Conditions: COVID-19 Pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 97
Healthy volunteers: no

Brief summary:
This study will assess the pharmacodynamics, pharmacokinetics, safety and efficacy of two different doses of tocilizumab (TCZ) in combination with standard-of-care (SOC) in hospitalized adult participants with moderate to severe COVID-19 pneumonia.

Detailed description:

Arms:
arm 1: Participants will receive intravenous (IV) tocilizumab (TCZ) at a dose of 8 mg/kg in addition to standard-of-care treatment. arm 2: Participants will receive IV tocilizumab (TCZ) at a dose of 4 mg/kg in addition to standard-of-care treatment.

Interventions: intervention 1: Tociliuzumab
Intervention descriptions: intervention 1: Participants will receive IV TCZ.

Protocol document:
Prot_000.pdf: 
FINAL PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Tocilizumab—F. Hoffmann-La Roche Ltd
Protocol CA42481, Version 2
PROTOCOL
TITLE:
A PHASE II, OPEN-LABEL, RANDOMIZED, 
MULTICENTER STUDY TO INVESTIGATE THE 
PHARMACODYNAMICS, PHARMACOKINETICS, 
SAFETY, AND EFFICACY OF 8 mg/kg OR 4 mg/kg 
INTRAVENOUS TOCILIZUMAB IN PATIENTS WITH 
MODERATE TO SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
CA42481
VERSION NUMBER:
2
IND NUMBER:
148225
NCT NUMBER:
NCT04363736
TEST PRODUCT:
Tocilizumab (RO4877533)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
15-May-2020 13:33:01
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Tocilizumab—F. Hoffmann-La Roche Ltd
2/Protocol CA42481, Version 2
PROTOCOL HISTORY
Protocol
Version
Date Final
1
15 April 2020


Tocilizumab—F. Hoffmann-La Roche Ltd
3/Protocol CA42481, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE
Protocol CA42481 has been amended in response to feedback from the U.S. Food and 
Drug Administration.  Changes to the protocol, along with a rationale for each change, 
are summarized below:

The primary pharmacodynamic (PD) endpointPD response to tocilizumab (TCZ)
treatment, as measured by C-reactive protein (CRP) level at Day 7has been
deleted.  In addition, the secondary clinical efficacy endpoints have been changed to 
exploratory endpoints (Section 2.4).

Day 7 has been included as a timepoint to the exploratory endpoint of clinical status, 
assessed using a 7-category ordinal scale in addition to Days 14 and 28
(Section 2.4).

The pharmacokinetic (PK) endpoint of the association between TCZ 
pharmacokinetics and CRP, interleukin-6, soluble IL-6 receptor, and ferritin has 
been moved from Section 2.2 and included as an exploratory biomarker endpoint in 
Section 2.5.

Figure 1, the study schema, has been revised to reflect clinical outcomes at Day 28, 
and reference to the primary efficacy endpoint was removed (Section 3.1.1). 

The rationale section for TCZ has been revised and text justifying CRP levels as a 
biomarker surrogate for the primary efficacy endpoint deleted (Section 3.2.2).

The determination of sample size (Section 6.1) has been updated.  The figure 
depicting the total sample (n) to declare the 4-mg/kg dose non-inferior to the 
8-mg/kg dose at Day 7 posttreatment has been deleted.

As a result of the efficacy endpoints being changed to exploratory endpoints, PD 
analyses (Section 6.4) specifying that model adjustments and sensitivity analyses of
different populations have deleted. 

The requirements for the scheduling of periodic safety reviews have been clarified
(Section 6.9.1).  The planned optional interim analysis has been removed 
(Section 6.9.2). 
In addition, the following changes have been made:

The Protocol Synopsis was revised based on amended changes made to the 
protocol.

The background section (Section 1.4) on the real-world experience with TCZ 
treatment in the treatment of COVID-19 pneumonia has been revised and updated.

The inclusion criterion requiring patient hospitalization with COVID-19 pneumonia 
confirmed by a positive polymerase chain reaction of any specimen (e.g., respiratory, 
blood, urine, stool, or other bodily fluids) and evidence of pneumonia on chest X-ray 
or computed tomography scan has been clarified, such that the onset of patient 
symptoms must be at least 3 days prior to enrollment (Section 4.1.1). 


Tocilizumab—F. Hoffmann-La Roche Ltd
4/Protocol CA42481, Version 2

Additional instructions permitting the signing and dating of the Informed Consent 
Form by the patient or the patient’s legally authorized representative, or where 
allowed, health care consent on behalf of the patient have been included
(Section 4.5.1).  Furthermore, where allowed, verbal consent may be given by the 
patient or the patient’s legally authorized representative and this must be 
documented by the investigator or authorized designee.

Reference to serum exploratory biomarkers samples has been corrected to include 
plasma samples (Section 4.5.6 and Appendices 1, 2, and 3).

The contact information for the primary Medical Monitor has been updated
(Section 5.4.1).

References have been revised (Section 10).

The schedule of activities to be performed on Days 1 and 2 (Appendix 1) has been 
corrected to remove assessments inadvertently repeated on Day 1 postinfusion 
(e.g., review of eligibility criteria, randomization, medical history).  In addition, the
Day 2 assessments have been revised to now include review of adverse events and 
concomitant medications, hematology, and chemistry panel, and ordinal scoring.

The schedule of activities to be performed on Days 2 and 3 (Appendix 2) has been 
revised to clarify study completion assessments column is for early study or 
treatment discontinuation.  A serum PK sample has been added on Day 3.  

The schedule of activities after Day 28 (Appendix 3) has been revised to include 
sample collection for viral load, peripheral blood mononuclear cells, and blood for 
RNA analysis at Day 60 (the study completion visit).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Tocilizumab—F. Hoffmann-La Roche Ltd 
5/Protocol CA42481, Version 2
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 20
1.1
Background on COVID-19 Pneumonia.................................. 20
1.2
Background on Tocilizumab .................................................. 20
1.3
Tocilizumab Treatment of Cytokine-Release 
Syndrome with CAR TCell Therapy..................................... 21
1.4
Real-World Experience with Tocilizumab in 
COVID-19 Pneumonia........................................................... 22
1.5
Study Rationale and BenefitRisk Assessment..................... 24
2.
OBJECTIVES AND ENDPOINTS ............................................................... 24
2.1
Pharmacodynamic Objective................................................. 24
2.2
Pharmacokinetic Objective .................................................... 24
2.3
Safety Objective .................................................................... 25
2.4
Exploratory Objective............................................................. 25
2.5
Exploratory Biomarker Objective ........................................... 26
3.
STUDY DESIGN......................................................................................... 26
3.1
Description of the Study......................................................... 26
3.1.1
Overview of Study Design ..................................................... 26
3.2
End of Study and Length of Study......................................... 28
3.3
Rationale for Study Design.................................................... 28
3.3.1
Rationale for Patient Population ............................................ 28
3.3.2
Rationale for Tocilizumab Dose Regimen.............................. 29
3.3.3
Rationale for Biomarker Assessments................................... 32
4.
MATERIALS AND METHODS .................................................................... 33
4.1
Patients.................................................................................. 33
4.1.1
Inclusion Criteria.................................................................... 33
4.1.2
Exclusion Criteria................................................................... 34
4.2
Method of Treatment Assignment.......................................... 35
4.2.1
Treatment Assignment........................................................... 35


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6/Protocol CA42481, Version 2
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 35
4.3.1
Study Treatment Formulation and Packaging........................ 35
4.3.1.1
Tocilizumab ........................................................................... 35
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 35
4.3.3
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 36
4.3.4
Continued Access to Tocilizumab.......................................... 37
4.4
Concomitant Therapy ............................................................ 37
4.4.1
Permitted Therapy................................................................. 37
4.4.2
Cautionary Therapy ............................................................... 38
4.4.2.1
Medications Given with Precaution due to Effects 
Related to CYP Enzymes ...................................................... 38
4.4.2.2
Herbal Therapies................................................................... 38
4.4.3
Prohibited Therapy ................................................................ 38
4.5
Study Assessments ............................................................... 39
4.5.1
Informed Consent Forms and Screening Log........................ 39
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 40
4.5.3
Physical Examinations........................................................... 40
4.5.4
Vital Signs and Oxygen Saturation........................................ 40
4.5.5
Assessments Specific to National Early Warning 
Score 2 .................................................................................. 41
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 41
4.5.7
Liver Function Monitoring ...................................................... 43
4.5.8
Chest X-Ray and CT Scan .................................................... 43
4.5.9
Electrocardiograms................................................................ 43
4.5.10
Ordinal Scale Determination.................................................. 44
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 44
4.6.1
Study Treatment Discontinuation........................................... 44
4.6.2
Patient Discontinuation from the Study.................................. 45
4.6.3
Study Discontinuation............................................................ 45


Tocilizumab—F. Hoffmann-La Roche Ltd 
7/Protocol CA42481, Version 2
4.6.4
Site Discontinuation............................................................... 46
5.
ASSESSMENT OF SAFETY....................................................................... 46
5.1
Safety Plan ............................................................................ 46
5.1.1
Risks Associated with Tocilizumab........................................ 46
5.1.1.1
Hypersensitivity Reactions, Including 
Anaphylaxis ........................................................................... 46
5.1.1.2
Serious Infections and Opportunistic Infections..................... 47
5.1.1.3
Gastrointestinal Perforations ................................................. 47
5.1.1.4
Hematologic Abnormalities.................................................... 47
5.1.1.5
Demyelinating Disorders........................................................ 48
5.1.1.6
Elevated Liver Enzymes ........................................................ 48
5.1.1.7
CYP450 Enzyme Normalization ............................................ 48
5.2
Safety Parameters and Definitions ........................................ 48
5.2.1
Adverse Events ..................................................................... 49
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 49
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 50
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 50
5.3.1
Adverse Event Reporting Period ........................................... 51
5.3.2
Eliciting Adverse Event Information....................................... 51
5.3.3
Assessment of Severity of Adverse Events ........................... 51
5.3.4
Assessment of Causality of Adverse Events ......................... 52
5.3.5
Procedures for Recording Adverse Events............................ 53
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 53
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 53
5.3.5.3
Persistent or Recurrent Adverse Events................................ 54
5.3.5.4
Abnormal Laboratory Values ................................................. 54
5.3.5.5
Abnormal Vital Sign Values ................................................... 55
5.3.5.6
Deaths ................................................................................... 55
5.3.5.7
Preexisting Medical Conditions.............................................. 56


Tocilizumab—F. Hoffmann-La Roche Ltd 
8/Protocol CA42481, Version 2
5.3.5.8
Lack of Efficacy or Worsening of COVID-19 
Pneumonia ............................................................................ 56
5.3.5.9
Hospitalization or Prolonged Hospitalization.......................... 56
5.3.5.10
Cases of Accidental Overdose or Medication 
Error....................................................................................... 57
5.3.5.11
Safety Biomarker Data........................................................... 58
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 58
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 59
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 59
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 59
5.4.2.2
Events That Occur after Study Drug Initiation........................ 60
5.4.3
Reporting Requirements for Pregnancies.............................. 60
5.4.3.1
Pregnancies in Female Patients............................................ 60
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 60
5.4.3.3
Abortions ............................................................................... 61
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 61
5.5
Follow-Up of Patients after Adverse Events .......................... 61
5.5.1
Investigator Follow-Up........................................................... 61
5.5.2
Sponsor Follow-Up ................................................................ 62
5.6
Adverse Events That Occur after the 
Adverse Event Reporting Period ........................................... 62
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 62
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 62
6.1
Determination of Sample Size ............................................... 63
6.2
Summaries of Conduct of Study............................................ 63
6.3
Summaries of Treatment Group Comparability ..................... 63
6.4
Pharmacodynamic Analyses................................................... 64
6.5
Pharmacokinetic Analyses..................................................... 64
6.6
Safety Analyses..................................................................... 64
6.7
Exploratory Analyses............................................................. 65


Tocilizumab—F. Hoffmann-La Roche Ltd 
9/Protocol CA42481, Version 2
6.8
Exploratory Biomarker Analysis............................................. 65
6.9
Interim Analyses .................................................................... 65
6.9.1
Periodic Safety Reviews........................................................ 65
7.
DATA COLLECTION AND MANAGEMENT ............................................... 65
7.1
Data Quality Assurance......................................................... 65
7.2
Electronic Case Report Forms............................................... 66
7.3
Source Data Documentation.................................................. 66
7.4
Use of Computerized Systems .............................................. 67
7.5
Retention of Records............................................................. 67
8.
ETHICAL CONSIDERATIONS.................................................................... 68
8.1
Compliance with Laws and Regulations ................................ 68
8.2
Informed Consent.................................................................. 68
8.3
Institutional Review Board or Ethics Committee.................... 69
8.4
Confidentiality........................................................................ 70
8.5
Financial Disclosure .............................................................. 70
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 71
9.1
Study Documentation ............................................................ 71
9.2
Protocol Deviations................................................................ 71
9.3
Management of Study Quality ............................................... 71
9.4
Site Inspections ..................................................................... 71
9.5
Administrative Structure......................................................... 71
9.6
Dissemination of Data and Protection of 
Trade Secrets........................................................................ 72
9.7
Protocol Amendments ........................................................... 73
10. REFERENCES ........................................................................................... 74
LIST OF TABLES
Table 1
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 52
Table 2
Causal Attribution Guidance ....................................................... 53


Tocilizumab—F. Hoffmann-La Roche Ltd 
10/Protocol CA42481, Version 2
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 27
Figure 2
Predicted Median Free sIL-6R Serum Concentrations versus 
Time (over 7 Days) in Patients Weighing 75 kg with RA 
(Assumption:  Similar IL-6R Levels as in Patients with RA) ........ 31
Figure 3
Predicted Median Free IL-6R Serum Concentration versus 
Time (over 7 Days) in Patients Weighing 75 kg (Assumption:  
10-Fold Higher IL-6R Levels Than in Patients with RA).............. 31
Figure 4
Predicted Median Free IL-6R Serum Concentrations versus 
Time (over 7 Days) in Patients Weighing 75 kg (Assumption:  
10-Fold Higher IL-6R Levels Than in Patients with RA, Two 
Doses of 4 mg/kg Administered 24 Hours Apart)........................ 32
LIST OF APPENDICES
Appendix 1
Schedule of Activities:  Days 1 and 2......................................... 76
Appendix 2
Schedule of Activities:  Days 328............................................. 80
Appendix 3
Schedule of Activities:  After Day 28.......................................... 83
Appendix 4
  National Early Warning Score 2 (NEWS2)................................ 85


Tocilizumab—F. Hoffmann-La Roche Ltd 
11/Protocol CA42481, Version 2
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, OPEN-LABEL, RANDOMIZED, 
MULTICENTER STUDY TO INVESTIGATE THE 
PHARMACODYNAMICS, PHARMACOKINETICS, 
SAFETY, AND EFFICACY OF 8 mg/kg OR 4 mg/kg 
INTRAVENOUS TOCILIZUMAB IN PATIENTS WITH 
MODERATE TO SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
CA42481
VERSION NUMBER:
2
IND NUMBER:
148225
NCT NUMBER:
NCT04363736
TEST PRODUCT:
Tocilizumab (RO4877533)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local monitor.


Tocilizumab—F. Hoffmann-La Roche Ltd 
12/Protocol CA42481, Version 2
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, OPEN-LABEL, RANDOMIZED, MULTICENTER 
STUDY TO INVESTIGATE THE PHARMACODYNAMICS, 
PHARMACOKINETICS, SAFETY, AND EFFICACY OF 8 mg/kg OR 
4 mg/kg INTRAVENOUS TOCILIZUMAB IN PATIENTS WITH 
MODERATE TO SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
CA42481
VERSION NUMBER:
2
IND NUMBER:
148225
NCT NUMBER:
NCT04363736
TEST PRODUCT:
Tocilizumab (RO4877533)
PHASE:
Phase II
INDICATION:
Moderate to severe COVID-19 pneumonia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This Phase II study will investigate the pharmacodynamics, pharmacokinetics, safety, and 
efficacy of tocilizumab (TCZ) at two different doses in combination with standard-of-care (SOC) 
treatment in hospitalized patients with moderate to severe COVID-19 pneumonia.  Specific 
objectives and corresponding endpoints for the study are outlined below.
Pharmacodynamic Objective
The pharmacodynamic (PD) objective for this study is to assess the differences between two doses of 
TCZ in combination with SOC for the treatment of moderate to severe COVID-19 pneumonia on 
the basis of the following endpoints:

Serum concentrations of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), ferritin, 
and C-reactive protein (CRP) following administration of 8 mg/kg and 4 mg/kg IV TCZ at 
specified timepoints
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of two 
different doses of TCZ in combination with SOC for the treatment of moderate to severe 
COVID-19 pneumonia on the basis of the following endpoints:

Serum concentrations of TCZ following administration of 8 mg/kg and 4 mg/kg IV TCZ at 
specified timepoints
Safety Objective
The safety objective for this study is to compare the safety of two different doses of TCZ in 
combination with SOC for the treatment of moderate to severe COVID-19 pneumonia on the 
basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)


Tocilizumab—F. Hoffmann-La Roche Ltd 
13/Protocol CA42481, Version 2

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) (COVID-19) viral load over 
time, as collected by nasopharyngeal swab and bronchoalveolar lavage (BAL) samples 
(if applicable)

Time to real-time polymerase chain reaction (RT-PCR) virus negativity

The proportion of patients with any posttreatment infection

Change from baseline in targeted clinical laboratory test results
Exploratory Objective
The exploratory objective for this study is to assess the efficacy of two different doses of TCZ in 
combination with SOC for the treatment of moderate to severe COVID-19 pneumonia on the 
basis of the following endpoints:

Clinical status, as assessed using a 7-category ordinal scale at Days 7, 14, and 28

Time to clinical improvement, defined as a National Early Warning Score 2 (NEWS2) score
of 2 maintained for 24 hours

Time to improvement in at least two categories relative to baseline on a 7-category ordinal 
scale of clinical status 

Duration of supplemental oxygen use

Incidence of intensive care unit (ICU) stays 

Incidence of mechanical ventilation

Duration of ICU stay

Time to clinical failure, defined as the time to death, mechanical ventilation, ICU admission, 
or withdrawal (whichever occurs first)
For patients entering the study already in an ICU, clinical failure is defined as a 
one-category worsening on the ordinal scale, withdrawal, or death.

Mortality rate at Days 7, 14, 21, 28, and 60

Time to hospital discharge or “ready for discharge” (as evidenced by normal body 
temperature and respiratory rate, and stable oxygen saturation on ambient air or 2 L 
supplemental oxygen)

Frequency of the addition of a second dose of TCZ (8 mg/kg or 4 mg/kg) at the discretion of 
the treating physician

Ventilator-free days from baseline to Day 28

Organ failurefree days from baseline to Day 28
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
could provide further evidence of TCZ pharmacologic activity (i.e., mechanism of action), on the 
basis of the following endpoints:

Assessments of exploratory biomarkers in relation to efficacy, exposure, and in both blood 
and tissue-derived samples

Association between TCZ pharmacokinetics and the following PD biomarkers:  CRP, IL-6, sIL-6R, 
and ferritin
Study Design
Description of Study
This is a Phase II, open-label, randomized, multicenter study to assess the pharmacodynamics, 
pharmacokinetics, safety and efficacy of two different doses of TCZ in combination with SOC in 
hospitalized adult patients with moderate to severe COVID-19 pneumonia.  The Sponsor 
intends to enroll approximately 100 patients who have been diagnosed with COVID-19 
pneumonia who meet the eligibility criteria at U.S. sites.


Tocilizumab—F. Hoffmann-La Roche Ltd 
14/Protocol CA42481, Version 2
Patients must be at least 18 years old with confirmed SARS-CoV-2 (COVID-19) pneumonia per
the World Health Organization criteria, including a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, or other bodily fluids).  At the time of enrollment, patients 
must be hospitalized and have respiratory symptoms and radiologic findings of pneumonia.  
Patients with severe COVID-19 pneumonia must have SpO2 93% or PaO2/FiO2 300 mmHg 
despite receiving SOC treatment, which may include anti-viral treatment, low-dose steroids, and 
supportive care.  Patients with moderate COVID-19 pneumonia are hospitalized patients not 
meeting the criteria of severe COVID-19 pneumonia and with CRP 2 the upper limit of 
normal (ULN).  For both patients with moderate and severe COVID-19, the onset of patient 
symptoms must be at least 3 days prior to enrollment.  
Patients who are on a mechanical ventilator 24 hours or extracorporeal membrane 
oxygenation (ECMO), in shock, or a combination thereof with other organ failure requiring 
treatment in an ICU will be excluded from the study.  Patients for whom, in the opinion of the 
treating physician, progression to death is imminent and inevitable within the next 24 hours,
irrespective of the provision of treatments, will be excluded from the study.  Patients with active 
TB or suspected active bacterial, fungal, viral, or other infection (other than COVID-19 
pneumonia) will be excluded from the study.  
Patients will be randomized as soon as possible after screening in a 1:1 ratio to receive 
treatment with either 8 mg/kg or 4 mg/kg IV TCZ.  Study treatment must be given in combination 
with SOC treatment.  
Patients assigned to the 8-mg/kg TCZ arm will receive one IV infusion of 8 mg/kg, with a 
maximum dose of 800 mg, and patients assigned to the 4-mg/kg TCZ arm will receive one IV 
infusion of 4 mg/kg TCZ.  In addition, patients in both arms will receive SOC treatment.  
For patients in both arms, if a patient has a sustained fever or clinically significant worsening of signs 
or symptoms (e.g., an increased supplemental oxygen requirement), one additional infusion of TCZ at 
the same dose as the initial infusion can be given within 8 to 24 hours after the initial TCZ
infusion.
Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity (for a total of two screenings per participant) at the 
investigator’s discretion.  Patients are not required to re-sign the consent form if they are 
re-screened within 7 days after previously signing the consent form.
The study assessments to be conducted include the following:  complete and limited physical 
examinations, measurement of vital signs and oxygen saturation, assessment of consciousness, 
presence and absence of respiratory support, adverse events, concomitant therapies, clinical 
laboratory tests, and nasopharyngeal swabs.
Patients will be followed for a total of 60 days after the first dose of study drug.  
If patients are discharged from the hospital prior to Day 28, follow-up visits should occur twice 
weekly through Day 28.  Patients are encouraged to return for onsite visits at least weekly if 
possible; other follow-up visits may be conducted by telephone or home visits.  Patients should 
return to the site for the Day 28 visit.  After Day 28, all patients should have follow-up visits on 
Days 35, 45, and 60; the Day 35 and 45 visits may be conducted by telephone or by home visits 
for patients who are discharged, while the Day 60 visit should be conducted onsite.
During the study, standard supportive care will be given according to clinical practice. 
Number of Patients
Approximately 100 patients will be enrolled in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form by any patient capable of giving consent, or, when the 
patient is not capable of giving consent, by his or her legally authorized representative

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol


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15/Protocol CA42481, Version 2

Hospitalization with COVID-19 pneumonia confirmed by a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, or other bodily fluids) and evidence of pneumonia on 
chest X-ray or computed tomography scan 
The onset of patient symptoms must be at least 3 days prior to enrollment.

For severe patients, SpO2 93% or PaO2/FiO2 300 mmHg  
If a patient is on supplemental oxygen with SpO2 93%, but desaturation to 93% on 
lower supplemental oxygen or ambient air is documented during screening, the inclusion 
criterion is met.

For moderate patients (those who do not qualify as severe based oxygen requirements), 
CRP 2 ULN is required

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 90 days after the final dose of TCZ.  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential 
may be adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not adequate methods of contraception.  If required per local guidelines or regulations, 
locally recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 60 days after the 
final dose of TCZ to avoid exposing the embryo.  Men must refrain from donating sperm 
during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not adequate methods of preventing drug exposure.  If required per local guidelines or 
regulations, information about the reliability of abstinence will be described in the local 
Informed Consent Form.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known severe allergic reactions to TCZ or other monoclonal antibodies

Active TB infection 

Suspected active bacterial, fungal, viral, or other infection (besides SARS-CoV-2) 

Patients who meet any of the following at the time of randomization:  on a mechanical ventilator 
24 hours, on ECMO, in shock, or with other organ failure requiring treatment in an ICU

In the opinion of the investigator, progression to death is imminent and inevitable within the 
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
Receipt of oral anti-rejection or immunomodulatory drugs (including TCZ) within the past 
3 months

Participation in other drug clinical trials (participation in COVID-19 anti-viral trials may be 
permitted if confirmed by the Medical Monitor)

ALT or AST 10ULN detected within 24 hours at screening or at baseline (according to 
local laboratory reference ranges)

ANC 1000/L at screening and baseline (according to local laboratory reference ranges)

Platelet count 50,000/L at screening and baseline (according to local laboratory 
reference ranges)

Pregnancy or breastfeeding, or positive pregnancy test at a predose examination

Treatment with an investigational drug within 5 drug-elimination half-lives or 30 days 
(whichever is longer) of randomization (investigational SARS-CoV-2 [COVID-19]) anti-viral 
agents may be permitted after consultation with the Medical Monitor)

Any serious medical condition or abnormality of clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the
study
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last datapoint required for the last follow-up is received from the last patient, 
whichever occurs later.  The end of the study is expected to occur approximately 2 months after 
the last patient is enrolled.
In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 months. 
Investigational Medicinal Products
The investigational medicinal product for this study is TCZ.
Test Products (Investigational Drugs)
Patients assigned to the 4-mg/kg arm will receive the 4-mg/kg TCZ dose by IV infusion.  The 
dose of TCZ infusion will be calculated on the basis of body weight measured prior to infusion.  
One additional infusion of TCZ can be given within 8 to 24 hours after the initial infusion.
Comparator
Patients assigned to the 8-mg/kg arm will receive the 8-mg/kg TCZ dose by IV infusion.  The 
dose of TCZ infusion will be calculated on the basis of body weight measured prior to infusion.  
One additional infusion of TCZ can be given within 8 to 24 hours after the initial infusion.
Statistical Methods
PD Analysis
The PD outcome measures for this study are serum IL-6, sIL-6R, ferritin, and CRP levels at baseline and 
at specified timepoints after initiation of study drug.  Data for all PD biomarkers will be presented using 
descriptive summary statistics, including the mean, median, range, standard deviation (SD), and 
coefficient of variation.
PK Analyses
The PK analysis population will consist of patients with sufficient data to enable estimation of key 
parameters (e.g., area under the concentrationcurve [AUC], maximum serum concentration observed 
[Cmax]), with patients grouped according to treatment received.  
Non-linear mixed effects modeling will be used to analyze the serum TCZ concentration over time data 
collected in this study using existing population-PK models.  Individual and mean serum TCZ 
concentration versus time data will be tabulated and plotted by dose level.  The serum pharmacokinetics 
of TCZ will be summarized by estimating the total exposure (AUC), Cmax, total clearance, and volume of 


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distribution.  Estimates for these parameters will be tabulated and summarized (mean, SD, co-efficient of 
variation, median, minimum, and maximum).  Interpatient variability will be evaluated.
Additional PK analyses will be conducted as appropriate.  The PK parameters derived from these analyses 
may be used for exploratory graphical analyses of the PD parameters.
Determination of Sample Size  
The purpose of this open-label study is the comparison of TCZ pharmacokinetics and PK-PD
relationship between two doses of TCZ (8 and 4 mg/kg) in hospitalized patients with moderate to 
severe COVID-19 pneumonia.  The comparison will be assessed using modeling and evaluating the 
safety and efficacy measures between Day 1 and Day 28 postrandomization.  Data from the follow-up 
period from Days 28 to 60 may also be assessed.  Approximately 100 patients will be enrolled and
randomized in a 1:1 ratio to the 8-mg/kg and 4-mg/kg IV TCZ arms in this study.  Disease severity 
type will also be stratified into moderate and severe COVID pneumonia, giving an overall equal four-way 
split between the two doses and type of disease severity and resulting in four groups of approximately 
25 patients each.  Patients may receive a repeat dose within 8 to 24 hours after the first TCZ dose if 
clinicians judge it is necessary (resulting in a TCZ dose range from 4 to 16 mg/kg, with a maximum
dose of 800 mg).  The variability of PK parameters of TCZ in a heterogeneous COVID-19 population in 
an acute setting is unknown; however, 20 to 30 patients is deemed adequate considering the 
between-subject variability in health volunteers and patients with RA provided by population-PK 
modeling.  Data quality issues, patient dropouts, and early hospital discharge may all lead to missing 
data, especially in a pandemic setting; thus, enrolling 50 patients according to dose and disease severity 
type (25 per arm) may offset missing data and allow an adequate volume of PK and PD data to inform the 
population-PK model and allow a comparison of the 4- and 8-mg/kg doses.
Interim Analysis
No interim analysis is planned for this study.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ARDS
acute respiratory distress syndrome
AUC
area under the concentrationtime curve
BAL
bronchoalveolar lavage
CAR
chimeric antigen receptor
Cmax
maximum serum concentration observed
CoV
coronavirus
CRP
C-reactive protein
CRS
cytokine-release syndrome
CTCAE
Common Terminology Criteria for Adverse Events
EC
Ethics Committee
eCRF
electronic Case Report Form
ECMO
extracorporeal membrane oxygenation
EDC
electronic data capture
FDA
(U.S.) Food and Drug Administration
FiO2
fraction of inspired oxygen
GCA
giant cell arteritis
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
ICU
intensive care unit
IL-6
interleukin-6
IL-6R
interleukin-6 receptor
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
mIL-6R
membrane-expressed IL-6R
mITT
modified intent to treat (population)
NCI
National Cancer Institute
NEWS2
National Early Warning Score 2
NGS
next-generation sequencing
PaO2
partial pressure of oxygen
PCR
polymerase chain reaction
PD
pharmacodynamic
PK
pharmacokinetic


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Abbreviation
Definition
PY
patient-year
RA
rheumatoid arthritis
RT-PCR
real-time polymerase chain reaction
SARS-CoV(-2)
severe acute respiratory syndrome corona virus
(strain) 2
SD
standard deviation
sIL6-R
soluble interleukin-6 receptor
sJIA
systemic juvenile idiopathic arthritis
SOC
standard of care
SpO2
blood oxygen saturation
TAK
Takayasu arteritis
TB
tuberculosis
TCZ
tocilizumab
TTCI
time to clinical improvement
ULN
upper limit of normal
WHO
World Health Organization


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1.
BACKGROUND
1.1
BACKGROUND ON COVID-19 PNEUMONIA
Coronaviruses (CoV) are positive-stranded RNA viruses, named for the crown-like 
appearance of their spike glycoproteins on the virus envelope.  They are a large family 
of viruses that cause illness ranging from the common cold to more severe diseases 
such as Middle East respiratory syndrome and severe acute respiratory syndrome 
(SARS-CoV).
COVID-19, which is the acronym of “coronavirus disease 2019,” is caused by a novel
coronavirus strain (SARS-CoV-2) and was newly named on 11 February 2020 by the 
World Health Organization (WHO).  An epidemic of cases with unexplained lower
respiratory tract infections was first detected in Wuhan, the largest metropolitan area in 
China’s Hubei province, and was reported to the WHO Country Office in China on 
31 December 2019.  The WHO subsequently declared a pandemic on 11 March 2020.
According to the WHO, as of 2 April 2020 more than 896,000 cases of COVID-19 
infection were reported in more than 200 countries and territories worldwide, with more 
than 45,500 deaths (WHO 2020a).  Up to approximately 20% of infected patients 
experience complications related to a severe form of interstitial pneumonia, which may 
progress to acute respiratory distress syndrome (ARDS) and/or multiple-organ failure 
and death (WHO 2020b).
To date, there is no vaccine and no specific anti-viral medicine shown to be effective in
preventing or treating COVID-19. Most patients with mild cases of disease recover with
symptomatic treatment and supportive care.  However, patients with more severe illness 
frequently require hospitalization (WHO 2020b).
1.2
BACKGROUND ON TOCILIZUMAB
Tocilizumab (TCZ) is a recombinant humanized antihuman monoclonal antibody of the 
IgG1 subclass directed against soluble interleukin-6 receptor (sIL-6R) and 
membrane-bound IL-6R.  TCZ binds specifically to both sIL-6R and membrane-bound 
IL-6R and has been shown to inhibit both soluble and membrane-bound IL-6Rmediated 
signaling.  Interleukin-6 (IL-6) is a pleiotropic pro-inflammatory multifunctional cytokine 
produced by a variety of cell types and has been shown to be involved in diverse 
physiologic processes, such as T-cell activation, induction of acute-phase proteins,
stimulation of hematopoietic precursor cell growth and differentiation, proliferation of 
hepatic, dermal, and neural cells, bone metabolism, lipid metabolism, hepatoprotection,
and fibrosis.  Elevated tissue and serum levels of IL-6 have been implicated in the 
disease pathology of several inflammatory and autoimmune disorders, including 
rheumatoid arthritis (RA), Castleman disease, systemic juvenile idiopathic arthritis (sJIA), 
polyarticular juvenile idiopathic arthritis (pJIA), giant cell arteritis (GCA), Takayasu 
arteritis (TAK), systemic sclerosis (SSc), and cytokine-release syndrome (CRS).  
Inhibition of the biological activity of IL-6 or IL-6R has been effective in the treatment of 


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these disorders, including chimeric antigen receptor (CAR) T cellinduced CRS, for 
which treatment with TCZ has been approved in many countries. 
TCZ has IV and SC formulations.  Some of the above-listed indications (RA, sJIA, and 
pJIA) have received approval for both the IV and SC formulations, whereas others have 
received approval exclusively for the IV (Castleman disease and CRS) or the SC (GCA 
and TAK) formulation.  
The estimated cumulative clinical trial exposure to TCZ from the Development 
International Birth Date (IBD) (28 April 1997) and until 10 April 2019 (the data lock point
for the Periodic BenefitRisk Evaluation Report) was 24,826 patients (40154.98 
patient-years [PYs]). Since the IBD (11 April 2005), the estimated cumulative market 
exposure to TCZ until 10 April 2019 was 1,301,050 patients (1,053,779 PYs). The 
combined cumulative postmarketing exposure of patients to IV TCZ is estimated to be 
896,672 patients (726,347 PYs). The combined cumulative postmarketing exposure of 
patients to SC TCZ is 404,378 (327,432 PYs).
Refer to the Tocilizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
TOCILIZUMAB TREATMENT OF CYTOKINE-RELEASE 
SYNDROME WITH CAR TCELL THERAPY
CRS has been identified as a clinically significant, on-target, off-tumor side effect of the 
CAR T-cell therapies used for the treatment of malignancies. Characteristics of CRS 
include fever, fatigue, headache, encephalopathy, hypotension, tachycardia, 
coagulopathy, nausea, capillary leak, and multiple-organ dysfunction. The reported 
incidence of CRS after CAR Tcell therapy ranges from 50% to 100%, with 13%48% of 
patients experiencing the severe or life-threatening form of CRS. Serum levels of 
inflammatory cytokines are elevated, particularly IL-6. The severity of symptoms may 
correlate with the serum cytokine concentrations and the duration of exposure to the 
inflammatory cytokines.
On 30 August 2017, the U.S. Food and Drug Administration (FDA) approved TCZ
(Actemra®) for the treatment of severe or life-threatening CAR T cellinduced CRS in 
adults and in pediatric patients 2 years of age and older. The approved dose is 8 mg/kg 
for body weight 30 kg and 12 mg/kg for body weight 30 kg.  Up to an additional three 
doses may be given there is if no improvement of signs and symptoms, and the interval 
between the subsequent doses should be at least 8 hours.  
The approval of TCZ was based on a retrospective analysis of data from patients treated 
with TCZ who developed CRS after treatment with tisagenlecleucel (Kymriah®) or
axicabtagene ciloleucel (Yescarta®) in prospective clinical trials (Le et al. 2018).  Of the 
45 patients, 31 patients (69%) from the CTL019 series achieved a response (defined as 
being afebrile and off vasopressors for at least 24 hours within 14 days of the first dose 


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of TCZ for a maximum of up to two doses and without use of additional treatment other 
than corticosteroids within 14 days of the first dose of TCZ), and the median time from 
the first dose to response was 4 days.  Eight of the 15 patients (53%) from the 
axicabtagene ciloleucel series achieved a response, and the median time to response 
was 4.5 days. The response rates were largely consistent with results from subgroup 
analyses of age group, sex, race, ethnicity, grade of CRS at first dose of TCZ, and 
duration of CRS prior to treatment with TCZ.  There were no reports of adverse reactions 
attributable to TCZ.
Pharmacokinetic (PK) data were available for 27 patients after the first dose of TCZ and 
for 8 patients after a second dose of TCZ.  Based on 131 PK observations, the 
geometric mean (% CV) maximum concentration of TCZ in the patients with 
CAR T cellinduced, severe or life-threatening CRS was 99.5 g/mL (36.8%) after the 
first infusion and 160.7 g/mL (113.8%) after the second infusion. The PK modeling 
analysis showed that patients with CRS had faster clearance of TCZ than healthy 
volunteers and other patient populations, and simulations showed that exposure was 
considered acceptable with up to four doses of TCZ administered at least 8 hours apart 
to patients with CRS.
TCZ is also approved for CAR T cellinduced severe or life-threatening CRS in the
European Union and certain other countries.
1.4
REAL-WORLD EXPERIENCE WITH TOCILIZUMAB IN
COVID-19 PNEUMONIA
Physicians in China initiated the off-label use of TCZ in the treatment of COVID-19 
pneumonia.  Based on the results from an initial 21-patient retrospective study in which 
patients with severe or critically ill patients with COVID-19 pneumonia were treated with 
TCZ (Xu et al. 2020). TCZ was included in the seventh updated diagnosis and treatment 
plan for COVID-19 issued by the China National Health Commission as one treatment 
option for severe or critical forms of COVID-19 pneumonia on 3 March 2020.  The 
Chinese Center for Disease Control and Prevention defined disease severity according 
to the following criteria:

Severe disease:  dyspnea, respiratory frequency 30/min, blood oxygen saturation 
(SpO2) 93%, partial pressure of oxygen (PaO2) to fraction of inspired oxygen (FiO2) 
ratio (the ratio of blood pressure of oxygen [PaO2] to the percentage of oxygen 
supplied [FiO2]) 300 mmHg, and/or lung infiltrates 50% within 24 to 48 hours; this 
occurred in 14% of cases

Critical disease: respiratory failure, septic shock, and/or multiple-organ dysfunction 
or multiple-organ failure; this occurred in 5% of cases (Wu et al. 2020)
Because body weight measurement is not always feasible in urgent circumstances, the
dose regimen used in China is a single fixed dose of 400 mg TCZ administered to 
patients by IV infusion (which equates to between 4 and 8 mg/kg based on the body 
weight range of the Chinese adult population), with the maximum single dose of no more 


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than 800 mg.  If clinical signs and symptoms do not improve, an additional dose can be 
administered after 12 hours. The guidance advises that no more than two doses should 
be given. TCZ treatment is not permitted for people with active infections, including
tuberculosis (TB), bacterial, or fungal infections.  
Results from 21 Patients Treated with Tocilizumab in China
In February 2020, 21 patients with severe or critical COVID-19 pneumonia were treated 
with IV TCZ (400 mg) plus standard of care (SOC).  The mean (SD) age of patients 
was 56.816.5 years, ranging from 25 to 88 years.  Seventeen patients (81.0%) were 
assessed as having severe cases and 4 patients (19.0%) were critical.  Most patients 
(85%) presented with lymphopenia.  C-reactive protein (CRP) levels were increased in 
all 20 patients (meanSD, 75.0666.80 mg/L).  The median procalcitonin value was 
0.330.78 ng/mL, and 2 of 20 patients (10.0%) presented with an abnormal value.  
The meanstandard deviation (SD) IL-6 level before TCZ treatment was 132.38278.54 
pg/mL (normal 7 pg/mL).
SOC consisted of lopinavir, methylprednisolone, other symptom relievers, and oxygen 
therapy, as recommended by the Diagnosis and Treatment Protocol for Novel 
Coronavirus Pneumonia (sixth revised edition).  All 21 patients had received routine 
SOC treatment for 1 week before deteriorating with sustained fever, hypoxemia, and 
worsening on chest computed tomography (CT) scan.  
Eighteen patients (85.7%) received TCZ once, and 3 patients (14.3%) had a second 
dose because of fever within 12 hours.  According to the authors, after TCZ treatment, 
fever returned to normal and all other symptoms improved remarkably.  Fifteen of the 
20 patients (75.0%) had lowered their oxygen intake and 1 patient needed no oxygen 
therapy.  CT scans showed significant remission of opacities in both lungs in 19 of 
20 patients (90.5%) after treatment with TCZ.  The percentage of lymphocytes in 
peripheral blood, which was decreased in 85.0% of patients (17 of 20 patients) prior to 
treatment (meanSD, 15.528.89%), returned to normal in 52.6% of patients (10 of 
19 patients) on the fifth day after treatment.  Abnormally elevated CRP levels decreased 
significantly in 84.2% of patients (16 of 19 patients).  No adverse drug reactions and no 
subsequent pulmonary infections were reported.  
Nineteen patients (90.5%) were discharged at the time of the report, including 2 critically 
severe patients.  There were no deaths among the 21 treated patients.
The study’s authors concluded that TCZ is an effective treatment for patients with severe 
COVID-19 pneumonia (Xu et al. 2020).  More recently, multiple prospective and retrospective 
studies have been conducted to describe the real-world experience with TCZ treatment of 
COVID-19 pneumonia (Alattar et al. 2020; Klopfenstein et al. 2020; Luo et al. 2020; Sciasci
et al. 2020; Toniati et al. 2020).  


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1.5
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
There are currently no drugs licensed for the treatment of patients with COVID-19 
pneumonia.  Given the results of studies outlined above, TCZ, along with SOC treatment,
may provide efficacy, offering the potential to treat COVID-19 in hospitalized populations 
more effectively than current SOC alone.  Extensive safety data have previously been 
generated on the use of TCZ in other indications.  COVACTA (clinicaltrial.gov number
NCT04320615) is an ongoing Phase III, randomized-controlled study evaluating the 
efficacy and safety of TCZ compared with placebo in patients with severe COVID-19 
pneumonia.  In the COVACTA study, the 8-mg/kg IV TCZ dose with an additional one 
infusion if clinical signs and symptoms worsen or do not improve was chosen based on 
the approved dose for CRS induced by CAR Tcell therapy in patients weighing 30 kg.  
The 21-patient study that supported the approval of TCZ in China used a fixed 400-mg 
dose of IV TCZ in combination with SOC treatment.  Therefore, the optimal dose of TCZ
in the treatment of COVID-19 is not known.  This open-label, randomized study in 
combination with SOC will evaluate in hospitalized patients with COVID-19 pneumonia 
whether a lower dose of TCZ could show similar pharmacological effects of IL-6 pathway 
inhibition as the 8-mg/kg IV dose approved in CRS and is being evaluated in the 
COVACTA study.   
2.
OBJECTIVES AND ENDPOINTS
This Phase II study will investigate the pharmacodynamics, pharmacokinetics, safety,
and efficacy of TCZ at two different doses in combination with SOC treatment in 
hospitalized patients with moderate to severe COVID-19 pneumonia.  Specific objectives 
and corresponding endpoints for the study are outlined below.
2.1
PHARMACODYNAMIC OBJECTIVE
The pharmacodynamic (PD) objective for this study is to assess the differences between two
doses of TCZ in combination with SOC for the treatment of moderate to severe 
COVID-19 pneumonia on the basis of the following endpoints:

Serum concentrations of IL-6, sIL-6R, ferritin, and CRP following administration of 
8 mg/kg and 4 mg/kg IV TCZ at specified timepoints (see Appendix 1, Appendix 2, and 
Appendix 3)
2.2
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the pharmacokinetics of two different 
doses of TCZ in combination with SOC for the treatment of moderate to severe 
COVID-19 pneumonia on the basis of the following endpoints:

Serum concentrations of TCZ following administration of 8 mg/kg and 4 mg/kg IV TCZ at 
specified timepoints (see Appendix 1, Appendix 2, and Appendix 3)


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2.3
SAFETY OBJECTIVE
The safety objective for this study is to compare the safety of two different doses of TCZ 
in combination with SOC for the treatment of moderate to severe COVID-19 pneumonia 
on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0)

SARS-CoV-2 (COVID-19) viral load over time, as collected by nasopharyngeal swab 
and bronchoalveolar lavage (BAL) samples (if applicable)

Time to real-time polymerase chain reaction (RT-PCR) virus negativity

The proportion of patients with any posttreatment infection

Change from baseline in targeted clinical laboratory test results
2.4
EXPLORATORY OBJECTIVE
The exploratory objective for this study is to assess the efficacy of two different doses of 
TCZ in combination with SOC for the treatment of moderate to severe COVID-19 
pneumonia on the basis of the following endpoints:

Clinical status, as assessed using a 7-category ordinal scale at Days 7, 14, and 28

Time to clinical improvement (TTCI), defined as a National Early Warning Score 2 
(NEWS2) score of 2 maintained for 24 hours

Time to improvement in at least two categories relative to baseline on a 7-category 
ordinal scale of clinical status 

Duration of supplemental oxygen use

Incidence of intensive care unit (ICU) stays 

Incidence of mechanical ventilation

Duration of ICU stay

Time to clinical failure, defined as the time to death, mechanical ventilation, 
ICU admission, or withdrawal (whichever occurs first)
For patients entering the study already in an ICU, clinical failure is defined as a 
one-category worsening on the ordinal scale, withdrawal, or death.

Mortality rate at Days 7, 14, 21, 28, and 60

Time to hospital discharge or “ready for discharge” (as evidenced by normal body 
temperature and respiratory rate, and stable oxygen saturation on ambient air or 
2 L supplemental oxygen)

Frequency of the addition of a second dose of TCZ (8 mg/kg or 4 mg/kg) at the 
discretion of the treating physician

Ventilator-free days from baseline to Day 28

Organ failurefree days from baseline to Day 28


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2.5
EXPLORATORY BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that could provide further evidence of TCZ pharmacologic activity 
(i.e., mechanism of action), on the basis of the following endpoints:

Assessments of exploratory biomarkers in relation to efficacy, exposure (listed in 
Section 4.5.6), and in both blood and tissue-derived samples

Association between TCZ pharmacokinetics and the following PD biomarkers:  
CRP, IL-6, sIL-6R, and ferritin
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design 
This is a Phase II, open-label, randomized, multicenter study to assess the
pharmacodynamics, pharmacokinetics, safety, and efficacy of two different doses of TCZ 
in combination with SOC in hospitalized adult patients with moderate to severe 
COVID-19 pneumonia.  The Sponsor intends to enroll approximately 100 patients who 
have been diagnosed with COVID-19 pneumonia who meet the eligibility criteria at 
U.S. sites.
Patients must be at least 18 years old with confirmed SARS-CoV-2 (COVID-19)
pneumonia per the WHO criteria, including a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, or other bodily fluids).  At the time of enrollment, 
patients must be hospitalized and have respiratory symptoms and radiologic findings of 
pneumonia.  Patients with severe COVID-19 pneumonia must have SpO2 93% or 
PaO2/FiO2 300 mmHg despite receiving SOC treatment, which may include anti-viral 
treatment, low-dose steroids, and supportive care.  Patients with moderate COVID-19 
pneumonia are hospitalized patients not meeting the criteria of severe COVID-19 
pneumonia and with CRP 2the upper limit of normal (ULN).  For both patients with 
moderate and severe COVID-19, the onset of patient symptoms must be at least 3 days 
prior to enrollment.  
Patients who are on a mechanical ventilator 24 hours or extracorporeal membrane 
oxygenation (ECMO), in shock, or a combination thereof with other organ failure requiring 
treatment in an ICU will be excluded from the study.  Patients for whom, in the opinion of 
the treating physician, progression to death is imminent and inevitable within the next 
24 hours, irrespective of the provision of treatments, will be excluded from the study.  
Patients with active TB or suspected active bacterial, fungal, viral, or other infection 
(other than COVID-19 pneumonia) will be excluded from the study.  
Patients will be randomized as soon as possible after screening in a 1:1 ratio to receive 
treatment with either 8 mg/kg or 4 mg/kg IV TCZ.  Study treatment must be given in 
combination with SOC treatment.  


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Patients assigned to the 8-mg/kg TCZ arm will receive one IV infusion of 8 mg/kg, with a 
maximum dose of 800 mg, and patients assigned to the 4-mg/kg TCZ arm will receive 
one IV infusion of 4 mg/kg TCZ.  In addition, patients in both arms will receive SOC 
treatment.  
The study design is presented in Figure 1.  The schedules of activities are presented in 
Appendix 1 (assessments to be performed on Days 1 and 2), Appendix 2 (assessments 
scheduled on Days 328), and Appendix 3 (assessments after Day 28).
Figure 1
Study Schema
For patients in both arms, if a patient has a sustained fever or clinically significant worsening 
of signs or symptoms (e.g., an increased supplemental oxygen requirement), one additional 
infusion of TCZ at the same dose as the initial infusion can be given within 8 to 24 hours 
after the initial TCZ infusion. 
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator’s discretion.  Patients are not required to re-sign the consent form if they 
are re-screened within 7 days after previously signing the consent form.   
The study assessments to be conducted include the following:  complete and limited 
physical examinations, measurement of vital signs and oxygen saturation, assessment 
of consciousness, presence and absence of respiratory support, adverse events, 
concomitant therapies, clinical laboratory tests, and nasopharyngeal swabs (refer to 
Section 4.5 for the complete list of study assessments).
Patients will be followed for a total of 60 days after the first dose of study drug.  
If patients are discharged from the hospital prior to Day 28, follow-up visits should occur 
twice weekly through Day 28.  Patients are encouraged to return for onsite visits at least 


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weekly if possible; other follow-up visits may be conducted by telephone or home visits.  
Patients should return to the site for the Day 28 visit.  After Day 28, all patients should 
have follow-up visits on Days 35, 45, and 60; the Day 35 and 45 visits may be conducted 
by telephone or by home visits for patients who are discharged, while the Day 60 visit 
should be conducted onsite.
During the study, standard supportive care will be given according to clinical practice. 
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the
date at which the last data point required for the last follow-up is received from the last 
patient, whichever occurs later.  The end of the study is expected to occur approximately 
2 months after the last patient is enrolled.
In addition, the Sponsor may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
The pneumonia caused by COVID-19 can be classified into four types:  mild, common or 
moderate, severe, and critically severe (National Health Commission, trial Version 5).  
Based on the current knowledge of COVID-19, approximately 80% of patients infected 
with SARS-CoV-2 (COVID-19) experience mild disease and can recover at home and 
require only simple symptomatic relief.  However, approximately 20% require 
hospitalization, owing to more severe disease (moderate, severe, or critically severe).  
Once hospitalized, 5%26% patients are transferred to an ICU, 2.3% are mechanically 
ventilated, and 1.4%15% of patients die (Huang et al. 2020; Guan et al. 2020; 
Wang et al. 2020).  
Given the significant unmet need in patients hospitalized with COVID-19 infection and 
based on the emerging evidence for TCZ use in patients with COVID-19 pneumonia, 
COVACTA study, a Phase III, randomized, double-blind, placebo-controlled study is 
being conducted to evaluate the efficacy and safety of TCZ versus placebo in patients 
with severe COVID-19 pneumonia.  Given that the optimal dose of TCZ in the treatment 
of COVID-19 pneumonia is not known, this Phase II, open-label, randomized study will 
investigate whether a lower dose of TCZ in combination with SOC could show similar 
pharmacologic effects of IL-6 pathway inhibition as the 8-mg/kg IV dose in combination 
with SOC treatment evaluated in the COVACTA study.  Given that a lower dose is being 
assessed, critically severe patients will be excluded from this study; however, because
hospitalized patients include those with moderate disease, patients with moderate and 
severe COVID-19 pneumonia will be included.


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Patients with severe COVID-19 pneumonia will be defined as patients hospitalized with 
COVID-19 pneumonia that is confirmed according to the WHO criteria (including a 
positive PCR of any specimen [e.g., respiratory, blood, urine, stool, or other bodily fluids]) 
that is evidenced on chest X-ray or CT scan.  Patients with severe COVID-19 may be 
mechanically ventilated for24 hours or have SpO2 93% or PaO2/FiO2 300 mmHg or 
are receiving supplemental oxygen with SpO2 93%, but desaturation to 93% on lower 
supplemental oxygen or ambient air is documented.  Patients not meeting the criteria of 
severe COVID-19 pneumonia will be considered as having moderate COVID-19 
pneumonia.  Patients with moderate COVID-19 pneumonia are required to have CRP 
2ULN.
3.3.2
Rationale for Tocilizumab Dose Regimen
On 30 August 2017, the U.S. FDA approved TCZ (Actemra®) for the treatment of severe 
or life-threatening CAR T cellinduced CRS in adults and in pediatric patients 2 years of 
age and older. The approved TCZ dose is 8 mg/kg for body weight 30 kg and 
12 mg/kg for body weight 30 kg.  Up to an additional three doses of TCZ may be given 
if there is no improvement in the signs and symptoms of CRS and the interval between 
subsequent doses should be at least 8 hours. 
This CRS label supported the selection of the dosing regimen in the ongoing COVACTA 
(WA42380) study, in which 8 mg/kg IV TCZ is administered to patients infected with 
severe COVID-19, with the possibility to repeat the dose within 8 to 24 hours after the 
initial infusion if clinically required. Nevertheless, the optimal dose and dosing frequency 
of TCZ in the treatment of CAR T cellinduced CRS are not known, and the dosing 
instructions provided in the current TCZ label provide only general recommendations for 
safe dosing (Le et al. 2018).
There is increasing evidence coming from real-world experience that lower doses of TCZ 
could show a similar efficacy in treating COVID-19 pneumonia as the one recommended 
in the CRS label.  Treating physicians in China used a single fixed dose of 400 mg IV 
TCZ, as body weight measurement was not feasible (which equates to between 4 and 
8 mg/kg based on the body weight range of the Chinese adult population).
In February 2020, 21 patients with severe or critical COVID-19 pneumonia were treated 
with IV TCZ (400 mg) in combination with SOC treatment. Nineteen patients (90.5%) 
were discharged at the time of the report, including 2 critically severe patients.  No deaths
were reported among the 21 treated patients. The study’s authors concluded that TCZ
is an effective treatment for patients with severe COVID-19 pneumonia (Xu et al. 2020).
TCZ competitively inhibits the binding of IL-6 to its sIL-6Rs and membrane-expressed 
IL-6Rs (mIL-6Rs). Inhibiting the entire receptor complex prevents IL-6 signal 
transduction to inflammatory mediators, including CRP, and significantly improves the 
chronic inflammatory process of RA (Rueda et al. 2011).


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After IV administration, the observed concentrations of TCZ declined slowly over time. 
Elimination of TCZ is assumed to be a combination of a linear elimination through the 
non-specific binding and a target-mediated elimination related to TCZ binding to both 
sIL-6R and mIL-6R and subsequent elimination of the drugtarget complex.
A PK/PD model (Gibiansky and Frey 2012) has been developed to describe the
relationship between the TCZ concentrationtime profile and the extent of target 
engagement as displayed by the sIL-6R time course. 
This model has been used to illustrate the expected decrease in estimated free sIL-6R 
levels achieved with different IV TCZ dosing regimens (Gibiansky and Frey 2012). It is 
worth highlighting that 8-mg/kg IV (tested in Phase III COVACTA trial) and 4-mg/kg IV 
dosing regimens elicit a similar onset and magnitude of the IL-6 pathway inhibition. The 
only difference lies with the duration of the inhibition as reflected by the sIL-6R blockade 
over a defined period of time. These results support the choice of testing 4 mg/kg IV
TCZ in patients presenting with COVID-19 pneumonia based on the understanding of 
the PKPD relationship of TCZ and on predictions from a well-established model in RA.
The level of target IL-6Rs in patients has the greatest effect on both the exposure of TCZ 
and the duration of the IL-6 pathway inhibition. Although these levels are well 
characterized in patients with RA, the level of IL-6Rs in patients with COVID-19
pneumonia is unknown at this stage.
To account for potentially higher levels of IL-6Rs in patients with severe COVID-19 
pneumonia, two approaches were investigated, the first assuming IL-6R levels were 
similar to levels in patients with RA. For each of these two approaches, simulated free 
sIL-6R levels were predicted for patients with a low body weight (50 kg), an average 
body weight (75 kg), and a higher body weight (100 kg). Because all three profiles are 
identical, only the plots for patients weighing 75 kg are reported below.
In the case in which the levels of IL-6Rs are similar to levels observed in patients with RA, 
the 4-mg/kg and 8-mg/kg inhibition profiles overlap over 7 days across the body range 
tested, showing an almost complete receptor blockade of up to 7 days following a single 
IV infusion of TCZ (see Figure 2).


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Figure 2
Predicted Median Free sIL-6R Serum Concentrations versus Time 
(over 7 Days) in Patients Weighing 75 kg with RA (Assumption:  
Similar IL-6R Levels as in Patients with RA)
IL-6Rinterleukin-6 receptor; RArheumatoid arthritis; sIL-6Rsoluble interleukin-6 receptor.
Under the assumption that the level of IL-6Rs in patients with COVID-19 pneumonia 
would be 10-fold higher than in patients with RA, the 4-mg/kg infusion results in the 
same inhibition level compared with 8-mg/kg up to 4 days after the infusion (see 
Figure 3); beyond that, a second infusion would be required to ensure maximal blockade 
for 7 days, mimicking the effect of one single IV infusion of 8 mg/kg (see Figure 4).
Figure 3
Predicted Median Free IL-6R Serum Concentration versus Time
(over 7 Days) in Patients Weighing 75 kg (Assumption: 10-Fold 
Higher IL-6R Levels Than in Patients with RA)
IL-6Rinterleukin-6 receptor; RArheumatoid arthritis; sIL-6Rsoluble interleukin-6 receptor.


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Figure 4
Predicted Median Free IL-6R Serum Concentrations versus Time 
(over 7 Days) in Patients Weighing 75 kg (Assumption:  10-Fold 
Higher IL-6R Levels Than in Patients with RA, Two Doses of 
4 mg/kg Administered 24 Hours Apart)
F-UPfollow-up; IL-6Rinterleukin-6 receptor; RArheumatoid arthritis; sIL-6Rsoluble 
interleukin-6 receptor.
In RA, there are sound scientific arguments supporting that 4 mg/kg IV TCZ can elicit a 
similar onset and magnitude of IL-6 pathway inhibition as 8 mg/kg IV TCZ. Nevertheless, 
it is acknowledged that the model may not accurately predict the pharmacokinetics and 
pharmacodynamics of TCZ in patients with COVID-19 pneumonia, given that the 
turnover rate and the level of target IL-6Rs in patients with moderate to severe COVID-19 
pneumonia is currently unknown.  However, these limitations are mitigated by 
considering significantly greater levels of sIL-6Rs in patients with COVID-19 compared 
with what is known in patients with RA and the possibility of administering a second dose 
of TCZ.
3.3.3
Rationale for Biomarker Assessments
COVID-19 is a heterogeneous disease, and patients with severe COVID-19 infection 
have shown various levels of IL-6 pathway activation (Xu et al. 2020). Therefore, all 
patients may not be equally likely to respond to TCZ treatment.  
PD biomarkers (i.e., IL-6, sIL-6R, CRP, and ferritin) will be assessed to demonstrate 
evidence of pharmacological activity of TCZ in patients, to support selection of a 
recommended dose and dosing regimen, and to inform potential revisions to the PK 
sample collection schedule. 
The exploratory biomarkers will be assessed to further characterize TCZ mechanism of 
action in relation to efficacy and exposure. 


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4.
MATERIALS AND METHODS
4.1
PATIENTS
This study aims to enroll approximately 100 hospitalized patients with moderate to 
severe COVID-19 pneumonia.
4.1.1
Inclusion Criteria

Signed Informed Consent Form by any patient capable of giving consent, or, when 
the patient is not capable of giving consent, by his or her legally authorized 
representative

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol

Hospitalization with COVID-19 pneumonia confirmed by a positive PCR of any 
specimen (e.g., respiratory, blood, urine, stool, or other bodily fluids) and evidence 
of pneumonia on chest X-ray or CT scan 
The onset of patient symptoms must be at least 3 days prior to enrollment.

For severe patients, SpO2 93% or PaO2/FiO2 300 mmHg
If a patient is on supplemental oxygen with SpO2 93%, but desaturation to 93% 
on lower supplemental oxygen or ambient air is documented during screening, 
the inclusion criterion is met.

For moderate patients (those who do not qualify as severe based oxygen 
requirements), CRP 2ULN is required

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 90 days after the final dose of 
TCZ.  Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and is not permanently infertile 
due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another 
cause as determined by the investigator (e.g., Müllerian agenesis).  The
definition of childbearing potential may be adapted for alignment with local 
guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not adequate methods of contraception.  If required per local 


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guidelines or regulations, locally recognized adequate methods of contraception 
and information about the reliability of abstinence will be described in the local 
Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
60 days after the final dose of TCZ to avoid exposing the embryo.  Men must 
refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not adequate methods of preventing drug exposure.  
If required per local guidelines or regulations, information about the reliability of 
abstinence will be described in the local Informed Consent Form.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known severe allergic reactions to TCZ or other monoclonal antibodies

Active TB infection 

Suspected active bacterial, fungal, viral, or other infection (besides SARS-CoV-2) 

Patients who meet any of the following at the time of randomization: on a mechanical 
ventilator 24 hours, on ECMO, in shock, or with other organ failure requiring 
treatment in an ICU

In the opinion of the investigator, progression to death is imminent and inevitable 
within the next 24 hours, irrespective of the provision of treatments

Receipt of oral anti-rejection or immunomodulatory drugs (including TCZ) within the 
past 3 months

Participation in other drug clinical trials (participation in COVID-19 anti-viral trials 
may be permitted if confirmed by the Medical Monitor)

ALT or AST 10ULN detected within 24 hours at screening or at baseline 
(according to local laboratory reference ranges)

ANC 1000/L at screening and baseline (according to local laboratory reference 
ranges)

Platelet count 50,000/L at screening and baseline (according to local laboratory 
reference ranges)

Pregnancy or breastfeeding, or positive pregnancy test at a predose examination

Treatment with an investigational drug within 5 drug-elimination half-lives or 30 days 
(whichever is longer) of randomization (investigational SARS-CoV-2 [COVID-19])
anti-viral agents may be permitted after consultation with the Medical Monitor)


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
Any serious medical condition or abnormality of clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion 
of the study
4.2
METHOD OF TREATMENT ASSIGNMENT
4.2.1
Treatment Assignment
This is a randomized, open-label study with an active comparator and no placebo.  After 
initial written informed consent has been obtained, all screening procedures and 
assessments have been completed and eligibility has been established for a patient, the 
study site will obtain the patient's identification number and treatment assignment from 
an interactive voice or web-based response system (IxRS).
Patients will be randomly assigned to one of two treatment arms:  8 mg/kg IV TCZ dose 
(the comparator) or 4 mg/kg IV TCZ (experimental treatment); in addition, patients in both 
arms will receive SOC treatment.  Randomization will occur in a 1:1 ratio through use of a 
permuted-block randomization method to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified by pneumonia type (moderate, severe).  
The number of patients who have moderate COVID-19 pneumonia will be capped at no 
more than 50% of the overall study population.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is IV TCZ.
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
Tocilizumab
TCZ will be supplied by the Sponsor as a sterile IV injection for reconstitution in 20-mL 
glass vials with a 10 mL fill in each (200 mg /10 mL of TCZ).  An appropriate number of 
vials (depending on the patient’s bodyweight) of TCZ will be assigned to each patient for 
the infusion.  The amount of solution that is withdrawn from each vial will depend on the 
patient’s allocated dose.  For information on the formulation and handling of TCZ, see 
the TCZ pharmacy manual and Tocilizumab Investigator's Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
TCZ will be administered to patients by IV infusion at doses of 8 mg/kg or 4 mg/kg.  The 
maximum dose of TCZ that will be administered is 800 mg. The dose of TCZ infusion 
will be calculated on the basis of body weight measured prior to infusion.  One additional 
infusion of TCZ can be given within 8 to 24 hours after the initial infusion.
TCZ must be administered under close supervision of the investigator in a setting where 
medications and resuscitation facilities are available.  Patients should be monitored for 
at least 2 hours after the TCZ infusion is completed. 


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TCZ vials will be stored at a temperature of 2C–8C. The infusion bag of TCZ should 
be diluted to 100-mL infusion bag using aseptic technique.  The fully diluted TCZ 
solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 
2C8C (36F46F) or at room temperature for up to 24 hours and should be 
protected from light.  
If stored at 2C8C (36F46F), the infusion bag should be allowed to return to room 
temperature prior to administration.  TCZ will be administered at room temperature by 
controlled infusion into a vein over a 1-hour period. In exceptional cases, this time may 
be extended up to 6 hours.  The infusion speed must be 10 mL/hr for 15 minutes and 
then increased to 130 mL/hr to complete the dosing in 1 hour.  The entire 100-mL
content of the infusion bag must be administered.  A total of 20 mL of normal saline will 
be administered following the infusion of study drug to flush the remaining study drug 
through the IV set.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration eCRF.  Cases of accidental overdose or medication error
along with any associated adverse events should be reported as described in 
Section 5.3.5.10.
Refer to the Tocilizumab Investigator’s Brochure for further instructions regarding 
recommended storage conditions and packaging configuration.
4.3.3
Investigational Medicinal Product Handling and Accountability
The IMP (TCZ) required for completion of this study will be provided by the Sponsor. 
The study site (i.e., investigator or other authorized personnel [e.g., pharmacist) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, 
IMP use by each patient, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that patients are provided with doses 
specified by the protocol.
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions, with access limited to the investigator and 
authorized staff.
Only patients enrolled in the study may receive TCZ, and only authorized staff may 
supply or administer TCZ.


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TCZ will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMP received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log.
Refer to the pharmacy manual and/or the Tocilizumab Investigator's Brochure for 
information on IMP handling, including preparation storage, and accountability. 
4.3.4
Continued Access to Tocilizumab
Since the TCZ treatment is not intended for continued therapy, the Sponsor does not 
have any plans to provide Roche TCZ or any other study treatments to patients who 
have completed the study.  
The Roche Global Policy on Continued Access to Investigational Medicinal Product, 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements, 
investigational anti-viral agents, blood products) used by a patient in addition to 
protocol-mandated treatment from 7 days prior to initiation of study drug to the study 
completion/discontinuation visit.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications electronic Case Report Form 
(eCRF).
4.4.1
Permitted Therapy
All patients will receive SOC treatment per local practice for the treatment of COVID-19 
pneumonia.  SOC may include anti-viral treatment, low-dose steroids, and supportive 
care.
Chloroquine or hydroxychloroquine (with or without azithromycin) is permitted as part of 
local practice. Chloroquine is recommended with a maximum dose of 400 mg twice a 
day.
Clinical management guidelines from the WHO recommend against the use of 
corticosteroids in patients with COVID-19 pneumonia.  However, region-specific 
guidelines recommend considering corticosteroids in some patients with COVID-19 
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If steroids are given, the Sponsor recommends a dose of no more than 1 mg/kg 
methylprednisolone or equivalent for no more than 5 days.
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, ranitidine), 
or equivalent medications per local standard practice.  Serious infusion associated 
events manifested by, for example, dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress should be managed with 
supportive therapies as clinically indicated (e.g., supplemental oxygen and 2-adrenergic 
agonists).
4.4.2
Cautionary Therapy
4.4.2.1
Medications Given with Precaution due to Effects Related to 
CYP Enzymes
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines 
(e.g., IL-6) during states of chronic inflammation.  Therefore, for molecules that 
antagonize cytokine activity, such as TCZ, it is expected that the formation of CYP450 
enzymes could be normalized.  When starting TCZ therapy, patients taking medications 
that are individually dose adjusted and metabolized by means of CYP450, CYP3A4, 
CYP1A2, or CYP2C9 (e.g., atorvastatin, calcium channel blockers, theophylline, warfarin, 
phenytoin, cyclosporine, or benzodiazepines) are recommended to be monitored as 
doses may need to be adjusted to maintain their therapeutic effect.
The above list of medications is not necessarily comprehensive.  The investigator should 
consult the prescribing information when determining whether a concomitant medication 
can be safely administered with study treatment.  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above.
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Treatment with any investigational agent (except for SARS-CoV-2 [COVID-19] 
anti-viral agents with approval of Medical Monitor), cell-depleting therapies, biologic 
agents (e.g., tumor necrosis factor antagonists or IL-6 and IL-6R therapies, including 
sarilumab, siltuximab), Janus kinase inhibitors (e.g., tofacitinib, baricitinib), alkylating 
agents (e.g., chlorambucil, cyclophosphamide), thalidomide, IV gamma globulin, 
anti-thymocyte globulin, and azathioprine during the study

Bone marrow transplantation with total lymphoid irradiation during the study


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
Plasmapheresis or extracorporeal photopheresis during the study

Immunization with a live or attenuated vaccine for the duration of a patient’s 
study participation
4.5
STUDY ASSESSMENTS 
The sequence of assessments at each visit will be standardized as follows (at visits 
required in the schedules of activities):

Efficacy assessments:  clinical status, clinical signs and symptoms, and 
oxygen saturation

Safety assessments:  recording of vital signs, review of adverse events, and 
concomitant medications

Laboratory samples:  On days when study drug is administered, all samples 
(including predose PK, safety, and biomarker samples) must be obtained within 
6 hours prior to study drug treatment, except for postdose samples for PK analyses, 
which will be obtained after study drug treatment.  

IV infusion of TCZ (only at baseline and an additional dose if needed)

Safety assessments and recording of vital signs post-TCZ administration (if 
applicable)
If patients are discharged from the hospital prior to Day 28, follow-up visits should occur 
twice a week through Day 28.  Patients are encouraged to return for onsite visits at least 
once a week, if possible; other follow-up visits may be conducted by telephone.  Patients 
should return to the site for the Day 28 visit.  After Day 28, all patients should have 
follow-up visits on Days 35, 45, and 60; the Day 35 and 45 visits may be conducted by 
telephone, whereas the Day 60 visit should be conducted in person. 
Patients who are discharged after Day 28 but prior to Day 60 should return for a study 
completion visit at Day 60 and be followed by telephone for visits at Days 35 and 45 if an
onsite visit is not feasible. 
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  The Informed 
Consent Form must be signed and dated by the patient or the patient's legally authorized 
representative or where allowed, health care provider consent on behalf of the patient before his or 
her participation in the study.  Due to the pandemic situation and restricted hospital access, 
where allowed, verbal consent may be given by the patient or the patient’s legally authorized 
representative and this must be documented by the investigator or authorized designee.  The case 
history or clinical records for each patient shall document the informed consent process and that 
informed consent was obtained prior to participation in the study.  Additional details concerning 
obtaining signed informed consent are available to sites and are based on the U.S. FDA’s updated 
guidance on conduct of clinical trials of medical products during COVID-19 public health 


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emergency (FDA 2020).  Informed Consent Forms for enrolled patients and for patients 
who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for
screening failure, as applicable.
4.5.2
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
home oxygen use, will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to the first 
dose of study drug will be recorded.  At the time of each follow-up physical examination, 
an interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal (GI), genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations may be performed at unscheduled 
postbaseline visits as clinically indicated.  Changes from baseline abnormalities should 
be recorded in patient notes.  New or worsened clinically significant abnormalities should 
be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs and Oxygen Saturation
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure, and body temperature. Peripheral oxygen saturation should 
also be measured at the same time as the vitals.  For patients requiring supplemental 
oxygen, the oxygen flow rate (in liters per minute [L/min]) and/or FiO2 should be 
recorded. 
In order to allow assessment of the NEWS2 score (see Section 4.5.5 and Appendix 4),
all of the vital sign parameters and oxygen saturation should be recorded together twice
per day, with approximately 12 hours in between, for the duration of a patient’s
hospitalization during the study. This is to ensure that the measurements reflect the 


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patient’s condition over the entire study day, whenever possible. If vital signs or oxygen 
saturation are measured more than once during a 12-hour period, the worst values 
(highest temperature, respiratory rate, and heart rate, lowest blood pressure, oxygen 
saturation, and consciousness level) during that period should be recorded on the eCRF.  
Following hospital discharge, these parameters should be recorded once at each return 
visit to the clinic. Vital signs and oxygen saturation will not be recorded if follow-up visits 
are conducted by telephone. 
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
4.5.5
Assessments Specific to National Early Warning Score 2
In addition to the vital measurements, the patient’s consciousness level and the 
presence or absence of respiratory support must be recorded.  The NEWS2 parameter 
for respiratory support is the selection of either air or “oxygen” and can include other 
forms of ventilation to maintain oxygen saturation (see Appendix 4).  The form of 
ventilation used should be recorded on the eCRF.
NEWS2 values do not need to be calculated by the site but will be calculated
electronically by the Sponsor based on vital sign parameters and NEWS2-related 
assessments recorded by the investigator on the appropriate eCRF. 
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Local Laboratory Assessments
Samples for the following laboratory tests will be measured by the study site's local 
laboratory:

Partial pressure of oxygen (PaO2, if arterial blood gases are performed during 
screening or follow-up)

Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes), and 
lymphocyte subsets (T cells, B cells, and natural killer cells; if the test is available at 
the site or if the site can ship the blood sample on the day of collection to the central 
laboratory for testing)

Chemistry panel (serum or plasma): bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, 
ALP, ALT, and/or AST, uric acid, LDH, D-dimer, CRP, and ferritin

Pregnancy test
All women of childbearing potential will have a pregnancy test at screening 
(urine or serum). If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test.


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
SARS-CoV-2 PCR (screening): nasopharyngeal swab, BAL or other respiratory
specimen, blood, urine, stool, or other bodily fluids
Central Laboratory Assessments
Samples for the following laboratory tests will be sent to designated central laboratories 
or to the Sponsor or a designee for analysis:

Serum samples for PK analysis

Serum and plasma samples for PD analysis (IL-6, sIL-6R, and CRP) and exploratory 
biomarker research

Serum samples for SARS-CoV-2 antibody titer

Nasopharyngeal swabs and BAL (if applicable) for SARS-CoV-2 virology tests 
(viral load and exploratory analysis)

Blood in PAXgene® tubes for RNA for sequencing or quantitative PCR

Blood for cryopreserved peripheral blood mononuclear cells isolation (for sites 
capable of sample collection or if the site can ship the blood sample on the day of 
collection to the central laboratory for isolation)

Blood for testing T cells, B cells, and natural killer cells (if the site ships the blood sample on 
the day of collection to the central laboratory for testing)
Exploratory biomarker research may include, but will not be limited to, analysis of 
inflammatory mediators and/or cytokines, ARDS-related variables, serum viral load, and 
virus resistance and mutation analysis.
In countries where acceptable, biomarker research may involve extraction of DNA, 
cell-free DNA, or RNA; analysis of mutations, single nucleotide polymorphisms, and 
other genomic variants; and genomic profiling through use of next-generation 
sequencing (NGS) of a comprehensive panel of genes.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions:

Serum samples collected for PK analysis may be needed for additional PK assay 
development and validation, and biomarker research; therefore, these samples will 
be destroyed no later than 15 years after the final Clinical Study Report has been 
completed.

Blood (serum, plasma, and peripheral blood mononuclear cells), blood RNA, and 
tissue-derived samples (nasopharyngeal swabs and BAL, if applicable) collected for 
PD analysis and biomarker research will be destroyed no later than 15 years after 
the final Clinical Study Report has been completed.


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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.7
Liver Function Monitoring
Patients should be assessed for liver function prior to each dose of TCZ.  On Day 1, the 
assessment is mandatory.  On Day 1, the local laboratory full blood chemistry panel 
required as part of screening can be used for this assessment or prior blood results if 
tests conducted within 24 hours prior to screening.  Results must be reviewed by the 
investigator prior to study drug administration.  Dosing will occur only if the clinical 
assessment and local laboratory liver chemistry panel values are acceptable.
4.5.8
Chest X-Ray and CT Scan
Either a chest CT scan or a chest X-ray are acceptable to determine eligibility and for 
follow-up. During the study, follow-up CT scans or chest X-rays will be performed 
according to the schedules of activities (see Appendix 1, Appendix 2, and Appendix 3).
Chest X-ray or CT scan findings should be recorded on the appropriate eCRF per the 
schedule of activities.  If additional chest X-rays or CT scans are performed per local 
practice, this information should be provided on the eCRF.
4.5.9
Electrocardiograms
Single ECG recordings will be obtained at screening, as outlined in the schedule of 
activities (see Appendix 1) and may be obtained thereafter as needed at the
investigator’s discretion.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  


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4.5.10
Ordinal Scale Determination
Assessment of clinical status using a 7-category ordinal scale will be recorded at 
baseline on Day 1 and then again once a day every morning (between 8 a.m. and 
12 p.m.) while a patient is hospitalized.  The ordinal scale categories are as follows:
1
Discharged (or “ready for discharge” as evidenced by normal body temperature and 
respiratory rate, and stable oxygen saturation on ambient air or 2 L supplemental 
oxygen)
2
Non-ICU hospital ward (or “ready for hospital ward”) not requiring supplemental 
oxygen
3
Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen
4
ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
5
ICU, requiring intubation and mechanical ventilation 
6
ICU, requiring ECMO or mechanical ventilation and additional organ support 
(e.g., vasopressors, renal replacement therapy)
7
Death
Patients who are ready to be discharged but are still hospitalized (e.g., because of 
non-medical or administrative reasons) will be assigned an ordinal scale category of 1. 
Patients in a non-ICU hospital ward who are eligible for ICU care based on clinical 
presentation but are awaiting ICU care will be assigned an ordinal scale category of 4.  
Patients in an ICU for administrative or non-medical reasons who are ready for a 
non-ICU hospital ward will be assigned an ordinal scale category of 2 (if not requiring 
supplemental oxygen), 3 (if requiring supplemental oxygen), or 4 (if requiring 
non-invasive ventilation or high-flow oxygen).
In general, patients with oxygen saturation consistently 90% should be considered for 
escalation to a higher clinical status category, while patients with oxygen saturation 
consistently 96% should be considered for de-escalation to a lower category.  Patients 
on supplemental oxygen should be evaluated at least daily and considered for reduction 
or discontinuation of oxygen support. Actual changes in level of support will be at the 
discretion of the clinician(s) treating the patient based on the patient’s overall condition 
and may be dictated by other clinical and nonclinical considerations. 
Normal body temperature is defined as oral, rectal, axillary, or tympanic temperature 
36.1C38.0C.  Normal respiratory rate is defined as 1220 breaths per minute.  
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment


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
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Any event that meets stopping criteria defined in Section 5.1.1

Severe allergic reaction to TCZ
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.
Patients who discontinue from the study treatment should continue in the study and 
complete all assessments through Day 60.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up
Every effort should be made to obtain a reason for patient discontinuation from the study.  
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  


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4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with TCZ in 
clinical studies and postmarketing experience.  The important safety risks for TCZ are 
outlined below.  Please refer to the Tocilizumab Investigator's Brochure for a complete 
summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events and laboratory abnormalities, including criteria for dosage modification 
and treatment interruption or discontinuation, are provided below.
5.1.1
Risks Associated with Tocilizumab
This section highlights the main risks for this study population and following one or two 
doses of TCZ.  For a complete list of all identified or potential risks of TCZ therapy, 
please refer to the current version of the Tocilizumab Investigator’s Brochure. 
5.1.1.1
Hypersensitivity Reactions, Including Anaphylaxis
An infusion reaction is defined as any adverse event that occurs during or within 
24 hours after the infusion.  This may include hypersensitivity or anaphylactic reactions.  
Stevens-Johnson syndrome has been reported during treatment with TCZ in the 
postmarketing setting.  Signs of a possible hypersensitivity reaction include, but are not 
limited to, the following:

Fever, chills, pruritus, urticaria, angioedema, and skin rash

Cardiopulmonary reactions, including chest pain, dyspnea, hypotension, or 
hypertension


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TCZ infusions will be administered to patients at the site under close supervision.  Health 
care professionals administering TCZ infusions should be trained in the appropriate 
procedures for TCZ administration, should be able to recognize the symptoms 
associated with potential hypersensitivity reactions, including anaphylaxis, and should 
have the appropriate medication available for immediate use in case of hypersensitivity 
reaction such as anaphylaxis during or after administration of TCZ.  The patient should 
be treated according to the SOC for management of the hypersensitivity reaction. 
If a patient has symptoms of serious hypersensitivity reactions, such as anaphylaxis, or 
requires an interruption of the study drug because of symptoms of hypersensitivity,
including anaphylaxis, administration of TCZ must be discontinued permanently.
5.1.1.2
Serious Infections and Opportunistic Infections
Physicians should exercise caution when considering the use of TCZ in patients at 
increased risk of infection, such as a history of recurring infections or with underlying 
conditions (e.g., diabetes mellitus), that may predispose patients to serious infections 
and opportunistic infections such as TB and viral reactivations (e.g., hepatitis B virus).  
Vigilance for timely detection of serious infection is recommended for patients receiving 
biologic agents, as signs and symptoms of acute inflammation may be lessened 
because of suppression of the acute-phase reaction.  The effects of TCZ on CRP and 
neutrophils, and the signs and symptoms of infection, should be considered when 
evaluating a patient for a potential infection.  It is recommended that neutropenic 
patients (ANC 1000/L) undergo weekly surveillance blood cultures during the study.
If a patient develops a serious infection, administration of TCZ should be discontinued.
5.1.1.3
Gastrointestinal Perforations
Symptomatic diverticulosis, diverticulitis, or chronic ulcerative lower GI disease, such as 
Crohn disease, ulcerative colitis, or other chronic lower GI conditions, might predispose 
patients to GI perforations.  Timely diagnosis and appropriate treatment may reduce the 
potential for complications of diverticular disease and thus reduce the risk of GI 
perforations.  
Discontinuation of TCZ is required for patients who develop GI perforations.
5.1.1.4
Hematologic Abnormalities
Decreases in neutrophil counts, platelet counts, and fibrinogen levels have been 
observed following treatment with TCZ for labeled indications.  Treatment-related 
neutropenia was not associated with serious infection in clinical trials in any indication,
and no association between decreases in platelet counts and serious bleeding events 
has been observed.


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5.1.1.5
Demyelinating Disorders
The effect of treatment with TCZ on demyelinating disorders is not known; events have 
been reported rarely.  Physicians should exercise caution when considering the use of 
TCZ in patients with preexisting or recent-onset demyelinating disorders.  
Patients should be closely monitored for signs and symptoms potentially indicative of 
central demyelinating disorders.  
5.1.1.6
Elevated Liver Enzymes
In clinical trials, mild and moderate elevations of hepatic transaminases have been 
observed with TCZ treatment. 
Recommended TCZ dose modifications for elevated liver enzymes in those populations 
are not applicable to this study owing to single-dose therapy (with possible additional 
infusion) with 4 mg/kg and 6 mg/kg TCZ.
Patients who develop elevated liver function test abnormalities during the study must 
have repeat tests performed as clinically indicated until levels return to baseline, even if 
they withdraw from the study. If the specialist deems a liver biopsy necessary, the 
prepared histologic slides will be requested by the Sponsor for central review by a third 
party, and the biopsy report should be forwarded to the Sponsor.
5.1.1.7
CYP450 Enzyme Normalization
The expression of hepatic cytochrome P450 (CYP450) enzymes is suppressed by
cytokines, such as IL-6, that stimulate chronic inflammation. TCZ normalizes expression 
of these enzymes.  The effect of TCZ on CYP450 enzymes (except CYP2C19 and
CYP2D6) is clinically relevant for CYP450 substrates with a narrow therapeutic index
and/or when the dose is individually adjusted.
When starting or stopping therapy with TCZ, patients taking medicines that are
individually dose adjusted and are metabolized by means of CYP450 CYP3A4, CYP1A2, 
CYP2B6, or CYP2C9 (e.g., atorvastatin, calcium-channel blockers, theophylline, warfarin,
phenprocoumon, phenytoin, cyclosporine, or benzodiazepines) should be monitored as
doses of these products may need to be adjusted to maintain their therapeutic effect.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.7
and 5.3.5.8 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.9)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 


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see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Serious and/or medically significant infections

Myocardial infarction or acute coronary syndrome

GI perforations

Anaphylaxis or hypersensitivity reactions 

Stroke

Serious and/or medically significant bleeding events

Serious and/or medically significant hepatic events

Demyelinating disorders
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported during the 60-day
follow-up period.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 1 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 1
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 2}:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
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Table 2
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.


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
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of COVID-19 pneumonia.


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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed solely to progression of COVID-19 pneumonia, "COVID-19 
pneumonia progression" should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.7
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.8
Lack of Efficacy or Worsening of COVID-19 Pneumonia
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events (with the exception of 
death due to COVID-19 pneumonia progression as described in Section 5.3.5.6).  These 
data will be captured as efficacy assessment data only.  If there is any uncertainty as to 
whether an event is due to disease progression, it should be reported as an adverse 
event.
5.3.5.9
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.10
Cases of Accidental Overdose or Medication Error
Accidental overdose and medication error hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For TCZ, 
adverse events associated with special situations should be recorded as described 
below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated TCZ, regardless of whether they result in an 
adverse event, should be recorded on the Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 


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dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.11
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Medical Monitors and Emergency Medical Contacts
Contact Information for All Sites
Medical Monitor:
, M.D. (Primary)
Telephone No.:
Alternate Contact Information for All Sites
Medical Monitor:
, M.D. (Secondary)
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.


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5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported during the 60-day follow-up period.  Investigators should record
all case details that can be gathered immediately (i.e., within 24 hours after learning of 
the event) on the Adverse Event eCRF and submit the report via the electronic data 
capture (EDC) system.  A report will be generated and sent to Roche Safety Risk 
Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should counsel 
the patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
60 days after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  


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If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.


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5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow-up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
60 days after study initiation), if the event is believed to be related to prior study drug
treatment.  These events should be reported through use of the Adverse Event eCRF.  
However, if the EDC system is not available, the investigator should report these events 
directly to the Sponsor or its designee, either by faxing or by scanning and emailing the 
paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
Tocilizumab
Tocilizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
A modified intent-to-treat (mITT) population will be used to perform all statistical 
analyses.  All patients randomized and receiving at least one dose of TCZ will be 
included.  All reasons for exclusion will be properly documented and the criteria for them 


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set before database lock.  Intercurrent events like rescue therapy will be addressed with 
sensitivity analyses defined in the Statistical Analysis Plan and Data Analysis Plan.
6.1
DETERMINATION OF SAMPLE SIZE
The purpose of this open-label study is the comparison of TCZ pharmacokinetics and PK-PD
relationship between two doses of TCZ (8 and 4 mg/kg) in hospitalized patients with 
moderate to severe COVID-19 pneumonia.  The comparison will be assessed using modeling 
and evaluating the safety and efficacy measures between Day 1 and Day 28 postrandomization.  
Data from the follow-up period from Days 28 to 60 may also be assessed.  Approximately
100 patients will be enrolled and randomized in a 1:1 ratio to the 8-mg/kg and 4-mg/kg 
IV TCZ arms in this study.  Disease severity type will also be stratified into moderate and 
severe COVID pneumonia, giving an overall equal four-way split between the two doses and type 
of disease severity and resulting in four groups of approximately 25 patients each.  Patients may 
receive a repeat dose within 8 to 24 hours after the first TCZ dose if clinicians judge it is 
necessary (resulting in a TCZ dose range from 4 to 16 mg/kg, with a maximum dose of 
800 mg).  The variability of PK parameters of TCZ in a heterogeneous COVID-19 population in 
an acute setting is unknown; however, 20 to 30 patients is deemed adequate considering the 
between-subject variability in health volunteers and patients with RA provided by population-PK 
modeling.  Data quality issues, patient dropouts, and early hospital discharge may all lead to 
missing data, especially in a pandemic setting; thus, enrolling 50 patients according to dose and 
disease severity type (25 per arm) may offset missing data and allow an adequate volume of PK 
and PD data to inform the population-PK model and allow a comparison of the 4- and 8-mg/kg 
doses.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (including, but not limited to, age, sex,
race/ethnicity, severity, NEWS2 score, ordinal scale for clinical status, IL-6, IL-6R, 
mechanical ventilation, anti-viral treatment, and previous and concomitant medications 
(e.g., steroids and drug exposure) will be summarized using means, SDs, medians, and 
ranges for continuous variables and proportions for categorical variables, as appropriate.  
Summaries will be presented overall and by treatment arm.
Medical history data, including surgery and procedures, and conditions other than 
COVID-19 pneumonia, will be summarized descriptively by treatment arm using the 
safety-evaluable population.


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6.4
PHARMACODYNAMIC ANALYSES
The PD outcome measures for this study are serum IL-6, sIL-6R, ferritin, and CRP levels at 
baseline and at specified timepoints after initiation of study drug.  Data for all PD biomarkers 
will be presented using descriptive summary statistics, including the mean, median, range, SD, 
and coefficient of variation.
6.5
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of patients with sufficient data to enable 
estimation of key parameters (e.g., area under the concentrationcurve [AUC], 
maximum serum concentration observed [Cmax]), with patients grouped according to 
treatment received.  
Non-linear mixed effects modeling will be used to analyze the serum TCZ concentration 
over time data collected in this study using existing population-PK models.  Individual 
and mean serum TCZ concentration versus time data will be tabulated and plotted by 
dose level.  The serum pharmacokinetics of TCZ will be summarized by estimating the 
total exposure (AUC), Cmax, total clearance, and volume of distribution.  Estimates for 
these parameters will be tabulated and summarized (mean, SD, co-efficient of variation, 
median, minimum, and maximum).  Interpatient variability will be evaluated.
Additional PK analyses will be conducted as appropriate.  The PK parameters derived 
from these analyses may be used for exploratory graphical analyses of the PD
parameters.
6.6
SAFETY ANALYSES
Safety assessments will be performed on the safety-evaluable population, which 
consists of all patients who receive any amount of study drug.  In all safety analyses, 
patients will be grouped according to the treatment that patients actually receive rather 
than the treatment assigned at randomization.  
Safety will be assessed through descriptive summaries of treatment emergent adverse 
events (nature, frequency, severity, and causality). Adverse events will also be listed.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0 scale.
The proportion of patients with any posttreatment infection will be summarized by 
timepoint, including Day 60.
A treatment-emergent adverse event is defined as any new adverse event reported or 
any worsening of an existing condition on or after the first dose of study drug.


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Separate summaries will be generated for serious adverse events, deaths, adverse 
events leading to discontinuation of study drug, and adverse events of special interest.
Adverse events will be summarized by MedDRA term, appropriate thesaurus level, and 
toxicity grade.
Descriptive summaries of laboratory values outside the normal range, including both higher 
and lower values, from baseline throughout the study will be tabulated by treatment arm.  
Values, along with change from baseline, will be summarized using descriptive statistics 
for each vital sign parameter.
COVID-19 (SARS-CoV-2) viral load over time, as collected by nasopharyngeal swab and 
BAL samples (if applicable) will be summarized descriptively by timepoint and treatment 
arm.
Time to RT-PCR COVID-19 virus negativity will be analyzed using similar methods to the 
other time to analyses.
6.7
EXPLORATORY ANALYSES
The exploratory objective for this study is to assess the efficacy of two different doses of 
TCZ in combination with SOC treatment for the treatment of moderate to severe 
COVID-19 on the basis of the endpoints presented in Section 2.4.
The analysis population for the exploratory analyses will consist of the mITT population (i.e., all 
randomized patients who receive at least one dose of TCZ).
Any subgroup analysis will be of exploratory nature.
6.8
EXPLORATORY BIOMARKER ANALYSIS
Although no formal statistical analysis of exploratory biomarkers will be performed, 
data may be analyzed in the context of this study and in aggregate with data from 
other studies.  
6.9
INTERIM ANALYSES
6.9.1
Periodic Safety Reviews
Periodic safety reviews will be performed on unblinded data when at least 10 patients 
per arm have been in the study for at least 7 days. The number of subsequent safety reviews, 
including PK data, will depend on the recruitment rate.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 


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eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Because of the pandemic situation, access to hospitals is restricted; therefore, only 
remote data monitoring will be performed for this study.  Study monitors will perform 
ongoing remote data review to confirm that critical protocol data (i.e., source data) 
entered on the eCRFs by authorized site personnel are accurate and complete. Sites 
will be asked to implement a quality control step of a second person reviewing the data 
entry on the eCRFs where possible.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at pharmacies, laboratories, and medico-technical departments involved in a clinical 
trial.


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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly on the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.


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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative or where allowed, health care provided consent on behalf of 
the patient before his or her participation in the study.  Due to the pandemic situation 
and restricted hospital access, where allowed, verbal consent may be given by the 
patient’s legally authorized representative and this must be documented by the 
investigator or authorized designee.  The case history or clinical records for each patient 
shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 


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to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators 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 health 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 (see definition of end of 
study in Section 3.2).


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks. Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters. Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed. Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted remotely by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.


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Approximately 25 sites in the United States will participate to enroll approximately 
100 patients.  Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 
Section 4.5.6.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
9.6
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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[FDA] Food and Drug Administration, Center for Drug Evaluation and Research, BLA 
Multidisciplinary Revew and Evaluation, BLA 125276 S-114, Actemra 
(tocilizumab), 2017. Reference ID: 414563. [Resource on the Internet.] 
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[FDA] Food and Drug Administration. FDA guidance on conduct of clinical trials of medical 
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hematological effects using a modeling approach. J Pharmacokinet Pharmacodyn 
2012;39:516. Epub: 19 November 2011.
Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in
China. N Engl J Med 2020. doi: 10.1056/NEJMoa2002032. [Epub ahead of print.]
Guo CG, Li B, Ma H, et al. Tocilizumab treatment in severe COVID-19 patients 
attenuates the 2 inflammatory storm incited by monocyte centric immune 
interactions 3 revealed by single-cell analysis [Resource on the internet].  Available 
from: https://www.biorxiv.org/content/10.1101/2020.04.08.029769v1; cited: 20 April 
2020. doi: https://doi.org/10.1101/2020.04.08.029769.
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lancet 2020;395:497506.
Klopfenstein T, Zayet S, Lohse A, et al. Tocilizumab therapy reduced intensive care unit 
admissions and/or mortality in COVID-19 patients, M´edecine et Maladies Infectieuses  
(2020). [Resource on the internet.] Available at: 
https://doi.org/10.1016/j.medmal.2020.05.001.
Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of 
chimeric antigen receptor T cell-induced severe or life-threatening cytokine release 
syndrome. Oncologist 2018;23:943–47.


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Luo P, Liu Y, Qiu L, et al. Tocilizumab treatment in COVID-19: a single center 
experience. J Med Virol 2020;1#5. doi: 10.1002/jmv.25801.
National Health Commission. China guidelines for the diagnosis and treatment plan of 
novel coronavirus (2019-nCoV) infection (trial Version 5). [Resource on the 
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e67/files/7a9309111267475a99d4306962c8bf78.pdf.
Rueda J, González-Gay MA, Blanco R. Tocilizumab for rheumatoid arthritis: results of 
the Phase III clinical trial program. Clin Invest 2011;1:345#54.
Sciascia S, Aprà F, Baffa A, et al. Pilot prospective open, single-arm mulicentre study on off-label 
use of tocilizumab in patients with severe COVID-19. Clin Exper Rheumatol 
2020;38:1#4
Toniati P, Piva S, Cattalini M, et al. Tocilizumab for the treatment of severe COVID-19 
pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single 
center study of 100 patients in Brescia, Italy. [Resource on the internet.] Autoimmunity 
Rev 2020. Available at: https://doi.org/10.1016/j.autrev.2020.102568.
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novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020. 
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[Resource on the internet]. 2020a [updated: 2 April 2020; cited: 2 April 2020]. 
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respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected
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from the Chinese Center for Disease Control and Prevention. JAMA 2020. 
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tocilizumab. ChinaXiv preprint. [Resource on the internet]. 2020 [updated: 5 March 
2020; cited: 17 March 2020]. Available at:
http://www.chinaxiv.org/abs/202003.00026.


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Appendix 1
Schedule of Activities:  Days 1 and 2
Time after Initial Treatment
(Assessment Window)
Screening a
Day 1
Day 2
Baseline
24 hr
4 hr)
Days
2 to 0
0
Predose 
(4 hr)
15 min Postinfusion
(1 hr)
Informed consent
x
Review of inclusion and exclusion 
criteria
x
x
Demographics
x
Randomization
x
Medical history
x
Complete physical examination c
x
Weight
x
COVID-19 diagnosis d
x
Chest X-ray or CT scan
x
ECG
x
Pregnancy test f
x
PaO2/FiO2 g
x
Optional
SpO2 h
x
x
x
x
Vital signs h
x
x
x
x
Ordinal scoring i
x
x
Adverse events j
x
x
Concomitant medications k
x
x


Appendix 1: Schedule of Activities:  Days 1 and 2 (cont.)
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Time after Initial Treatment
(Assessment Window)
Screening a
Day 1
Day 2
Baseline
24 hours
4 hr)
Days
2 to 0
0
Predose 
(4 hr)
15 minutes 
Postinfusion
(1 hr)
Hematology l
x
(24 hr) m
x
x
Chemistry panel n
x
(24 hr) m
x
x
Study drug administration o
x
Central laboratory assessments
Serum PD sample (CRP, IL-6,
and sIL-6R) p
x p
x p
x
Serum PK sample q
x q
x q
x
Serum and plasma samples for 
exploratory biomarkers 
x
x
SARS-CoV-2 viral load r
x
x
Serum SARS-CoV-2 antibody titer
x
Cryopreserved PBMCs s
x
x
Blood in PAXgene® tubes for RNA 
analyses t
x
CRPC-reactive protein; CTcomputed tomography; ECGelectrocardiogram; eCRFelectronic Case Report Form; 
IL-6interleukin-6; NEWS2National Early Warning Score 2; PaO2/FiO2 arterial oxygen partial pressure/fraction of 
inspired oxygen; PBMCperipheral blood mononuclear cell; PCRpolymerase chain reaction; 
PDpharmacodynamic; PK pharmacokinetic; SARS-CoV-2severe acute respiratory syndrome corona virus (strain) 
2; sIL-6Rsoluble interleukin-6 receptor; SpO2peripheral capillary oxygen saturation; TCZtocilizumab.


Appendix 1: Schedule of Activities:  Days 1 and 2 (cont.)
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Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a Results from standard-of-care tests or examinations performed prior to obtaining informed consent and within
48 hours before randomization may be used; such tests do not need to be repeated for screening.  An exception to 
this is clinical chemistry and hematology tests obtained prior to informed consent, which do not need to be repeated for 
screening if conducted within 24 hours before randomization.
b Informed consent must be documented before any study-specific screening procedure is performed.
c A complete physical examination, performed at screening and per the investigator’s discretion during the study, 
includes an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality identified at 
screening should be recorded on the General Medical History and Baseline Conditions eCRF. New or worsened 
clinically significant abnormalities identified during the study should be reported as adverse events. 
d COVID-19 test (SARS-CoV2 PCR) to confirm diagnosis should be performed within 7 days of randomization. 
e Screening chest X-ray or CT scans should be performed within 48 hours prior to randomization.  If additional chest 
X-rays or CT scans are taken per local practice during the study, this information should be provided on the eCRF. 
f
For women of childbearing potential, including those who have had a tubal ligation, positive urine test results will be 
confirmed with a serum pregnancy test.  Study drug infusion must not be administered unless the serum pregnancy 
test result is negative.
g If arterial blood gases are measured.
h All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body 
temperature), oxygen saturation and NEWS2-specific assessments (i.e., consciousness and presence or absence 
of oxygen support) should be recorded together twice daily with approximately 12 hours in between while the 
patient remains hospitalized.  If measured more than once during a 12-hour period, the worst values (highest 
temperature, respiratory rate, and heart rate; lowest blood pressure, oxygen saturation, and consciousness level) 
during that period should be recorded on the eCRF.  
i
Assessment of clinical status using the ordinal scale should be recorded at baseline (Day 1, Visit 1) and then again 
daily every morning (between 8 a.m. and 12 p.m.) for patients who remain hospitalized.
j
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused 
by a protocol-mandated intervention should be reported.  After initiation of study drug, all adverse events will be 
reported until 60 days after the final dose of study drug.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior study drug 
treatment (see Section 5.6).


Appendix 1: Schedule of Activities:  Days 1 and 2 (cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
79/Protocol CA42481, Version 2
k Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study 
drug to the study completion/discontinuation visit.
l
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes), and lymphocyte subsets (T cells, B cells, and 
natural killer cells; if the test is available at the site).
m Hematology and chemistry panel assessments performed as part of standard of care, prior to consent but within 24 hours of 
randomization, do not need to be repeated.
n Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for 
the region), sodium, potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total bilirubin, ALP, ALT, and/or AST, uric acid, LDH, CRP, ferritin, and D-dimer.
o Study drug should be administered after collection of all samples for PK, PD, and exploratory biomarkers.  The 
initial study drug infusion should be given within 4 hours of randomization.  For patients in both arms of the study, if a 
patient has a sustained fever or clinically significant worsening of signs or symptoms (e.g., an increased supplemental oxygen 
requirement), one additional infusion of TCZ at the same dose as the initial infusion can be given within 8 to 24 hours after the 
initial TCZ infusion.
p On Day 1, CRP, IL-6, and sIL-6R samples should be drawn 04 hours before the start of infusion and then within 
15 minutes (to 1 hour) after the end of the infusion from the opposite arm as the infusion.  Patents receiving a 
second infusion of study drug should provide extra samples for CRP, IL-6, and sIL-6R prior to and 15 minutes after 
the end of the infusion from the opposite arm as the infusion. If the second infusion falls within the window for the 
Day 2 PD sample (2024 hours) for the first infusion, it can be combined with the postinfusion sample for the second infusion.
q On Day 1, PK samples should be drawn 04 hours before the start of infusion and then within 15 minutes (to 
1 hour) after the end of the infusion from the opposite arm as the infusion.  Patents receiving a second infusion of 
study drug should provide an extra PK sample prior to and 15 minutes (to 1 hour) after the end of the infusion from
the opposite arm as the infusion.  If the second infusion falls within the window for the Day 2 PK sample (2024 hours) for 
the first infusion, it can be combined with the postinfusion sample for the second infusion.
r
Viral load will be assessed by nasopharyngeal swab.  Patients who are intubated and undergo bronchoalveolar 
lavage will have samples taken for virological assessment.  It may only be possible to access one nostril if a patient 
has a nasogastric tube in place, in which case sites may collect a sample from one nostril only and when possible 
the same nostril should be used. 
s
For sites capable of sample collection for analysis of T cells by high-dimensional cytometry.
t
The PAXgene® blood tube should be the last tube drawn in the phlebotomy procedure to avoid contact with the RNA 
preservation reagent inside the tube.


Tocilizumab—F. Hoffmann-La Roche Ltd
80/Protocol CA42481, Version 2
Appendix 2
Schedule of Activities:  Days 328
Study Day
Days 328 a
Early Tx or
Study
Discon
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Chest X-ray or CT scan
x
x
x
x
x
Vital signs b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PaO2/FiO2 c
Optional 
Optional
SpO2 b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Ordinal scoring d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology g
x
x
x
x
x
x
x
Chemistry profile h
x
x
x
x
x
x
x
Central laboratory assessments
Serum PD sample (CRP, 
IL-6, and sIL-6R)
x
x
x
x
x
x
Serum PK sample
x
x
x
x
x
x
Serum and plasma samples
for exploratory biomarkers
x
x
x
x
x
x
SARS-CoV-2 viral load i
x
x
x
x
x
x
x
x
x
x
Serum SARS-CoV-2 
antibody titer
x
x
Cryopreserved PBMCs j
x
x
x
x
x
x


Appendix 2: Schedule of Activities:  Days 328 (cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
81/Protocol CA42481, Version 2
Study Day
Days 328 a
Early Tx or 
Study
Discon
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Blood in PAXgene®
tubes for RNA analyses k
x
x
x
x
CRPC-reactive protein; CTcomputed tomography; Discondiscontinuation; ECG electrocardiogram; eCRFelectronic Case Report Form; 
IL-6interleukin-6; NEWS2National Early Warning Score; PaO2/FiO2arterial oxygen partial pressure/fraction of inspired oxygen;
PBMCperipheral blood mononuclear cell; PDpharmacodynamic; PKpharmacokinetic; SARS-CoV-2severe acute respiratory syndrome corona 
virus (strain) 2; sIL-6Rsoluble interleukin-6 receptor; SpO2peripheral capillary oxygen saturation; Txtreatment; TCZtocilizumab.
Note:  For patients who have been discharged, all assessments should be performed within 3 days of the scheduled onsite visit.
a If patients are discharged from hospital prior to Day 28, follow-up visits should occur twice weekly through Day 28.  Patients are encouraged to 
return for onsite visits at least weekly if possible; other follow-up visits may be conducted by telephone or home visits.  Patients should return to 
the site for the Day 28 visit.
b All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body temperature), oxygen saturation 
and NEWS2-specific assessments (i.e., consciousness and presence or absence of oxygen support) should be recorded together twice daily 
with approximately 12 hours in between while the patient remains hospitalized.  If measured more than once during a 12-hour period, the worst 
values (highest temperature, respiratory rate, and heart rate; lowest blood pressure, oxygen saturation, and consciousness level) during that 
period should be recorded on the eCRF.  Following hospital discharge these parameters should be recorded once at each return visit to the 
clinic.  Vital signs and oxygen saturation will not be recorded if follow-up visits are conducted by telephone. 
c If arterial blood gases are measured.
d Assessment of clinical status using the ordinal scale should be recorded at baseline (Day 1, Visit 1) and then again daily every morning (between 
8 a.m. and 12 p.m.) for patients who remain hospitalized.
e After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 60 days after the final dose of study drug.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to 
prior study drug treatment (see Section 5.6).
f
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug to the study completion/discontinuation visit. 
g Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes), and lymphocyte subsets (T cells, B cells, and natural killer cells; if the test is available at the site).


Appendix 2: Schedule of Activities:  Days 328 (cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
82/Protocol CA42481, Version 2
h Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and/or AST, 
uric acid, LDH, ferritin, and D-dimer.
i
Viral load will be assessed by nasopharyngeal swab.  Patients who are intubated and undergo bronchoalveolar lavage will have samples taken 
for virological assessment.  It may only be possible to access one nostril if a patient has a nasogastric tube in place, in which case sites may 
collect a sample from one nostril only and when possible the same nostril should be used.
j
For sites capable of sample collection for analysis of T cells by high-dimensional cytometry.
k The PAXgene® blood tube should be the last tube drawn in the phlebotomy procedure to avoid contact with the RNA preservation reagent inside the 
tube..


Tocilizumab—F. Hoffmann-La Roche Ltd
83/Protocol CA42481, Version 2
Appendix 3
Schedule of Activities:  After Day 28
Study Day
(Assessment Window)
Study Completion
35 a
(3 days)
45 a
(3 days)
60
(3 days)
Chest X-ray or CT scan
x
SARS-CoV-2 viral load b
x
x
x
Vital signs c
x
x
x
SpO2 c
x
x
x
Ordinal scoring d
x
x
x
Adverse events e
x
x
x
Concomitant medications f
x
x
x
Hematology g
x
x
x
Chemistry panel h
x
x
x
Central laboratory assessments
Serum PD sample (CRP, IL-6, and sIL-6R)
x
x
Serum PK sample
x
x
Serum and plasma samples for exploratory biomarkers
x
x
SARS-CoV-2 viral load i
x
Cryopreserved PBMCs j
x
Blood in PAXgene® tubes for RNA analyses k
x
Serum SARS-Cov-2 antibody titer
x
CRPC-reactive protein; CTcomputed tomography; eCRFelectronic Case Report Form; IL-6interleukin-6; 
PDpharmacodynamic; PK pharmacokinetic; SARS-CoV-2severe acute respiratory syndrome corona virus (strain) 2; 
sIL-6Rsoluble interleukin-6 receptor; SpO2peripheral capillary oxygen saturation.


Appendix 3: Schedule of Activities:  After Day 28 (cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
84/Protocol CA42481, Version 2
a If patients are unable to return for onsite visits at Day 35 and/or Day 45, these may be conducted by telephone or 
home visits.  Patients should return to the site for the Day 60 study completion visit.
b Patients who remain in hospital will have viral load assessed by nasopharyngeal swabs; these will be done if there is 
evidence of ongoing infection.
c For patients who remain in the hospital, vital sign measurements and NEWS2-specific assessments should be 
conducted twice daily.  Following hospital discharge, these parameters should be recorded once at each return visit to 
the clinic.  Vital signs and oxygen saturation will not be recorded if follow-up visits are conducted by telephone.
d Assessment of clinical status using the ordinal scale should be recorded at baseline (Day 1, Visit 1)and then again 
daily every morning (between 8 a.m. and 12 p.m.) for patients who remain hospitalized.
e After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a 
protocol-mandated intervention should be reported.  After initiation of study drug, all adverse events will be reported 
until 60 days after the final dose of study drug.  After this period, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior study drug treatment 
(see Section 5.6).
f
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug 
to the study completion/discontinuation visit.
g Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes), and lymphocyte subsets (T cells, B cells, and natural killer cells).  
Hematology labs will not be performed if follow-up visits are conducted by telephone.
h Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the 
region), sodium, potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, 
total bilirubin, ALP, ALT, and/or AST, uric acid, LDH, ferritin, and D-dimer.  Chemistry laboratory assessments will not 
be performed if follow-up visits are conducted by telephone.
i
Viral load will be assessed by nasopharyngeal swab.  Patients who are intubated and undergo bronchoalveolar lavage will have 
samples taken for virological assessment.  It may only be possible to access one nostril if a patient has a nasogastric tube in place, 
in which case sites may collect a sample from one nostril only and when possible the same nostril should be used.
j
For sites capable of sample collection for analysis of T cells by high-dimensional cytometry.
k The PAXgene® blood tube should be the last tube drawn in the phlebotomy procedure to avoid contact with the RNA preservation 
reagent inside the tube.


Tocilizumab—F. Hoffmann-La Roche Ltd
85/Protocol CA42481, Version 2
Appendix 4
National Early Warning Score 2 (NEWS2)
SpO2oxygen saturation. 
Oxygen saturation (SpO2) should be scored according to either the SpO2 Scale 1 or 2 
presented in the table above.  The SpO2 Scale 2 is for patients with a target oxygen 
saturation requirement of 88%92% (e.g., in patients with hypercapnic respiratory failure 
related to advanced lung diseases, such as chronic obstructive pulmonary disease).  
This should only be used in patients confirmed to have hypercapnic respiratory failure by 
blood gas analysis on either a prior or their current hospital admission.
The decision to use the SpO2 Scale 2 should be made by the treating physician and 
should be recorded in the eCRF.  In all other circumstances, the SpO2 Scale 1 should be 
used.
For physiological parameter “Air or Oxygen?”:  Any patients requiring the use of oxygen 
or other forms of ventilation to maintain oxygen saturations and support respiration 
should be assigned a score of 2.
The consciousness level should be recorded according to the best clinical condition of 
the patient during the assessment.  Patients who are assessed as “Alert” (A) should be 
assigned a score of 0.  Patients assessed as “New Confusion” (C), “Responsive to Voice” 
(V), “Responsive to Pain” (P), or “Unconscious” should be assigned a score of 3.


Appendix 4: National Early Warning Signs Score 2 (NEWS2) (cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
86/Protocol CA42481, Version 2
Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and 
temperature according to the table above. 
NEWS2 values will be calculated electronically throughout the study by the Sponsor 
based upon entry of vital sign parameters by the investigator on the appropriate 
electronic Case Report Form.
Example Case Calculation:
An 82-year-old woman was admitted, tested positive to COVID-19, and admitted to 
high-dependency unit for non-invasive ventilation.  Her taken observations and 
corresponding NEWS2 score are as follows: 
Physiological Parameter 
Observation
Component Score
Respiratory rate (per minute)
26
3
Oxygen saturation (SpO2 %)
95%
1
Supplemental oxygen 
Yes
2
Systolic blood pressure (mmHg)
95
2
Pulse rate (bpm)
109
1
Conscious level
New confusion
3
Temperature (oC)
39
1
Total NEWS2 score
13
REFERENCE
Royal College of Physicians. National early warning score (NEWS) 2. Standardizing the 
assessment of acute-illness severity in the NHS. London: RCP, 2017.

SAP_001.pdf: 
 
Official Title: 
A Phase II, Open-Label, Randomized, Multicenter Study to 
Investigate The Pharmacodynamics, Pharmacokinetics, Safety, And 
Efficacy of 8 Mg/Kg or 4 Mg/Kg Intravenous Tocilizumab in Patients 
With Moderate to Severe Covid-19 Pneumonia 
NCT Number: 
NCT04363736 
Document Date: 
SAP Version 2: 01-September-2020 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd
Tocilizumab—F. Hoffmann-La Roche Ltd.
Statistical Analysis Plan CA42481
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE II, OPEN-LABEL, RANDOMIZED, 
MULTICENTER STUDY TO INVESTIGATE THE 
PHARMACODYNAMICS, PHARMACOKINETICS, 
SAFETY, AND EFFICACY OF 8 mg/kg OR 
4 mg/kg INTRAVENOUS TOCILIZUMAB IN 
PATIENTS WITH MODERATE TO SEVERE 
COVID-19 PNEUMONIA
PROTOCOL NUMBER:
CA42481
STUDY DRUG:
Tocilizumab (RO4877533)
VERSION NUMBER:
2
IND NUMBER:
148225
EUDRACT NUMBER:
2020-001154-22
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
Version 1: 19 June 2020
DATE AMENDED
Version 2: See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
01-Sep-2020 12:30:07
Company Signatory


Tocilizumab—F. Hoffmann-La Roche Ltd.
2/Statistical Analysis Plan CA42481
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
The Statistical Analysis Plan version 2 for Study CA42481 was amended from version 1 
as follows:
1.
Time to event analyses clearly estate that proportional hazard models for both 
cause-specific hazards and subdistribution hazards will be implemented according 
to Grambauer et al. (2010)
2.
Additional measures of treatment effect were added for the ordinal scale: 
1) competing probability over time and 2) median of pair-wise differences
3.
Time to event endpoints were changed from “time from randomization” to “time from 
first dose of study drug”
4.
The censoring rules for the time to event endpoints were updated
5.
Removed error mentioning placebo-treated group in the analysis of ordinal data
6.
Added section specifying organ failure-free days (OFD) endpoint
7.
The handling of patients who withdraw not during hospitalization in the analysis of 
the time to clinical failure was clarified
8.
Added statement that for pharmacokinetic (PK), pharamcodynamic (PD) and 
efficacy, estimates will be provided within strata, and also, when appropriate, across 
strata, i.e., Competing Probability for the Ordinal Scale.
9.
Added an appendix describing handling of below the limit of quantification (BLQ)
data in PK and PD
10. Added an appendix with additional time window descriptions
11. Added clarification on what to consider time to clinical improvement
Additional minor changes have been made to improve clarity and consistency.


Tocilizumab—F. Hoffmann-La Roche Ltd.
3/Statistical Analysis Plan CA42481
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 8
2.
STUDY DESIGN........................................................................................... 8
2.1
Protocol Synopsis.................................................................. 10
2.2
Objectives.............................................................................. 10
2.2.1
Pharmacodynamic Objective................................................. 10
2.2.2
Pharmacokinetic Objectives .................................................. 11
2.2.3
Exploratory Efficacy Objectives ............................................. 11
2.2.4
Biomarkers ............................................................................ 12
2.2.5
Safety Endpoints ................................................................... 13
2.3
Determination of Sample Size ............................................... 13
2.4
Analysis Timing ..................................................................... 14
3.
STUDY CONDUCT..................................................................................... 14
3.1
Randomization, Stratification and Blinding ............................ 14
3.2
Data Monitoring ..................................................................... 15
4.
STATISTICAL METHODS .......................................................................... 15
4.1
Analysis Populations ............................................................. 15
4.1.1
Modified Intent-to-Treat Population ....................................... 15
4.1.2
Safety Population .................................................................. 15
4.1.3
Pharmacokinetics Population ................................................ 15
4.2
Analysis of Study Conduct..................................................... 15
4.3
Analysis of Treatment Group Comparability .......................... 16
4.3.1
Demographics ....................................................................... 16
4.3.2
Disease Characteristics......................................................... 16
4.3.3
Medical History...................................................................... 17
4.3.4
Surgeries and Procedures..................................................... 18
4.3.5
Previous and Concomitant Medications................................. 18
4.4
Visit Labels ............................................................................ 18
4.5
Pharmacodynamic, Pharmacokinetic, and 
Efficacy Objectives ................................................................ 20
4.5.1
Pharmacodynamic and Pharmacokinetic 
Objectives.............................................................................. 20


Tocilizumab—F. Hoffmann-La Roche Ltd.
4/Statistical Analysis Plan CA42481
4.5.2
Efficacy Endpoints................................................................. 20
4.5.2.1
Ordinal 7-Category Scale ...................................................... 20
4.5.2.2
Time-to-Event Analyses......................................................... 21
4.5.2.3
Incidence Endpoints .............................................................. 25
4.5.2.4
Duration Endpoints Ventilator-Free Days .............................. 25
4.5.2.5
Duration of Supplemental Oxygen (Days) ............................. 26
4.5.2.6
Duration of ICU Stay (Hours)................................................. 26
4.5.2.7
Organ failure-free days.......................................................... 27
4.5.3
Controlling for Type I Error .................................................... 27
4.5.4
Subgroup Analyses ............................................................... 27
4.6
Safety Analyses..................................................................... 28
4.6.1
Exposure to Study Drug......................................................... 28
4.6.2
Adverse Events ..................................................................... 28
4.6.3
Laboratory Data..................................................................... 30
4.6.4
Vital Signs.............................................................................. 30
4.7
Interim Analyses .................................................................... 31
5.
REFERENCES ........................................................................................... 32
LIST OF TABLES
Table 1
Time Windows for Assigning Assessment Study Days to 
Study Visits for PD Parameters................................................... 19
Table 2
Time to Clinical Improvement and Censoring ............................. 22
Table 3
Time to Improvement in Ordinal Clinical Status 
and Censoring............................................................................. 23
Table 4
Time to Hospital Discharge or “Ready for Discharge” 
and Censoring............................................................................. 24
Table 5
Time to Clinical Failure and Censoring ....................................... 24
LIST OF FIGURES
Figure 1
Study CA42481 Schema............................................................. 10


Tocilizumab—F. Hoffmann-La Roche Ltd.
5/Statistical Analysis Plan CA42481
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 33
Appendix 2
Schedule of Activities: Days 1 and 2........................................... 39
Appendix 3
Schedule of Activities: Days 328............................................... 43
Appendix 4
Schedule of Activities:  After Day 28........................................... 46
Appendix 5
National Early Warning Score 2 (NEWS2).................................. 48
Appendix 6
Cochran-Mantel-Haenszel Test .................................................. 50
Appendix 7
Handling of Values Below the Limit of Quantification (BLQ) ....... 52
Appendix 8
Additional descriptions of time windows...................................... 53


Tocilizumab—F. Hoffmann-La Roche Ltd.
6/Statistical Analysis Plan CA42481
GLOSSARY OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AEGT
adverse event grouped term
AESI
adverse events of special interest
BAL
Broncho alveolar lavage
BAP
Biomarker Analysis Plan
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus 2019/ SAS-CoV-2
CPAP
Clinical Pharmacology Analysis Plan
CRP
C-reactive protein
ECMO
extracorporeal membrane oxygenation
eCRF
electronic Case Report Form
ICU
intensive care unit
IL-6
interleukin 6
IL-6R
interleukin-6 receptor
IV
intravenous
LDH
lactose dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NEWS2
National Early Warning Score 2
OFD
Organ failure-free days
PCR
polymerase chain reaction
PD
pharmacodynamic
PK
pharmacokinetic
PT
preferred term
Pt
prothrombin time
RT-PCR
reverse-transcriptase polymerase chain reaction
SAE
serious adverse event
SAP
Statistical Analysis Pan
sIL-6R
soluble interleukin-6 receptor
SMQ
Standard MedDRA Query
SMT
study management team


Tocilizumab—F. Hoffmann-La Roche Ltd.
7/Statistical Analysis Plan CA42481
Abbreviation
Definition
SoC
standard of care
SOC
System Organ Class
SpO2
blood oxygen saturation
TB
tuberculosis
TCZ
Tocilizumab
TTCI
time to clinical improvement
ULN
Upper limit of normal
VFDs
ventilator-free days 
WHO
World Health Organization


Tocilizumab—F. Hoffmann-La Roche Ltd.
8/Statistical Analysis Plan CA42481
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and
statistical methods for the clinical efficacy and clinical safety for Study CA42481. The 
primary pharmacodynamic (PD) and pharmacokinetic (PK) objectives will be covered in 
a separate Clinical Pharmacology Analysis Plan (CPAP). Any analyses of additional
biomarkers will be covered in a separate Biomarker Analysis Plan (BAP). 
There are currently no drugs licensed for the treatment of patients with severe acute 
respiratory syndrome corona virus 2 (SARS-CoV-2) (COVID-19). Based on the results 
from an initial 21-patient retrospective observational study, in which patients with severe 
COVID-19 pneumonia were treated with tocilizumab (TCZ) off-label (Xu et al. 2020), 
along with standard-of-care (SoC) treatment, could provide efficacy, offering the 
potential benefit to treat COVID-19 in hospitalized populations; with the limitation for this 
observational study of a lack of a proper control as a comparator.
The COVACTA (Study WA42380) study (clinicaltrial.gov number: NCT04320615) was 
designed to validate the previous findings. COVACTA is a Phase III, randomized, 
double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of 
TCZ in combination with SoC compared with matching placebo in combination with SoC 
in hospitalized adult patients with severe COVID19 pneumonia. Nevertheless, the 
optimal dose of TCZ in the treatment of COVID19 is not known. The COVACTA study 
is assessing the 8-mg/kg TCZ dose, but Xu et al. (2020) used 400 mg dose (which 
equates to between 4 and 8 mg/Kg based on body weight range of the Chinese adult 
population). Study CA42481 will compare two different doses of TCZ: 4 mg/kg and 
8 mg/kg.
2.
STUDY DESIGN
Study CA42481 is a Phase II, open-label, randomized, multicenter study to assess the 
pharmacodynamics, pharmacokinetics, safety and efficacy of two different doses of TCZ 
in combination with SoC in hospitalized adult patients with moderate and severe 
COVID-19 pneumonia. 
The Sponsor intends to enroll approximately 100 patients who have been hospitalized
with COVID-19 pneumonia. The study is open-label and is unblinded. Blinding was not 
considered necessary given that the main objectives of the study involve PD and PK
(such as interleukin-6 [IL-6], interleukin-6 receptor [IL-6R], and C-reactive protein [CRP]) 
outcomes.
Patients must be at least 18 years old with confirmed SARS-CoV-2 (COVID-19) infection 
per the World Health Organization (WHO) criteria, including a positive polymerase chain 
reaction (PCR) of any specimen (e.g., respiratory, blood, urine, stool, other bodily fluids). 
At the time of enrollment, patients are categorized as having severe or moderate
COVID-19 pneumonia. Severe patients must have blood oxygen saturation (SpO2)


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93% or PaO2/FiO21 <300 mmHg despite being on SoC, which may include anti-viral 
treatment, low-dose steroids, and supportive care. Moderate patients do not need to 
meet these oxygen requirements but must have elevated CRP levels to at least 2 times 
the upper limit of normal (ULN).
Patients in whom, in the opinion of the treating physician, progression to death is 
imminent and inevitable within the next 24 hours, irrespective of the provision of 
treatments, will be excluded from the study. Patients with active tuberculosis (TB) or 
suspected active bacterial, fungal, viral, or other infection (besides COVID-19) will be 
excluded from the study.
Patients will be randomized at a 1:1 ratio to receive open-label TCZ treatment with either 
4 mg/kg or 8 mg/kg in addition to SoC per local practice. Randomization will be stratified 
by disease status: moderate or severe. The proportion of patients with moderate 
symptoms will be capped at no more than 50% of the overall study population.
For both arms, if the clinical signs or symptoms worsen or do not improve (e.g., a patient
has a sustained fever or experiences clinically significant worsening of signs or 
symptoms such as an increased supplemental oxygen requirement,), one additional 
infusion of unblinded treatment of either 4 or 8 mg/kg can be given within 8 to 24 hours 
after the initial infusion. The maximum dose per infusion is 800 mg.
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator’s discretion. The investigator will record the reasons for screen failure in 
the screening log. 
The study assessments to be conducted include the following: physical examination, 
vital signs, oxygen saturation, assessment of consciousness, presence and absence of 
respiratory support, adverse events (AEs), concomitant therapies, clinical laboratory 
tests, and nasopharyngeal swabs. Please see Appendix 2, Appendix 3, and Appendix 4.
for details concerning the timing of these assessments.
The Study CA42481 protocol was amended with substantial changes to the outcomes.
All outcomes in this SAP are exploratory. Population PK modelling and biomarker 
analyses will be dealt with in additional plans.
Figure 1 presents an overview of the study design. The schedules of activities are
provided in Appendix 2, Appendix 3, and Appendix 4.
                                           
1 The ratio between the blood pressure of the oxygen (partial pressure of oxygen, PaO2) and the 
percentage of oxygen supplied (fraction of inspired oxygen, FiO2).


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Figure 1
Study CA42481 Schema
IV=intravenous; TCZ=tocilizumab.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is provided in Appendix 1. For additional details, see the 
schedule of activities in Appendix 2, Appendix 3, and Appendix 4.
2.2
OBJECTIVES
This study will evaluate the pharmacodynamics, pharmacokinetics, safety, and efficacy 
of two doses of TCZ in combination with SoC in hospitalized patients with severe or 
moderate COVID-19 pneumonia. Specific objectives and corresponding endpoints for 
the study are outlined below.
For PK, PD and efficacy, results will be given within strata and as pooled estimates 
across strata when appropriate.
2.2.1
Pharmacodynamic Objective
The PD objective for this study is to assess the differences between two doses of TCZ in 
combination with SoC for the treatment of moderate to severe COVID-19 pneumonia on 
the basis of the following endpoints:

Serum concentrations of IL-6, sIL-6R, ferritin, and CRP following administration of 
8 mg/kg and 4 mg/kg intravenous (IV) TCZ at specified timepoints


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2.2.2
Pharmacokinetic Objectives
The PK objective for this study is to characterize the pharmacokinetics of two different 
doses of TCZ in combination with SoC for the treatment of moderate to severe 
COVID-19 pneumonia on the basis of the following endpoints:

Serum concentrations of TCZ following administration of 8 mg/kg and 4 mg/kg IV 
TCZ at specified timepoints (see Appendix 2, Appendix 3, and Appendix 4)
The characterization of serum concentrations at pre-specified timepoints of 4 mg/kg and 
8 mg/kg in combination with SoC as well as the association between pharmacokinetics 
and pharmacodynamics of TCZ over all timepoints will be described in a separate
CPAP.
2.2.3
Exploratory Efficacy Objectives
All efficacy objectives in this study are exploratory, hence differences and 95% 
confidence intervals (CIs) of differences but not p-values will be reported. The
objectives will compare the efficacy of 4-mg/kg TCZ dose against 8-mg/kg TCZ dose in 
combination with SoC for the treatment of severe and moderate COVID-19 pneumonia.
The main analysis population will be the modified intent-to-treat (mITT) population
defined in Section 4.1.1, and the 4-mg/kg TCZ dose will contain both single and double 
doses of 4mg/kg presented by randomized group. Likewise, the 8-mg/kg TCZ dose will 
be treated similarly. Further exploratory efficacy analyses may use the safety population 
to compare actually received treatments, i.e., 4, 44, 8, combined (44 and 8), and 88.
The National Early Warning Score 2 (NEWS2) values will be calculated by the Sponsor 
based on vital sign parameters and NEWS2-related assessments recorded by the 
investigator on the appropriate electronic Case Report Form (eCRF).
In addition to vital measurements, the patient’s consciousness level and the presence or 
absence of respiratory support will be recorded. The NEWS2 parameter for respiratory 
support is the selection of either “air” or “oxygen,” which can include other forms of 
ventilation to maintain oxygen saturation (see Appendix 5).
The following endpoints are considered:

Clinical status as assessed using a 7-category ordinal scale over time and 
specifically at Days 7, 14, and 28
The ordinal scale categories are as follows:
1.
Discharged (or “ready for discharge” as evidenced by normal body temperature 
and respiratory rate, and stable oxygen saturation on ambient air or2 L 
supplemental oxygen)
2.
Non-intensive care unit (ICU) hospital ward (or “ready for hospital ward”) not 
requiring supplemental oxygen
3.
Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental 
oxygen


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4.
ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow 
oxygen
5.
ICU, requiring intubation and mechanical ventilation
6.
ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical 
ventilation and additional organ support (e.g. vasopressors, renal-replacement 
therapy)
7.
Death

Time to clinical improvement (TTCI), defined as a NEWS2 score of 2 maintained 
for 24 hours

Time to improvement of at least 2 categories relative to baseline on a 7-category 
ordinal scale of clinical status. Patients that are in category 2 at baseline will need 
to achieve category 1 to meet the endpoint of recovery.

Duration of supplemental oxygen

Incidence of ICU stay

Incidence of mechanical ventilation

Duration of ICU stay

Time to clinical failure, defined as the time to death, mechanical ventilation, ICU 
admission, or withdrawal (whichever occurs first). For patients entering the study 
already in ICU or on mechanical ventilation, clinical failure is defined as a one-
category worsening on the ordinal scale, withdrawal or death. 

Mortality at Day 7, 14, 21, 28 and day 60 will be summarized descriptively.

Time to hospital discharge or “ready for discharge” (as evidenced by normal body 
temperature and respiratory rate, and stable oxygen saturation on ambient air or 2
L supplemental oxygen)

Frequency of the addition of a second dose of TCZ (either 8 mg/kg or 4 mg/kg) at 
the discretion of the treating physician

Organ failure-free days (OFD) from baseline to Day 28

Ventilator-free days (VFD) from baseline to Day 28
Withdrawals are patients for which a discontinuation form is completed. Withdrawals for 
different reasons, e.g. lack of efficacy vs. administrative censoring, are not distinguished.
2.2.4
Biomarkers
The exploratory biomarker objectives for this study are to further evidence of TCZ 
pharmacological activity (i.e., PD biomarkers), and overall increase our knowledge and 
understanding of disease pathogenesis and drug safety, on the basis of the following 
endpoint:

Exploratory analysis of individual biomarkers in relation to efficacy and safety (listed 
in Section 4.5.6, “Laboratory, Biomarker, and Other Biological Samples” of the 
protocol), and in both blood- and tissue-derived samples.


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A separate BAP details how data collected in CA42481 will be used to enhance our 
understanding of PD, and Efficacy-Response biomarkers of TCZ in the moderate and/or 
severe COVID-19 pneumonia population.
2.2.5
Safety Endpoints
The safety objective for this study is to compare the safety profile of 4 mg/kg TCZ dose 
against that of 8 mg/kg TCZ dose in combination with SoC for the treatment of severe 
and moderate COVID-19 pneumonia on the basis of the following endpoints:

Incidence and severity of AEs, with severity determined according to National 
Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) v5.0

SARS-CoV-2 (virus causing COVID-19) viral load over time, as collected by 
nasopharyngeal swab and bronchoalveolar lavage (BAL) samples (if applicable)

Time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity

The proportion of patients with any post-treatment infection

Change from baseline in targeted clinical laboratory test results
2.3
DETERMINATION OF SAMPLE SIZE
The purpose of this open-label study is the comparison of TCZ pharmacokinetics and 
PK-PD relationship between two doses of TCZ (8 and 4 mg/kg) in hospitalized patients 
with moderate to severe COVID-19 pneumonia. The comparison will be assessed using 
modeling and evaluating the safety and efficacy measures between Day 1 and Day 28 
post-randomization.
Data from the follow-up period from Days 28 to 60 may also be assessed. 
Approximately 100 patients will be enrolled and randomized in a 1:1 ratio to the 8-mg/kg 
and 4-mg/kg IV TCZ arms in this study. Disease severity type will also be stratified into 
moderate and severe COVID pneumonia, giving an overall equal four-way split between 
the two doses and type of disease severity and resulting in four groups of approximately 
25 patients each. Patients may receive a repeat dose within 8 to 24 hours after the first 
TCZ dose if clinicians judge it is necessary (resulting in a TCZ dose range from 4 to 
16 mg/kg, with a maximum dose of 800 mg). The variability of PK parameters of TCZ in 
a heterogeneous COVID-19 population in an acute setting is unknown; however, 20 to 
30 patients is deemed adequate considering the between-subject variability in healthy
volunteers and patients with rheumatoid arthritis (RA) provided by population-PK
modeling. Data quality issues, patient dropouts, and early hospital discharge may all 
lead to missing data, especially in a pandemic setting; thus, enrolling 50 patients 
according to dose and disease severity type (25 per arm) may offset missing data and 
allow an adequate volume of PK and PD data to inform the population-PK model and 
allow a comparison of the 4- and 8-mg/kg TCZ doses.


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2.4
ANALYSIS TIMING
The primary study analysis will occur when the last patient enrolled has completed study 
visit Day 28 or has withdrawn, and will be based on cleaned data for all patients up to 
and including this point.
There will be an additional analysis on the final data when all patients have either 
completed study visit Day 60 or withdrawn and all data are available. Analyses from the 
first reporting event, restricted to data up to Day 28, will not be updated based on the 
final snapshot.
3.
STUDY CONDUCT
This study will enroll approximately 100 patients that have been diagnosed with 
COVID-19 pneumonia and meet the entry criteria in United States centers. Patients will 
be randomized at a 1:1 ratio to receive unblinded treatment with either 4 or 8 mg/kg TCZ 
in addition to SoC. For both arms, if the clinical signs or symptoms worsen or do not 
improve, one additional infusion of the original TCZ concentration can be given within
8 to 24 hours after the initial infusion.
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator’s discretion.
Patients will be followed up for a total of 60 days after first dose of study medication.
If patients are discharged from hospital prior to Day 28, follow-up visits should occur 
twice weekly through Day 28. Patients are encouraged to return for onsite visits at least 
weekly if possible; other follow-up visits may be conducted by telephone or home visits.
Patients should return to the site for a Day 28 visit. After Day 28, all patients should 
have follow-up visits on Day 35, Day 45, and Day 60; the Day 35 and Day 45 visits may 
be conducted by telephone or by home visits for discharged patients, while the Day 60 
visit should be conducted onsite.
During the study, standard supportive care will be given according to clinical practice.
3.1
RANDOMIZATION, STRATIFICATION AND BLINDING
Patients will be randomized as soon as possible after screening at a 1:1 ratio to receive 
unblinded treatment of either 4 or 8 mg/Kg TCZ, respectively. Study treatment must be 
given in combination with SoC. The randomization will be stratified by disease severity 
(severe or moderate); and will occur through use of a permuted-block randomization 
method to ensure a balanced assignment to each treatment arm. The proportion of 
patients with moderate symptoms at the time of randomization will be capped at no more 
than 50% of the overall study population. The study is open-label and is unblinded; thus 


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the study team will monitor safety on an ongoing basis, i.e., there will be no independent 
Data Monitoring Committee.
3.2
DATA MONITORING
The study management team (SMT) will monitor the incidence of all serious adverse 
events (SAEs), adverse events of special interest (AESI) and any anticipated events 
during the study. 
Regular safety reviews will begin after approximately 10 to 20 patients have been 
enrolled and reached Day 7 of the study. Following this and additional safety reviews, 
the SMT may recommend to continue the study without modifications, modify the 
conduct of the study, or discontinue the study as described in Section 4.6.3 Study 
Discontinuation, of the protocol.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
Disposition summaries will be based on an all-patient population (all patients 
randomized and/or receiving study drug). Efficacy analyses will be based on the mITT 
population, if not otherwise specified. Analysis of safety data, and PD data will be based 
on the safety population.
4.1.1
Modified Intent-to-Treat Population
The mITT population is defined as all patients randomized in the study who receive any 
amount of study drug, with patients grouped according to the treatment assignment at 
randomization.
4.1.2
Safety Population
Safety population will consist of all patients who receive any amount of study drug. In all 
safety, PK and PD analyses, patients will be grouped according to the first treatment that 
patients receive rather than the treatment assigned at randomization.
4.1.3
Pharmacokinetics Population
The PK population is defined as the subset of the safety population with at least one 
valid PK result.
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients enrolled, discontinued, or who complete the study will be 
summarized to Day 28 and to the end of the study. Reasons for premature study 
discontinuation will be listed and summarized to Day 28, as well as the end of the study.
Listing of randomized patients and a listing of investigators will be produced.
The number of patients discharged from hospital will also be summarized by visit.


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Eligibility criteria and other major protocol deviations will be listed and summarized by 
treatment group.
The patients excluded from the safety and mITT populations will be summarized, 
including the reason for exclusion by treatment group. A summary of enrollment by 
investigator name will be produced.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (including, but not limited to, age, sex, race, 
geographic region, NEWS2, ordinal scale for clinical status, IL-6, sIL-6R, mechanical 
ventilation, anti-viral treatment at baseline, steroids at baseline) will be summarized 
using means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate. Summaries will be presented by 
treatment group and will be presented for the mITT population and may, in addition, be 
presented for the safety population.
4.3.1
Demographics
The key demographic parameters are the following:

Sex

Age

Weight

Race

Ethnicity

Female fertility status

Smoking history (never, current, or former)
– Former/current user: number of years a patient smoked (years), nicotine 
exposure reported in pack years
– E-cigarettes use (yes or no)
4.3.2
Disease Characteristics
The key disease characteristics are:

Disease severity

NEWS2

Ordinal scale for clinical status

IL-6

sIL-6R

Ferritin

CRP

D-dimer


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
Prothrombin Time (Pt)

activated Partial Thromboplastin Time (aPTT)

Platelets

lactose dehyodrogenase (LDH)

WBC (including neutrophils % and count –ANC-)

Lymphocyte count and %.

Median time from symptom onset to first dose

Median oxygen saturation or PaO2:FiO2 ratio

Mechanical ventilation (levels 5-6 of ordinal scale for clinical status)

Admission to ICU
Use of continuous renal-replacement therapy

Steroid use for up to 7 days prior to randomisation (to be derived from concomitant 
medication)

Anti-viral treatment for up to 7 days prior to randomisation (to be derived from 
concomitant medication)

Symptoms at time of COVID-19 diagnosis
–
Fever
–
Cough
–
Shortness of breath
–
Gastrointestinal symptoms (e.g., diarrhea, nausea and loss of appetite)
–
Headache
–
Fatigue
–
Other

Number of days from first COVID-19 symptom at baseline

COVID-19 diagnosis based on PCR of specimen type

Number of days from first COVID-19 diagnosis at baseline

Specimen type at screening

Quantitative PCR result

Overall SARS-CoV-2 antibodies
Central laboratory results will be used whenever available. Only in the case of missing 
central laboratory results, local laboratory results could be used.
4.3.3
Medical History
Medical history data will be summarized descriptively by treatment group using the 
safety population. A glossary showing the mapping of investigator verbatim terms to 
diseases will be produced for the medical history data.


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4.3.4
Surgeries and Procedures
A listing of any previous or ongoing surgeries and procedures will be produced for the 
safety population.
4.3.5
Previous and Concomitant Medications
Previous and concomitant treatments will be summarized descriptively by treatment 
group for the safety population. Previous treatments that have been stopped prior to 
study Day 1 will be summarized separately. There will be a summary of all concomitant 
treatments, including those that were initiated prior to study Day 1. In addition, there will 
be a summary of all anti-viral treatments, as previous medical treatment and/or 
concomitant medication, with the indication given as COVID-19, COVID prophylaxis, 
COVID pneumonia, pneumonia or similar. Any of these treatments categorized under 
the Medication Class of Investigational Drug will be summarized with the proximity (up to 
7 days prior randomization) of administration relative to tocilizumab.
A glossary showing the mapping of investigator verbatim terms to medication-coded 
terms will be produced for previous or concomitant medication.
4.4
VISIT LABELS
For summaries of data not collected by visit, such as AEs, medical history, and 
concomitant medications all data up to the end of study will be included. Exceptions to 
this include death and discharge; which will be summarized weekly in descriptive 
summaries, following the time windowing approach described below.
Deaths will also be captured on the ordinal scale of clinical status, where the completion 
of an unscheduled ordinal scale value of 7 will be recorded in eCRF. Deaths confirmed 
by public record are also captured on the eCRF, which may not have been captured as 
AEs for patients who are withdrawn from the study. These events will also be 
incorporated into the windowing for death.
Patient assessments that are collected at scheduled visits will be assigned to a study 
visit using the actual study day of the assessment; this includes data from withdrawal 
visits and any unscheduled visits. Time windows will be continuous from the midpoint 
between two consecutive study visits to the next midpoint, and will be dependent on the 
schedule of assessments for each variable independently. An example of time 
windowing for the PD biomarkers is shown below (Table 1).


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Table 1
Time Windows for Assigning Assessment Study Days to 
Study Visits for PD Parameters
Scheduled Study Day
Efficacy Time Window (days) a
Day 1 (Baseline)b
Day 2
Day 3
1
2
3
7 (Week 1)
3 to 10
14 (Week 2)
10 to 17
21 (Week 3)
17 to 24
28 (Week 4)
24 to 28
35 (Week 5)
28 to 38
Day 60
38 to 67
a From Week 1 onward use value nearest to scheduled study day. Day 1 includes at least two 
samples (one at baseline and the second 15 minutes after infusion).
b A second postdose sample on Day 1 will be taken from patients given a second dose of TCZ 
(see SOA).
Where there is more than one efficacy assessment within a time window, then the
non-missing assessment nearest in time to the expected time window will be assigned to 
that visit. If two or more assessments are equidistant from the scheduled timepoint, then 
the latest assessment will be used for efficacy (other than death, in which case the 
assessment prior to the visit week will be used).
For safety parameters such as laboratory parameters and vital signs the “worst case” will 
be used.
The last value from screening will be used for baseline assessments if there is no 
baseline (study Day 1) value. Pretreatment assessments will be used preferentially on 
study Day 1 for baseline.


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4.5
PHARMACODYNAMIC, PHARMACOKINETIC, AND EFFICACY 
OBJECTIVES
4.5.1
Pharmacodynamic and Pharmacokinetic Objectives
The main PD endpoints in this study are IL-6, sIL-6R, ferritin and CRP levels measured 
at baseline and then at Days 1, 3, 7, 14, 21, and 28 post-randomization. The median, 
standard error of the median, minimum and maximum values will be summarized by day 
for each dose using the mITT population. The median of all pairwise differences 
between the 4 mg/kg and the 8 mg/kg will also be reported for the mITT population. 
Standard error of medians will be obtained via bootstrapping. Results will be reported 
with both tables and plots.
The population is the safety population defined in this study. The estimate is the median 
difference in IL6, sIL-6R, CRP and ferritin levels between treatments across all visits 
from baseline to Day 28.
Likewise, PK data will be summarized similarly over time using the PK population.
This information will help inform prescribers about the potentially similar 
pharmacodynamics effects of a 4-mg/kg dose compared to an 8-mg/kg dose of TCZ in 
COVID-19 patients.
4.5.2
Efficacy Endpoints
All efficacy endpoints are exploratory. All efficacy analyses will use the mITT population.
Sensitivity analyses to evaluate the robustness of results to the analysis methods (e.g., 
handling of withdrawals) may be conducted and are described in this SAP in each 
relevant section.
Descriptive subgroup analyses to evaluate the consistency of results across prespecified
subgroups may also be conducted as specified in Section 4.5.4.
4.5.2.1
Ordinal 7-Category Scale
The median clinical status according to the 7-category ordinal scale and its 95% CI via 
bootstrapping for the 4-mg/kg and the 8-mg/kg will be tabulated and plotted for all days 
between baseline and Day 28. The magnitude of the difference between doses will also 
be assessed at Days 7, 14 and 28 via the van Elteren test adjusted for baseline 
stratification factors and by a proportional odds model where the odds ratio and 95% CI 
will be reported. Also the median of all pair-wise differences (Hodges-Lehmann 
estimator) between doses will be plotted over time with 95% CI obtained by 
bootstrapping. All analyses will use the mITT population.
The assumption of proportional odds will be evaluated by visually comparing the fitted 
proportions of patients across the ordinal scale from the model with the observed data.


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The competing probability of observing patients on the 4 mg/kg dose having ordinal 
scores higher than patients on the 8 mg/kg dose plus half of the probability of having 
equal scores will be plotted daily with 90% CIs (Zhao et al. 2012).
In addition to imputing the ordinal scale at Day 28 with an earlier death or discharge 
(without re-admittance), this imputation rule will also be followed at earlier timepoints.
A death or discharge (unless the patient is re-admitted) will always be carried forward to 
all subsequent assessments regardless of what is recorded for the ordinal scale. If 
discharge is to a nursing facility then the ordinal scale should be still collected, otherwise 
it will be set to missing. For patients who withdraw before Day 28, their last post 
baseline ordinal category prior to withdrawal will be used in the primary analysis, unless 
death within the time frame was captured from public records or otherwise; in which 
case death will be used in the analysis.
Moreover, the ordinal scale will be summarized by visit and treatment showing n and 
percentage in each category, as well as missing data. A stacked bar chart of the ordinal 
scale will be produced by treatment group, the bars will total to 100% and the categories, 
including “missing,” will be shown. 
Assessment of patient status using this ordinal scale will be recorded at baseline and 
once daily in the morning (between 8 a.m. and 12 p.m.) while hospitalized.
Additionally, for patients that withdraw prior to Day 28, the 50th percentile of the data 
from those that complete the study to Day 28 will be used as imputed value.
4.5.2.2
Time-to-Event Analyses
Time-to-event endpoints will be compared between the low and high TCZ doses using 
the stratified (moderate vs. severe) proportional hazard models using the mITT 
population. In all analyses apart from time to clinical failure, death will be a competing 
risk. Models for the cause-specific hazards, i.e., Cox model, and also for the 
subdistribution hazards (Fine and Grey 1999) will be used. The subdistribution hazards 
model assumes death to be right censored and death times happening after 28 days on 
trial (672 hours) minus the number of hours from midnight to the time of first treatment in 
each patient. Non-parametric cumulative incidence functions for the event of interest, 
with 95% CIs, will be obtained using the Aalen-Johansen estimator. In addition to 
hazard ratios, the difference in cumulative incidence curves between the low and high 
TCZ doses at days 7, 14 and 28 will be provided.
For time to event endpoints that include discharge as an event, the earliest time of 
discharge or “ready for discharge” from the different sources of discharge will be used in 
all analyses. If a patient is discharged and re-admitted more than 12 hours later, then 
the first discharge will be considered as meeting the event. If a patient is readmitted 
within 12 hours of discharge, then they will not have met the endpoint at this time. If 


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they are discharged later in the study (without re-admittance within 12 hours), then the
later time of discharge will be used.
Time-to-event endpoints include:

TTCI in hours
Defined as time from first dose of study drug to NEWS2 score of2 maintained 
for 24 hours
Intercurrent events are those that occur after treatment initiation and either preclude 
observation of the variable or affect its interpretation. Intercurrent events, such as 
patients who are lost to follow-up, die or discontinue for any reason prior to achieving the
event or do not have the event, will be accounted for through censoring rules, as 
described in Table 2.
Partial date times may be imputed based on available data, following a conservative 
approach. The NEWS2 is to be assessed twice daily, with approximately 12 hours 
between each assessment. At least two scheduled assessments with a score of 2 
covering a span of at least 21.5 hours, with a maximum of 26.5 hours between the first 
and last of these assessments (there must be no assessments with a score 2 in 
between), will be required to meet the criterion. If a patient has a score of 2 and is then 
discharged from hospital within 26.5 hours, with no subsequent scores 2 before the 
discharge they will have met the endpoint.
Table 2
Time to Clinical Improvement and Censoring
Event
Censor
Date and Time
Hospital discharge prior to clinical improvement 
criterion met
Yes
Hospital discharge
Hospital discharge and hospital re-admission 
within 12 hours and continue study
No
Not applicable
Death prior to clinical improvement criterion met
No (competing 
risk)
Death
Discontinuation or lost to follow-up for any 
reason prior to clinical improvement criterion met
Yes
Last scheduled vital sign 
assessment
No clinical improvement
Yes
Last vital sign assessment 
within Day 28 time window
Other time-to-event endpoints include the following:

Time to improvement in ordinal clinical status (days)
Defined as time from first dose of study drug to the time when at least a 2-category 
improvement in the 7-category ordinal scale is observed.


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For patients in category 2 at baseline, discharge will be considered as meeting the 
threshold. For patients who are discharged and the ordinal scale assessment has not 
been completed at discharge, they will be assumed to be in category one of the ordinal 
scale at the point of discharge, unless they are re-admitted within 12 hours. Intercurrent
events, such as patients who are lost to follow-up, die or discontinue for any reason prior 
to achieving the event or do not have the event, will be accounted for through censoring 
rules, as described in Table 3.
Table 3
Time to Improvement in Ordinal Clinical Status and Censoring
Event
Censor
Date and Time
Hospital discharge and hospital re-admission 
within 12 hours and continue study
No
Not applicable
Death prior to improvement in ordinal clinical 
status criterion met
No 
(competing 
risk)
Death
Discontinuation or lost to follow-up for any reason 
prior to improvement in ordinal clinical status 
criterion met
Yes
Last ordinal scale 
assessment 
No improvement in ordinal clinical status
Yes
Last ordinal scale 
assessment within Day 28 
time window

Time from first dose of study drug to hospital discharge or “ready for discharge” 
(hours)
Ready for discharge; defined as normal body temperature and respiratory rate, and 
stable oxygen saturation on ambient air or ≤2L supplemental oxygen (ordinal scale 
category one).
Intercurrent events, such as patients who are lost to follow-up, die or discontinue for any 
reason prior to achieving the event or do not have the event, will be accounted for 
through censoring rules, as described in Table 4.


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Table 4
Time to Hospital Discharge or “Ready for Discharge” 
and Censoring
Event
Censor
Date and Time
Hospital discharge and hospital re-admission 
within 12 hours and continue study
No
Not Applicable
Death prior to discharge
No (Competing 
Risk)
Death
Discontinuation or lost to follow-up for any reason 
prior to discharge or “ready for discharge” 
criterion met
Yes
Last ordinal scale 
assessment 
Not discharged or “ ready for discharge”
Yes
last Ordinal scale 
assessment within Day 28 
time window

Time to clinical failure (days)
Defined as the time from first dose of study drug to first occurrence on study of 
death, mechanical ventilation, ICU admission or withdrawal (discontinuation from 
study due to lack of drug efficacy), whichever occurs first. For patients entering the 
study already in ICU or on mechanical ventilation, clinical failure is defined as a one-
category worsening on the ordinal scale, withdrawal or death.
Intercurrent events, such as patients who are lost to follow-up or discontinue for any 
reason prior to the event or do not have the event, will be accounted for through 
censoring rules, as described in Table 5 below.
Table 5
Time to Clinical Failure and Censoring
Event
Censor
Date and Time
Hospital discharge not followed by 
death or re-admittance
Yes
Last scheduled vital sign assessment (or 
discharge if no post-discharge vital sign data is 
available)
Hospital discharge and hospital re-
admission within 12 hours and 
continue study
No
Not Applicable
Lost to follow-up prior to clinical 
criterion met not followed by death
Yes
Last scheduled vital sign assessment or ordinal 
scale assessment
Clinical failure criterion not met
Yes
Last of scheduled vital sign assessments or 
ordinal scale assessments within Day 28 time 
window
The NEWS2 score and clinical failure status as defined above will be summarized
descriptively by visit.


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4.5.2.3
Incidence Endpoints
Exploratory efficacy incidence endpoints will be analyzed using the 
Cochran-Mantel-Haenszel (CMH) test statistic adjusted by the stratification factors at 
baseline disease status severe or moderate using the mITT population, unless stated 
otherwise. The weighted difference in proportions for the treatment group comparison 
will be presented, together with a 95% CI (see Appendix 6). All the incidence endpoints 
will use the same method.

Incidence of mechanical ventilation by Day 28

Incidence of ICU stay by Day 28
For incidence of mechanical ventilation or incidence of intensive care stay by Day 28 for 
patients that have withdrawn or died prior to Day 28, the non-responder rule will be 
applied, i.e., it will be assumed that the patient required mechanical ventilation, or has 
had an ICU stay by Day 28 in the analysis. Patients without either mechanical 
ventilation or intensive care stay, respectively, prior to discharge, will be assumed to be 
responders in the analysis, unless the patient is re-admitted to the hospital within 
12 hours or the patient dies by Day 28.
The number and proportion of patients requiring mechanical ventilation or an ICU stay
will be summarized descriptively by study week.

Difference in mortality at Day 7, 14, 21, 28 and 60
The difference in proportion of patients that have died by Day 28 will be compared 
using the CMH test as described above as the main analysis method. All deaths 
reported post-discontinuation and discharge will be included in these analysis.
Deaths occurring between each visit, and cumulative deaths by visit will be
summarized descriptively to Day 60.

Frequency of the addition of a second dose of TCZ (either 8 mg/kg or 4 mg/kg) at 
the discretion of the treating physician
Treating physicians can prescribe a second identical TCZ dose within 8 to 24 hours after 
the first one if patients do not show signs of improvement. No patient can receive more 
than a total of 800 mg of TCZ per infusion.
4.5.2.4
Duration Endpoints Ventilator-Free Days
The number of ventilator-free days (VFDs) is defined as the number of days from Day 1 
to Day 28 when the patient is alive and breathes without invasive assistance of the 
mechanical ventilator. VFDs will be derived from the vital signs and oxygen saturation 
log; if invasive mechanical ventilation or ECMO is recorded for any part of the day, the 
day will not be counted as a VFD.


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VFDs will be zero if the patient is mechanically ventilated from Day 1 to Day 28. VFDs 
will be zero if a patient dies on or prior to Day 28.
For patients withdrawn early from the study but not discharged, if patients were on 
invasive mechanical ventilation at the point of discontinuation it will be assumed that the 
remaining days to Day 28 are not VFDs. For patients not using invasive mechanical 
ventilation at point of withdrawal, it will be assumed the period to Day 28 are VFDs. For 
patients that are discharged, days from discharge to Day 28 will be counted as VFDs.
VFDs will be analyzed using the Van Elteren test, including the stratification factors at 
randomization (disease status: severe vs. moderate). The median VFDs for each 
treatment group and the corresponding 95% CI for the median will be presented, as well 
as the difference in medians and a 95% CI for the difference. A cumulative distribution 
plot of VFDs will be produced.
VFDs during hospitalization will also be summarized descriptively using the medians, 
with 95% CIs by treatment group for those patients alive at Day 28, with a count of the 
number of patients assigned zero VFDs due to death by Day 28.
4.5.2.5
Duration of Supplemental Oxygen (Days)
Duration of supplemental oxygen (days) will also be derived from the vital signs and 
oxygen saturation log, where study days with “supplemental oxygen or other forms of 
ventilation” will be summed up to and including Day 28. Patients without any 
supplemental oxygen use will assigned a duration of zero days. For patients withdrawn 
early from the study but not discharged, if the patient was receiving supplemental 
oxygen at the point of withdrawal, it will be assumed that the remaining days to Day 28
were on supplemental oxygen. For patients not using supplemental oxygen at point of 
withdrawal, it will be assumed supplemental oxygen is not required to Day 28. For 
patients that are discharged, days from discharge to Day 28 will be counted as days 
without supplemental oxygen (unless supplemental oxygen use is recorded during follow 
up visits). Duration of supplemental oxygen use will be 28 days if a patient dies on or 
prior to Day 28.
Days of supplemental oxygen use will be analyzed and summarized descriptively in a 
similar method to VFDs. In addition, the number and the proportion of patients receiving
supplemental oxygen using the observed data will be summarized by visit to Day 60.
4.5.2.6
Duration of ICU Stay (Hours)
Duration of ICU stay (hours) will be calculated as the sum of the number of hours spent 
in an ICU, up to and including Day 28, based on the admission and discharge date times 
from the ICU stay information log (ICU discharge date time – ICU admission date time). 
Multiple periods of ICU stay will be summed. Patients without any ICU stays will be
assigned a duration of zero hours.


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Partial admission and discharge times may be imputed based on available data, 
following a conservative approach. For patients that discharged, any ongoing ICU stays 
without an end date will be imputed from the date of discharge as appropriate and it will 
be assumed that days from discharge to Day 28 do not involve an ICU stay. For 
patients not in the ICU at the point of withdrawal from study it will be assumed that the 
period to Day 28 has no incidences of ICU stay post withdrawal. For patients in ICU on 
the day of withdrawal it will be assumed that they are in the ICU throughout the period to 
Day 28. For patients that die on or prior to Day 28 all days will count as an ICU stay.
Hours of ICU stay will be analyzed and summarized descriptively in a similar method to 
VFDs.
4.5.2.7
Organ failure-free days
Days without organ failure will be summarized descriptively through Week 4. In addition, 
a summary of individual organ failure over time will be provided.
Organ failure is defined as present on any day when the most abnormal vital 
signs/abnormal lab value meets the definition of clinically significant organ failure
(Bernard et al, 1995; NHLBI ARDS Clinical Trials Network 2014). Cardiovascular and 
central nervous system function will be assessed through blood pressure and pH (and 
responsiveness to fluids), and alert, respectively. Pulmonary organ failure will be 
counted as anyone with PaO2:FiO2 ratio300 or SpO293% or using supplemental 
oxygen or on mechanical ventilation. Renal, hepatic and coagulation parameters will be 
assessed via blood tests in order that the presence of clinically significant organ failure 
can be determined. Each day a patient is alive and free of a given clinically significant 
organ failure will be scored as a failure-free day for that organ. In the case of missing 
data for a particular organ the last observation post-baseline will be carried forward until 
the next observation. Any day that a patient is alive and free of all 5 organ failures 
(pulmonary, cardiovascular, renal, hepatic, central nervous system) will be considered 
OFD.
If a patient dies on or before Day 28, they will be assigned a value of zero OFD. For 
patients that are discharged, days from discharge to Day 28 will be counted as OFD, 
unless they are readmitted in which case the available data will be used.
4.5.3
Controlling for Type I Error
All efficacy analyses in this study are exploratory and type I error correction will not be 
implemented.
4.5.4
Subgroup Analyses
The odds ratio for mortality for 4-mg/kg versus 8-mg/kg doses at Day 28 will be analyzed 
by logistic regression, including covariates of interest as well as the stratification factors 
in the model. The odds ratio for the treatment effect by sex, race, age (1864 years, 
6584 years and85 years), region and mechanical ventilation will be determined. 


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Other subgroup analyses may also be performed such as baseline ordinal status 2, 3-4, 
and 45. There should not be patients with baseline score of 6 as those on
extracorporeal membrane oxygenation (ECMO), Multi-organ Failure (MOF) and in shock 
will be excluded.
4.6
SAFETY ANALYSES
Safety assessments will be performed on the safety population. In all safety analyses, 
patients will be grouped according to the first treatment that the patients received rather 
than the treatment assigned at randomization. 
Descriptive summaries of laboratory values and change from baseline throughout the 
study will be tabulated by treatment arm. For selected parameters, changes from the 
proportion of patients experiencing clinically significant changes relative to baseline will 
be summarized by treatment arm.
Values, along with change from baseline, will be summarized using descriptive statistics
for each vital sign parameter.
COVID-19 (SARS-CoV-2) viral load over time, as collected by nasopharyngeal swab and 
BAL samples (if applicable) will be summarized descriptively by timepoint and treatment 
group. The number and proportion of patients negative and positive will be displayed, 
and for those positive the quantitative result will be summarized.
Time to RT-PCR COVID-19 virus negativity will be analyzed using similar methods to 
those for the other time-to-event analyses.
Overall SARS-CoV-2 antibody concentration will be measured at baseline and Day 28. 
The median percentage change from baseline will be summarized across groups.
4.6.1
Exposure to Study Drug
Exposure to study drug will be summarized including number of patients with one or two 
doses and number of patients with dose modification by treatment group.
A listing of patients by treatment group will be prepared detailing dosing of study drug, 
volume administered and any dose modification.
4.6.2
Adverse Events
Medical Dictionary for Regulatory Activities (MedDRA) will be used as the thesaurus for 
AEs and disease codes, and the WHO Drug Global B3 Format dictionary will be used for 
treatments. A glossary of these codes will be produced.
Only treatment-emergent AEs will be summarized. Treatment-emergent events are 
defined as those AEs with observed or imputed onset date on or after the start date of 
study treatment. Only where the most extreme severity is greater than the initial severity 


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(or if most extreme severity is not missing and initial severity is missing) will events with 
an onset date prior to the start of trial treatment be considered treatment emergent. An 
AE with a completely missing start date will be assumed to be treatment emergent 
unless the AE has a complete non-imputed end date that is prior to Day 1.
Adverse events will be coded and tabulated by system organ class (SOC), and/or 
preferred term (PT) and treatment arm. In tabulations, PTs and their associated SOC 
will be presented in order of descending frequency summed across the treatment 
groups.
Adverse events will also be tabulated by severity, as graded according to NCI CTCAE 
v5.0 scale, and relationship to study medication as indicated by the investigator.
The following will also be summarized:

SAEs

AEs leading to withdrawal of study drug

AEs leading to discontinuation from the study

AEs leading to death

Hypersensitivity AEs (AEs occurring immediately after or within 24 hours of the end 
of an infusion that are not deemed “unrelated” to study treatment)
AESI will be defined using SOC, published Standard MedDRA Queries (SMQs) or 
Adverse Event Grouped Terms (AEGTs) defined by Roche Drug Safety. The groupings 
of AEs will include, but may not be limited to, the following:

Infections (Infections and Infestations SOC)

Opportunistic infections (Roche Standard AEGT Basket)

Malignancies (Malignant or Unspecified tumors SMQ Narrow)

Hepatic events (Hepatic failure, Fibrosis, and Cirrhosis and Other Liver 
Damage-related Conditions SMQ Wide or Hepatitis, non-infectious SMQ Wide)

Stroke (Ischemic Cerebrovascular Conditions SMQ Wide or Hemorrhagic 
Cerebrovascular SMQ Wide)

Myocardial infarction (MI) (MI SMQ Wide)

Hypersensitivity reactions (Hypersensitivity SMQ Narrow)

Anaphylactic reaction events (utilizing Roche Standard AEGT Basket according to 
Sampson’s criteria) (Sampson et al. 2006) occurring immediately after or within 24 
hours of injection of tocilizumab; and a separate summary using the Anaphylactic 
Reaction SMQ Narrow for events occurring immediately after or within 24 hours of 
injection of tocilizumab

Gastrointestinal perforations (Gastrointestinal perforation SMQ Wide)

Bleeding events (Hemorrhages SMQ Wide)


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
Demyelinating events (Demyelination SMQ Narrow)
A glossary showing the mapping of investigator verbatim terms to PTs will be produced 
for all AEs included in the analysis. For each AE of special interest table based on 
SMQs/AEGTs, a corresponding listing of the PTs that comprise the SMQ will be 
produced.
Listings of AEs and SAEs will be produced. AESI will also be listed.
AEs and SAEs will be summarized by age category (1864, 6584, and 85 years).
The exposure duration on study (exposure duration is the date of the last safety 
assessment or death if present, minus the date of the first dose of TCZ plus one divided 
by 365.25) will be summarized.
4.6.3
Laboratory Data
Laboratory values will be converted to Système International units, and data will be 
transformed to a common Roche standard reference range.
Summary tables will detail the actual values and changes from baseline of the laboratory 
parameters over visits by treatment arm. Arterial blood gases will be summarized
separately. Summaries of the number of patients by NCI CTCAE grade for hematology
and hepatic laboratory parameters (alkaline phosphatase [ALP], alanine 
aminotransferase [ALT], and aspartate aminotransferase [AST]), and total bilirubin) will 
be produced (for summaries referring to NCI CTCAE grading).
For neutrophils, platelets, lymphocytes and hepatic lab parameters, the number of 
patients will be summarized by CTCAE grade category for baseline and worst post 
baseline result.
Patients with values outside the reference will be listed with an indication of the direction 
of the abnormality (High or Low).
A listing of all pregnancies will be presented.
4.6.4
Vital Signs
Summary statistics on absolute values and their change from baseline for all observed 
vital signs (diastolic blood pressures, systolic blood pressures, respiratory rate, pulse 
rate, body temperature, and peripheral oxygen saturation) will be presented over time by 
treatment group. Baseline is defined as the last assessment prior to treatment. 
Additionally, a graphical representation of means over time of oxygen saturation and 
temperature (Daily to Week 4) will be presented.


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For patients requiring supplemental oxygen, summary statistics on absolute values of 
the oxygen flow rate (in liters per minute [L/min]) and/or fraction of inspired oxygen 
(FiO2) will be produced by visit, timepoint, and treatment group.
The level of consciousness will be summarized over time.
The number and proportion of patients requiring oxygen supplementation or other form 
of ventilation will be summarized over time, including type of support given.
Non-invasive mechanical ventilation will be summarized overall as well as by its 
component types (continuous-positive airway pressure [C-PAP], bilevel-positive airway 
pressure [BiPAP], and other). Invasive mechanical ventilation will also be summarized
overall and by component types (endotracheal tube, tracheostomy tube).
A listing of patients with chest X-ray, CT scan, location of opacities, and ECG results (as 
a separate listing) with clinically significant abnormalities will be produced.
4.7
INTERIM ANALYSES
There are no interim analyses planned in this study.


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5.
REFERENCES
Bernard GR, Doig G, Hudson LD, et al. Quantification of organ failure for clinical trials
and clinical practice. Am J Respir Crit Care Med 1995;151:Suppl:A323-A323.
Fine JP and Grey RJ. A proportional hazards model for the subdistribution of a 
competing risk. Journal of the American Statistical Association, 1999; 94:496-509.
National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD,
Bernard GR, et al. Rosuvastatin for sepsis-associated acute respiratory distress
syndrome. N Engl J Med. 2014;370(23):2191-2200.
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report—Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. J Allergy Clin Immunol 2006;117:391–7.
Xu X, Han M, Li, T, et al. Effective treatment of severe COVID-19 patients with 
tocilizumab. Submitted manuscript. [Resource on the internet]. 2020 [updated: 
5 March 2020; cited: 17 March 2020]. Available at:
http://www.chinaxiv.org/abs/202003.00026.
Zhao YD, Rahardja D, Dmitrienko A. Estimation of the competing probability for the van 
Elteren test. Model Assisted Statistics and Applications, 2012; 7:41-47.


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Appendix 1 Protocol Synopsis
TITLE:
A PHASE II, OPEN-LABEL, RANDOMIZED, MULTICENTER 
STUDY TO INVESTIGATE THE PHARMACODYNAMICS, 
PHARMACOKINETICS, SAFETY, AND EFFICACY OF 8 mg/kg OR 
4 mg/kg INTRAVENOUS TOCILIZUMAB IN PATIENTS WITH 
MODERATE TO SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
CA42481
VERSION NUMBER:
2
IND NUMBER:
148225
NCT NUMBER:
NCT04363736
TEST PRODUCT:
Tocilizumab (RO4877533)
PHASE:
Phase II
INDICATION:
Moderate to severe COVID-19 pneumonia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This Phase II study will investigate the pharmacodynamics, pharmacokinetics, safety, and 
efficacy of tocilizumab (TCZ) at two different doses in combination with standard-of-care (SOC) 
treatment in hospitalized patients with moderate to severe COVID-19 pneumonia.  Specific 
objectives and corresponding endpoints for the study are outlined below.
Pharmacodynamic Objective
The pharmacodynamic (PD) objective for this study is to assess the differences between two doses of 
TCZ in combination with SOC for the treatment of moderate to severe COVID-19 pneumonia on 
the basis of the following endpoints:

Serum concentrations of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), ferritin, 
and C-reactive protein (CRP) following administration of 8 mg/kg and 4 mg/kg IV TCZ at 
specified timepoints
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of two 
different doses of TCZ in combination with SOC for the treatment of moderate to severe 
COVID-19 pneumonia on the basis of the following endpoints:

Serum concentrations of TCZ following administration of 8 mg/kg and 4 mg/kg IV TCZ at 
specified timepoints
Safety Objective
The safety objective for this study is to compare the safety of two different doses of TCZ in 
combination with SOC for the treatment of moderate to severe COVID-19 pneumonia on the 
basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)


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
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) (COVID-19) viral load over 
time, as collected by nasopharyngeal swab and bronchoalveolar lavage (BAL) samples 
(if applicable)

Time to real-time polymerase chain reaction (RT-PCR) virus negativity

The proportion of patients with any posttreatment infection

Change from baseline in targeted clinical laboratory test results
Exploratory Objective
The exploratory objective for this study is to assess the efficacy of two different doses of TCZ in 
combination with SOC for the treatment of moderate to severe COVID-19 pneumonia on the 
basis of the following endpoints:

Clinical status, as assessed using a 7-category ordinal scale at Days 7, 14, and 28

Time to clinical improvement, defined as a National Early Warning Score 2 (NEWS2) score
of 2 maintained for 24 hours

Time to improvement in at least two categories relative to baseline on a 7-category ordinal 
scale of clinical status 

Duration of supplemental oxygen use

Incidence of intensive care unit (ICU) stays 

Incidence of mechanical ventilation

Duration of ICU stay

Time to clinical failure, defined as the time to death, mechanical ventilation, ICU admission, 
or withdrawal (whichever occurs first)
For patients entering the study already in an ICU, clinical failure is defined as a 
one-category worsening on the ordinal scale, withdrawal, or death.

Mortality rate at Days 7, 14, 21, 28, and 60

Time to hospital discharge or “ready for discharge” (as evidenced by normal body 
temperature and respiratory rate, and stable oxygen saturation on ambient air or 2 L 
supplemental oxygen)

Frequency of the addition of a second dose of TCZ (8 mg/kg or 4 mg/kg) at the discretion of 
the treating physician

Ventilator-free days from baseline to Day 28

Organ failurefree days from baseline to Day 28
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
could provide further evidence of TCZ pharmacologic activity (i.e., mechanism of action), on the 
basis of the following endpoints:

Assessments of exploratory biomarkers in relation to efficacy, exposure, and in both blood 
and tissue-derived samples

Association between TCZ pharmacokinetics and the following PD biomarkers:  CRP, IL-6, sIL-6R, 
and ferritin


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Study Design
Description of Study
This is a Phase II, open-label, randomized, multicenter study to assess the pharmacodynamics, 
pharmacokinetics, safety and efficacy of two different doses of TCZ in combination with SOC in 
hospitalized adult patients with moderate to severe COVID-19 pneumonia.  The Sponsor 
intends to enroll approximately 100 patients who have been diagnosed with COVID-19 
pneumonia who meet the eligibility criteria at U.S. sites.
Patients must be at least 18 years old with confirmed SARS-CoV-2 (COVID-19) pneumonia per
the World Health Organization criteria, including a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, or other bodily fluids).  At the time of enrollment, patients 
must be hospitalized and have respiratory symptoms and radiologic findings of pneumonia.  
Patients with severe COVID-19 pneumonia must have SpO2 93% or PaO2/FiO2 300 mmHg 
despite receiving SOC treatment, which may include anti-viral treatment, low-dose steroids, and 
supportive care.  Patients with moderate COVID-19 pneumonia are hospitalized patients not 
meeting the criteria of severe COVID-19 pneumonia and with CRP 2 the upper limit of 
normal (ULN).  For both patients with moderate and severe COVID-19, the onset of patient 
symptoms must be at least 3 days prior to enrollment.  
Patients who are on a mechanical ventilator 24 hours or extracorporeal membrane 
oxygenation (ECMO), in shock, or a combination thereof with other organ failure requiring 
treatment in an ICU will be excluded from the study.  Patients for whom, in the opinion of the 
treating physician, progression to death is imminent and inevitable within the next 24 hours, 
irrespective of the provision of treatments, will be excluded from the study.  Patients with active 
TB or suspected active bacterial, fungal, viral, or other infection (other than COVID-19 
pneumonia) will be excluded from the study.  
Patients will be randomized as soon as possible after screening in a 1:1 ratio to receive 
treatment with either 8 mg/kg or 4 mg/kg IV TCZ.  Study treatment must be given in combination 
with SOC treatment.  
Patients assigned to the 8-mg/kg TCZ arm will receive one IV infusion of 8 mg/kg, with a 
maximum dose of 800 mg, and patients assigned to the 4-mg/kg TCZ arm will receive one IV 
infusion of 4 mg/kg TCZ.  In addition, patients in both arms will receive SOC treatment.  
For patients in both arms, if a patient has a sustained fever or clinically significant worsening of signs 
or symptoms (e.g., an increased supplemental oxygen requirement), one additional infusion of TCZ at 
the same dose as the initial infusion can be given within 8 to 24 hours after the initial TCZ
infusion. 
Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity (for a total of two screenings per participant) at the 
investigator’s discretion.  Patients are not required to re-sign the consent form if they are 
re-screened within 7 days after previously signing the consent form.
The study assessments to be conducted include the following:  complete and limited physical 
examinations, measurement of vital signs and oxygen saturation, assessment of 
consciousness, presence and absence of respiratory support, adverse events, concomitant 
therapies, clinical laboratory tests, and nasopharyngeal swabs.
Patients will be followed for a total of 60 days after the first dose of study drug.  
If patients are discharged from the hospital prior to Day 28, follow-up visits should occur twice 
weekly through Day 28.  Patients are encouraged to return for onsite visits at least weekly if 
possible; other follow-up visits may be conducted by telephone or home visits.  Patients should 
return to the site for the Day 28 visit.  After Day 28, all patients should have follow-up visits on 
Days 35, 45, and 60; the Day 35 and 45 visits may be conducted by telephone or by home visits 
for patients who are discharged, while the Day 60 visit should be conducted onsite.
During the study, standard supportive care will be given according to clinical practice. 
Number of Patients
Approximately 100 patients will be enrolled in this study.


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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form by any patient capable of giving consent, or, when the 
patient is not capable of giving consent, by his or her legally authorized representative

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol

Hospitalization with COVID-19 pneumonia confirmed by a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, or other bodily fluids) and evidence of pneumonia on 
chest X-ray or computed tomography scan 
The onset of patient symptoms must be at least 3 days prior to enrollment.

For severe patients, SpO2 93% or PaO2/FiO2 300 mmHg  
If a patient is on supplemental oxygen with SpO2 93%, but desaturation to 93% on 
lower supplemental oxygen or ambient air is documented during screening, the inclusion 
criterion is met.

For moderate patients (those who do not qualify as severe based oxygen requirements), 
CRP 2 ULN is required

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 90 days after the final dose of TCZ.  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential 
may be adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not adequate methods of contraception.  If required per local guidelines or regulations, 
locally recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 60 days after the 
final dose of TCZ to avoid exposing the embryo.  Men must refrain from donating sperm 
during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not adequate methods of preventing drug exposure.  If required per local guidelines or 
regulations, information about the reliability of abstinence will be described in the local 
Informed Consent Form.


Tocilizumab—F. Hoffmann-La Roche Ltd.
37/Statistical Analysis Plan CA42481
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known severe allergic reactions to TCZ or other monoclonal antibodies

Active TB infection 

Suspected active bacterial, fungal, viral, or other infection (besides SARS-CoV-2) 

Patients who meet any of the following at the time of randomization:  on a mechanical ventilator 
24 hours, on ECMO, in shock, or with other organ failure requiring treatment in an ICU

In the opinion of the investigator, progression to death is imminent and inevitable within the 
next 24 hours, irrespective of the provision of treatments

Receipt of oral anti-rejection or immunomodulatory drugs (including TCZ) within the past 
3 months

Participation in other drug clinical trials (participation in COVID-19 anti-viral trials may be 
permitted if confirmed by the Medical Monitor)

ALT or AST 10ULN detected within 24 hours at screening or at baseline (according to 
local laboratory reference ranges)

ANC 1000/L at screening and baseline (according to local laboratory reference ranges)

Platelet count 50,000/L at screening and baseline (according to local laboratory 
reference ranges)

Pregnancy or breastfeeding, or positive pregnancy test at a predose examination

Treatment with an investigational drug within 5 drug-elimination half-lives or 30 days 
(whichever is longer) of randomization (investigational SARS-CoV-2 [COVID-19]) anti-viral 
agents may be permitted after consultation with the Medical Monitor)

Any serious medical condition or abnormality of clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last datapoint required for the last follow-up is received from the last patient, 
whichever occurs later.  The end of the study is expected to occur approximately 2 months after 
the last patient is enrolled.
In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 months. 
Investigational Medicinal Products
The investigational medicinal product for this study is TCZ.
Test Products (Investigational Drugs)
Patients assigned to the 4-mg/kg arm will receive the 4-mg/kg TCZ dose by IV infusion.  The 
dose of TCZ infusion will be calculated on the basis of body weight measured prior to infusion.  
One additional infusion of TCZ can be given within 8 to 24 hours after the initial infusion.
Comparator
Patients assigned to the 8-mg/kg arm will receive the 8-mg/kg TCZ dose by IV infusion.  The 
dose of TCZ infusion will be calculated on the basis of body weight measured prior to infusion.  
One additional infusion of TCZ can be given within 8 to 24 hours after the initial infusion.


Tocilizumab—F. Hoffmann-La Roche Ltd.
38/Statistical Analysis Plan CA42481
Statistical Methods
PD Analysis
The PD outcome measures for this study are serum IL-6, sIL-6R, ferritin, and CRP levels at 
baseline and at specified timepoints after initiation of study drug. Data for all PD biomarkers will 
be presented using descriptive summary statistics, including the mean, median, range, standard 
deviation (SD), and coefficient of variation.
PK Analyses
The PK analysis population will consist of patients with sufficient data to enable estimation of 
key parameters (e.g., area under the concentrationcurve [AUC], maximum serum 
concentration observed [Cmax]), with patients grouped according to treatment received.  
Non-linear mixed effects modeling will be used to analyze the serum TCZ concentration over 
time data collected in this study using existing population-PK models.  Individual and mean 
serum TCZ concentration versus time data will be tabulated and plotted by dose level.  The 
serum pharmacokinetics of TCZ will be summarized by estimating the total exposure (AUC), 
Cmax, total clearance, and volume of distribution.  Estimates for these parameters will be 
tabulated and summarized (mean, SD, co-efficient of variation, median, minimum, and 
maximum).  Interpatient variability will be evaluated.
Additional PK analyses will be conducted as appropriate.  The PK parameters derived from 
these analyses may be used for exploratory graphical analyses of the PD parameters.
Determination of Sample Size  
The purpose of this open-label study is the comparison of TCZ pharmacokinetics and PK-PD 
relationship between two doses of TCZ (8 and 4 mg/kg) in hospitalized patients with moderate 
to severe COVID-19 pneumonia.  The comparison will be assessed using modeling and 
evaluating the safety and efficacy measures between Day 1 and Day 28 postrandomization.  
Data from the follow-up period from Days 28 to 60 may also be assessed.  Approximately 100 
patients will be enrolled and randomized in a 1:1 ratio to the 8-mg/kg and 4-mg/kg IV TCZ arms 
in this study.  Disease severity type will also be stratified into moderate and severe COVID 
pneumonia, giving an overall equal four-way split between the two doses and type of disease 
severity and resulting in four groups of approximately 25 patients each.  Patients may receive a 
repeat dose within 8 to 24 hours after the first TCZ dose if clinicians judge it is necessary 
(resulting in a TCZ dose range from 4 to 16 mg/kg, with a maximum dose of 800 mg).  
The variability of PK parameters of TCZ in a heterogeneous COVID-19 population in an acute 
setting is unknown; however, 20 to 30 patients is deemed adequate considering the 
between-subject variability in health volunteers and patients with RA provided by population-PK 
modeling.  Data quality issues, patient dropouts, and early hospital discharge may all lead to 
missing data, especially in a pandemic setting; thus, enrolling 50 patients according to dose and 
disease severity type (25 per arm) may offset missing data and allow an adequate volume of PK 
and PD data to inform the population-PK model and allow a comparison of the 4- and 8-mg/kg 
doses.
Interim Analysis
No interim analysis is planned for this study.


Tocilizumab—F. Hoffmann-La Roche Ltd.
39/Statistical Analysis Plan CA42481
Appendix 2
Schedule of Activities: Days 1 and 2
Time after Initial Treatment
(Assessment Window)
Screening a
Day 1
Day 2
Baseline
24 hr
4 hr)
Days
2 to 0
0
Predose 
(4 hr)
15 min Postinfusion
(1 hr)
Informed consent
x
Review of inclusion and exclusion 
criteria
x
x
Demographics
x
Randomization
x
Medical history
x
Complete physical examination c
x
Weight
x
COVID-19 diagnosis d
x
Chest X-ray or CT scan
x
ECG
x
Pregnancy test f
x
PaO2/FiO2 g
x
Optional
SpO2 h
x
x
x
x
Vital signs h
x
x
x
x
Ordinal scoring i
x
x
Adverse events j
x
x


Tocilizumab—F. Hoffmann-La Roche Ltd.
40/Statistical Analysis Plan CA42481
Appendix 2
Schedule of Activities: Days 1 and 2 (cont.)
Time after Initial Treatment
(Assessment Window)
Screening a
Day 1
Day 2
Baseline
24 hours
4 hr)
Days
2 to 0
0
Predose 
(4 hr)
15 minutes 
Postinfusion
(1 hr)
Concomitant medications k
x
x
Hematology l
x
(24 hr) m
x
x
Chemistry panel n
x
(24 hr) m
x
x
Study drug administration o
x
Central laboratory assessments
Serum PD sample (CRP, IL-6,
and sIL-6R) p
x p
x p
x
Serum PK sample q
x q
x q
x
Serum and plasma samples for 
exploratory biomarkers 
x
x
SARS-CoV-2 viral load r
x
x
Serum SARS-CoV-2 antibody titer
x
Cryopreserved PBMCs s
x
x
Blood in PAXgene® tubes for RNA 
analyses t
x


Tocilizumab—F. Hoffmann-La Roche Ltd.
41/Statistical Analysis Plan CA42481
Appendix 2
Schedule of Activities: Days 1 and 2 (cont.)
CRPC-reactive protein; CTcomputed tomography; ECGelectrocardiogram; eCRFelectronic Case Report Form; IL-6interleukin-6; 
NEWS2National Early Warning Score 2; PaO2/FiO2 arterial oxygen partial pressure/fraction of inspired oxygen; PBMCperipheral blood 
mononuclear cell; PCRpolymerase chain reaction; PDpharmacodynamic; PK pharmacokinetic; SARS-CoV-2severe acute respiratory
syndrome corona virus (strain) 2; sIL-6Rsoluble interleukin-6 receptor; SpO2peripheral capillary oxygen saturation; TCZ tocilizumab
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a Results from standard-of-care tests or examinations performed prior to obtaining informed consent and within 48 hours before randomization 
may be used; such tests do not need to be repeated for screening.  An exception to this is clinical chemistry and hematology tests obtained prior to 
informed consent, which do not need to be repeated for screening if conducted within 24 hours before randomization.
b Informed consent must be documented before any study-specific screening procedure is performed.
c A complete physical examination, performed at screening and per the investigator’s discretion during the study, includes an evaluation of the 
head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurologic systems.  Any abnormality identified at screening should be recorded on the General Medical History and Baseline Conditions eCRF.
New or worsened clinically significant abnormalities identified during the study should be reported as adverse events. 
d COVID-19 test (SARS-CoV2 PCR) to confirm diagnosis should be performed within 7 days of randomization. 
e Screening chest X-ray or CT scans should be performed within 48 hours prior to randomization.  If additional chest X-rays or CT scans are taken 
per local practice during the study, this information should be provided on the eCRF. 
f
For women of childbearing potential, including those who have had a tubal ligation, positive urine test results will be confirmed with a serum 
pregnancy test.  Study drug infusion must not be administered unless the serum pregnancy test result is negative.
g If arterial blood gases are measured.
h All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body temperature), oxygen saturation 
and NEWS2-specific assessments (i.e., consciousness and presence or absence of oxygen support) should be recorded together twice daily 
with approximately 12 hours in between while the patient remains hospitalized.  If measured more than once during a 12-hour period, the worst 
values (highest temperature, respiratory rate, and heart rate; lowest blood pressure, oxygen saturation, and consciousness level) during that 
period should be recorded on the eCRF.  
i
Assessment of clinical status using the ordinal scale should be recorded at baseline (Day 1, Visit 1) and then again daily every morning (between 
8 a.m. and 12 p.m.) for patients who remain hospitalized.
j
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 60 days after the final dose of study drug.


Tocilizumab—F. Hoffmann-La Roche Ltd.
42/Statistical Analysis Plan CA42481
Appendix 2
Schedule of Activities: Days 1 and 2 (cont.)
j
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related 
to prior study drug treatment (see Section 5.6).
k
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug to the study completion/discontinuation visit.
l
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes), and lymphocyte subsets (T cells, B cells, and natural killer cells; if the test is available at the site).
m
Hematology and chemistry panel assessments performed as part of standard of care, prior to consent but within 24 hours of randomization, do 
not need to be repeated.
n
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and/or AST, uric acid, 
LDH, CRP, ferritin, and D-dimer.
o
Study drug should be administered after collection of all samples for PK, PD, and exploratory biomarkers.  The initial study drug infusion 
should be given within 4 hours of randomization.  For patients in both arms of the study, if a patient has a sustained fever or clinically significant 
worsening of signs or symptoms (e.g., an increased supplemental oxygen requirement), one additional infusion of TCZ at the same dose as the 
initial infusion can be given within 8 to 24 hours after the initial TCZ infusion.
p
On Day 1, CRP, IL-6, and sIL-6R samples should be drawn 04 hours before the start of infusion and then within 15 minutes (to 1 hour) after 
the end of the infusion from the opposite arm as the infusion.  Patents receiving a second infusion of study drug should provide extra samples for 
CRP, IL-6, and sIL-6R prior to and 15 minutes after the end of the infusion from the opposite arm as the infusion.  If the second infusion falls within 
the window for the Day 2 PD sample (2024 hours) for the first infusion, it can be combined with the post infusion sample for the second infusion.
q
On Day 1, PK samples should be drawn 04 hours before the start of infusion and then within 15 minutes (to 1 hour) after the end of the 
infusion from the opposite arm as the infusion.  Patents receiving a second infusion of study drug should provide an extra PK sample prior to and 
15 minutes (to 1 hour) after the end of the infusion from the opposite arm as the infusion.  If the second infusion falls within the window for the Day 
2 PK sample (2024 hours) for the first infusion, it can be combined with the post infusion sample for the second infusion.
r
Viral load will be assessed by nasopharyngeal swab.  Patients who are intubated and undergo bronchoalveolar lavage will have samples taken 
for virological assessment.  It may only be possible to access one nostril if a patient has a nasogastric tube in place, in which case sites may collect 
a sample from one nostril only and when possible the same nostril should be used.
s
For sites capable of sample collection for analysis of T cells by high-dimensional cytometry.
t
The PAXgene® blood tube should be the last tube drawn in the phlebotomy procedure to avoid contact with the RNA preservation reagent 
inside the tube.


Tocilizumab—F. Hoffmann-La Roche Ltd.
43/Statistical Analysis Plan CA42481
Appendix 3
Schedule of Activities: Days 328
Study Day
Days 328 a
Early Tx or 
Study
Discon
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Chest X-ray or CT scan
x
x
x
x
x
Vital signs b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PaO2/FiO2 c
Optional 
Optional
SpO2 b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Ordinal scoring d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology g
x
x
x
x
x
x
x
Chemistry profile h
x
x
x
x
x
x
x
Central laboratory assessments
Serum PD sample (CRP, 
IL-6, and sIL-6R)
x
x
x
x
x
x
Serum PK sample
x
x
x
x
x
x
Serum and plasma samples
for exploratory biomarkers
x
x
x
x
x
x
SARS-CoV-2 viral load i
x
x
x
x
x
x
x
x
x
x
Serum SARS-CoV-2 
antibody titer
x
x
Cryopreserved PBMCs j
x
x
x
x
x
x


Tocilizumab—F. Hoffmann-La Roche Ltd.
44/Statistical Analysis Plan CA42481
Appendix 3
Schedule of Activities: Days 328 (cont.)
Study Day
Days 328 a
Early Tx or 
Study
Discon
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Blood in PAXgene®
tubes for RNA analyses k
x
x
x
x
CRPC-reactive protein; CTcomputed tomography; Discondiscontinuation; ECG electrocardiogram; eCRFelectronic Case Report Form; 
IL-6interleukin-6; NEWS2National Early Warning Score; PaO2/FiO2arterial oxygen partial pressure/fraction of inspired oxygen;
PBMCperipheral blood mononuclear cell; PDpharmacodynamic; PKpharmacokinetic; SARS-CoV-2severe acute respiratory syndrome corona 
virus (strain) 2; sIL-6Rsoluble interleukin-6 receptor; SpO2peripheral capillary oxygen saturation; Txtreatment; TCZtocilizumab.
Note:  For patients who have been discharged, all assessments should be performed within 3 days of the scheduled onsite visit.
a If patients are discharged from hospital prior to Day 28, follow-up visits should occur twice weekly through Day 28.  Patients are encouraged to 
return for onsite visits at least weekly if possible; other follow-up visits may be conducted by telephone or home visits.  Patients should return to 
the site for the Day 28 visit.
b All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body temperature), oxygen saturation 
and NEWS2-specific assessments (i.e., consciousness and presence or absence of oxygen support) should be recorded together twice daily 
with approximately 12 hours in between while the patient remains hospitalized.  If measured more than once during a 12-hour period, the worst 
values (highest temperature, respiratory rate, and heart rate; lowest blood pressure, oxygen saturation, and consciousness level) during that 
period should be recorded on the eCRF.  Following hospital discharge these parameters should be recorded once at each return visit to the 
clinic.  Vital signs and oxygen saturation will not be recorded if follow-up visits are conducted by telephone. 
c If arterial blood gases are measured.
d Assessment of clinical status using the ordinal scale should be recorded at baseline (Day 1, Visit 1) and then again daily every morning (between 
8 a.m. and 12 p.m.) for patients who remain hospitalized.
e After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 60 days after the final dose of study drug.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to 
prior study drug treatment (see Section 5.6).


Tocilizumab—F. Hoffmann-La Roche Ltd.
45/Statistical Analysis Plan CA42481
Appendix 3
Schedule of Activities: Days 328 (cont.)
f
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug to the study completion/discontinuation visit. 
g Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes), and lymphocyte subsets (T cells, B cells, and natural killer cells; if the test is available at the site).
h Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and/or AST, 
uric acid, LDH, ferritin, and D-dimer.
i
Viral load will be assessed by nasopharyngeal swab.  Patients who are intubated and undergo bronchoalveolar lavage will have samples taken 
for virological assessment.  It may only be possible to access one nostril if a patient has a nasogastric tube in place, in which case sites may 
collect a sample from one nostril only and when possible the same nostril should be used.
j
For sites capable of sample collection for analysis of T cells by high-dimensional cytometry.
k
The PAXgene® blood tube should be the last tube drawn in the phlebotomy procedure to avoid contact with the RNA preservation 
reagent inside the tube


Tocilizumab—F. Hoffmann-La Roche Ltd.
46/Statistical Analysis Plan CA42481
Appendix 4 Schedule of Activities:  After Day 28
Study Day
(Assessment Window)
Study Completion
35 a
(3 days)
45 a
(3 days)
60
(3 days)
Chest X-ray or CT scan
x
SARS-CoV-2 viral load b
x
x
x
Vital signs c
x
x
x
SpO2 c
x
x
x
Ordinal scoring d
x
x
x
Adverse events e
x
x
x
Concomitant medications f
x
x
x
Hematology g
x
x
x
Chemistry panel h
x
x
x
Central laboratory assessments
Serum PD sample (CRP, IL-6, and sIL-6R)
x
x
Serum PK sample
x
x
Serum and plasma samples for exploratory biomarkers
x
x
SARS-CoV-2 viral load i
x
Cryopreserved PBMCs j
x
Blood in PAXgene® tubes for RNA analyses k
x
Serum SARS-Cov-2 antibody titer
x
CRPC-reactive protein; CTcomputed tomography; eCRFelectronic Case Report Form; IL-6interleukin-6; 
PDpharmacodynamic; PK pharmacokinetic; SARS-CoV-2severe acute respiratory syndrome corona virus (strain) 2; 
sIL-6Rsoluble interleukin-6 receptor; SpO2peripheral capillary oxygen saturation.


Tocilizumab—F. Hoffmann-La Roche Ltd.
47/Statistical Analysis Plan CA42481
Appendix 4 Schedule of Activities:  After Day 28 (cont.)
a If patients are unable to return for onsite visits at Day 35 and/or Day 45, these may be conducted by telephone or 
home visits.  Patients should return to the site for the Day 60 study completion visit.
b Patients who remain in hospital will have viral load assessed by nasopharyngeal swabs; these will be done if there is 
evidence of ongoing infection.
c For patients who remain in the hospital, vital sign measurements and NEWS2-specific assessments should be 
conducted twice daily.  Following hospital discharge, these parameters should be recorded once at each return visit to 
the clinic.  Vital signs and oxygen saturation will not be recorded if follow-up visits are conducted by telephone.
d Assessment of clinical status using the ordinal scale should be recorded at baseline (Day 1, Visit 1)and then again 
daily every morning (between 8 a.m. and 12 p.m.) for patients who remain hospitalized.
e After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a 
protocol-mandated intervention should be reported.  After initiation of study drug, all adverse events will be reported 
until 60 days after the final dose of study drug.  After this period, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior study drug treatment 
(see Section 5.6).
f
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug 
to the study completion/discontinuation visit.
g Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes), and lymphocyte subsets (T cells, B cells, and natural killer cells).  
Hematology labs will not be performed if follow-up visits are conducted by telephone.
h Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the 
region), sodium, potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, 
total bilirubin, ALP, ALT, and/or AST, uric acid, LDH, ferritin, and D-dimer.  Chemistry laboratory assessments will not 
be performed if follow-up visits are conducted by telephone.
i
Viral load will be assessed by nasopharyngeal swab.  Patients who are intubated and undergo bronchoalveolar lavage will have 
samples taken for virological assessment.  It may only be possible to access one nostril if a patient has a nasogastric tube in place, 
in which case sites may collect a sample from one nostril only and when possible the same nostril should be used.
j
For sites capable of sample collection for analysis of T cells by high-dimensional cytometry.
k The PAXgene® blood tube should be the last tube drawn in the phlebotomy procedure to avoid contact with the RNA preservation 
reagent inside the tube.


Tocilizumab—F. Hoffmann-La Roche Ltd.
48/Statistical Analysis Plan CA42481
Appendix 5
National Early Warning Score 2 (NEWS2)
SpO2oxygen saturation. 
Oxygen saturation (SpO2) should be scored according to either the SpO2 Scale 1 or 2 
presented in the table above.  The SpO2 Scale 2 is for patients with a target oxygen 
saturation requirement of 88%92% (e.g., in patients with hypercapnic respiratory failure 
related to advanced lung diseases, such as chronic obstructive pulmonary disease).  
This should only be used in patients confirmed to have hypercapnic respiratory failure by 
blood gas analysis on either a prior or their current hospital admission.
The decision to use the SpO2 Scale 2 should be made by the treating physician and 
should be recorded in the eCRF.  In all other circumstances, the SpO2 Scale 1 should be 
used.
For physiological parameter “Air or Oxygen?”:  Any patients requiring the use of oxygen 
or other forms of ventilation to maintain oxygen saturations and support respiration 
should be assigned a score of 2.
The consciousness level should be recorded according to the best clinical condition of 
the patient during the assessment.  Patients who are assessed as “Alert” (A) should be 
assigned a score of 0.  Patients assessed as “New Confusion” (C), “Responsive to 
Voice” (V), “Responsive to Pain” (P), or “Unconscious” should be assigned a score of 3.
Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and 
temperature according to the table above. 


Tocilizumab—F. Hoffmann-La Roche Ltd.
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Appendix 5
National Early Warning Score 2 (NEWS2) (cont.)
NEWS2 values will be calculated electronically throughout the study by the Sponsor 
based upon entry of vital sign parameters by the investigator on the appropriate 
electronic Case Report Form.
Example Case Calculation:
An 82-year-old woman was admitted, tested positive to COVID-19, and admitted to 
high-dependency unit for non-invasive ventilation.  Her taken observations and 
corresponding NEWS2 score are as follows: 
Physiological Parameter 
Observation
Component Score
Respiratory rate (per minute)
26
3
Oxygen saturation (SpO2 %)
95%
1
Supplemental oxygen 
Yes
2
Systolic blood pressure (mmHg)
95
2
Pulse rate (bpm)
109
1
Conscious level
New confusion
3
Temperature (oC)
39
1
Total NEWS2 score
13
REFERENCE
Royal College of Physicians. National early warning score (NEWS) 2. Standardizing the 
assessment of acute-illness severity in the NHS. London: RCP, 2017.


Tocilizumab—F. Hoffmann-La Roche Ltd.
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Appendix 6
Cochran-Mantel-Haenszel Test

The weighted difference in proportions is the difference in the response rates in the 
experimental treatment group compared with the control treatment group, adjusted 
for any stratification factors. With two stratification factors, the number of patients in 
each strata is defined as nijk where i is the level of the first stratification factor and j 
is the level of the second stratification factor and k is treatment group (experimental 
or control). The number of events in each strata is denoted by xijk, where i, j and k 
are as above. The proportion of responders in each strata will be calculated by:
where i, j and k are as above

The difference in proportions for each strata will then be calculated as the proportion 
of patients in each strata in the experimental treatment group (EXP) minus the 
proportion of patients in each strata in the control treatment group (CON) and 
denoted 
, for i and j as above.

The weights for each strata (i, j) will be calculated as follows:

Within each strata, the weighted differences in the proportions in each of the 
treatment groups will be calculated as follows:

and then summed:

After calculation of the weighted difference in proportions, the calculation of the 
95% CI is as follows:

Continuity-corrected Proportions

Variances
ijk
ijk
ijk
n
x
p

ijCON
ijEXP
ij
p
p
d


ijCON
ijEXP
ijCON
ijEXP
ij
n
n
n
n
w


*
ij
ij
ij
d
w
wd 


i
j
ij
wd
WD
1
5.0
#



ijk
ijk
ijk
n
x
p
















ijCON
ijCON
ijCON
ijEXP
ijEXP
ijEXP
ij
ij
n
p
p
n
p
p
w
Up
#
#
#
#
2
1
1
var


Tocilizumab—F. Hoffmann-La Roche Ltd.
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Appendix 6
Cochran-Mantel-Haenszel Test (cont.)

To calculate the sum of the weights and variances over all strata:
Sum over Strata
(sum of weights)
(sum of variances)
Point Estimate and Standard Error
; 
Stratified 95% Confidence Intervals
Lower Limit
Upper Limit


i
j
ij
w
W


i
j
ij
Up
Var
var
W
WD
d 
2
W
Var
se 
se
d
96
.1


se
d
96
.1




Tocilizumab—F. Hoffmann-La Roche Ltd.
52/Statistical Analysis Plan CA42481
Appendix 7 Handling of Values Below the Limit of 
Quantification (BLQ)
PD and PK values can be below the limit of quantification (BLQ). The rules to 
handle those values are specified next.
If less than 50% of the PK values at a given time point are BLQ then we will 
follow the ½ Cmax rule:
1.
Set all BLQ/LTR observations to zero if BLQ/LTR occurs prior to cmax.
2.
Set all BLQ/LTR observations to missing if BLQ/LTR occurs after cmax.
3.
If > 1/2 of the values are LTR/BLQ (i.e., percentage sample with LTRs/BLQs > 50%) 
then, FLAGSUM = 3, otherwise missing.
If more than 1/3 of the PD values at a given time point are BLQ then we will 
follow the 1/3 rule:
1.
For pre-dose PK samples (i.e. nominal time <= 0) if sample result is LTR/BLQ (i.e. if 
PC.PCSTRESC in ('LTR', 'BLQ')) then the result is replaced as 0 (i.e. SUMMCONC = 0 and 
GRAFCONC=0)
2.
For post-dose PD samples (i.e. nominal time > 0) then those LTR values are replaced by 
1/2*LLOQ (i.e. if PC.PCSTRESC in ('LTR', 'BLQ') then SUMMCONC=0.5*LLOQ and 
GRAFCONC=0.5*LLOQ)
3.
If > 1/3 sample results are LTR/BLQ (i.e., percentage of sample with LTRs/BLQs > 33%) 
then FLAGSUM=2, otherwise missing.
*LTR: Less Than Reportable


Tocilizumab—F. Hoffmann-La Roche Ltd.
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Appendix 8 Additional descriptions of time windows
Headings mean:
AVISIT: character representation of visit
AVISITN: numeric representation of visit
AWTARGET: target day (approximately the window midpoint)
AWLO: lower window range
AWHI: higher window range
All vital signs, including oxygen saturation and NEWS2
AVISIT
AVISITN
AWTARGET
AWLO
AWHI
PRE-BASELINE
0
1
.
1
BASELINE
1
1
.
1
Day 1 (Postdose)
1.5
1
1
1
Day 2
2
2
2
2
Day 3
3
3
3
3
Week 1
7
7
4
10
Week 2
14
14
11
17
Week 3
21
21
18
24
Week 4
28
28
25
28
Week 5
35
35
29
38
Day 45
45
45
39
52
Day 60
60
60
53
>60
Safety labs
AVISIT
AVISITN
AWTARGET
AWLO
AWHI
PRE-BASELINE
0
1
.
1
BASELINE
1
1
.
1
Day 1 (Postdose)
1.5
1
1
1
Day 2
2
2
2
2
Day 3
3
3
3
3
Day 7
7
7
4
8


Tocilizumab—F. Hoffmann-La Roche Ltd.
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Appendix 8 Additional descriptions of time windows (cont.)
Day 10
10
10
9
12
Week 2
14
14
13
17
Week 3
21
21
18
24
Week 4
28
28
25
28
Week 5
35
35
29
38
Day 45
45
45
39
52
Day 60
60
60
53
>60
PD and PK parameters
AVISIT
AVISITN
AWTARGET
AWLO
AWHI
BASELINE
1
1
.
1
Day 1 (Postdose)
1.5
1
1
1
Day 2
2
2
2
2
Day 3
3
3
3
3
Week 1
7
7
4
10
Week 2
14
14
11
17
Week 3
21
21
18
24
Week 4
28
28
25
28
Week 5
35
35
29
38
Day 60
60
60
39
>60
Death and discharge
AVISIT
AVISITN
AWTARGET
AWLO
AWHI
PRE-BASELINE
0
1
.
1
BASELINE
1
1
.
1
Week 1
7
7
1
7
Week 2
14
14
8
14
Week 3
21
21
15
21


Tocilizumab—F. Hoffmann-La Roche Ltd.
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Appendix 8 Additional descriptions of time windows (cont.)
Week 4
28
28
22
28
Week 5
35
35
29
35
Day 45
45
45
36
45
Day 60
60
60
46
>60
Ordinal scoring and all other incidence measures
AVISIT
AVISITN
AWTARGET
AWLO
AWHI
PRE-BASELINE
0
1
.
1
BASELINE
1
1
.
1
Day 2
2
2
2
2
Day 3
3
3
3
3
Week 1
7
7
4
10
Week 2
14
14
11
17
Week 3
21
21
18
24
Week 4
28
28
25
28
Week 5
35
35
29
38
Day 45
45
45
39
52
Day 60
60
60
53
>60