

While participant is hospitalized, if possible, use the same respiratory rate 
measurement methodology for all patients enrolled at the site.


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
Prior to the measurement, participant needs to be rested for at least 5 minutes, 
and preferably 10 minutes in a quiet setting without distractions.

Participant can be in either a sitting or supine position.

Respiratory rate measurements can be assessed with an automated device or 
with manual measurement (no preference).

If manual measurement is used, inspection (preferred) or auscultation of the 
lungs (alternative) are considered acceptable.

If manual measurement, 30 seconds (minimum) or 1 minute (preferred) count 
are considered acceptable.
Temperature

While participant is hospitalized, if possible, use the same type of 
temperature measurement methodology for all participants enrolled at the 
site.

Electronic devices (tympanic, oral) are preferred over traditional mercury 
thermometers (for oral temperature).

Tympanic (preferred) or oral (alternative) temperature measurements are
considered acceptable. Axillary temperature should be avoided since it 
provides the worst estimate of core temperature and it is largely influenced 
by environmental conditions.
SpO2

While participant is hospitalized, if possible, use the same type of probe for 
all patients enrolled at the site.

Prior to the measurement, participant needs to be rested for at least 5 minutes, 
and preferably 10 minutes in a quiet setting without distractions.

Participant can be in either a sitting or supine position.

Pulse oximetry measurements using finger, toe, earlobe or frontal sensors are 
considered acceptable. If using the digits, assess for warmth and capillary 
refill, since adequate arterial pulse strength is necessary for obtaining 
accurate SpO2 measurements.

Avoid placing the sensor on sites distal to indwelling arterial catheters, blood 
pressure cuffs, or venous engorgement (eg, arteriovenous fistulas, blood 
transfusions).

For hospitalized participants receiving supplemental O2, the measurement 
should be performed after 5 minutes on room air.

If it is determined by the investigator that it is unsafe to remove the 
participant’s supplemental O2 for assessment of O2 saturation (eg, participant 
is on high-flow mask), then it should be recorded in the source documentation 
as not assessed and the reason should be documented.


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10.11. Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 4 (15 September 2020)
Overall Rationale for the Amendment: The protocol has been amended to allow for an Interim Analysis 
(IA) to be performed when approximately 20% of the planned number of participants have reached Day 28 
or discontinued earlier.
Activation of sites outside the US is delayed until availability of the IA results.
In addition, to accommodate for feedback received from investigators about the challenges when using a 
central laboratory, the safety laboratory assessments (hematology, chemistry, coagulation tests) will be 
performed by local laboratories.
Further, to accommodate for feedback received from investigators, the sponsor has optimized the 
mandatory laboratory tests to be performed.
Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
1.1 Synopsis
1.2 Schema
4.1 Overall Design
6.3 Measures to Minimize Bias: Randomization 
and Blinding
9.5 Interim Analysis
10.4.6 Committees Structure
A non-binding unblinded Interim 
Analysis (IA) for futility will be 
performed by the sponsor on the primary 
endpoint when approximately 20% of the 
planned number of participants have 
reached Day 28 or discontinued earlier.
In view of the mixed 
results of emerging 
clinical data with IL-6 
receptor inhibitors, 
the purpose of this IA 
is to perform a futility 
analysis to determine 
further study conduct.
1.3 Schedule of Activities (SoA)
5.1 Inclusion Criteria
8 STUDY ASSESSMENTS AND 
PROCEDURES
8.1.3 Virology Assessments
10.2 Appendix 2: Clinical Laboratory Tests
10.3 Appendix 3: Clinical and Laboratory 
Assessments Described per Day
Only PCR-based tests are allowed for 
detection of SARS-CoV-2 infection.
To prevent possible 
false positive results 
by using a rapid 
antigen test at time of 
screening.
1.3 Schedule of Activities (SoA)
10.2 Appendix 2: Clinical Laboratory Tests
The required use of a central laboratory 
for the safety laboratory assessments
(hematology, chemistry, coagulation 
tests) is no longer in place.
To limit changes in 
the laboratory safety 
assessments and allow 
fast availability of 
laboratory results.
1.3 Schedule of Activities (SoA)
8 STUDY ASSESSMENTS AND 
PROCEDURES
8.2.5 Pregnancy Testing
The mandatory laboratory tests to be 
performed have been optimized.
To accommodate for 
feedback received 
from investigators.
10.3 Appendix 3: Clinical and Laboratory 
Assessments Described per Day
The assessments as described in the 
Schedule of Activities have now also 
been described per day in a protocol 
appendix.
To add clarity and be 
more user-friendly.
5.2 Exclusion Criteria
Exclusion criterion 13 has been reworded. To accommodate for 
feedback from 
investigators.


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
Throughout the protocol
Minor grammatical, formatting, or 
spelling changes were made.
Minor errors were 
noted.
Amendment 3 (23 July 2020)
Overall Rationale for the Amendment: The protocol has been amended to state that all clinical laboratory 
tests are to be performed by the central laboratory, except for screening visit assessments, and to allow 
flexibility concerning the sourcing of placebo as the study has been extended from a single-country trial to 
a global trial. The frequency of Data Monitoring Committee (DMC) review has been adapted to allow for 
flexibility in alignment with recruitment rates. A separate sample for SARS-CoV-2 specific antibodies 
testing has been added. Furthermore, clarifications, minor updates and corrections have been made 
throughout the protocol.
Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
1.3 Schedule of Activities (SoA)
8.3.6 Adverse Events of Special Interest
10.2 Appendix 2: Clinical Laboratory Tests
Hematology, chemistry, coagulation and 
pregnancy tests will be done by the 
central laboratory instead of the local 
laboratory, with exception of the tests that 
are performed during the screening visit.
As the study is 
extended to become a 
global trial, central 
laboratory testing is 
being implemented.
1.1 Synopsis
1.2 Schema
10.1 Appendix 1: Abbreviations and Definitions
10.3.6 Committees Structure
The DMC review frequency has been 
changed from weekly to regularly.
Allow for flexibility 
in alignment with 
recruitment rates.
6.1 Study Intervention(s) Administered
Footnote has been added to clarify that 
placebo will be provided locally by the 
study site or centrally by the sponsor.
Allow flexibility 
concerning the 
sourcing of placebo 
based on local 
regulations in 
participating 
countries.
1.3 Schedule of Activities (SoA)
8.2.5 Pregnancy Testing
10.2 Appendix 2: Clinical Laboratory Tests
Pregnancy assessment has been added to 
the baseline visit. Furthermore, it has 
been clarified that urine pregnancy testing 
is only acceptable for the screening visit 
(in emergency situations).
Allow for pregnancy 
testing by central 
laboratory at baseline. 
1.3 Schedule of Activities (SoA)
A separate sample for SARS-CoV-2 
specific antibody testing has been added 
to the baseline, Day 14, and Day 28 visit.
Allow flexibility on 
the type of assays to 
be performed on these 
samples.


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
1.3 Schedule of Activities (SoA)
Hematology, chemistry and coagulation 
testing has been added to the baseline 
visit and footnote dd has been removed 
for the screening visit. The statement 
'preferred daily testing if per local 
standard of care, otherwise as a minimum 
on' has been removed. Furthermore, 
footnote l and footnote ee have been 
reworded.
Allow for 
hematology, 
chemistry and 
coagulation testing by 
the central laboratory 
at baseline and at 
specific time points 
between Day 2 and 
discharge.
Optional time points for collection of 
blood samples for biomarker research 
have been removed. In addition, 
footnote v has been removed for the 
Day 28 visit and footnote x has been 
reworded.
Separate sample for 
central procalcitonin 
testing no longer 
required between 
Day 2 and Day 28.
Footnote cc has been edited to clarify that 
the 
relevant 
respiratory 
function 
assessments, completed maximum 1 day 
before discharge do not need to be 
repeated on the day of discharge provided 
that no clinically relevant changes were 
noted in the results and the participant was 
declared ‘ready to be discharged’ on the 
day before discharge. 
Clarification
1.1 Synopsis
1.3 Schedule of Activities (SoA)
8.6 Biomarkers
10.2 Appendix 2: Clinical Laboratory Tests
The words 'sample collection' have been 
removed from the subtitle to clarify that 
multiple samples will be used for the 
assessment of the exploratory biomarkers. 
Furthermore, the description of the type 
of biomarker parameters to be evaluated 
in the biomarker blood samples has been 
removed. 
Clarification.
1.3 Schedule of Activities (SoA)
5.1 Inclusion Criteria #4
Lung ultrasound has been added as an 
option for the assessment of inclusion 
criterion 4 and to the SoA if a pulmonary 
assessment with X-ray would not be 
available.
Allow flexibility to 
assess eligibility 
based on local 
standard of care 
practices. 
5.1 Inclusion Criteria #5
The requirement of supplemental oxygen 
to sustain a SpO2 >93% is to be 
documented by an SpO2 of ≤93% on room 
air or on supplemental oxygen.
Clarification
5.2 Exclusion Criteria #10
Participants can receive anticoagulant 
therapies for underlying conditions, or as 
systematic thromboprophylaxis due to 
COVID-19, or as part of the treatment of 
complications of COVID-19, but cannot 
participate in a clinical study with 
anticoagulants for COVID-19. This has 
been added to exclusion criterion 10.
Broadening of the 
eligible patient 
population.


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
6.1 Study Intervention(s) Administered
6.2 Preparation/Handling/Storage/Accountability
10.1 Appendix 1: Abbreviations and Definitions
Footnote has been added to clarify that 
dextrose is commonly known and referred 
to as glucose.
Clarification.
6.3 Measures to Minimize Bias: Randomization 
and Blinding
It has been specified that the interactive 
web response system (IWRS) will assign 
a unique intervention code for the 
participants assigned to the active study 
treatment.
Clarification.
8.1.3 Virology Assessments
Stool sample collection post hospital 
discharge has been removed.
Correction.
Throughout protocol
Minor updates, corrections or additions 
have been made.
Correction, 
clarification and 
consistency.
Amendment 2 (17 June 2020)
Overall Rationale for the Amendment: Following investigator feedback and given the evolving 
COVID-19 landscape, the protocol has been amended to allow enrollment of a broader patient population 
into the study. In addition, incidence of all-cause mortality has been elevated to be a key secondary 
endpoint. Furthermore, clarifications, minor updates and corrections have been made throughout the 
protocol.
Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
1.1 Synopsis
1.3 Schedule of Activities (SoA)
3 OBJECTIVES AND 
ENDPOINTS
8.6 Biomarkers
IgG and IgM are no longer specified as SARS-CoV-2 
specific antibodies to evaluate the humoral immune 
response to SARS-CoV-2. The humoral immune 
response assays are still to be determined. 
Allow flexibility as the 
immunity assays are 
still to be determined.
1.1 Synopsis
3 OBJECTIVES AND 
ENDPOINTS
9.2 Sample Size Determination
9.4 Statistical Analyses
9.4.2 Primary Endpoint
9.4.3.1 Key Secondary Endpoints
9.4.4 Other Secondary Endpoints
Incidence of all-cause mortality (up to Day 28) has 
been elevated to be a key secondary endpoint 
(instead of othher secondary endpoint). 
A hierarchical testing strategy will be used for the 
primary and key secondary endpoints. 
For the mortality rate in the control arm, a range from 
30% to 50% is considered for the sample size 
determination. For the considered absolute difference 
in mortality rate, a power of at least 80% is retained 
for this range and the power will be higher in case the 
mortality rate in the control arm will be near the 
lower end of the considered range. 
Updated to be able to 
assess the mortality rate 
as a key secondary 
analysis.
A stratified log-rank test (instead of a Gehan-
Wilcoxon test) will be used in the analyses of the 
primary parameter. 
Key secondary endpoints will be analyzed using the 
Cochrane-Mantel-Haenszel test for difference in 
proportions.
A graphical presentation over time to analyze the 
6-point ordinal clinical recovery scale of the clinical 
Update on statistical 
tests to be used 


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
status has been added to the protocol. The 
proportional odds model has been updated from each 
day up to Day 28 to Days 7, 14, 21 and 28.
1.1 Synopsis
1.2 Schema
4.1 Overall Design
9.4 Statistical Analyses
9.5 Interim Analysis
10.3.6 Committees Structure
The Data Monitoring Committee (DMC) interim data 
review will focus on safety data. Therefore, the DMC 
details have been removed from the interim analysis 
sections. 
Clarification 
1.1 Synopsis
9.3 Populations for Analysis Sets
9.4.2 Primary Endpoint
9.4.7 Other Analyses
The ITT (Intent-to-Treat) population will be used for 
statistical analyses instead of the ITT-i (or ITT-
infected, defined as the population with a central 
laboratory confirmed SARS-COV-2 test at baseline). 
The ITT population comprises all study participants; 
all participants are required to have a local 
laboratory-confirmed SARS-CoV-2 infection prior to 
randomization per inclusion criterion 3. 
Update of the 
population to be used 
for statistical analyses
1.3 Schedule of Activities (SoA)
Footnote added to clarify that in participants still 
hospitalized post Day 28 additional blood sampling 
for hematology, chemistry and coagulation should be 
done per SOC with a minimum of every 7 days and 
at Day of discharge. 
Clarification
Footnote clarifying that, for participants discharged 
prior to Day 28, assessments completed maximum 1 
day before discharge do not need to be repeated on 
the day of discharge.
Clarification 
Footnote clarifying that pulmonary X-ray, 12-lead 
ECG, hematology, chemistry, coagulation sample,
and stool sample do not need to be repeated at 
baseline if done at screening. Screening and baseline 
cells in SoA have therefore been merged. 
Clarification
Stool sample collection post Day 28 has been 
removed in the SoA as this sample cannot be 
collected at home due to safety reasons. 
Removal of stool 
sample collection post 
Day 28 due to 
non-feasibility for 
safety reasons
1.2 Schema
1.3 Schedule of Activities (SoA)
5 STUDY POPULATION
8 STUDY ASSESSMENTS AND 
PROCEDURES
Further clarifying text on timing of screening and/or 
baseline assessments to be conducted prior to 
randomization has been added.
Clarification
1.3 Schedule of Activities (SoA)
5 STUDY POPULATION
5.1 Inclusion Criteria #3
8 STUDY ASSESSMENTS AND 
PROCEDURES
8.1.3 Virology Assessments
It has been added that the any other commercial or 
public health assay that could be used to determine 
SARS-CoV-2 positivity, must be approved or 
authorized for (emergency) use.
Clarification
2.1.1 Background
2.2 Dose Rationale
11 REFERENCES
Additional information regarding sirukumab IL-6 
affinity and serum concentrations has been added to 
Clarification


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
clarify the expected free IL-6 suppression for at least 
4 weeks.
1.3 Schedule of Activities (SoA)
5.1 Inclusion Criteria #5
Participants not receiving supplemental oxygen and 
having a blood oxygen saturation ≤93% sustained for 
5 minutes have been added as being eligible. The 
required supplemental oxygen flow rate of ≥6 L/min 
has been removed.
The limitation of the invasive mechanical ventilation 
to <24h at screening has been extended to <48h.
Furthermore, it has been added that participants on 
veno-venous ECMO <48h are also allowed.
The note concerning the requirement of supplemental 
oxygen at ≥6 L/min has been removed.
Broadening of the 
eligible patient 
population   
1.2 Schema
1.3 Schedule of Activities (SoA)
2.3.1 Risks for Study Participation
5.2 Exclusion Criteria #1
Participants on veno-venous ECMO for >48 hours at 
time of screening are excluded.
Clarification
2.3.1 Risks for Study Participation
5.2 Exclusion Criteria #3
6.8 Prestudy and Concomitant 
Therapy
11 REFERENCES
Administration of agents with demonstrated in 
vitro-effect against SARS-CoV-2 (as mentioned in 
the CDC guidelines) or convalescent plasma within 
30 days prior to the planned study intervention or 
during the study is allowed provided it is not via a 
blinded clinical study. 
The risk of an additional protein load associated with 
co-administration of convalescent plasma has been 
added to the Benefit-Risk Assessment. 
Broadening of the 
eligible patient 
population and of the 
accepted concomitant 
therapies  
5.2 Exclusion Criteria #4
Exclusion criterion #4 is now limited to: Current 
confirmed or high suspicion for pulmonary embolus, 
hemodynamic significant pericardial effusion, 
myocarditis, or Class 3 or 4 congestive heart failure 
as defined by the New York Heart Association 
Functional Classification AND/OR Current Evidence 
of active cardiac ischemia.
Broadening of the 
eligible patient 
population   
5.2 Exclusion Criteria #5
Exclusion criterion #5 is now limited to: Currently 
active clinically significant (eg, causing 
hemodynamic instability and/or causing hypoxemia) 
and uncontrolled arrhythmia. 
Broadening of the 
eligible patient 
population  
5.2 Exclusion Criteria #8
Exclusion criterion #8 is now limited to: 
Has a history of chronic respiratory condition (ie, 
asthma, chronic obstructive pulmonary disease 
[COPD], cystic fibrosis, fibrotic lung disease) that 
requires home oxygen supplementation, supportive 
non-invasive ventilation, or is status/post lung 
volume reduction surgery (LVRS).
Participants with sleep apnea using a supportive non-
invasive ventilation (continuous positive airway 
pressure [CPAP]) at screening may be included. This 
has been added as exception to exclusion criterion 8. 
Broadening of the 
eligible patient 
population   
5.2 Exclusion Criteria #10
Absolute neutrophil count (ANC) values have been 
adjusted from <2.0 × 103 cells/μL to 
<1.0 × 103 cells/μL (SI: <1.0 × 109 cells/L). 
Broadening of the 
eligible patient 
population   


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
Platelet count values have been adjusted from 
<100 × 103 cells/μL to <50 × 103 cells/μL (SI: 
<50 × 109 cells/L).
Transaminase values have been adjusted from 
ALT/AST > 5x ULN to ALT > 5x ULN.
6.8 Prestudy and Concomitant 
Therapy
Participants on chronic (for >3 months in duration) 
prednisone in a dose higher than 10mg/day or other 
oral corticosteroids at an equivalent dose for any 
condition are not eligible for the study.
Clarification 
Throughout protocol 
Minor updates, corrections or additions have been 
made.
Correction, clarification 
and consistency
Amendment 1 (24 April 2020)
Overall Rationale for the Amendment: Following Health Authority, Data Monitoring Committee and 
investigator feedback, the protocol has been amended to allow enrollment of a diverse patient population 
into the study (by removing the requirement for participants to understand English), to also allow 
enrollment of breastfeeding women if the benefit outweighs the risk, to ensure that at least one 12-lead ECG 
is taken after study intervention and to simplify the requirements for nasopharyngeal swabs and other 
specimens (by making one more time point optional). Furthermore, clarifications, additions and corrections 
have been made throughout the protocol. 
Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
1.1 Synopsis
1.2 Schema
2.3.1 Risks for Study Participation
2.3.3 Benefit-Risk Assessment for 
Study Participation
4.1 Overall Design
6.3 Measures to Minimize Bias: 
Randomization and Blinding
9.4 Statistical Analyses
9.4.1 General Considerations
9.5 Interim Analysis
10.1 Appendix 1: Abbreviations and 
Definitions
10.3.6 Committees Structure
A Data Monitoring Committee (DMC) instead of a 
Data Review Committee will be established in this 
study.
Correction on 
terminology
It has been added that the DMC will also weekly 
evaluate the accumulating safety data of all 
participants in the study.
Clarification
1.1 Synopsis
9.4.3.1 Key Secondary Endpoint
9.4.4 Other Secondary Endpoints
The difference in cumulative incidence at Day 28 
will be estimated using the Nelson-Aalen estimator 
of the cumulative hazard in each treatment group. 
This has been added instead of a logistic regression 
model.
Update on more 
appropriate statistical 
test to be used 
1.1 Synopsis
9.4.7 Other Analyses
Details addressing the statistical analysis on the 
SARS-CoV-2 viral loads have been added. 
Clarification, for 
completeness.
1.3 Schedule of Activities (SoA)
8.1.6 Arterial Blood Gas Test
10.2 Appendix 2: Clinical 
Laboratory Tests
SaO2 has been removed as blood gas parameter to be 
assessed, as it is not captured in the CRF.
In addition, blood gas has been specified as arterial. 
Correction
For completeness and 
consistency


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
1.3 Schedule of Activities (SoA)
It has been added that one ECG is to be taken 
between Day 4 and Day 8, as a minimum.
To ensure that at least 
one 12-lead ECG is 
taken after study 
intervention
1.3 Schedule of Activities (SoA)
The Day 5 nasopharyngeal swab, endotracheal 
sample and stool sample have been made optional.
Decrease sampling 
burden for participants 
and the sites
1.3 Schedule of Activities (SoA)
8.1.3 Virology Assessments
Stool samples will only be collected if feasible for 
the site. ‘Optional’ has been removed and replaced 
by ‘if feasible’.
Clarification 
1.3 Schedule of Activities (SoA)
8 STUDY ASSESSMENTS AND 
PROCEDURES
Clarifying text on which screening or baseline 
assessments are to be conducted prior to 
randomization (ie, those to verify study eligibility 
criteria and those allowing baseline assessment of the 
6-point ordinal clinical recovery category) has been 
added.
Clarification
1.3 Schedule of Activities (SoA)
5.2 Exclusion Criteria
Text regarding exclusion of a participant from study 
participation if he or she no longer meets eligibility 
criteria due to clinical status changes occurring after 
screening but before the study intervention is given 
has been corrected to before randomization. 
Correction
1.3 Schedule of Activities (SoA)
8.2.1 Physical Examinations
Targeted physical examinations are to be performed 
as per local standard of care. 
Clarification
It has been added, that if body weight cannot be 
measured at screening or is not already available in 
the participant’s chart, weight for dose calculations 
can be verbally reported. 
Clarification
1.3 Schedule of Activities (SoA)
8.1.4 Supplemental Oxygen Use
Wording has been added to clarify that if more than 
one device is being used for supplemental oxygen 
delivery, the worst (highest) FiO2 value measured on 
the highest level of intervention will be recorded as 
well as the worst recording on each device 
separately.
Clarification and 
consistency
1.3 Schedule of Activities (SoA)
10.2 Appendix 2: Clinical 
Laboratory Tests
Following lab parameters also need to be tested and 
have thus been added: conjugated bilirubin (direct), 
unconjugated bilirubin (indirect), and international 
normalized ratio (INR). 
For completeness and 
consistency 
1.3 Schedule of Activities (SoA)
8.1.3 Virology Assessments
The possibility of home visits by health care 
professionals during follow-up period, has been 
added. 
Allow health care 
professional home visits 
during follow-up
1.3 Schedule of Activities (SoA)
8 STUDY ASSESSMENTS AND 
PROCEDURES
A statement has been added as footnote ‘ee’ to clarify 
that for those participants discharged prior to Day 28, 
all Day 28 assessments should be done at day of 
discharge. 
Clarification 
2.3.1 Risks for Study Participation
6.8 Prestudy and Concomitant 
Therapy
It has been added that antivirals must have 
‘demonstrated in-vitro effect’, as mentioned in the 
CDC Guidelines to be allowed as concomitant 
medication.
For completeness and 
consistency
5.1 Inclusion Criteria
The requirement to understand English language has 
been removed from the inclusion criterion 6. 
To increase participant 
diversity in this clinical 
study


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
The informed consent for the optional DNA research 
will be obtained in the main study informed consent 
form (ie, by a tick box) instead of through a separate 
informed consent form. 
Clarification
5.2 Exclusion Criteria
Participants with currently active uncontrolled 
arrhythmia will be excluded if ‘clinically significant’. 
Clinically significant has been added.
Clarification and 
consistency across the 
section
Participants with prothrombin time/international 
normalized ratio >1.5xULN or (instead of ‘and’) 
activated partial thromboplastin time >1.5xULN 
(unless abnormalities are unrelated to coagulopathy 
or bleeding disorder) screening laboratory test results 
will be excluded. 
Correction
It has been added that breastfeeding women should 
be excluded unless, in the opinion of the investigator, 
the benefits outweigh the risks. 
Clarification
6.2 Preparation/Handling/Storage/
Accountability
The IV infusion rate has been changed from 
100mL/min to 100 mL/h. 
Correction 
6.4 Study Intervention Compliance
The weight of IV infusion bag, including the infusion 
line before and after the completion of the IV 
infusion does not need to be recorded and has thus 
been removed.
Correction
6.8 Prestudy and Concomitant 
Therapy
Leflunomide has been removed from the list of drugs 
disallowed from 2 weeks prior to randomization, as it 
is later stated that leflunomide is disallowed from 8 
weeks prior to randomization until the end of the 
study. 
It has also been adjusted that prestudy therapies must 
be recorded if taken up to 30 days before obtaining 
informed consent (instead of drugs taken up to 
30 days before study intervention having to be 
recorded).
Consistency across the 
section
Correction 
8.1.1 Six-point Ordinal Clinical 
Recovery Scale
Text regarding declining care that requires an ICU 
level of intervention, has been removed from the 
footnote (as ICU stay is not part of the 6-point 
ordinal scale).
Correction 
8.1.6 Arterial Blood Gas Test
Supplemental oxygen/FiO2 ‘and resting SpO2’ must 
be recorded at the same time as when an arterial 
blood gas is obtained. Resting SpO2 has been added.
Consistency across the 
section
8.2.3 Electrocardiograms
It has been added that ECG strips or reports may be 
requested in case of documentation of a 
cardiovascular SAE.
Clarification
8.2.6 Vital Status
Vital status recording at Day 28 if discharge occurred 
before Day 28, has been added.
Clarification and 
consistency
8.3.1 Time Period and Frequency 
for Collecting Adverse Event and 
Serious Adverse Event Information
Spontaneously reported SAEs through the Week 16 
visit instead of within 30 days after the last dose of 
study intervention, must be reported using an SAE 
form.
Clarification and 
consistency
9.4.4 Other Secondary Endpoints
Clarifications on the analyses are provided. 
It has also been added that drugs used in the SOC at 
baseline will also be tabulated by treatment group. 
Clarification


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Main Changes 
Section Number and Name
Description of Change
Brief Rationale 
9.4.5 Exploratory Endpoint(s)
In addition to NP swabs, SARS-CoV-2 viral load will 
also be measured in endotracheal, blood, and stool 
samples.
Clarification and 
consistency
6.2 Preparation/Handling/Storage/
Accountability
10.3.8 Data Quality Assurance
10.3.11 Monitoring
10.3.12 Audits
Language on on-site monitoring visits and on-site 
audits has been updated to allow flexibility during 
the COVID-19 pandemic. 
Allow flexibility 
regarding on-site visits 
and audits. 
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities (SoA)
2.2 Dose Rationale
3 OBJECTIVES AND 
ENDPOINTS
6.3 Measures to Minimize Bias: 
Randomization and Blinding
6.8 Prestudy and Concomitant 
Therapy
8.1 Efficacy Assessments
8.1.1 Six-point Ordinal Clinical 
Recovery Scale
8.1.2 Level of Consciousness
8.1.3 Virology Assessments
8.2.7 Self-reported Oxygen Need
9.3 Populations for Analysis Sets
9.4.4 Other Secondary Endpoints
9.5 Interim Analysis
10.1 Appendix 1: Abbreviations and 
Definitions
10.2 Appendix 2: Clinical 
Laboratory Tests
10.3.6 Committees Structure
Minor corrections or additions have been made.
Correction, clarification 
and consistency


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11.
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Bai B, hu Q, hu H, et al. Virus-like particles of SARS-like coronavirus formed by membrane proteins from 
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Baran P, Hansen S, Waetzig GH, et al. The Balance of Interleukin (IL)-6, IL-6·soluble IL-6 Receptor (sIL-6R), 
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Bhatraju PK , Ghassemieh BJ, Nichols M, et al. Covid-19 in Critically Ill Patients in the Seattle Region —
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Butt Y, Kurdowska A, Allen TC .Acute lung injury: a clinical and molecular review. Arch Pathol Lab Med. 
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Chan JF, Lau SK, To KK, Cheng VC, Woo PC, Yuen KY. Middle East respiratory syndrome coronavirus: 
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Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of 
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Chen J, Lau YF, Lamirande EW, et al. Cellular immune responses to severe acute respiratory syndrome 
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Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel 
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INVESTIGATOR AGREEMENT
PPD
PPD

SAP_001.pdf: 
1
V2.0, 28 June 2021
Janssen Research & Development
Statistical Analysis Plan
Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and 
Safety of Sirukumab in Confirmed COVID-19 Severe Disease
Protocol CNTO136COV2001; Phase 2 
CNTO136COV2001  (Sirukumab)
Status:
    V3.0
Date:
    28 June 2021
Prepared by:
     
 (Janssen R&D), 
 (Janssen R&D),  
 
(Janssen R&D),
 (Janssen R&D) 
Document No.:
    EDMS-RIM-315595
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT04380961
PPD
PPD
PPD
PPD
PPD


CNTO136COV2001  (Sirukumab)
Statistical Analysis Plan for the Primary Analysis      
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 5
1
INTRODUCTION.................................................................................................................................. 7
1.1
Trial Objectives ................................................................................................................................ 7
1.2
Trial Design ...................................................................................................................................... 9
1.3
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4
Sample Size Justification ............................................................................................................... 10
1.5
Randomization and Blinding .......................................................................................................... 11
2
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 13
2.1
Visit Windows and Phase Definitions............................................................................................. 13
2.1.1
Phase Definitions........................................................................................................................ 15
2.2
Analysis Sets.................................................................................................................................. 15
2.2.1
All Randomized (RAND) Analysis Set........................................................................................ 15
2.2.2
Intent-to-Treat (ITT) Analysis Set ............................................................................................... 15
2.2.3
Primary Analysis Set................................................................................................................... 15
2.2.4
All Subjects Treated (AST) Analysis Set .................................................................................... 16
2.2.5
Pharmacokinetics (PK) Analysis Set .......................................................................................... 16
2.2.6
Immunogenicity (IMG) Analysis set............................................................................................ 16
2.2.7
Per-Protocol (PP) Analysis Set................................................................................................... 16
2.3
Study Day 1.................................................................................................................................... 16
2.4
Imputation of Missing Time Portion of Date/Time Field................................................................. 16
2.5
Baseline Value ............................................................................................................................... 16
2.6
Definition of Subgroups.................................................................................................................. 17
2.6.1
Pooling Algorithm for Analysis Centers ...................................................................................... 18
3
DATA REVIEW COMMITTEE, INTERIM ANALYSIS....................................................................... 19
3.1
Data Monitoring Committee ........................................................................................................... 19
3.2
Interim Analyses............................................................................................................................. 19
4
SUBJECT INFORMATION................................................................................................................ 19
4.1
General........................................................................................................................................... 19
4.2
Demographics and Baseline Characteristics ................................................................................. 19
4.3
Disposition Information................................................................................................................... 21
4.4
Extent of Exposure and Treatment Compliance ............................................................................ 21
4.5
Protocol Deviations ........................................................................................................................ 21
4.6
Prior and Concomitant Medications ............................................................................................... 21
4.7
Medical history ............................................................................................................................... 23
4.8
Physical Examinations and Pregnancy Test Results..................................................................... 23
4.9
Results by Sub-groups................................................................................................................... 23
5
EFFICACY ......................................................................................................................................... 24
5.1
Analysis Specifications................................................................................................................... 24
5.1.1
Level of Significance................................................................................................................... 24
5.1.2
Stratification Factors................................................................................................................... 24
5.2
Primary Efficacy Endpoint(s).......................................................................................................... 24
5.2.1
Definitions ................................................................................................................................... 24
5.2.2
Primary Estimand ....................................................................................................................... 26
5.2.3
Analysis Methods........................................................................................................................ 27
5.3
Key Secondary Endpoints.............................................................................................................. 28
5.3.1
Definitions ................................................................................................................................... 28
5.3.2
Key Secondary Estimands.......................................................................................................... 29


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5.3.3
Analysis Method ......................................................................................................................... 30
5.4
Other Secondary Endpoints........................................................................................................... 31
5.4.1
Definitions ................................................................................................................................... 31
5.4.2
Analysis Methods........................................................................................................................ 34
6
VIROLOGY ASSESSMENTS............................................................................................................ 36
6.1
General........................................................................................................................................... 36
6.2
Definitions ...................................................................................................................................... 36
6.3
Data Handling Rules ...................................................................................................................... 36
6.4
Analysis Methods ........................................................................................................................... 36
6.5
Analysis of Undetectability of Viral Load........................................................................................ 37
6.6
Analysis of Virus Variants .............................................................................................................. 38
6.6.1
Time Points and Samples........................................................................................................... 39
6.6.2
Definitions ................................................................................................................................... 39
6.6.3
Parameters to Analyze ............................................................................................................... 39
6.6.4
Analysis Methods........................................................................................................................ 40
7
BIOMARKERS................................................................................................................................... 41
7.1
General........................................................................................................................................... 41
7.2
Data Handling Rules ...................................................................................................................... 41
7.3
Analysis Methods ........................................................................................................................... 42
7.3.1
Analysis of Biomarkers ............................................................................................................... 42
7.3.2
Analysis of SARS-CoV-2 Antibodies (Ab) .................................................................................. 42
8
PHARMACOKINETICS (PK) AND IMMUNOGENICITY (IMG) ........................................................ 42
8.1
General........................................................................................................................................... 42
8.2
Data Handling Rules ...................................................................................................................... 43
8.3
Analysis Methods ........................................................................................................................... 43
8.3.1
Analysis Methods for Pharmacokinetics..................................................................................... 43
8.3.2
Analysis Methods for Immunogenicity........................................................................................ 44
9
SAFETY............................................................................................................................................. 45
9.1
Adverse Events (AE)...................................................................................................................... 45
9.1.1
General ....................................................................................................................................... 45
9.1.2
Definitions ................................................................................................................................... 45
9.1.3
Analysis Methods........................................................................................................................ 46
9.2
Clinical Laboratory Tests................................................................................................................ 47
9.2.1
General ....................................................................................................................................... 47
9.2.2
Data Handling Rules................................................................................................................... 47
9.2.3
Analysis Methods........................................................................................................................ 48
9.3
Vital signs....................................................................................................................................... 49
9.3.1
General ....................................................................................................................................... 49
9.3.2
Data Handling Rules................................................................................................................... 49
9.3.3
Analysis Methods........................................................................................................................ 49
9.4
Electrocardiogram (ECG)............................................................................................................... 49
9.4.1
General ....................................................................................................................................... 49
9.4.2
Definitions ................................................................................................................................... 50
9.4.3
Data Handling Conventions........................................................................................................ 50
9.4.4
Analysis Methods........................................................................................................................ 50
ATTACHMENTS......................................................................................................................................... 51
ATTACHMENT 1.
WHO GRADING SCALE VITAL SIGNS ................................................................... 51
ATTACHMENT 2.
ECG ABNORMALITIES ............................................................................................ 52
ATTACHMENT 3.
CRS DERIVATION .................................................................................................... 53
Some examples .......................................................................................................................................... 55


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Statistical Analysis Plan for the Primary Analysis      
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AMENDMENT HISTORY
NAP


CNTO136COV2001  (Sirukumab)
Statistical Analysis Plan for the Primary Analysis      
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V2.0, 28 June 2021
ABBREVIATIONS
Ab
Antibodies
AE
Adverse event
ALT
Alanine aminotransferase
AST
All subjects treated / Aspartate aminotransferase
BIPAP
Bi-level positive airway pressure
BMI
Body mass index
CI
Confidence interval
CPAP
Continuous positive airway pressure
CRP
C-Reactive protein
CRS
Clinical recovery scale
CTP
Clinical trial protocol
CU
Confirmed undetectability (of viral loads)
DBP
Diastolic blood pressure
DMC
Data monitoring committee
DMID
Division of Microbiology and Infectious Diseases
DPS
Data presentation specifications
ECG
Electrocardiogram
ECMO
Extracorporeal membrane oxygenation
eCRF
Electronic case report form
HR
Heart rate
IA
Interim analysis
ICF
Informed consent form
ICH
International conference on harmonization
ICU
Intensive care unit
IMV
Invasive mechanical ventilator/ventilation
IMG
Immunogenicity
IQR
Interquartile range
ITT
Intent-to-treat
IV
Intravenous
IWRS
Interactive web response system
KM
Kaplan Meier
LDH
Lactate dehydrogenase
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
LOQ
Limit of quantification
MedDRA
Medical dictionary for regulatory activities
NGS
Next generation sequencing
NOS
Not otherwise specified
NP
Nasopharyngeal
PK
Pharmacokinetic(s)
PP
Per-protocol
PT
Preferred term
qRT-PCR
Quantitative real time polymerase chain reaction
RAND
Randomized
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure


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SD
Standard deviation 
SE
Standard error
SOC
Standard of care
SOC-Med
System organ class as per MedDRA
TFL
Tables, figures, and listings
ULN
Upper limit of normal
ULOQ
Upper limit of quantification
VOC
Variant of concern
VOI
Variant of interest


CNTO136COV2001  (Sirukumab)
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1
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables and 
statistical methods for the analysis of efficacy and safety of the investigational compound 
Sirukumab (CNTO136COV2001). A document ’Data Presentation Specifications (DPS)’ for 
mock shells and table of contents for Tables, Figures and Listings (TFLs) is also produced. The 
SAP is to be interpreted in conjunction with the protocol. The current SAP will cover the primary 
analysis and the final analysis.  Primary analysis will be performed when all randomized 
participants reach the Day 28 assessment of the study or discontinued earlier. The final analysis 
will be performed using all data available (including the information from the follow-up visits) 
after all randomized and/or treated participants reach the end of the study (Week 16) or 
discontinued earlier.  The analysis methods will essentially remain the same for the two analyses.
1.1
Trial Objectives
Primary Objective
The primary objective of the study is to evaluate the clinical response of Sirukumab (administered 
as a single IV dose) with standard-of-care (SOC) treatment compared to placebo with SOC in 
confirmed critical COVID-19 disease and as measured by the time to sustained improvement of at 
least 2 categories relative to baseline on the 6-point ordinal clinical recovery scale (CRS) (up to 
Day 28).
Secondary Objectives
Objectives
Endpoints
Key Secondary
To evaluate the clinical response of
Sirukumab + SOC compared to 
placebo + SOC in confirmed critical 
COVID-19 disease

Proportion of participants with an improvement on 
Day 28 of at least 2 categories relative to Baseline 
on the 6-point ordinal clinical recovery scale.

Incidence of all-cause mortality (up to Day 28)
Other Secondary
To evaluate the clinical response of
Sirukumab+ SOC compared to 
placebo + SOC in confirmed severe 
or critical COVID-19 disease

Time to sustained improvement of at least 2 
categories relative to Baseline on the 6-point 
ordinal clinical recovery scale (up to Day 28)
To evaluate the clinical response of 
Sirukumab + SOC compared to 
placebo + SOC in confirmed severe 
or critical COVID-19 disease

Proportion of participants with an improvement on 
Day 28 of at least 2 categories relative to Baseline 
on the 6-point ordinal clinical recovery scale

Incidence of all-cause mortality (up to Day 28)
To evaluate the safety of Sirukumab
+ SOC compared to placebo + SOC 

Incidence of SAEs (up to Day 28)


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in confirmed (a) critical and (b) 
severe or critical COVID-19 disease 

Incidence of related AEs (up to Day 28)

Proportion of participants with severe or life-
threatening bacterial, invasive fungal, viral or
opportunistic infections (other than SARS-CoV-2) 
(up to Day 28)

Incidence of grade 3 and 4 neutropenia and
lymphocytopenia (up to Day 28)

Incidence of increased ALT ≥3xULN combined 
with increased bilirubin >2xULN (up to Day 28)
To evaluate the clinical response of 
Sirukumab + SOC compared to 
placebo + SOC in confirmed (a) 
critical and (b) severe or critical 
COVID-19 disease

Time to sustained improvement of at least 1 
category relative to Baseline on the 6-point ordinal 
clinical recovery scale (up to Day 28)

Proportion of participants with an improvement on 
Day 28 of at least 1 category relative to Baseline 
on the 6-point ordinal clinical recovery scale

Time from study intervention to end of oxygen
supplementation (up to Day 28)

Time from study intervention to hospital discharge
among the surviving participants (up to Day 28)

Total length of hospitalization among the surviving
participants (up to Day 28)

Number of ventilation free days (up to Day 28)

Participant’s clinical status at Day 7, 14, 21, 28 (6-
point ordinal clinical recovery scale)

Total time on invasive mechanical ventilation

Proportion of participants with a worse category
relative to Baseline on the 6-point ordinal clinical
recovery scale (up to Day 28)

Proportion of participants on extracorporeal 
membrane oxygenation (ECMO) over time

Total time on ECMO
To evaluate the safety during follow-
up for (a) critical and (b) severe or 
critical COVID-19 disease

Proportion of alive participants at Day 28, Week 8,
and Week 16

Proportion of alive participants that required 
readmission at Week 8 and Week 16 (if previously 
discharged)

Incidence of SAEs up to Week 16



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Exploratory
To evaluate biomarkers that may be
associated with response to or
complications of Sirukumab
treatment
Evaluations may include, but are not limited to, IL-6,
procalcitonin, C-Reactive protein (CRP), ferritin, LDH
and D-dimer serum concentrations (through Day 28)
To explore changes in SARS-CoV-2
viral load and viral genome

Time to SARS-CoV-2 undetectable viral load by 
RT-PCR (up to Day 28)

SARS-CoV-2 viral load over time by RT-PCR (up 
to Day 28)

Proportions of participants with undetectable viral 
load (at multiple time points up to Day 28)

Development of SARS-CoV-2 variants
To evaluate the incidence of SARS-
CoV-2 viremia

Proportion of participants with SARS-CoV-2 
viremia (as multiple time points up to Day 28) 
To evaluate pharmacokinetics 
following Sirukumab 5 mg/kg 
treatment 

Sirukumab serum concentration
To evaluate immunogenicity 
following Sirukumab treatment

Proportion of participants with Sirukumab 
antibodies (Day 28 or at discharge if discharged 
after Day 28)
To evaluate SARS-CoV-2 humoral 
immunity

Serum levels of SARS-CoV-2 specific antibodies
At the time of data analysis, additional endpoints may be considered for analysis in function of the 
evolution in scientific knowledge on COVID-19.
1.2
Trial Design
This is a randomized, double-blind, placebo-controlled, multicenter, interventional Phase 2 study 
in hospitalized participants with confirmed COVID-19 disease, at risk for progressing to severe 
ARDS. 
Up to protocol amendment 4, target was to randomly assign 270 participants with confirmed severe
or critical COVID-19 in a 2:1 ratio (Sirukumab: placebo) to receive 1 of the following 2 treatments: 

Treatment Arm: Sirukumab 5 mg/kg IV single dose infusion on Day 1 + SOC treatment 

Control Arm: placebo IV single dose infusion on Day 1 + SOC treatment
As of protocol amendment 5 (please also see section 1.4: ‘Sample Size Justification’ for revised 
sample size calculations), the study aims to enroll approximately 111 participants with confirmed 
critical COVID-19 disease overall in the study. The primary and key secondary analyses will be 
tested on the participants with confirmed critical COVID-19 disease. 


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At the time of release of protocol amendment 5, approximately 100 participants with confirmed 
severe COVID-19 disease had been enrolled. The overall population of participants with 
confirmed severe or critical COVID-19 disease will be analyzed as part of secondary objectives of 
the study.
Randomization is stratified by age (<65 and ≥65 years of age) and by use of invasive mechanical 
ventilation (yes/no) at the time of randomization.
The study will include a ‘Screening Phase’, a ‘Day 1 to Day 28’ Phase (‘Treatment Phase’) and a 
Post Day 28 ‘Follow-up Phase’ to include phone calls on Week 8, Week 12 and Week 16. The 
entire study duration for each participant will be 16 weeks with daily study assessments up to Day 
28 or day of discharge (whichever comes first), and phone call assessments thereafter, ie, at Day 
28 in case of discharge prior to Day 28, at Week 8, 12 and 16. The assessment schedule will be on 
a weekly basis for participants still hospitalized after Day 28. The study is considered completed 
with the completion of the last study assessment (phone call assessment at Week 16) for the last 
participant in the study or the discontinuation of the last participant in the study, whichever comes 
last. 
1.3
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is that Sirukumab in combination with SOC results in a 
statistically significant shorter time to sustained improvement (defined as a sustained improvement 
of at least 2 categories relative to baseline on the 6-point ordinal CRS) versus placebo in 
combination with SOC, in participants with confirmed critical COVID-19 disease.
1.4
Sample Size Justification
The study was targeted to enroll 270 participants with confirmed severe or critical COVID-19
disease in a 2:1 manner, with approximately 180 participants in the Sirukumab treatment arm and
approximately 90 participants in the control arm. However, based on the rapidly evolving space of
COVID-19 therapeutics focusing on the highly impacted population of critical patients together
with the results from the interim analysis, the study population is being limited with protocol
amendment 5 to a subset of the currently eligible population, ie, those with confirmed critical
COVID-19 disease.
At the time of release of protocol amendment 5, approximately 100 participants with confirmed
severe COVID-19 had been enrolled.
The study aims to enroll approximately 111 participants with confirmed critical COVID-19 disease
overall in the study, with approximately 74 participants in the Sirukumab treatment arm and
approximately 37 participants in the control arm.
The primary endpoint in this study is the time to sustained improvement of at least 2 categories 
relative to
Baseline on the 6-point ordinal clinical recovery scale, with participants who die prior to Day 28
treated as right censored at Day 28. For the sample size calculation on the primary endpoint, the
following assumptions are used for survivors and participants who die prior to Day 28:


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
For survivors in the control arm, it is assumed that the log transformed time to sustained 
improvement (days) follows a normal distribution with mean of log 28 and a standard 
deviation 0.9. Sirukumab is assumed to reduce the median time to sustained clinical 
improvement from 28 days to 16.8 days (40% reduction) in the surviving participants and 
is assumed to have the same standard deviation of 0.9.

For the mortality rate in the control arm, 40% by Day 28 is assumed. Sirukumab is assumed 
to reduce the mortality with an absolute difference of 20%: from a mortality rate of 40% 
in the control arm to 20% (50% relative reduction).
Under these assumptions, at least 111 participants with confirmed critical COVID-19 disease are
required to have at least 80% power to demonstrate a difference with the log-rank test, at a
significance level of 5% two-sided.
The proportion of participants with a clinical improvement of at least 2 categories at Day 28 is a
key secondary endpoint. Based on simulations using the above assumptions, the rate with clinical
improvement at Day 28 in the control arm is expected to be 30%. The targeted treatment effect is
an absolute increase of 25% (from 30% in the control arm to 55% in the Sirukumab arm) on this
key secondary endpoint. The mortality by Day 28 is considered another key secondary endpoint.
The targeted treatment effect is an absolute reduction in mortality by 25% (from 40% in the control
arm to 15% in the Sirukumab arm). Under the aforementioned assumptions and with a sample size
of 111, at least 80% power is obtained for both key secondary endpoints a 1-sided significance
level of 5%.
1.5
Randomization and Blinding
Randomization
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 treatment arms in a 2:1 ratio (Sirukumab: placebo) based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor. The 
randomization will be balanced by using randomly permuted blocks and will be stratified for age
(<65 and ≥ 65 years) and IMV (yes/no) at randomization. The interactive web response system 
(IWRS) will assign a unique intervention code, which will dictate the intervention assignment and 
matching study intervention kit for the participant assigned to the active study treatment. The 
requestor must use his or her own user identification and personal identification number when 
contacting the IWRS and will then give the relevant participant details to uniquely identify the 
participant.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant. 


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Data that may potentially unblind the treatment assignment (ie, preparation) will be handled with 
special care to ensure that the integrity of the blind is maintained and the potential for bias is 
minimized. 
The participants, study-site personnel, and investigators will be blinded to treatment allocation 
throughout the study, except for the designated pharmacist(s) or independent qualified staff 
member(s) with primary responsibility for study preparation. These unblinded members will not 
be part of the team performing the evaluations. The infusion administrator will be blinded and can 
perform other study evaluations. The sponsor study team will be blinded to study treatment 
allocation until the database release of the primary analysis.
Under normal circumstances, the blind should not be broken until the database for the primary 
analysis is locked. However, for the IA, the randomization codes and the translation of 
randomization codes into treatment and control groups were disclosed to those authorized and only 
for those participants included in the IA. Details on the level of unblinding and the parties 
authorized unblinded during the interim analysis were specified in the IA SAP. Otherwise, the 
blind should be broken only if specific emergency treatment/course of action would be dictated by 
knowing the treatment status of the participant. In such cases, the investigator may in an emergency 
determine the identity of the intervention by contacting the IWRS. While the responsibility to 
break the intervention code in emergency situations resides solely with the investigator, it is 
recommended that the investigator contact the sponsor or its designee if possible, to discuss the 
particular situation, before breaking the blind. Telephone contact with the sponsor or its designee 
will be available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor 
must be informed as soon as possible. The date and reason for the unblinding must be documented 
in IWRS, in the appropriate section of the eCRF and in the source document. The documentation 
received from the IWRS indicating the code break must be retained with the participant's source 
documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for
scheduled evaluations. 
In general, randomization codes will be disclosed fully only at the timing of the primary analysis 
and when the clinical database is closed. However, for the analyses performed for the DMC review 
or for the interim analysis, the randomization codes and, if required, the translation of 
randomization codes into intervention and control groups were disclosed to those authorized and 
only for those participants included in the DMC or interim analysis.


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2
GENERAL ANALYSIS DEFINITIONS 
All analysis dataset preparations and statistical analyses will be performed using SAS® version 9.4
or higher.
2.1
Visit Windows and Phase Definitions
The study is set up as shown in Figure 1 and Figure 2. The phases will be constructed as shown in 
Table 1.
Figure 1: Schematic Overview of the Study up to Protocol Amendment 4
SARS-CoV-2 PCR positivity at any time before screening will be accepted. Results from local 
laboratory, ECGa, and pulmonary imaging assessments taken up to 2 days prior to screening will 
be accepted for screening assessments.
Screeningb assessments start after signing of the ICF and can continue on the next calendar day, 
if needed. All screening and baseline assessments may also take place on the same day.
                                                
a As of protocol amendment 5
b If the participant is on invasive mechanical ventilation or veno-venous ECMO, duration may not be >48 hours at time of 
screening.


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Participants need to receive study intervention preferably within 4 hours but no later than 6 hours 
after randomization.
During the period covered up to and including protocol amendment 4:
The DMC reviewed the interim data as soon as the first 30 participants with confirmed severe 
or critical COVID-19 disease had been dosed and had had at least 7 days of follow-up after 
study intervention.
An IA for futility was performed when approximately 20% of the planned number of 
participants with confirmed severe or critical COVID-19 disease have reached Day 28 or 
discontinued earlier.
Figure 2: Schematic Overview of the Study as of Protocol Amendment 5
As of protocol amendment 5, participants with confirmed severe COVID-19 disease are no 
longer enrolled in the study and the study aims to enroll approximately 111 participants with 
critical COVID-19 overall in the study. At the time of release of protocol amendment 5, 
approximately 100 participants with confirmed severe COVID-19 disease had been enrolled.


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2.1.1 Phase Definitions
Table 1: Construction of phases
Study Phase
Start Date/Time
End Date/Time
Screening
(phase 1)
The date & time 
of signing the 
informed 
consent*1
1 minute before the study drug intake 
Treatment 
(phase 2) 
Date & time of 
study drug 
administration 
(Sirukumab or 
Placebo)*2
Minimum of:  
a. Day 28 Visit at 23.59h or if Discharged earlier 
phone call Day 28 at 23.59h 
b. Date of study discontinuation before Day 28*3
c. Date of death*3
If a), b) c) did not occur then count 28 days after 
drug administration at 23.59h 
Follow-up 
(phase 3) 
End of the 
treatment phase 
+1 minute 
Maximum of:  
a.
Date of last contact3*
b.
Date of study discontinuation3*  
*1: if no time is available then impute with 00:00  
*2: in case the time part of the study drug administration is missing then time part will be imputed by time 
of randomization 
*3:  Time will be imputed with 23:59  
2.2
Analysis Sets
2.2.1 All Randomized (RAND) Analysis Set
The RAND analysis set consists of all participants who were randomized in the study. Analysis 
based on this analysis set will use the randomized treatment group assigned by IWRS (All 
randomized analysis set as Randomized).
2.2.2 Intent-to-Treat (ITT) Analysis Set
The ITT analysis set consists of all participants who were randomized and treated in the 
study. This analysis set will be used for the analysis of efficacy, subject information and virology 
assessments. Treatment group as randomized will be used for these analyses (ITT analysis set as 
Randomized).   
2.2.3 Primary Analysis Set 
The Primary analysis set consists of all participants in the ITT analysis set with confirmed critical 
COVID-19 disease defined as score of 4 or 5 on the CRS scale at baseline.  For more details on 
CRS score please refer to Section 5: Efficacy. Treatment groups as randomized will be used for 
the analysis using this analysis set (Primary analysis set as Randomized).


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2.2.4 All Subjects Treated (AST) Analysis Set
The AST analysis set consists of all participants who received the study drug. This analysis set 
will be used to evaluate the safety of drug, using the actual treatment received by a participant
(AST analysis set as Treated)
2.2.5 Pharmacokinetics (PK) Analysis Set
The PK analysis set includes all participants in the AST analysis set with no interruption of study 
medication and who also had at least 1 valid blood sample drawn for PK analysis after dose of 
Sirukumab.  This analysis set will be used to analyze the PK concentration using actual treatment 
received by a participant (PK analysis set as Treated).
2.2.6 Immunogenicity (IMG) Analysis set
The IMG analysis set consists of participants in AST analysis set who received a dose (full or 
partial) of Sirukumab during the study and have at least one valid blood sample for 
immunogenicity analysis after Sirukumab dose.  This analysis set will be used to analyze 
immunogenicity using the actual treatment received by a participant (IMG analysis set as Treated).
2.2.7 Per-Protocol (PP) Analysis Set
The PP analysis set consists of participants in ITT analysis set who don’t have any major protocol 
deviations that could have influenced the efficacy of Sirukumab during the study. This analysis set 
will be used for exploratory analysis of primary efficacy endpoint if more than 10% of ITT 
participants have major protocol deviations that could have influenced the efficacy evaluation.
2.3
Study Day 1
Study Day 1 refers to the day/date of the study drug administration (which is the same as the 
treatment phase start date).
2.4
Imputation of Missing Time Portion of Date/Time Field
Each measurement/observation which is supposed to have date and time associated with it may 
sometimes have the time portion of date/time as missing.  If time is missing, then the 
measurement/observation is assumed to be at the start of the day (that is, missing time is imputed 
as 00:00:00 hours/minutes/seconds). Therefore, a measurement/observation with missing time on 
Day 1 is assumed to be pre-dose unless information on eCRF clearly mentions that it is post-dose.
2.5
Baseline Value
The baseline values for efficacy endpoints are defined in section 5: Efficacy. 
For demographics and other measurements during the study, a baseline is defined as the last 
value/measurement (1) on or after informed consent date/time, AND (2) before the date/time of 
study drug administration.  
However, following exceptions apply to define the baseline.
(1) For electrocardiogram (ECG) measurements, for participants who were enrolled before 
protocol amendment 5, the baseline is defined as the last value/measurement (1) on or after 


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informed consent date/time, AND (2) before the date/time of study drug administration.
For participants who were enrolled based on protocol amendment 5, the baseline may be 
defined using information from up to 2 days prior to the informed consent date.  
(2) Local labs tests (blood chemistry, hematology, coagulation tests), pregnancy tests and chest 
imaging, the baseline may be defined using the information from up to 2 days prior to the 
informed consent date.
(3) It is possible that for some biomarkers there are multiple samples taken at the same 
date/time providing different test results corresponding to the same date/time. In such 
cases when there are multiple pre-dose measurements exactly on the same date/time that 
are closest to date/time of study drug administration then average of these measurements 
is used as baseline value. [Note: Measurements below lower limits of quantification
(LLOQ) will be imputed by LLOQ/2 and measurements above upper limits of 
quantification (ULOQ) by ULOQ prior to taking the average, if required.]
(4) The baseline for viral load may be a post-dose measurement, for more details please see 
section 6.2: Virology Assessments- Definitions.  
(5) If pre-dose height and weight values are not available, then earliest post-dose values on 
day of study drug administration may be used as the baseline values for height and weight.
[Note: As mentioned in section 2.4, a measurement/observation with missing time on Day 1 is 
assumed to be pre-dose unless information on eCRF clearly mentions that it is post-dose.]
2.6
Definition of Subgroups
Subgroups used for analyses of different endpoints are defined in the Table 2 below.
Descriptive statistics will be produced for the different subgroups. 
Table 2: Subgroup definition
Subgroup
Definition
Endpoints
Age group (years)
<65 years
≥ 65 years
-
Participants’ demographics information, baseline 
disease characteristics, and disposition information
-
Selected Efficacy 
-
Safety (selected laboratory test results and AE tables)
-
CRS score at baseline1
CRS <= 3
CRS <= 4
CRS=4
CRS=5
-
Participants’ demographics information, baseline
disease characteristics, and disposition information
-
Selected Efficacy
-
Safety (selected laboratory test results and Adverse 
events results)
-
o


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Subgroup
Definition
Endpoints
Center2
Highest 
recruiter 
center (located 
over 2 sites)
All other 
centers
-
Efficacy (primary and key secondary endpoints)
Interim Analysis
Included in
Interim 
Analysis
Not included in
Interim 
Analysis
-
Efficacy (primary and key secondary endpoints)
Free IL-6 at screening
<= 33% 
percentile
> 33 and <=
66% 
percentile
> 66% 
percentile
-
Efficacy (primary and key secondary endpoints)
CRP at screening
<= 33% 
percentile
> 33 and <=
66% 
percentile
> 66% 
percentile
-
Efficacy (primary and key secondary endpoints)
1 CRS=5 corresponds to “Use of IMV at the time of randomization”. For descriptive statistics, CRS score at 
baseline with the subgroups as defined will be used. For inferential statistics, the models should include a baseline 
CRS flag (<=3/> 3) in combination with the stratification factor. Baseline CRS will not be included in the model.
2 Highest recruiter center (located over 2 sites: US1006 & US10033)
Additional subgroup analysis may be specified in a separate analysis plan and reported separately 
from the clinical study report. These may include subgroups according to baseline C-Reactive 
Protein or baseline Albumin values. 
2.6.1 Pooling Algorithm for Analysis Centers 
As per the information in Table 2, certain analysis will be performed using the participants in the 
following 2 subgroups of the study centers. 

US1006 and US10033.

All other centers


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3
DATA REVIEW COMMITTEE, INTERIM ANALYSIS
A Data Monitoring Committee (DMC) was established to monitor unblinded data to ensure the 
continuing safety and well-being of the participants. Also, an interim analysis (IA) was conducted 
during the study. Details for these are described in the next sections.  
3.1
Data Monitoring Committee
A DMC consisting of internal and external members was established to monitor unblinded data to 
ensure the continuing safety and well-being of the participants enrolled in this study. The DMC 
regularly evaluated the cumulative safety data of all participants in the study. As soon as the first 
30 participants received study intervention and had at least 7 days of follow-up after study 
intervention, the DMC performed an interim data review focused on safety. During this data 
review enrollment was continued, however, it was planned that recruitment would be halted should 
60 patients had been enrolled before the outcome of the data review was known. All data available 
at the time of the interim data review was included. In case recruitment were to be halted, it was 
planned to resume the enrollment following a positive assessment of results of these interim data 
by DMC.
The DMC responsibilities, authorities, and procedures are documented in its charter.  
3.2
Interim Analyses
A non-binding unblinded interim analysis (IA) for futility was performed by the sponsor on the 
primary endpoint when approximately 20% of the planned number of participants had reached 
Day 28 or could have reached Day 28 by the date of data cut-off for the IA. Results have been 
discussed with the DMC.
The randomization codes and the translation of randomization codes into treatment and control 
groups were disclosed to those authorized and only for those participants included in the IA.
Following this IA, the study was not stopped for futility. 
A separate SAP is available for the interim analysis (IA).
4
SUBJECT INFORMATION
4.1
General
Participants’ information will be presented using the ITT and Primary analysis sets unless specified 
otherwise for a specific display. If there is a difference in allocation (>5 participants) between the 
ITT and the AST sets the disposition information and demographic and baseline disease 
characteristics will also be provided for the AST. 
For continuous data descriptive statistics will be reported (n, mean, SD, median, range, IQR range), 
for categorical data frequencies and percentages will be displayed. 
4.2
Demographics and Baseline Characteristics
The summary tables for demographic characteristics and baseline values will be generated.
Tables summarizing the following demographic characteristics and baseline values for different 
measurements during the study are planned.  


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Demographic and baseline parameters:

Age (years) including categories (<65; ≥65) 

Sex (Male, Female) 

Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multiple. (‘Not Reported’ and 
‘Unknown’ for race will be considered as missing)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 

Baseline weight (kg) 

Baseline height (cm) 

BMI at baseline = Weight at baseline (kg) / (Height at baseline (m))2 (If available in 
the raw data, BMI will be recalculated from last weight and height measurement 
before start of treatment) and categories (<18.5, 18.5-25, 25-30, >=30) 

Smoker (No, Yes - Current, Yes - Former)
Baseline disease characteristics:

Days from Onset of First Symptoms to Randomization

Level of Hospital Care at Baseline (Hospital inpatient department (ward), Intensive 
care unit, Step down unit)

Days from Onset of First Symptoms to First Admission in Hospital (Regardless of 
Level of Care)

Days from First Admission in Hospital (Regardless of Level of Care) to screening

Days from First Admission in ICU to screening

Days from First Symptoms to IMV and/or ECMO

Chest Imaging (Normal, Abnormal, Unilateral findings, Bilateral findings)

Clinical Status at Randomization (Hospitalized - requiring low flow supplemental 
oxygen, Hospitalized -on non-invasive pressure ventilation or high flow, 
Hospitalized - on IMV or ECMO)
Use of IMV at baseline (based on eCRF data, if not available on eCRF then on IWRS system) 
(Yes, No)
Tables summarizing biomarkers and relevant lab tests at baseline will be generated: 

The biomarkers of CRP, D-Dimer, Serum Ferritin, Pro-Calcitonin and Free IL-6 (all 
from central labs), will be summarized by mean (SD), median, tertiles, IQR, 
minimum, and maximum. [Note: Measurements below the lower or above the upper 
limits of quantification (LLOQ, ULOQ) will be imputed as LLOQ/2 or ULOQ, 
respectively.

Lab tests of White Blood cell count, Lymphocyte count, Platelets, Alanine 
Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Creatinine (all 
from local labs) will be summarized as per Division of Microbiology and Infectious 
Diseases (DMID) grades.

Lab tests of Lactate Dehydrogenase (LDH), Albumin, Troponin-I, and Troponin-T 
(all from local labs) will be displayed by n and percentages of participants with 
values of normal, and high/below normal range.


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4.3
Disposition Information
Summary tables for the following information showing number and percentages of participants 
will be generated.

Participants ‘screened’, ‘screen failures, ‘randomized and treated’, ‘randomized and 
not treated’, ‘not randomized and treated’.  The table will include all screened 
participants (only number of participants will be displayed on the table),  

Participants in different analysis sets (only number of participants will be displayed 
on the table),

Participants who are ongoing in study, completed the study, discontinued the study 
and the reasons for discontinuation.
Participants are randomized by two stratification factors (1) Age categories (< 65, >= 65 years), 
and (2) Use of IMV at randomization (Yes, No).  It is very unlikely but possible that participants 
are not correctly randomized in the right stratum and that there are discrepancies between IWRS 
system and information on eCRF pages. A table showing the discrepancies between IWRS system 
and information on eCRF pages will be generated for participants in RAND analysis set.
4.4
Extent of Exposure and Treatment Compliance
A listing with extent of exposure data (duration of infusion, interruption, and length of 
interruption) and drug administration information (total calculated dose, participant’s weight, total 
volume prepared, volume added to IV container) will be provided for each treated participant.
A listing of participants randomized will be generated to show the actual treatment received and 
randomized treatment and the date/time of the treatment received.
4.5
Protocol Deviations
For the participants in the ITT and Primary analysis sets, the number and percentage of participants 
with major protocol deviations (using coded major protocol deviations) and number and 
percentage of participants with major protocol deviations that are considered as affecting the 
efficacy evaluations will be tabulated. A listing will be generated for screened participants with 
any major protocol deviations and the major protocol deviations affecting the efficacy evaluations 
will be flagged.
4.6
Prior and Concomitant Medications
Information on prior and concomitant medications will be provided for the ITT and Primary 
analysis sets.
Medications taken until the end of study will be summarized by treatment group and overall, by 
preferred term as frequency tables for the prior and concomitant medications separately: 
1. Prior medication: medication that started before the date of the first dose of study drug, 
regardless of the stop date of the medication. 


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2. Concomitant medication: (1) medication received on or after the date of first dose of 
study drug, and (2) medication that was received before dosing date and continued after 
dosing of study drug, or medication with missing stop date. 
It should be noted that a medication may be classified both as prior and concomitant medication. 
The classification of a medication will be based only on the date of start/end of the medication and 
the date of start of study dose; and time portion of medication and study dose will not be 
considered. Therefore, if a medication started on the study dose date then it is considered as a 
concomitant medication.
If a medication record has missing components of its start and/or stop dates (day and/or month 
and/or year), the following rules will be used to impute the missing date or its component:
1. In case of partial start or stop date, the concomitant therapy records will be allocated to 
prior/concomitant using the available partial information, without imputations. 
2. In case of a completely missing start date, the prior/concomitant therapy will be 
considered as having started before the trial. 
3. In case of a completely missing end date, the prior/concomitant therapy will be 
considered as ongoing at the end of the trial.
The analysis of prior/concomitant medications will use the coded terms from the WHO drug 
dictionary as provided in the clinical database.
The number and percentage of participants with prior and concomitant medications will be 
summarized by ATC levels 1, 2, 3, and by standardized medication names (coded terms).
Medications of interests with COVID-19: The following medication groups of the prior and 
concomitant medications of interests with COVID-19 will be summarized showing number and 
percentage of participants by medication groups/coded terms:

Covid-19 direct antiviral, 

Remdesivir and Glucocorticosteroids, 

Glucocorticosteroids for systemic use,

Antibacterial for systemic use, 

Antimycotics for systemic use, and 

Antithrombotic agents (excluding antiplatelets)

Convalescent plasma

Interleukin Inhibitors

COVID-19 Vaccine
The above groups and corresponding coded terms will be listed in the DPS.


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Duration of medications of interests with COVID-19: The median, range and interquartile range 
of duration (Days) of treatment with Remdesivir and Glucocorticosteroids during the study will be 
tabulated.
4.7
Medical history
Medical history for each participant will be collected at screening visit. Summary of medical 
history will be presented using the ITT and the Primary analysis sets.
General medical history and COVID-19 related medical history are collected on separate pages of 
the eCRF. COVID-19 related medical history included the following pre-specified symptoms: 
Fever, Cough, Sour Throat, Rhinorrhea, Wheezing, Chest Pain, Myalgia, Fatigue/Malaise, and
Dyspnea.  Any other reported COVID-19 related symptoms not pre-specified in the CRF will be 
presented under 'Other' with subcategories of Gastrointestinal symptoms, loss of taste/smell, 
headache, and other. General medical history terms are coded using Medical Dictionary for 
Regulatory Activities (MedDRA).  
General medical history will be tabulated by System Organ Classes (SOC-Med) and Preferred 
Terms (PT) using MedDRA coding, and by splitting them by those ‘being currently active’ and 
‘history and not active’.  Additionally, a summary table showing only COVID-19 related medical 
history will be generated.  
Relevant comorbidities at screening are defined by ongoing general medical history related to 
symptoms of Diabetes, Serious Heart Conditions/Coronary Heart Disease, Chronic Obstructive 
Pulmonary Disease, Chronic Kidney Disease, Cancer, and Obesity (defined as BMI >= 30 kg/m2
based on height (meter) and weight (kg) at screening). A summary table with number and 
percentages of participants in each of these comorbidities will be generated. The coded terms (PT) 
corresponding to comorbidities will be listed in the DPS.
4.8
Physical Examinations and Pregnancy Test Results
For all participants, the targeted physical examinations are performed at screening. Any new
findings or worsening of conditions are reported as adverse events (AEs).
For female participants in the AST analysis set, the results of the pregnancy tests at 
screening/baseline and at Day 28/discharge visits will be listed.
4.9
Results by Sub-groups
As mentioned in the section 2.6, subgroup analysis is planned based on subgroups of (1) age (<= 
65 and > 65 years) and (2) CRS score at baseline (<= 3, <= 4, 4, 5) to investigate the disposition 
of participants during the study, demographic information, and baseline disease characteristics.


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5
EFFICACY
Descriptive statistics will be used for all efficacy endpoints and will be tabulated by treatment arm 
and by the subgroups as specified in table 2.
All efficacy analyses will be performed in the Primary and ITT analysis sets as randomized.
5.1
Analysis Specifications
5.1.1 Level of Significance
The primary endpoint will be tested for superiority of Sirukumab in combination with SOC over 
placebo in combination with SOC at the 2-sided 5% significance level.
The key secondary endpoints and other secondary endpoints will be tested at the 1-sided 5% 
significance level.
5.1.2 Stratification Factors
The actual values of the stratification factors will be used for all analyses.
5.2
Primary Efficacy Endpoint(s)
5.2.1 Definitions
Six-point ordinal clinical recovery scale
The 6-point ordinal clinical recovery scale (CRS) provides 6 mutually exclusive conditions 
ordered from best to worst, and the score reflects the participant’s worst situation on the day of 
the assessment:
1.    Not hospitalized
2.    Hospitalized, not requiring supplemental oxygen
3.    Hospitalized, requiring low flow supplemental oxygen
4.    Hospitalized, on non-invasive ventilation, nonrebreather mask or high flow oxygen device
5.    Hospitalized, on IMV or ECMO
6.    Death
The CRS can be derived from baseline up to and including day 28. The CRS will be missing 
after trial discontinuation if the participant discontinued the trial for other reason than death.
Participants who die before day 28 (before or after discharge from hospital) will be considered to 
continue the trial up to and including day 28.
The CRS categories are defined below. For ease of categorization, the categories are defined 
from worst to best. A participant will be evaluated in the same ordering of the categories as 
below. Once a participant fulfils the criteria for a category, the category is assigned to the 
participant and the evaluation stops.
6.    Death
o    Participant died at any time on the day of assessment or earlier (all-cause mortality).
5.    Hospitalized, on IMV or ECMO


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o    IMV or ECMO is used at any time on the day of assessment, OR
o    From a Medical Perspective, the participant should have been on IMV on the day of 
the assessment
4.    Hospitalized, on non-invasive ventilation, nonrebreather mask, or high flow oxygen device
o   The participant is on supplemental oxygen and the worst FiO2 is >=50%.
3.    Hospitalized, requiring low flow supplemental oxygen
o    On supplemental oxygen with worst FiO2<50 % and the participant was not able to 
sustain a blood oxygen saturation of >93% when breathing room air, OR 
o    Not on supplemental oxygen and the minimum of all available SpO2 values during 
the day is <= 93%
2.    Hospitalization, not requiring supplemental oxygen
o    Hospitalized according to the status described below
1.    Not hospitalized, including subjects on low level of oxygen
o
A distinction will be made between subjects discharged and in need of (score 1.2) or
not in need of (score 1.1) oxygen supplementation as indicated by the investigator on 
the discharge questionnaire. This distinction will not be made when calculating 
improvements on the CRS, for which score 1 will be used in both cases.
Hospitalization status
The hospitalization status considered for the definition of the CSR will be defined according to 
the rules described below. The hospitalization status will be evaluated in the same ordering of 
rules. Once a participant fulfils the criteria, the hospitalization status is defined and the 
evaluation stops. 
1.
If a participant is discharged to the alternate care settings ‘different hospital’, ‘acute care 
facility’, ‘subacute care facility’ or ‘hospice/palliative discharge’, the participant will be 
considered hospitalized until day 28 or trial discontinuation, whichever comes first. The 
participant will be categorized in the category the participant was in at time of discharge
until trial discontinuation. 
2. If a participant is discharged ‘against medical advice’, the participant will be considered 
hospitalized on the day of discharge and on the day after discharge, unless the participant 
discontinued the trial. The participant will be categorized in the category the participant 
was in at time of discharge. The CRS will be considered missing from 2 days after 
discharge onwards.
3. If a participant is hospitalized although ‘ready for discharge’ according to the 
investigator, the participant will be considered hospitalized up to and including the first 
day on which the participant was considered ready for discharge. The participant will be 
considered “Not hospitalized” from the day after until day 28 or trial discontinuation, 
whichever comes first (unless the status changes back to “not ready for discharge”).
4. If a participant is discharged although ‘not ready for discharge’ according to the 
investigator, the participant will be considered hospitalized up to and including 1 day 


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after the day of discharge, unless the participant discontinued the trial. The participant
will be categorized in the category the participant was in at time of discharge. The 
participant will be considered non hospitalized from 2 days after the day of discharge 
onwards until day 28 or trial discontinuation, whichever comes first.
5. If a participant is discharged from the hospital, the day of discharge will be considered as 
“hospitalized”. The participant will be categorized in the category the participant was in 
at time of discharge. After this day, the participant will be considered “Not hospitalized”
until day 28 or trial discontinuation, whichever comes first.
Baseline 
The 6-point ordinal CRS at the time of randomization request will be used as the baseline. If the 
baseline assessment of the CRS is missing, the first available assessment within 12 hours after
randomization will be used. If the latter is also missing, the last available assessment prior to 
baseline will be used.
Sustained Clinical Improvement
Clinical Improvement is obtained if the score on the CRS improved with at least 2 categories
with respect to the baseline score. 
Sustained clinical improvement is defined as a clinical improvement without documented loss of 
this clinical improvement up to and including day 28 or until trial discontinuation, whichever 
comes first.  
5.2.2 Primary Estimand
Population: The population of interest are hospitalized patients between ≥18 and <85 years old 
with confirmed critical COVID-19 disease. 
Endpoint: Time to sustained clinical improvement.
Interventions: Received Sirukumab 5 mg/kg (IV single dose infusion on Day 1) and placebo (IV 
infusion on Day 1), both on top of SOC.
Intercurrent Events:

Death as intercurrent event is handled in a composite strategy as it is the worst category on 
the clinical scale. 

The intercurrent event of the use of prohibited medication is handled in a treatment policy 
strategy: data will be used as observed.


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
The intercurrent event of discharge to the alternate care settings ‘different hospital’, 
‘acute care facility’, ‘subacute care facility’ or ‘hospice/palliative discharge’ is handled in 
a while on treatment strategy: see section 5.2.1

The intercurrent event of discharge ‘against medical advice’ is handled in a hypothetical 
strategy: see section 5.2.1
Population-level summary measure: 
Hazard ratio of ‘Sustained clinical improvement’ for experimental treatment versus placebo, from 
baseline until day 28.
5.2.3 Analysis Methods
All participants for which the trial is still ongoing at Day 28 and without sustained clinical 
improvement by Day 28 will be censored on Day 28. Participants that discontinue the study before 
day 28 will be censored at the last assessment of the CRS, unless they had an event of sustained 
clinical improvement prior to discontinuation. Participants that died at day 28 or earlier will be 
censored at day 28, irrespective of whether a clinical improvement occurred prior to death.  
The primary hypothesis of this study is that Sirukumab in combination with SOC results in a 
statistically significant shorter time to sustained improvement (defined as an improvement of at 
least 2 categories relative to baseline on the 6-point ordinal CRS) versus placebo in combination
with SOC, in participants with confirmed critical COVID-19. 
The primary hypothesis will be evaluated based on the Logrank test, stratified for the stratification 
factors (age [<65 and ≥65 years] and use of IMV [yes/no]). This test will be performed 2-sided at 
a 5% significance level. The actual values of the stratification factors will be used, not as 
randomized.
The hazard ratio of sustained clinical improvement for experimental treatment versus placebo, 
from baseline until day 28 will be considered as the population-level summary measure of the 
treatment effect for the primary estimand. The hazard ratio will be estimated in a Cox proportional 
hazards model stratified for the stratification factors and with treatment as a single covariate. A 
value larger than 1 indicates the chance of improvement is larger in the experimental treatment 
group. The 95% Wald confidence interval will be added.
The Log-rank test might generate a different p-value compared to that of the Wald test of the 
hazard ratio. The Logrank test will be used for formal inference (and not the Wald p-value or CI 
from the hazard ratio).
Cumulative proportion of patients with clinical improvement, by treatment, will be provided using 
the complement of the Kaplan Meier curve. The analyses will be completed with the median time 
to clinical improvement (if reached) and the proportion of participants who had their clinical 
improvement on day 7, 14, 21 and 28; all per Kaplan Meier method. The complementary log-log 
transform method is used to calculate the 95% confidence intervals.


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As a sensitivity analysis, a Cox proportional hazards model will be estimated that is stratified for 
the stratification factors, but also adjusted for additional baseline covariates on top of treatment. 
The covariates are the following: CRS at baseline (<=3 vs > 3), Remdesivir at baseline (yes/no), 
Glucocorticoids at baseline (yes/no), Number of Comorbidities (0/1/2/≥3), Sex (Male/Female), 
Race (Asian/Black or African American/White/Unknown or Not reported), Ethnicity (Hispanic or 
Latino/Not Hispanic or Latino), Free IL-6 at screening, CRP at screening, ferritine at screening, 
LDH at screening (high/low/normal) and albumin (low/not low) at screening. Each of the 
additional baseline covariates will be added to the model to estimate the individual effect of these 
covariates, after which a stepwise selection method will be applied. A covariate will be added to 
the model if it is significant at the 25% significance level, while the covariate in the model has to 
be significant at the 0.15% level for it to remain in the model. The hazard ratio will be estimated 
in the final Cox proportional hazard model.
Comorbidities considered: Obesity (BMI>=30),  Diabetes, Serious Heart Condition/Coronary 
Heart Disease, Chronic Obstructive Lung Disease, Chronic Kidney Disease and cancer.Time to 
sustained clinical improvement can be considered as a composite of two endpoints: time to 
improvement in the survivors as well as death by day 28. These two components will therefore 
also be analyzed separately. That is, the analyses described in the previous paragraph will be 
repeated in the subgroup of participants that do not die by day 28 and the analyses for the endpoint 
of death by day 28 are described in section 5.3.
At this moment it is difficult to predict whether prohibited medication will be used, in what 
frequency in the two treatment arms and what their efficacy might be. Therefore, the impact of 
prohibited meditation will be explored retrospectively.
Analyses of qualitative comparison between pre-interim analysis and post-interim analysis for 
treatment effect on the primary endpoint in the population with confirmed critical COVID-19 
disease will be conducted to check the consistency in the study.
The primary analysis will be repeated for the ITT population, including the participants with severe 
confirmed COVID-19 disease.
5.3
Key Secondary Endpoints
5.3.1 Definitions
Similar as for the primary endpoint, the definitions as specified in section 5.2.1 will be used for 
the key secondary endpoints.
Clinical improvement at Day 28
Clinical Improvement is obtained if the score on the CRS improved with at least 2 categories at 
Day 28 with respect to the baseline score. 
All-cause mortality up to Day 28
All-cause mortality is defined as score 6 on the CRS at Day 28.


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5.3.2 Key Secondary Estimands
Clinical improvement at Day 28
Population: The population of interest are hospitalized patients between ≥18 and <85 years old 
with confirmed critical COVID-19 disease. 
Endpoint: Sustained clinical improvement at Day 28 (yes/no)
Interventions: Received Sirukumab 5 mg/kg (IV single dose infusion on Day 1) and placebo (IV 
infusion on Day 1), both on top of SOC.
Intercurrent Events:

Death as intercurrent event is handled in a composite strategy as it is the worst category on 
the clinical scale. Participants that died at Day 28 or earlier will be considered as failure 
(Sustained clinical improvement at Day 28=no), irrespective of whether a clinical 
improvement occurred prior to death.  

The intercurrent event of the use of prohibited medication is handled in a treatment policy 
strategy: data will be used as observed.

The intercurrent event of discharge to the alternate care settings ‘different hospital’, ‘acute 
care facility’, ‘subacute care facility’ or ‘hospice/palliative discharge’ is handled in a while 
on treatment strategy: see section 5.2.1 

Participants that discontinue the study before Day 28 will be considered as failure 
(Sustained clinical improvement at Day 28=no), unless they had an event of sustained 
clinical improvement prior to discontinuation. In the latter scenario it will be considered a 
success (Sustained clinical improvement at day 28=yes).
Population-level summary measure: 
The difference in proportion of participants with of ‘Sustained clinical improvement at Day 
28’ for experimental treatment versus placebo.
All-cause mortality up to Day 28
Population: The population of interest are hospitalized patients between ≥18 and <85 years old 
with confirmed critical COVID-19 disease. 
Endpoint: Death by Day 28 (Yes/No) 
Treatment: Sirukumab 5 mg/kg (IV single dose infusion on Day 1) and placebo (IV infusion on 
Day 1), both on top of SOC.
Intercurrent events:

The intercurrent event of the use of prohibited medication is handled in a treatment policy 
strategy: data will be used as observed.

Participants that discontinue the study before Day 28 with a score > 1 on the CRS will be 
analyzed according to the composite strategy and will be considered as death on day 28 
(Death by day 28=yes).


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
Participants whose last score on the CRS was equal to 1 and that were not reported as 
having died before or at day 28 will be analyzed according to the composite strategy and 
they will be considered as alive (Death at Day 28=no). 
Population level summary measure: 
The difference in proportion of participants with ‘Death by day 28’ for experimental 
treatment versus placebo.
5.3.3 Analysis Method
The data will be analyzed according to the randomized treatment. 
For the key secondary endpoints, the CMH analysis for difference in proportions, adjusted for  the 
stratification factors (age [<65 and ≥65 years] and use of IMV [yes/no]) will be performed. The 
comparison between treatment groups will be based on CI-estimates and p-values obtained from 
this analysis.
A positive value on the common proportion (risk) difference using the Mantel-Haenszel method 
indicates that the proportion of participants with ‘Sustained clinical improvement at day 28’/’death 
by day 28’ is larger in the experimental treatment group. The actual values of the stratification 
factors will be used, not as randomized.
As a sensitivity analysis,  a logistic regression model will be estimated that is adjusted for the 
treatment group, but also adjusted for additional baseline covariates. The covariates are the 
following: CRS at baseline (<=3 vs > 3), Remdesivir at baseline (yes/no), Glucocorticoids at 
baseline (yes/no), Number of Comorbidities (0/1/2/≥3), Sex (Male/Female), Race (Asian/Black 
or African American/White/Unknown or Not reported),  Ethnicity (Hispanic or Latino/Not 
Hispanic or Latino), Free IL-6 at screening, CRP at screening, ferritine at screening, LDH at 
screening (high/low/normal) and albumin (low/not low) at screening. Each of the additional 
baseline covariates will be added to the model to estimate the individual effect of these covariates, 
after which a stepwise selection method will be applied. A covariate will be added to the model if 
it is significant at the 25% significance level, while the covariate in the model has to be significant 
at the 0.15% level for it to remain in the model. In the final logistic regression model the treatment 
difference in proportions will be estimated. This will be done as follows: in each treatment group 
the proportion of participants with improvement will be estimated using the average value
observed the study (across treatment groups) for both the continues and categorical covariates 
(based on 0/1 coding for categorical). The delta method will be used for the confidence interval.
Comorbidities considered: Obesity (BMI>=30), Diabetes, Serious Heart Condition/Coronary 
Heart Disease, Chronic Obstructive Lung Disease, Chronic Kidney Disease and Cancer.
Analyses of qualitative comparison between pre-interim analysis and post-interim analysis for 
treatment effect on the key secondary endpoints in the population with confirmed critical COVID-
19 disease will be conducted to check the consistency in the study.


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The key secondary analyses will be repeated for the ITT population, including the participants 
with severe confirmed COVID-19 disease.
5.4
Other Secondary Endpoints
5.4.1 Definitions
CRS (As observed)
The CRS defined for the primary analysis is derived based on a combination of the hospitalization 
and oxygen supplementation status of the participant. More specifically, the status is considered 
as the status in which the participant would have been, according to the investigator, in case all 
circumstances were optimal. As an alternative measure, the CRS (As observed) will be derived 
using only the information on the actual status of the participant, ignoring alternative choices made 
because of lack of resources, participants choice and others. 
Similar as for the derivation of the CRS, a participant will be evaluated in the same ordering of the 
categories as below. Once a participant fulfils the criteria for a category, the category is assigned 
to the participant and the evaluation stops. The actual hospitalization status will be considered in 
this derivation.
•
Score 6: Based on the status of the participant on the day of the assessment (based on the 
date of death).
Based on Type of Oxygen Supplementation page:
•
Score 5: At least one of the following scores is ticked: 
o
IMV
o
Extra Corporeal Membrane Oxygenation
•
Score 4: 
o
Non-invasive mechanical ventilation (CPAP or BIPAP), high-flow nasal cannula,
non-rebreather device or OxyMask is used at any time on the day, OR
•
Score 3: 
o
Receiving supplemental oxygen through a face mask, nasal cannula or other 
•
Score 2:
o
Hospitalized as reported
•
Score 1:
o
Not hospitalized as reported: a distinction will be made between subjects 
discharged and in need of (score 1.2) or not in need of (score 1.1) oxygen 
supplementation as indicated by the investigator on the discharge questionnaire. 
This distinction will not be made when calculating improvements on the CRS (As 
observed), for which score 1 will be used in both cases.
Further Definitions for Other Secondary Endpoint
Formulae to be used for derived variables, including data conversions, are provided in the tables
below. 


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Measurement
Formula/Definition
Time to sustained
improvement of at least 1
category relative to 
baseline on the 6-point 
ordinal CRS (up to Day 
28) (days) [Time-to 
event]
Similar as for the primary endpoint, but with an improvement of 1 
category (instead of 2 categories).
The parameter name for the analysis will be “Time to sustained 
improvement with at least 1 category on the CRS”
Time to sustained
improvement of at least 2 
categories relative to 
baseline on the CRS (As 
observed) (up to Day 28) 
(days) [Time-to event]
Similar as for the primary endpoint, but with an improvement of at 
least 2 categories on the CRS (As observed).
The parameter name for the analysis will be “Time to sustained 
improvement with at least 2 categories on the CRS (As observed)”
Time 
from 
study 
intervention to end of 
oxygen 
supplementation 
(up to Day 28) (days) 
[Time-to event]
The event of end of oxygen supplementation is obtained when a 
participant reaches a CRS score of 2 or 1.1, provided the event is not 
followed by a documented deterioration* up to and including day 28 
or until trial discontinuation, whichever comes first. 
Participants who are discharged from hospital but reported as still in 
need of supplemental oxygen (score 1.2) will be censored on the day 
after hospital discharge, unless they die at or before day 28.
Participants who discharge on score 1.2 and die at of before day 28 
will be censored on day 28.
Participants who are still hospitalized and on oxygen at day 28 will 
be censored on day 28.
Participants who discontinue the trial before day 28 while still on 
oxygen will be censored on the day of discontinuation.
* In the context of this endpoint, a score of 3,4,5,6 would imply a 
deterioration with respect to the event. 
The parameter name for the analysis will be “Time to end of oxygen 
supplementation (up to Day 28) (days)”
Time from study 
intervention to hospital 
discharge (up to Day 28)
(days) [Time-to event]
Similar as for the primary endpoint, but with a score of 1.1 or 1.2 on 
the CRS (instead of an improvement of 2 categories).
The parameter name for the analysis will be “Time to discharge (or 
readiness to discharge) to home (up to day 28)”


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Time 
from 
study 
intervention to hospital 
discharge (up to Day 28)
(days) 
among 
the 
surviving 
participants
[Time-to event]
Similar as for the primary endpoint, but with a score of 1.1 or 1.2 on 
the CRS (instead of an improvement of 2 categories).
This endpoint will be evaluated in the subgroup of participants who 
were still alive at day 28.
Time to Mechanical 
Ventilation (up to Day 28) 
(days) among participants 
not on mechanical 
ventilation at Baseline
[Time-to event]
Similar as for the primary endpoint, but with a score of 5 on the CRS 
(instead of an improvement of 2 categories).
Participants who did not evolve to score 5 and who die will be 
censored at the day of death.
This endpoint will be evaluated in the subgroup of participants for 
which the CRS is less than 5 at Baseline.
Time from study 
intervention to ICU 
discharge (up to Day 28) 
among the participants on 
ICU at baseline (days) 
[Time-to event]
Subjects who die at or before day 28 will be censored on day 28.
Subjects alive on day 28: 
Only ICU periods with a starting day <= day 28 are taken into 
account.
Missing end dates of ICU periods are imputed with the cut-off date 
(for 
ongoing 
subjects) 
or 
the 
date 
of 
study 
discontinuation/completion
- If last ICU stay end date < minimum(date visit day 28, study 
discontinuation, study completion), 
  -> the subject has an event on the last day in the ICU + 1 day.
- If last ICU stay end date >= minimum (date visit day 28, study 
discontinuation, study completion), 
  -> the subject will be censored on minimum(day 28, day study 
discontinuation, day study completion).
Total length of 
hospitalization among the 
surviving participants (up 
to Day 28) (days) 
[Duration]
The total number of days a subject stayed in the hospital during the 
period from study drug intake until day 28, calculated as sum of the 
individual hospitalization periods, including re-hospitalizations.
This endpoint will be evaluated in the subgroup of participants who
were still alive at day 28
The total length of hospitalization will be missing for participants 
who discontinue the trial for other reason than death before day 28.
Number of ventilation 
free days in participants 
on IMV/ECMO at 
baseline (up to Day 28)
(days) [Duration]
Calculated as:
Date day 28 – maximum date of day with sore >=5
Participants who die will be considered as being on IMV/ECMO 
until day 28.


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Improvement at day 28 on 
the CRS with at least 1
category at day 28 (or at
discharge/discontinuation)
[Incidence]
CRS improved with at least 1 category at day 28 (or at 
discharge/discontinuation) when compared to baseline (Yes/No)
Improvement at day 28 on 
the CRS (As observed) 
with at least 2 categories 
at day 28 (or at 
discharge/discontinuation)
[Incidence]
The CRS (As observed) improved with at least 2 categories at day 
28 (or at discharge/discontinuation) when compared to baseline 
(Yes/No)
CRS worsening relative to 
Baseline (up to Day 28)
[Incidence]
CRS worsened with at least 1 category between day 5 and day 28
(Yes/No)
Ventilation free survival 
at Day of Discharge/Day 
28
[Incidence]
CRS score 1, 2, 3 or 4 at Day 28.
Participants with a missing score at Day 28 will not be considered
CRS at Day 7, 14, 21 and 
28
[Proportions]
See section 5.2.1.
5.4.2 Analysis Methods
The secondary endpoint evaluation will be conducted on the primary and on the ITT population.
Time-to event parameters
The time-to-event parameters will be evaluated based on the log-rank test, stratified for the 
stratification factors (age [<65 and ≥65 years] and use of IMV [yes/no]). The tests will be 
performed 1-sided at a 5% significance level. The actual values of the stratification factors will be 
used, not as randomized.
Cumulative proportion of patients with an event, by treatment, will be provided using the 
complement of the Kaplan Meier curve. The analyses will be completed with the median time to 
event (if reached) and the proportion of participants who with an event on day 7, 14, 21 and 28; 
all per Kaplan Meier method. The complementary log-log transform method is used to calculate 
the 90% confidence intervals.
Duration parameters
Descriptive statistics of the duration parameters will be shown for all participants that were still 
alive at day 28. 
Total length of hospitalization and number of ventilation free days will be analyzed in the subgroup 
of participants that were still alive at day 28 by using the Hodges-Lehman approach. 
Corresponding 90% CIs will be presented as well.


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Incidence parameters
For each parameter the number and percentage of participants in each category and subcategory 
will be tabulated and listed. All participants in the applicable analysis set will be counted for the 
denominator of the proportion.
The occurrence (yes/no) as described for the incidence parameters will be analyzed using logistic 
regression as described above (section 5.3). 
Proportions: CRS outcome and CRS (As observed) outcome 
A tabulation will be made of the CRS and CRS (As observed) outcomes at each day, taking only 
non-missing values into account (i.e.: the percentages of the six categories per day should sum up 
to 100%). 
A proportional odds model will be used as model to analyze the CRS and CRS (As observed) on 
days 7, 14, 21 and 28, modeling the common odds ratio of improvement on the ordinal scale of 
active treatment versus placebo using the 6-point CRS (scores 1.2 and 1.1 will be pooled into a 
single category 1) The model will include treatment, CRS at baseline (<=3 vs > 3) and the 
stratification factors. The proportional odds assumption in the treatment effect will be tested in a 
model that includes both separate slopes and common slopes for treatment. In case the validity of 
this model is questionable (eg. due to quasi-complete separation of data points), categories on the 
CRS will be merged (eg. category 2 with category 1). If the assumption of the proportional odds 
is acceptable, in a first step equal slopes (i.e. proportional odds) for the treatment effect only and 
unequal slopes for the other covariates, will be modeled. If this model cannot be estimated, a full 
proportional odds model will be applied, i.e. implying proportional odds for all covariates in the 
model. The common odds ratio from the final model will be considered as the estimate of the 
treatment effect. The actual values of the stratification factors will be used for all models, not as 
randomized. The proportional odds model will be defined in such a way that a common odds ratio 
smaller than 1 indicates larger improvement in the active treatment group. 
If the assumption of the proportional odds would not hold for the treatment effect, the Van Elteren 
test will be used in a sensitivity analysis and the resulting p-value would be used in the formal 
testing.
Graphical displays and tabulations will be provided showing the proportion of subjects per CRS
category and day. Also, shift tabulations will be provided of the CRS category over time versus 
the baseline CRS category


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6
VIROLOGY ASSESSMENTS
6.1
General
Analysis of viral load is considered an exploratory analysis.
The virology assessments (copies/mL) will be analysed using ITT and Primary analysis sets. 
SARS-CoV-2 viral load will be measured during the study by a qRT-PCR assay on 
Nasopharyngeal (NP) swabs, endotracheal aspirate (if participant is intubated) and on plasma 
samples. 
6.2
Definitions
Baseline Value: For each of the assays, the baseline value of viral load is defined as the last 
measurement before the intake of the study drug.  If no measurements are available prior to the 
dose of the study drug, then the first measurement obtained up to and including 60 minutes after 
the study dose will be considered as the baseline.
6.3
Data Handling Rules
In case there are multiple post-dose viral load measurements on a day for the same assay, then the 
highest value on that day will be used for the analysis.
All analyses on viral loads from central lab (Covance) will be performed after transforming the 
non-missing viral load measurements to log10 scale.  In the database, the missing values are shown 
as ‘Inconclusive’, ‘Indeterminate’ or ‘Not done’ and will be excluded from the analysis.
The lower limit of quantification (LLOQ) values for assay on nasopharyngeal (NP) swabs and 
endotracheal aspirate are 1018 copies/mL, and for plasma samples it is 1660 copies/mL. The 
measurements below LLOQ may or may not be detectable. If the viral load measurements are 
below the LLOQ then these are imputed as 1 copy/mL if viral load is undetectable, or as LLOQ/2 
if it is detectable. 
6.4
Analysis Methods
Two summary tables showing N, mean, SE, median, inter-quartile range, minimum and 
maximum values over time of (1) viral loads (log10 scale) and (2) change from baseline (change 
in log10 values) will be generated. Over time tables will use all measurements (planned and 
unscheduled) for the NP assay at Baseline, Day 3, 7, 10, 14, 21, 28. 
To compare the two treatment arms for the viral loads (only for assay of NP) over time 3 plots of 
viral loads (log10 scale) will be generated: (1) Mean values, (+/- SE), (2) Median/IQ values, and 
(3) Mean Change from baseline (+/- SE). Over time plots will use all (planned and unscheduled) 
measurements at Baseline, Day 3, 7, 10, 14, 21, 28.  
For each participant, a plot showing viral loads (log10 scale) for Nasopharyngeal swabs, 
endotracheal aspirate and on plasma samples over time (all scheduled and unscheduled 
measurements) will be generated. To understand the viral load profiles properly, the LLOQs will 
be shown by horizontal reference lines. Study days of first onset of COVID-19 symptoms, of 


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discharge from hospital and of death will be shown by vertical reference lines on each plot. The 
CRS score at baseline will also be shown on the plot.
6.5
Analysis of Undetectability of Viral Load
For the analysis of undetectability of viral load all subjects with at least a post-baseline 
measurement of viral load by Nasopharynx assay will be considered.  
For the primary analysis, all measurements of viral load up to Day 31 of the study (i.e. protocol 
window: Day 28+3 days) by the NP assay from central lab (central lab) will be used. Plots for 
individual participants will be generated using data up to Week 16.
Time (Days) to undetectability of virus load will be evaluated using the First confirmed 
undetectability (CU) approach as described below.
First confirmed undetectability (CU)
A participant is said to have (CU) of viral load if (1) participant has two consecutive undetectable 
viral loads, or (2) if the last viral load in the database is undetectable.  
If there is at least one incidence of the CU then the date of the first undetectability among all CUs
will be used to find the days from the study dose date to first CU of viral load.  If there is no CU 
until study Day 31 then participant will be censored at date of last viral load assessment until study 
Day 31.
Following rules will be applied to derive the flags for event (of first CU) or censoring, and to 
derive the Days to event or censoring.  
[For clarity, in the examples below of different cases a detectable viral load is denoted by ‘D’, 
and undetectable by ‘U’, and ‘x’ will represent any type of load (undetectable or detectable)].
(1) Case when a participant has only 1 viral load measurement in database (therefore it is 
also the last viral load measurement): 
a.
If the viral load is undetectable then censor flag = No (same as Event = Yes) 
[example: U => censor flag = No],
Days to event = date of last viral load measurement – dose date + 1.
b. Otherwise if the viral load is detectable then censor flag = Yes (same as Event 
= No),
[example: D => censor flag = Yes].
Days to censoring = date of last viral load assessment – dose date + 1.
(2) Case when a participant has more than 1 viral load measurements in the database: 
a.
if there are no cases of ‘CU cases based on 2 consecutive viral loads’ then 
i.if last viral load in the database is undetectable then


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censor flag = No (same as Event = Yes),
[example: U1DDU2DU3DU4  => censor flag = No], 
ii.if last viral load in the database is detectable then 
censor flag = Yes (same as Event = No),
[example: U1DDU2DU3D => censor flag = Yes], 
In both these cases a(i) and a(ii), the ‘Days to event/censoring’ will be based on 
the date of last viral load measurement until study Day 31 in the database. 
b. If there are one or more CU cases based on 2 consecutive viral loads then 
censor flag = No (same as Event = Yes), 
and ‘Days to event/censoring’ will be derived using date of first viral load 
among the viral loads resulting in CU cases.
[examples: DU1DU2U3D or U1DU2U3U4DU5U6 => censor flag = No, 
and in both cases ‘Days to event/censoring’ = Days to U2).]
Summary and Kaplan-Meier Analysis of Time to Undetectability of Viral Load:
The analysis of time-to first CU of viral load is planned by the Kaplan-Meier (KM) analysis. Days 
to first CU of viral load will also be summarized using the quartiles (and their confidence 
intervals). The analysis will be performed for ITT and Primary analysis sets. (Note: As per the 
inclusion criteria of the protocol all participants in the study are detectable for viral load at baseline.  
Therefore, all participants in the ITT and Primary analysis sets will be included for these analyses, 
respectively).
For the primary analysis, non-missing planned and unscheduled measurements will be used to 
generate the summary tables showing n and percentage (cumulative) of participants with CU by 
Day 3, 7, 10, 14, 21, 28/31. For the final analysis, table will also include Week 16.
6.6
Analysis of Virus Variants
SARS-CoV-2 viral genome sequence analysis will be performed using Next Generation 
Sequencing (NGS) using the ARTIC primers/protocol on Illumina platform to evaluate the 
presence polymorphisms and genetic variations on the amino acid level.
Sequence results will be presented only for the spike protein. The assignment of approximate 
lineages is based on the predefined set of S amino acid substitutions agreed with the known 
circulating lineages based on the GISAID database (https://www.gisaid.org/) and the CDC 
guidelines (https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-
surveillance/variant-info.html). 
The SARS-Cov-2 Variant of Concern (VOC) and the SARS-Cov-2 variants of Interest (VOI), 
listed on the timing of database lock, will be included in the analysis. 


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6.6.1 Time Points and Samples
Samples for viral sequencing are taken throughout the protocol Time&Event schedule, but 
sequencing is triggered at the discretion of the virologist considering the SARS-CoV-2 viral load 
levels and the limitations of the sequencing assays. By preference, the screening/baseline sample 
is selected. If the viral load of this sample is below the limit of detection of the sequencing assay, 
another sample as close as possible to the baseline timepoint, is selected. 
For the statistical analysis, results from all available samples will be considered and data will not 
be reported by timepoint.
6.6.2 Definitions
Polymorphisms, ie genetic variations, are defined as amino acid changes from the SARS-CoV-2 
Wuhan-Hu1 Reference Sequence.
Wild type: If at certain position the amino acid in the participant sequence matches the reference 
sequence, that is no genetic variation is present at that position, the virus is considered to be wild 
type at that position.
6.6.3 Parameters to Analyze
The following parameters will be analyzed:
Number (%) of participants with a specific virus variant specific substitution profile.
SARS-Cov-2 Virus Variants: 
To classify SARS-CoV-2 S sequences into their most probable lineages the following predefined 
substitution profiles were used:


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Variant Name
Spike Protein Substitutions
First Detected
B.1.526
T95I, D253G, D614G
United States (New 
York) 
B.1.526.1
D80G, Δ144, F157S, L452R, D614G, D950H
United States (New 
York) 
B.1.525
A67V, Δ69/70, Δ144, E484K, D614G, Q677H, F888L
United 
Kingdom/Nigeria 
P.2
E484K, D614G, V1176F
Brazil 
B.1.1.7
Δ69/70, Δ144, N501Y, A570D, D614G, P681H, T716I, 
S982A, D1118H 
United Kingdom
P.1
L18F, T20N, P26S, D138Y, R190S, K417T, E484K, 
N501Y, D614G, H655Y, T1027I
Japan/Brazil
B.1.351
D80A, D215G, Δ241/242/243, K417N, E484K, N501Y, 
D614G, A701V
South Africa
B.1.427
L452R, D614G
United States 
(California)
B.1.429
S13I, W152C, L452R, D614G
United States 
(California)
B.1.617
L452R, E484Q, D614G
India
B.1.617.1
G142D, E154K, L452R, E484Q, D614G, P681R, 
Q1071H
India
B.1.617.2
T19R, Δ156, Δ157, R158G, L452R, T478K, D614G, 
P681R, D950N
India
B.1.617.3
T19R, G142D, L452R, E484Q, D614G, P681R, D950N India
6.6.4 Analysis Methods
Frequencies and percentages will be presented for the variants detected. The denominator is the 
number of participants with sequencing data. Summaries will be provided by subgroup and 
intervention arm. Subgroups will be: 
•
Baseline CRS score (<=3, <=4, 4, 5)
•
Center (US10006 and US10033, other)
Tabulation to investigate how the virus variants are spread during the entire study duration will 
also be provided.


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7
BIOMARKERS
7.1
General
The biomarkers will be analysed using AST and Primary analysis sets. 
The biomarkers are measured at scheduled visits during the study as mentioned in the protocol.  
A table in section 7.2 below provides the list of biomarkers included for the analysis.
7.2
Data Handling Rules
Missing values will not be imputed and not used for the analysis.  The measurements below the 
LLOQ will be imputed as LLOQ/2, and measurements above ULOQ by ULOQ. 
In case measurements are not observed exactly on the scheduled days as per protocol, the 
measurements from adjacent days as shown below (as Measurement Day) may be used for the 
analysis. The measurement closest to the analysis day will be used.  In case there are two 
measurements equidistant from the analysis day then the later of the two measurements will used 
for the analysis of different biomarkers, the table below provides the analysis day (target day) and 
the corresponding study days of measurements to be included in the windows.
Biomarker (Central lab)
Study Days of 
Measurements
Analysis Day
(Target Day)
CRP
D-Dimer 
Pro-calcitonin  
Serum Ferritin
2, 3
3
4, 5, 6
5
7, 8, 9
7
12 to 16
14
19 to 23
21
26 to 30
28
Cytokines 
•
Interferon Gamma
•
Interleukin 1 Beta
•
Interleukin 2
•
Interleukin 4
•
Interleukin 8 
•
Interleukin 10
•
Interleukin 12p70 (or Interleukin 12)
•
Interleukin 13
•
Tumor Necrosis Factor (or TNF-Alpha)
Chemokines 
•
Eotaxin-3 (or CCL26)
•
IP-10 (or IFNGIP10 or CXCL10)
4 to 6
5
12 to 16
14
19 to 23
21
26 to 30
28


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Biomarker (Central lab)
Study Days of 
Measurements
Analysis Day
(Target Day)
•
Macrophage Inflammatory Protein 1 Alpha (or CCL3)
•
Macrophage Inflammatory Protein 1 Beta (or CCL4)
•
Monocyte Chemotactic Protein 1 (or CCL2)
•
Monocyte Chemotactic Protein 4 (or CCL13)
•
Macrophage-Derived Chemokine (or CCL22)
•
TARC (or CCL17)
Free IL-6
Total IL-6 
12 to 16
14
19 to 23
21
26 to 30
28
SARS-CoV-2 Ab
(IgA, IgG, IgM)
5 to 9
7*
12 to 16
14
19 to 23
21*
26 to 30
28
* No samples are scheduled on these days, but window may include unscheduled visits or final visit.  
7.3
Analysis Methods
7.3.1 Analysis of Biomarkers 
Over time tables and plots will show the results at target days.
The baseline values of biomarkers will be summarized (see Section 4.1 for more details).
Biomarkers will be summarized over time showing n, Geometric Mean, SE of Geometric Mean, 
Median, IQR, Minimum, and Maximum. For post-baseline visits, tables will include descriptive 
statistics (n, Mean, SE, Median, Tertiles, IQR, Minimum, and Maximum) for ratio (visit value/ 
baseline value). Box plots of values over time will be provided displaying the actual values (using 
log2 scale on Y-axis) and presenting the geometric mean values. Box plots for ratio of visit 
value/baseline value (log2(visit value / baseline value)) over time will also be generated.
7.3.2 Analysis of SARS-CoV-2 Antibodies (Ab)
For each SARS-CoV-2 antibodies (IgA, IgG, IgM) a stacked bar chart with percentage of subjects 
with positive, negative or borderline results over time will be presented. Time points will be those 
as defined in section 7.2. 
8
PHARMACOKINETICS (PK) AND IMMUNOGENICITY (IMG)
8.1
General
As mentioned earlier in section 2.2 of the SAP, the Pharmacokinetics (PK) analysis set includes 
all participants in the AST analysis set with no interruption of study medication and who also had 


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at least 1 valid blood sample drawn for PK analysis after dose of Sirukumab.  The PK analysis will 
be performed using the PK analysis set and will exclude any participant who received the Placebo.
The PK concentration of Sirukumab is evaluated pre- and post-dose on Day 1 and at Day 14, 21 
and 28.
Serum samples to evaluate the antibodies to Sirukumab are collected on Day 1 pre-dose and on 
Day 28.  As mentioned in section 2.2 the Immunogenicity (IMG) analysis set consists of 
participants in AST analysis set who received a dose (full or partial) of Sirukumab during the study 
and have at least one valid blood sample for immunogenicity analysis after Sirukumab dose, and 
will exclude any participant who received the placebo. This analysis set will be used to analyze 
immunogenicity using the actual treatment received by a participant (IMG analysis set as Treated).
8.2
Data Handling Rules
For the analysis of serum Sirukumab concentration, the concentration values below the LLOQ (= 
0.1 ug/mL) will be imputed as 0 ug/mL, and all non-missing measurements (planned and 
unscheduled) will be used.
8.3
Analysis Methods
8.3.1 Analysis Methods for Pharmacokinetics 
For participants in PK analysis set, descriptive statistics (n, mean, SD, coefficient of variation, 
median, range and IQR) of serum Sirukumab concentration (µg/mL) will be tabulated over time.   
The PK concentrations at scheduled visits (pre- and post-dose on Day 1, Day 14, 21 and 28) will 
be summarized in a table. 
Descriptive statistics will also be tabulated by following baseline subgroups:
(1) By median baseline body weight (kg): <= median, and > median at baseline,
(2) By CRS score at baseline (<=3, 4, 5),
(3) By baseline Free IL-6 (ng/L) tertiles: <= 33%, > 33% and <= 66%, and > 66% percentiles
at baseline, and
(4) By baseline CRP (mg/L) tertiles: <= 33%, > 33% and <= 66%, and > 66% percentiles at 
baseline.
(Note: participants with missing baseline values of subgroup variable will not be used for the 
subgroup analysis.)
Following plots (Y-axis using scale of Log10, and if mean of values at any visit becomes less than 
0 then it will be shown as <0.01 on Y-axis) for serum Sirukumab concentration over time at 
scheduled visits (post- baseline on Day 1, Day 14, 21 and 28) will be generated:
(1) Mean and SD over time,
(2) Median and IQR over time,
(3) Median and IQR over time by CRS score at baseline (<= 3, 4, 5),
(4) Median and IQR over time by baseline Free IL-6 (ng/L) tertiles: <= 33%, > 33% and <= 
66%, and > 66% percentiles at baseline), and


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(5) Median and IQR over time by baseline CRP (mg/L) tertiles: <= 33%, > 33% and <= 66%, 
and > 66% percentiles at baseline).
It is possible that a few participants experienced some interruptions during the infusion of the study 
drug. If greater than 10 subjects had dose interruption, a sensitivity analysis is planned for the 
participants in the PK analysis set who did not have any such interruptions. Sensitivity analysis 
will include the descriptive statistics (n, mean, SD, coefficient of variation, median, range and 
IQR) of serum Sirukumab concentration (μg/mL) over time.
If data permit, the relationships between serum Sirukumab concentrations and biomarkers or 
efficacy may be analyzed graphically. If any visual trend is observed, a suitable population PK/PD 
model may be developed to describe the exposure-response relationship. The results of the 
population PK/PD analysis will be presented in a separate technical report.
8.3.2 Analysis Methods for Immunogenicity 
Analysis of immunogenicity information will be performed using participants in IMG analysis set.
A participant is said to be positive for antibodies to Sirukumab if participant was positive for 
antibodies to Sirukumab at any time after Sirukumab administration until Day 28 of the study. A 
participant is classified as negative for antibodies to Sirukumab only if he/she was not positive at 
any time through Day 28 (that means participant must be negative for antibodies all through Day 
28).
For participants who had 1 or more evaluable samples obtained after Sirukumab administration 
through study Day 28, a table showing number and percent of participants with positive results 
and negative results for antibodies to Sirukumab will be generated.  Number of participants with 
peak titers will be shown in the table.
For Day 1 (pre- and post-dose), Day 14, 21 and 28 of the study, a table with summary statistics of 
serum Sirukumab concentrations (n, mean, SD, coefficient of variation, median, min and max) 
will be provided by participants with negative and positive for antibodies to Sirukumab.
A plot showing median and IQ range of serum Sirukumab concentrations over time by antibody 
status will be generated.  Plots showing median and IQ range of serum Sirukumab concentrations 
over time by antibody status will be generated by the following subgroups:
(1) Median and IQR over time by baseline Free IL-6 (ng/L) tertiles: <= 33%, > 33% and <= 
66%, and > 66% percentiles at baseline), and
(2) Median and IQR over time by baseline CRP (mg/L) tertiles: <= 33%, > 33% and <= 66%, 
and > 66% percentiles at baseline).
A listing of participants positive for antibodies to Sirukumab any time through Day 28 will be 
generated.


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9
SAFETY
All safety analyses will be performed on the AST and Primary analysis sets. 
The safety assessments to be evaluated include AEs, clinical laboratory tests, vital signs, and 
electrocardiogram (ECG).
Deaths during the study are evaluated as an efficacy endpoint.
9.1
Adverse Events (AE)
9.1.1 General
All adverse events and special reporting situations, whether serious or non-serious, are recorded 
on eCRF from the time a signed and dated ICF is obtained until completion of the participant’s 
last study related procedure, which may include phone call contact for the follow-up of safety.
9.1.2 Definitions
Coding of an AE
The verbatim terms used in the eCRF by investigators to identify AEs will be coded (for system 
organ class (SOC-Med) and preferred term (PT)) using the Medical Dictionary for Regulatory 
Activities (MedDRA).
Phase allocation of an AE
AEs will be allocated to different study phases based on their start date/time. (Note: In addition 
to the date information, time information is also taken into account to allocate AEs to phases.)
In general, the following rule is used to allocate a phase to an AE:
Rule: phase start date/time ≤ AE start date/time ≤ phase end date/time
If the start date/time of an AE is before the start of the treatment phase, then it is allocated to the 
screening phase. If AE onset is on or after the treatment phase start date/time and prior to follow-
up phase start date/time, then AE is allocated to treatment phase. If AE onset date/time is on or 
after the start of follow-up phase, then AE is allocated to follow-up phase. In case of incomplete 
AE dates and or times (i.e. time and/or day and/or month and/or year missing) the following 
conventions are used:

In case of partial AE start dates and or times, the events are allocated to the phases using the 
available partial information on start and end datetime; no imputation will be done. If, for 
instance, for the AE start date only month and year are available, these data are compared to 
the month and year information of the phases. This rule may result in an AE to be allocated to
more than one phase. In case of a completely missing AE start date, the event is allocated to 
the treatment phase, except if the end date of the AE falls before the start of the treatment 
phase.

In case of a completely missing AE end date, the following rules apply: 
-
in case the date is identified as unknown then date will remain as missing,


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-
in case the date is not flagged as unknown the date is assumed to be the cut-off date of 
the analysis for participants still ongoing in the study, and the end date of the last phase 
for participants who discontinued or completed the study. 
Examples:
Screening phase: start date: 02JAN2017, end date: 28JAN2017
Treatment phase: start date: 29JAN2017, end date: 12AUG2017
1) Adverse event: start date: JAN2017, end date: 15JUL2017
As the AE start date only has information about month and year, only this information will 
be used from the phases and therefore the AE will be assigned to the screening phase as well 
as to the treatment phase.
2) Adverse event: start date: JAN2017, end date 27JAN2017 As the AE ends before or at the start 
of the treatment phase, it is only assigned to the Screening phase.
Attributes of an adverse event
For the analysis, the following attributes are assigned to an adverse event:

Study Phase of an AE (Screening, Treatment and Follow-up phase),

Verbatim Term, SOC-Med and PT,

Serious AE (Yes/No), if yes AEs will be listed as well,

AE grade (Grades 1, 2, 3, and 4),

Relation to study treatment (related, not related),

Outcome of AE (Fatal, Recovered/Resolved, not recovered/not resolved, 
recovering/resolving, unknown),

AE leading to death (Yes/No),

AE of special interest (Serious Infections, Hypersensitivity, Hematologic Events, Liver 
Enzymes).
9.1.3 Analysis Methods
There will be no formal statistical testing for the AEs.
A summary table will be generated for the following attributes of AEs for 2 study phases
(treatment phase, follow-up phase): 

any AE, 

serious AEs, 

AEs leading to death,  

AEs with grade >= 3,

AEs with grade >= 3 and related to study drug,

AEs related to study drug, 

AEs of special interest,

AEs of special interest and related to study drug.


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AE incidence tables will be generated showing the SOC-Med and PT separately in two phases 
(treatment and follow-up), in descending order of frequency in Sirukumab treatment arm. For each 
AE, the percentage of participants who experience at least 1 occurrence of the given event will be 
summarized. The tables will be provided for the following attributes:

AEs by SOC-Med and PT,

Serious AEs by SOC-Med and PT,

AEs of special interest,

AEs related to study drug,

AEs with Grade >= 3,

AEs leading to death.
Separate listings of participants with serious AE, AEs leading to death and AE >=3 grade and AE 
related to study drug will be generated.
A table showing number of participants with SOC-Med of Infection and Infestation vs 
Lymphocytopenia Grade 3-4 during treatment phase will be generated.
Subgroup Analysis:
Tables for the following AE attributes will be generated by 2 subgroups: (Age: < 65, >= 65 years, 
CRS score at baseline: <=3, <=4, 4, 5).

Serious AEs,

AEs of special interest, AEs related to study drug,

AEs with Grade >= 3,

AEs leading to death.
9.2
Clinical Laboratory Tests
9.2.1 General
The laboratory parameters are measured pre- and post-dose multiple times during the study. Some 
of these parameters are considered biomarkers for this study and their analyses are described in 
Section 7 “Biomarkers” of this document. This section describes the analyses of laboratory 
parameters whose test samples are collected at local labs and are not described under biomarkers.
9.2.2 Data Handling Rules
For lab tests from local labs the local lab reference ranges will be used to determine the lab 
abnormalities. 
Imputations of numerical values expressed as characters
In case a laboratory test result is censored (no numeric value is available, but only a verbatim 
term), the following rules are applied:

‘<x’ or ‘>x’: a numeric value will be imputed by the cut-off value decreased or increased with 
one unit respectively


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
‘≤x’ or ‘≥x’: imputation by x.
Toxicity grades and abnormalities for laboratory parameters
The laboratory toxicity will be determined according to the criteria specified in the adult toxicity 
grading table by ‘Division of Microbiology and Infectious Diseases’ (DMID). In case no toxicity 
grades are defined for a test, the abnormalities (above/below normal range) will be used. 
In determining toxicity grades/abnormalities for each subject the following rules are applied:

Baseline toxicity grade/abnormality will be based on the baseline value (see section 4.1 for 
the baseline definition).

Worst grades/abnormalities during treatment phase are determined over the treatment phase, 
including all scheduled and unscheduled measurements of that phase.

The abnormalities “abnormally low” and “abnormally high” are considered equally important, 
i.e. if a subject has an abnormally low as well as an abnormally high value post-baseline, both 
abnormalities will be shown in the tables. (This implies that the sum of the percentages can 
be more than 100%).

If, for a specific test, the grading list provides distinct limits for abnormally low (=hypo) 
values as well as for abnormally high (=hyper) values, this test should be repeated for hyper 
and hypo limits separately in cross-tabulations.
Treatment-emergent definition for toxicity grades and abnormalities
A toxicity grade/abnormality will be considered treatment-emergent if it is worse than the baseline 
grade/abnormality. If the baseline grade/abnormality is missing, the abnormality is always 
considered as treatment-emergent. A shift from “abnormally low” at baseline to “abnormally high” 
post-baseline (or vice versa) is also treatment-emergent. 
9.2.3 Analysis Methods
Tables showing n and percent of participants with treatment-emergent worst toxicity grades (for 
tests with defined toxicity grades) and treatment-emergent worst abnormalities (for tests without 
a defined toxicity grades) during treatment phase will be generated.  
A shift table showing the number and percent of participants with different toxicities at baseline 
vs treatment phase will be presented for lab tests with defined toxicity grades.
Shift tables showing n and percent of participants with various levels of abnormalities for 
Troponin-I and -T during treatment phase versus baseline will be generated.
Two eDISH plots showing peak total bilirubin vs peak ALT (and separately for peak AST) 
measurements during the treatment phase will be generated. Peak values (using log10 scale) on the 
plot will show the maximum values that occur post-baseline during treatment phase (not 
necessarily concurrent events). Points on the plot will be distinguished for the two treatment 
groups.  Two reference lines at 2xULN for total bilirubin and at 3xULN for ALT/AST will be 
shown on the plots. These reference lines will divide the plot into 4 sections showing (1) 
Hyperbilirubinemia, (2) Hy’s Law range, (3) Normal range, and (4) Temple’s Corollary range.


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A listing of participants with treatment-emergent toxicities/abnormalities will be provided. This 
listing will include all other timepoints for the corresponding participant/lab test.
A listing of participants with Grade 3 or higher toxicity laboratory values will be provided.
9.3
Vital signs
9.3.1 General
Temperature, pulse rate, respiratory rate, oxygen saturation and blood pressure may be measured
once or multiple times during screening/baseline and every day during the treatment phase.
9.3.2 Data Handling Rules
Because of the participants’ disease severity, the vital signs may be measured in any position 
(supine, standing, semi-recumbent, or sitting).  For the analysis all measurements irrespective of 
the position during the assessment will be considered.
All non-missing measurements will be considered for finding the worst abnormalities on a given 
study day or during the treatment phase.
Vital Signs abnormalities will be determined according to the WHO grading scale boundaries as 
mentioned in Attachment 1.
For each participant, baseline abnormality will be based on the baseline value (see section 4.1 for 
the baseline definition).  The worst abnormality is determined for the treatment phase. All 
measurements including all post-baseline scheduled and unscheduled measurements during 
treatment phase will be used to evaluate worst abnormality during the treatment phase.  
An abnormality (based on normal ranges) will be considered treatment-emergent if it is worse than 
the baseline abnormality. If the baseline abnormality is missing, the abnormality is always 
considered as treatment-emergent. A shift from “abnormally low” at baseline to “abnormally high” 
post-baseline (or vice versa) is also considered treatment-emergent.
9.3.3 Analysis Methods 
A table showing number and percentage of participants with treatment-emergent worst 
abnormality during the treatment phase will be generated.
Vital signs data for participants having at least one treatment-emergent abnormality during 
treatment phase will be listed.
9.4
Electrocardiogram (ECG)
9.4.1 General
ECG measurements (in supine position) for PR interval, QRS interval, Heart Rate (HR) and QTc 
intervals (using Bazett’s correction formula and Fridericia's correction formula) during screening 
and treatment phases are recorded on the eCRF. 


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9.4.2 Definitions
Treatment-emergent Abnormalities
ECG abnormalities will be determined according to the boundaries defined in Attachment 2.
For each participant, baseline abnormality (i.e., assessments that are out of normal ranges) will be 
based on the baseline value (see section 4.1 for the baseline definition).  An abnormality during 
treatment phase will be considered treatment-emergent if it is worse than the baseline abnormality. 
If the baseline abnormality is missing, the abnormality is always considered as treatment-
emergent. A shift from “abnormally low” at baseline to “abnormally high” post-baseline (or vice 
versa) is also considered treatment-emergent. 
9.4.3 Data Handling Conventions
Investigator reported ECG related values (irrespective of the participant’s position at ECG 
evaluation) on the eCRF will be used for analysis without any recalculation. If on a day the ECG 
is performed multiple times, then for descriptive statistics the mean of the non-missing post-dose 
ECG evaluations will be used as the value for each specific parameter and study day.
All measurements at scheduled and unscheduled visits during the treatment phase will be 
considered in determining worst case values during the treatment phase.
9.4.4 Analysis Methods
Number and percent of participants in different categories of worst (and if treatment emergent)
ECG abnormalities during treatment phase will be tabulated.  The ECG abnormalities based on 
the change from baseline QTc values will be tabulated.  Tables to show the shift from baseline to 
maximum corrected QT interval (actual values and change from baseline values) during treatment 
phase will be provided.  A table showing shift in frequencies of ECG Interpretations reporting ‘ST 
or T Waves, Ischemia or Infarction’ from baseline values (Yes, No, or missing) to post-base values
(Yes, No, or missing) will be generated.
Listings of ECG values and Troponin I/T; of participants with Abnormal ST or T Wave, Ischemia, 
or Infarction; and with ECG abnormalities will be generated.


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ATTACHMENTS
ATTACHMENT 1.
WHO GRADING SCALE VITAL SIGNS
The following abnormalities are defined for vital signs:
Vital Signs parameter
Abnormality Code 
Pulse
DBP*
SBP*
Abnormally low
< 45 bpm
≤ 50 mmHg
≤ 90 mmHg
Grade 1 or mild
-
> 90 mmHg - < 100 mmHg
> 140 mmHg - < 160 mmHg
Grade 2 or moderate 
-
≥100 mmHg - < 110 mmHg
≥160 mmHg - < 180 mmHg
Grade 3 or severe
-
≥ 110 mmHg
≥ 180 mmHg
Abnormally high 
≥ 120 bpm
-
-
* The classification of AEs related to hypotension and hypertension will be done according to the WHO grading 
scale
Abnormality Code
Vital Signs parameter
Temperature
(°C/°F)
Respiratory rate
(breaths per minute)
Grade 1 or mild
> 38.0 -<= 38.6 °C or
> 100.4 - <= 101.5 °F
17-20
Grade 2 or moderate
> 38.6 - <= 39.3 °C or
> 101.5 - <= 102.7 °F
21-25
Grade 3 or severe
> 39.3 - <= 40.0 °C or
> 102.7 - <= 104.0 °F
>25
Grade 4 or potentially life-
threatening
>40.0°C or
> 104.0°F


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ATTACHMENT 2.
ECG ABNORMALITIES 
The following abnormalities are defined for ECG:
Abnormality Code
ECG parameter
HR
PR
QRS
QTcorrected
Abnormalities on actual values
Abnormally low
< 45 bpm
< 110 ms
-
-
Abnormally high
120 bpm
> 220 ms
120 ms
-
Borderline prolonged QT (males)
-
-
-
450 ms < QTc 480 ms
Borderline prolonged QT (females)
-
-
-
470 ms < QTc 480 ms
Prolonged QT
-
-
-
480 ms < QTc < 500 ms
Pathologically prolonged QT
-
-
-
QTc > 500 ms
Abnormalities on changes from baseline (∆QTc)
Normal QTc change
-
-
-
∆QTc < 30 ms
Borderline QTc change
-
-
-
30 ms < ∆QTc < 60 ms
Abnormally high QTc change
-
-
-
∆QTc > 60 ms


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ATTACHMENT 3.
CRS DERIVATION
The CRS categories should be evaluated from 6 to 1. First check if the subject falls in category 6 
(has the subject died?) if not then we evaluate category 5, if not 5 then evaluate category 4 and so 
on.
The CRS is evaluated at baseline and per day, relative to the start of the study drug intake. 
The baseline CRS is based on the data obtained at the time of randomization. 
Notes:
o
The CRS scores will be calculated up to day 28 for subjects who are still in the trial at 
day 28. Participants who die before they discontinued the trial before day 28 will be 
considered to continue the trial up to and including day 28.
o
If the subject has different types of oxygen supplementation on a single day, the worst 
type will be considered to derive the score.
o
In case the subject withdrew from the study for other reason than death, the CRS will not 
be calculated from the next day onwards. A record indicating this type of missing scores 
should be foreseen in the ADAM data sets. 
o
Intermittent missing values can occur (eg. Due to incomplete supplementary oxygen 
information). For intermittent missing values, a record should be foreseen in the adam 
dataset. It should be possible to make the distinction between this type of missing values 
and the missing values due to trial discontinuation.
Hospitalized and Not Hospitalized
Rules will be applied in the order as described below. The first rule fulfilled by a subject will be 
considered.
1. If a subject is discharged to the alternate care settings “2. Different hospital”, “3. Acute 
Care Facility”, “4. Subacute care facility” or “7. Hospice/Palliative Discharge”, the 
subject  will be considered hospitalized until day 28 or until trial discontinuation. The 
subject will be categorized in the category the subject was in at the moment of discharge. 
2. If a subject is discharged ‘against medical advice’, the subject  will be considered 
hospitalized on the day of discharge and on the day after discharge (unless the subject 
discontinued the trial). The subject will be categorized in the category the subject was in 
at the moment of discharge. The CRS will be considered missing on subsequent days. 
3. If a subject is hospitalized, but is ‘ready for discharge’ according to the investigator, the 
subject will be considered hospitalized up to and including the first day on which the 
subject was considered ready for discharge. The subject will be considered “Not 
hospitalized” from the day after until day 28/trial discharge (unless the status changes 
back to “not ready for discharge”).
4. If a subject is discharged, but is ‘not ready for discharge’ according to the investigator, 
the subject will considered hospitalized up and including 1 day after the day of discharge 
or until trial discontinuation. The subject will be categorized in the category the subject 
was in at the moment of discharge. The subject will be considered non hospitalized from 
2 days after the day of discharge onwards until day 28/trial discontinuation.
5. If a subject is discharged from the hospital, the day of discharge will be considered as 
“hospitalized”. The subject will be categorized in the category the subject was in at the 
moment of discharge. After this day, the subject will be considered “Not hospitalized” 
until day 28/trial discontinuation.


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CRS Derivation
The Ordinal Clinical Recovery Scale can be derived from Baseline up to and including Day 28, 
or until trial discontinuation. Participant who died before day 28 (before or after hospital 
discharge, but before trial discontinuation) will be considered to continue the trial up to and 
including day 28. 
For the derivation, we will start with the highest score. 
If the subject didn’t fall into this category, we will check for the next highest score.
•
Score 6: Based on the status of the participant on the day of the assessment (based on the 
date of death).
Based on Type of Oxygen Supplementation page:
•
Score 5: At least one of the following scores is ticked: 
o
IMV
o
Extra Corporeal Membrane Oxygenation
o
The question “Is the subject on Mechanical Ventilation” is answered “No”, and 
the question “From a Medical Perspective, should the patient be on IMV?” is 
answered “Yes”. (on Subject Status Form)*
* To comply with the note: “If a participant declines medically-indicated mechanical ventilation, 
the participant will be categorized according to the care they would otherwise have received on 
that day”
•
Score 4: 
o
Subject is on supplemental oxygen and the FiO2 is >=50%.
•
Score 3: 
o
Hospitalized & requiring low flow supplemental oxygen, defined as
o
Receiving supplemental oxygen (through a face mask, nasal cannula, high 
flow nasal canula or other where FiO2 is < 50%) & the patient was not 
able to sustain a blood oxygen saturation of >93% when breathing room 
air:
If assessed for blood oxygen saturation when breathing room air, 
SpO2 value should be <=93%
If not assessed for blood oxygen saturation when breathing room 
air (for any reason), SpO2 value is assumed to be <=93
OR
o
Not on supplemental oxygen and the minimum of all measured SpO2 
values during the day <= 93% (as this will be measured at least 4 
times/day)
•
Score 2:
o
Hospitalized according to hospitalization rules as discussed earlier. 
•
Score 1:
o
Not hospitalized, including subjects on low level of oxygen. 
A distinction will be made between subjects discharged and in need of (score 1.2) or not in need 
of (score 1.1) oxygen supplementation as indicated by the investigator on the discharge 
questionnaire. This distinction will not be made when calculating improvements on the CRS, for 
which score 1 will be used in both cases.


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Some examples
Case 1: Discharged from hospital on Day 6 (Rule 5)
Case 1
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 28
Against 
medical 
advice?
--/NO
Status (SS*)
hospitalized
hospitalized
hospitalized
Discharged
Discharged 
to**
1/5/..
ready (SS*)
--/Not ready
--/Not ready
--/Not ready
--/Ready
CRS
>1
>1
>1
>1
1
1
Case 2: Alternate care setting (rule 1): hospitalized until Day 28
Case 2
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 28
Against 
medical 
advice?
--/NO/YES
Status(SS*)
Hospitalized
hospitalized
hospitalized
Discharged
Discharged 
to**
2/3/..
ready (SS*)
--/Not ready
--/Not ready
--/Not ready
--/Ready/
Not ready
CRS
>1
>1
>1
>1
>1
>1
Case 3: Against medical advice (rule 2): hospitalized on Day 6 and 7, missing thereafter
Case 3
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 28
Against 
medical 
advice?
YES
Status(SS*)
hospitalized
hospitalized
hospitalized
Discharged
Discharge to**
1/5/.. 
ready (SS*)
--/Not ready
--/Not ready
--/Not ready
--/Ready/
Not ready
CRS
>1
>1
>1
>1
>1
Missing
*SS = Subject Status
1= not hospitalized; > 1 = hospitalized
** 1=Patient's Home; 2=Different Hospital; 3=Acute Care Facility;4=Subacute care facility
     5=Long-Term Facility; 6=Rehab Facility; 7=Hospice/Palliative Discharge; 8=Other


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Case 4: Ready for discharge at Day 5 (rule 3)
Case 4
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
hospitalized
hospitalized
Discharged
Discharge to**
1/5/.. 
ready (SS*)
--/Not ready
--/Not ready
Ready
--/Ready
--/Ready
CRS
>1
>1
>1
1
1
1
Case 5: Discharged from hospital on Day 6, but not ready for dicharge (Rule 4)
Case 5
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
hospitalized
Discharged
Discharged 
to**
1/5/..
ready (SS*)
--/Not ready
--/Not ready
--/Not ready
Not ready
CRS
>1
>1
>1
>1
>1
1
Case 6: Ready for discharge at Day 5, Not ready for discharge at Day 6 (rule 3)
Discharged from hospital on Day 7 (Rule 5)
Case 6
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
hospitalized
hospitalized
Discharged
Discharge to**
1/5/.. 
ready (SS*)
--/Not ready
--/Not ready
Ready
Not ready
--/Ready
CRS
>1
>1
>1
>1
>1
1
*SS = Subject Status
1= not hospitalized; > 1 = hospitalized
** 1=Patient's Home; 2=Different Hospital; 3=Acute Care Facility;4=Subacute care facility
     5=Long-Term Facility; 6=Rehab Facility; 7=Hospice/Palliative Discharge; 8=Other


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Case 7: Ready for discharge at Day 4, Not ready for discharge at Day 5 (rule 3)
Discharged from hospital on Day 6, but not ready for discharge (Rule 4)
Case 7
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
hospitalized
Discharged
Discharge to**
1/5/.. 
ready (SS*)
--/Not ready
Ready
Not ready
Not ready
CRS
>1
>1
>1
>1
>1
1
Case 8: Ready for discharge at Day 4, Not ready after ready at Day 6 (Rule 3)
Discharged from hospital on Day 6, but not ready (Rule 4)
Case 8
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
hospitalized
Discharged
Discharge to**
1/5/.. 
ready (SS*)
Not ready
Ready
--/Ready
Not ready
CRS
>1
>1
1
>1
>1
1
Case 9: Ready for discharge at Day 5 (rule 3)
Case 9
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
hospitalized
hospitalized
Discharged
Discharge to**
1/5/.. 
ready (SS*)
--/Not ready
--/Not ready
Ready
--
--/Ready
CRS
>1
>1
>1
1
1
1
*SS = Subject Status
1= not hospitalized; > 1 = hospitalized
** 1=Patient's Home; 2=Different Hospital; 3=Acute Care Facility;4=Subacute care facility
     5=Long-Term Facility; 6=Rehab Facility; 7=Hospice/Palliative Discharge; 8=Other


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Case 10: Rule 3 (ready at day 6)
Case 10
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
hospitalized
hospitalized
Discharged
Discharge to**
1/5/..
ready (SS*)
Not ready
Not ready
Not ready
Ready
--/Ready
CRS
>1
>1
>1
>1
1
1
Case 11: Not ready after ready (Rule 3)
   Discharged while not ready on Day 6 (Rule 4)
Case 11
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
hospitalized
Discharged
Discharge to**
1/5/.. 
ready (SS*)
Not ready
Not ready
Ready
Not ready
CRS
>1
>1
>1
>1
>1
1
Case 12: Ready for discharge at Day 5 (rule 3)
   Alternate care setting (rule 1): hospitalized until Day 28
Case 12
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8 to Day 
28
Against 
medical 
advice?
--/NO
Status(SS*)
hospitalized
hospitalized
Hospitalized
Discharged
Discharge to**
2/3/..
ready (SS*)
--/Not ready
Ready
--
--/Ready
CRS
>1
>1
1
>1
>1
>1
*SS = Subject Status
1= not hospitalized; > 1 = hospitalized
** 1=Patient's Home; 2=Different Hospital; 3=Acute Care Facility;4=Subacute care facility
     5=Long-Term Facility; 6=Rehab Facility; 7=Hospice/Palliative Discharge; 8=Other