Clinical trial NCT04320615
Conditions: COVID-19 Pneumonia
Sponsor: Hoffmann-La Roche
Start date: 2020-04-03; Completion date: 2020-07-28
Enrollment: 452 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of tocilizumab (TCZ) compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with severe COVID-19 pneumonia.

Detailed description:

Arms: arm 1: Participants will receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement. arm 2: Participants will receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.
Interventions: intervention 1: Tocilizumab (TCZ) intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 1 dose of IV TCZ. 1 additional dose may be given if clinical symptoms worsen or show no improvement. intervention 2: Participants will receive 1 dose of IV placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.

Protocol documents:
Prot_000.pdf: 
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 WA42380, Version 3
PROTOCOL
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
TOCILIZUMAB IN PATIENTS WITH SEVERE 
COVID-19 PNEUMONIA
PROTOCOL NUMBER:
WA42380
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001154-22
IND NUMBER:
148225
NCT NUMBER:
NCT04320615
TEST PRODUCT:
Tocilizumab (RO4877533)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below
 
11-Jun-2020 19:02:50
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Tocilizumab—F. Hoffmann-La Roche Ltd
2/Protocol WA42380, Version 3
PROTOCOL HISTORY
Protocol
Version
Date Final
2
14 April 2020
1
18 March 2020


Tocilizumab—F. Hoffmann-La Roche Ltd
3/Protocol WA42380, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol WA42380 has been amended to better align with the statistical analysis plan
(SAP). Changes to the protocol, along with a rationale for each change, are 
summarized below:

An additional secondary efficacy endpoint of time to recovery was added to facilitate
comparison with other trials of treatments for COVID-19 (Sections 2.1.2 and 6.4.2).

Text on the sample size and power calculation was updated to incorporate the 
increased enrollment target to maintain 90% power for the primary endpoint, as 
described in the SAP (Sections 3.1, 4.1, 6.1, 9.5).  The potential for an increase in 
enrollment was included in Version 2 of the protocol, and the confirmation of 
increased enrollment was communicated to sites, Agencies, and ethics committees 
in the week of 4 May 2020.

The geographic stratification factors were updated to address the inclusion of only 
North American and Europe because no sites outside of these regions were 
included in the study (Sections 3.1, 4.2.1, 6.1, 6.4.2).

Text on the reporting of pregnancies in partner of male patients was removed to 
align with the informed consent form and recommendations for tocilizumab in other 
indications (Section 5.4.3).

The method of analysis for the primary endpoint was updated to utilize a 
non-parametric method that was determined to be a more appropriate method, as 
described in the SAP (Sections 6.1 and 6.4.1).  

The method of analysis for the secondary endpoint of clinical status at additional 
timepoints was updated to utilize a non-parametric method that was determined to
be a more appropriate method, as described in the SAP (Section 6.4.2).

Selected secondary efficacy endpoints were specified as key secondary endpoints 
to address Type I error control, as described in the SAP (Section 6.4.2).

For clarity and as described in the SAP, language on the planned interim analyses 
was updated to address the increased enrollment target to maintain 90% power for 
the primary endpoint and the criteria for not conducting the interim analyses 
(Section 6.9). 
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.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 20
1.1
Background on COVID-19 Pneumonia.................................. 20
1.2
Background on Tocilizumab .................................................. 20
1.3
Tocilizumab Treatment in Cytokine-Release 
Syndrome of CAR-T therapy ................................................. 21
1.4
Real World Experience with Tocilizumab in 
COVID-19 Pneumonia........................................................... 22
1.5
Study Rationale and Benefit-Risk Assessment...................... 23
2.
OBJECTIVES AND ENDPOINTS ............................................................... 24
2.1
Efficacy Objectives ................................................................ 24
2.1.1
Primary Efficacy Objective..................................................... 24
2.1.2
Secondary Efficacy Objectives .............................................. 24
2.1.3
Exploratory Efficacy Objective............................................... 25
2.2
Safety Objective .................................................................... 25
2.3
Pharmacodynamic Objective................................................. 25
2.4
Pharmacokinetic Objective .................................................... 25
2.5
Biomarker Objective .............................................................. 26
3.
STUDY DESIGN......................................................................................... 26
3.1
Description of the Study......................................................... 26
3.2
End of Study and Length of Study......................................... 28
3.3
Rationale for Study Design.................................................... 28
3.3.1
Rationale for Tocilizumab Dose and Schedule...................... 28
3.3.2
Rationale for Patient Population ............................................ 29
3.3.3
Rationale for Control Group................................................... 29
3.3.4
Rationale for Biomarker Assessments................................... 30
4.
MATERIALS AND METHODS .................................................................... 30
4.1
Patients.................................................................................. 30
4.1.1
Inclusion Criteria.................................................................... 30


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4.1.2
Exclusion Criteria................................................................... 31
4.2
Method of Treatment Assignment and Blinding..................... 32
4.2.1
Treatment Assignment........................................................... 32
4.2.2
Blinding.................................................................................. 32
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 33
4.3.1
Study Treatment Formulation and Packaging........................ 33
4.3.1.1
Tocilizumab and Placebo....................................................... 33
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 33
4.3.2.1
Tocilizumab and Placebo....................................................... 33
4.3.3
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 34
4.3.4
Continued Access to Tocilizumab.......................................... 35
4.4
Concomitant Therapy ............................................................ 35
4.4.1
Permitted Therapy................................................................. 35
4.4.2
Cautionary Therapy ............................................................... 36
4.4.2.1
Medications Given with Precaution due to Effects 
Related to CYP Enzymes ...................................................... 36
4.4.2.2
Herbal Therapies................................................................... 36
4.4.3
Prohibited Therapy ................................................................ 36
4.5
Study Assessments ............................................................... 37
4.5.1
Informed Consent Forms and Screening Log........................ 37
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 38
4.5.3
Physical Examinations........................................................... 38
4.5.4
Vital Signs and Oxygen Saturation........................................ 38
4.5.5
Assessments Specific to National Early Warning 
Score 2 .................................................................................. 39
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 39
4.5.7
Liver Function Monitoring ...................................................... 41
4.5.8
Chest X-Rays and CT Scan................................................... 41
4.5.9
Electrocardiograms................................................................ 41
4.5.10
Ordinal Scale Determination.................................................. 42


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4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 43
4.6.1
Study Treatment Discontinuation........................................... 43
4.6.2
Patient Discontinuation from the Study.................................. 43
4.6.3
Study Discontinuation............................................................ 44
4.6.4
Site Discontinuation............................................................... 44
5.
ASSESSMENT OF SAFETY....................................................................... 44
5.1
Safety Plan ............................................................................ 44
5.1.1
Risks Associated with Tocilizumab........................................ 44
5.1.1.1
Hypersensitivity Reactions, Including 
Anaphylaxis ........................................................................... 44
5.1.1.2
Serious Infections and Opportunistic Infections..................... 45
5.1.1.3
Gastrointestinal Perforations ................................................. 45
5.1.1.4
Hematologic Abnormalities.................................................... 46
5.1.1.5
Demyelinating Disorders........................................................ 46
5.1.1.6
Elevated Liver Enzymes ........................................................ 46
5.1.1.7
CYP450 Enzyme Normalization ............................................ 46
5.2
Safety Parameters and Definitions ........................................ 47
5.2.1
Adverse Events ..................................................................... 47
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 47
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 48
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 49
5.3.1
Adverse Event Reporting Period ........................................... 49
5.3.2
Eliciting Adverse Event Information....................................... 49
5.3.3
Assessment of Severity of Adverse Events ........................... 49
5.3.4
Assessment of Causality of Adverse Events ......................... 50
5.3.5
Procedures for Recording Adverse Events............................ 51
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 51
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 51
5.3.5.3
Persistent or Recurrent Adverse Events................................ 52


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5.3.5.4
Abnormal Laboratory Values ................................................. 52
5.3.5.5
Abnormal Vital Sign Values ................................................... 53
5.3.5.6
Abnormal Liver Function Tests.............................................. 53
5.3.5.7
Deaths ................................................................................... 54
5.3.5.8
Preexisting Medical Conditions.............................................. 54
5.3.5.9
Lack of Efficacy or Worsening of COVID-19 
Pneumonia ............................................................................ 55
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 55
5.3.5.11
Cases of Accidental Overdose or Medication 
Error....................................................................................... 55
5.3.5.12
Safety Biomarker Data........................................................... 56
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 56
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 57
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 58
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 58
5.4.2.2
Events That Occur after Study Drug Initiation........................ 58
5.4.3
Reporting Requirements for Pregnancies.............................. 58
5.4.3.1
Pregnancies in Female Patients............................................ 58
5.4.3.2
Abortions ............................................................................... 59
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 59
5.5
Follow-Up of Patients after Adverse Events .......................... 59
5.5.1
Investigator Follow-Up........................................................... 59
5.5.2
Sponsor Follow-Up ................................................................ 59
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 60
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 60
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 60
6.1
Determination of Sample Size ............................................... 61
6.2
Summaries of Conduct of Study............................................ 61
6.3
Treatment Group Comparability ............................................ 62


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6.4
Efficacy Analyses .................................................................. 62
6.4.1
Primary Efficacy Endpoint...................................................... 62
6.4.2
Secondary Efficacy Endpoints............................................... 63
6.4.3
Exploratory Efficacy Endpoints.............................................. 65
6.5
Safety Analyses..................................................................... 65
6.6
Pharmacodynamic Analyses ................................................. 66
6.7
Pharmacokinetic Analyses..................................................... 66
6.8
Biomarker Analyses............................................................... 67
6.9
Planned Interim Analyses...................................................... 67
7.
DATA COLLECTION AND MANAGEMENT ............................................... 68
7.1
Data Quality Assurance......................................................... 68
7.2
Electronic Case Report Forms............................................... 69
7.3
Source Data Documentation.................................................. 69
7.4
Use of Computerized Systems .............................................. 70
7.5
Retention of Records............................................................. 70
8.
ETHICAL CONSIDERATIONS.................................................................... 70
8.1
Compliance with Laws and Regulations ................................ 70
8.2
Informed Consent.................................................................. 70
8.3
Institutional Review Board or Ethics Committee.................... 72
8.4
Confidentiality........................................................................ 72
8.5
Financial Disclosure .............................................................. 73
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 73
9.1
Study Documentation ............................................................ 73
9.2
Protocol Deviations................................................................ 73
9.3
Management of Study Quality ............................................... 73
9.4
Site Inspections ..................................................................... 74
9.5
Administrative Structure......................................................... 74
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 74
9.7
Protocol Amendments ........................................................... 75
10. REFERENCES ........................................................................................... 76


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LIST OF TABLES
Table 1
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 50
Table 2
Causal Attribution Guidance ....................................................... 51
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 28
LIST OF APPENDICES
Appendix 1
Schedule of Activities: Days 1 and 2........................................... 77
Appendix 2
Schedule of Activities: Days 328............................................... 81
Appendix 3
Schedule of Activities: After Day 28............................................ 84
Appendix 4
National Early Warning Score 2 (NEWS2).................................. 86


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
TOCILIZUMAB IN PATIENTS WITH SEVERE 
COVID-19 PNEUMONIA
PROTOCOL NUMBER:
WA42380
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001154-22
IND NUMBER:
148225
NCT NUMBER:
NCT04320615
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 as 
instructed by the CRO.


Tocilizumab—F. Hoffmann-La Roche Ltd
11/Protocol WA42380, Version 3
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF TOCILIZUMAB IN PATIENTS WITH SEVERE 
COVID-19 PNEUMONIA
PROTOCOL NUMBER:
WA42380
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001154-22
IND NUMBER:
148225
IND NUMBER:
NCT04320615
TEST PRODUCT:
Tocilizumab (RO4877533)
PHASE:
Phase III
INDICATION:
Severe COVID-19 pneumonia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of 
tocilizumab (TCZ) compared with a matching placebo in combination with standard of care 
(SOC) in hospitalized patients with severe COVID-19 pneumonia.  Specific objectives and 
corresponding endpoints for the study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of TCZ compared with 
placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the 
basis of the following endpoint:

Clinical status assessed using a 7-category ordinal scale at Day 28 
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of TCZ compared with 
placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the 
basis of the following endpoints:

Time to clinical improvement (TTCI) defined as a National Early Warning Score 2 (NEWS2) 
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 

Incidence of mechanical ventilation

Ventilator-free days to Day 28

Incidence of intensive care unit (ICU) stay 

Duration of ICU stay


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
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 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 2L 
supplemental oxygen)

Time to recovery, defined as discharged or “ready for discharge” (as evidenced by normal 
body temperature and respiratory rate, and stable oxygen saturation on ambient air or 
2L supplemental oxygen); OR, in a non-ICU hospital ward (or “ready for hospital 
ward”) not requiring supplemental oxygen

Duration of supplemental oxygen
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of TCZ compared with 
placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the 
basis of the following endpoints:

Incidence of vasopressor use 

Duration of vasopressor use

Incidence of extracorporeal membrane oxygenation (ECMO)

Duration of ECMO

Organ failure-free days to Day 28
Safety Objective
The safety objective for this study is to evaluate the safety of TCZ compared with placebo in 
combination with SOC for the treatment of 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 (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 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
Pharmacodynamic Objective
The pharmacodynamic objective for this study is to characterize the pharmacodynamic effects 
of TCZ in patients with COVID-19 pneumonia via longitudinal measures of the following 
analytes relative to baseline

Serum concentrations of IL-6, sIL-6R, and CRP at specified timepoints 
Pharmacokinetic Objective
The PK objective for this study is to characterize the TCZ PK profile in patients with COVID-19 
pneumonia on the basis of the following endpoint:

Serum concentration of TCZ at specified timepoints
Biomarker Objective
The exploratory biomarker objectives for this study are to identify and/or evaluate biomarkers 
that could be predictive of response to TCZ (i.e., predictive biomarkers), may serve as early 
surrogates of efficacy, may be associated with progression to a more severe disease state 


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(i.e., prognostic biomarkers), may be associated with susceptibility to developing adverse 
events or could lead to improved adverse event monitoring or investigation (i.e., safety 
biomarkers), could further evidence of TCZ pharmacological activity (i.e., pharmacodynamic 
biomarkers), and overall increase our knowledge and understanding of disease pathogenesis 
and drug safety, on the basis of the following endpoint:

Assessments of individual biomarkers in relation to efficacy, safety, exposure and in both 
blood- and tissue-derived samples
STUDY DESIGN
Description of the Study
This 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.  The 
Sponsor intends to enroll approximately 450 patients that have been diagnosed with COVID-19 
pneumonia and meet the entry criteria in centers globally.  
Patients must be at least 18 years of age with confirmed SARS-CoV-2 (COVID-19) infection per 
WHO criteria, including a positive PCR of any specimen (e.g., respiratory, blood, urine, stool, 
other bodily fluid).  At the time of enrollment, patients must have SpO2 93% or PaO2/FiO2
300 mmHg despite being on SOC, which may include anti-viral treatment, low dose steroids, 
and supportive care.
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 as soon as possible after screening at a 2:1 ratio to receive blinded 
treatment of either TCZ or a matching placebo, respectively.  Study treatment must be given in 
combination with SOC.  The randomization will be stratified by geographic region (North 
America and Europe) and mechanical ventilation (yes, no). The proportion of patients who are 
on a mechanical ventilator at the time of randomization will be capped at no more than 50% of 
the overall study population.
Patients assigned to the TCZ arm will receive one infusion of TCZ 8 mg/kg, with a maximum 
dose of 800 mg, and patients assigned to the placebo arm will receive one infusion of placebo, 
both in addition to SOC.  
For both arms, if the clinical signs or symptoms worsen or do not improve (reflected by 
sustained fever or at least a one-category worsening on the 7-category ordinal scale of clinical 
status), one additional infusion of blinded treatment of TCZ or placebo can be given, 8–24 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 2 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: physical examination, vital signs, 
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 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. 


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Number of Patients
This study aims to enroll approximately 450 hospitalized patients with severe COVID-19 
pneumonia.
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 legal/authorized representative

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Hospitalized with COVID-19 pneumonia confirmed per a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT 
scan 

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 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 study drug.  
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 study drug 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


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
Active TB infection 

Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) 

In the opinion of the investigator, progression to death is imminent and inevitable within the 
next 24 hours, irrespective of the provision of treatments

Have received oral anti-rejection or immunomodulatory drugs (including TCZ) with the past 
3 months

Participating in other drug clinical trials (participation in COVID-19 anti-viral trials may be 
permitted if approved by Medical Monitor)

ALT or AST 10 x ULN detected within 24 hours at screening (according to local laboratory 
reference ranges)

ANC 1000/L at screening (according to local laboratory reference ranges)

Platelet count 50,000/L at screening (according to local laboratory reference ranges)

Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination

Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of 
randomization (investigational COVID-19 antivirals 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 (LPLV) occurs or the 
date at which the last data point required for 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 6 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
Patients assigned to the active arm will receive one or two doses of tocilizumab (TCZ) via IV 
infusion at a dose of 8 mg/kg IV to a maximum of 800 mg per dose.  
Comparator
Patients assigned to the comparator arm will receive one or two doses of placebo via IV.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of TCZ plus standard of 
care, compared with placebo plus standard of care using the following endpoint:

Clinical status assessed using a 7-category ordinal scale at Day 28 
Assessment of patient status using an ordinal scale will be recorded at baseline and daily in the 
morning (between 8 am and 12 pm) while 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 2L 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 


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6.
ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g.,
vasopressors, renal replacement therapy)
7.
Death
The estimand is the difference in distributions between TCZ plus SOC and placebo plus SOC,
which will be tested using a non-parametric method, the Van Elteren test, including the 
stratification factors at randomization (region [North America, Europe] and mechanical 
ventilation [yes, no]).  The median ordinal scale result for each treatment group and the 
corresponding 95% CI for the median will be presented along with the Van Elteren p-value, 
as well as the difference in medians and a 95% CI for the difference.
Further details of the primary endpoint analysis will be included in the SAP.
As an additional analysis, the clinical status according to the 7-category ordinal scale will be  
compared between the TCZ group and the placebo group at Day 28, using a proportional odds 
model accounting for stratification factors at randomization in the model (region [North 
America, Europe] and mechanical ventilation [yes, no]).  The odds ratio, p-value, and 95% 
confidence interval will be presented.
For patients who withdraw before Day 28, their last post baseline ordinal category prior to 
withdrawal will be used in the analysis.  Any other missing data handling rules for the primary 
endpoint will be specified in the SAP.
Determination of Sample Size  
The estimated sample size was determined for the primary endpoint of comparison of clinical 
status based on a 7-category ordinal scale at Day 28 using the Van Elteren test. 
The total mITT sample size of 450 with a 2:1 randomization of TCZ to placebo patients provides 
approximately 90% power to detect a difference in distribution between the treatment groups 
of the ordinal scale at Day 28 using a two-sided Van Elteren test at the 5% significance level 
under the following assumptions of the expected probability distribution of patients in the 
placebo arm:
1 (discharge)
2
3
4
5
6
7 (death)
0.58
0.05
0.09
0.09
0.02
0.02
0.15
And, assuming proportional odds with an odds ratio of 2, the expected distribution in the TCZ 
arm with would be:
1 (discharge)
2
3
4
5
6
7 (death)
0.734
0.039
0.064
0.058
0.012
0.012
0.081
In addition, this sample size provides approximately 90% power to detect a ratio of 2 (TCZ to 
PBO) for the odds of being in a category or a better using a proportional odds model with a 
two-sided p-value at the 5% significance level.
Assuming proportional odds and the given distribution of the placebo group, the smallest odds 
ratio that could be statistically significant would be approximately 1.5.
This sample size also provides approximately 90% power to detect a 10% absolute difference 
in mortality rate under the assumption of a 15% mortality rate in the placebo group.
Planned Interim Analyses
Up to three interim looks for efficacy will be carried out on the data with mortality rate at 28 days 
(secondary endpoint) evaluated for interim efficacy analyses.  The interim looks will occur after 
roughly 111, 222, and 333 patients are enrolled, but all interims are subject to change 
depending on enrollment. If the sample size is increased during the study, the remaining 
efficacy interims will be performed at similar proportions of information to the original planned 
efficacy interim analyses.
The first efficacy interim analysis will be conducted when approximately 111 patients (74 TCZ 
and 37 placebo) have reached the 28-day follow-up time point and will be based on the 
mortality rate at 28 days (secondary endpoint).  If the results of one of the interim analyses 
meets the pre-specified criteria for efficacy, further enrollment in the placebo arm will be 
discontinued and all enrolled patients will receive open-label TCZ.  At this point, efficacy will be 


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declared.  If the study is at least 90% enrolled within 5 weeks (28 days follow up plus 1 week 
to perform the analysis) of the 111th patient being enrolled, then no interim analyses will be 
conducted.
If there is a potential for further recruitment into the placebo arm to be stopped for positive 
efficacy because of the interim analysis, the type I error rate will be controlled to ensure 
statistical validity is maintained.  Specifically, the Lan-DeMets -spending function that 
approximates the O’Brien-Fleming boundary will be applied to determine the critical value for 
stopping for positive efficacy at the interim analysis (DeMets and Lan 1994).  Interim analyses 
for efficacy will use the Fisher’s exact test for difference in proportions and will utilize an 
O’Brien-Fleming alpha-spending function.  The efficacy boundaries for the z-scores at the four 
looks (three interim looks and final analysis) are 4.364, 2.986, 2.377, and 2.011.  
The critical value at the final analysis will be adjusted accordingly to maintain the protocol-
specified overall type I error rate, per standard Lan-DeMets methodology.
The study management team will remain blinded unless the results meet the efficacy criteria. 
The interim efficacy analyses will be produced by a statistical programmer independent of the 
study management team and will reviewed by a Data Monitoring Committee (DMC). 
Full statistical details of the planned interim analyses, along with the rationale and timing will be 
documented in an interim statistical analysis plan, which will be made available to the relevant 
health authorities before the data snapshot for the first interim.
A Data Monitoring Committee will also evaluate safety according to policies and procedures 
detailed in a DMC Charter.  Regular safety reviews will begin after approximately 15 patients 
(10 TCZ, 5 placebo) have been enrolled and reached 14-day follow-up.  Early stopping criteria 
based on compelling efficacy or an imbalance in adverse events will be detailed in the DMC 
charter.  The safety interim analyses will also be conducted by a statistical programmer 
independent from the study management team and will be reviewed by the DMC.  Interactions 
between the DMC and Sponsor will be carried out as specified in the DMC Charter.
The Data Monitoring Committee may initially consist of Sponsor representatives not involved in 
any operational aspects of the study before transitioning to a fully independent data monitoring 
committee (iDMC) when feasible.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ARDS
acute respiratory distress syndrome
AUC
area under the curve
BAL
bronchoalveolar lavage
CAR
chimeric antigen receptor
Cmax
maximum serum concentration observed
CMH
Cochran-Mantel-Haenszel
CoV
coronaviruses
CRO
contract research organization
CRP
C-reactive protein
CRS
cytokine-release syndrome
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
EC
Ethics Committee
eCRF
electronic Case Report Form
ECMO
extracorporeal membrane oxygenation
EDC
electronic data capture
FDA
Food and Drug Administration
GCA
giant cell arteritis
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
LPLV
last patient, last visit
MERS-CoV
Middle East respiratory syndrome
MOD
multiple organ dysfunction
MOF
multi organ failure
NCI
National Cancer Institute
NEWS2
National Early Warning Score 2
PaO2
partial pressure of oxygen
PCR
polymerase chain reaction
pJIA
polyarticular juvenile idiopathic arthritis
PK
pharmacokinetic


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Abbreviation
Definition
PRO
patient-reported outcome
PY
patient years
QTcF
QT interval corrected through use of Fridericia’s 
formula
QW
once a week
Q2W
every 2 weeks
RA
rheumatoid arthritis
RBR
Research Biosample Repository
RT-PCR
real time polymerase chain reaction
SAP
Statistical Analysis Plan
SARS-CoV
severe acute respiratory syndrome
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 (MERS-CoV) 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 
December 31, 2019.  A pandemic was subsequently declared by the WHO on 11 March 
2020.
According to the WHO, as of 12 April 2020 over 1,600,000 cases of COVID-19 were 
reported in over 200 countries and territories worldwide, with over 105,000 deaths (WHO 
2020a).  Up to ~20% of infected patients experienced complications related to a severe 
form of interstitial pneumonia, which may progress to acute respiratory distress 
syndrome (ARDS) and/or multi organ failure (MOF) and death (WHO 2020b).
To date, there is no vaccine and no specific antiviral 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 and membrane-bound IL-6R.  TCZ binds 
specifically to both soluble IL-6R (sIL-6R) and membrane-bound IL-6R and has been 
shown to inhibit both soluble and membrane-bound IL-6Rmediated signaling.  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 physiological 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 


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effective in the treatment of 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 tocilizumab from the DIBD (28 April 
1997) and until 10 April 2019 (DLP for PBRER) is 24,826 patients (40154.98 patient 
years [PY]). Since the IBD (11 April 2005), the estimated cumulative market exposure to 
tocilizumab until 10 April 2019 is 1,301,050 patients (1,053,779 PY). The combined 
cumulative post-marketing exposure of patients to IV tocilizumab is estimated to be 
896,672 patients (726,347 PY). The combined cumulative postmarketing exposure of 
patients to SC tocilizumab is 404,378 (327,432 PY).
Refer to the Tocilizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
TOCILIZUMAB TREATMENT IN CYTOKINE-RELEASE 
SYNDROME OF CAR-T THERAPY
CRS has been identified as a clinically significant, on-target, off-tumor side effect of the 
CAR T-cell therapies used for treatment of malignancies. Characteristics of CRS include 
fever, fatigue, headache, encephalopathy, hypotension, tachycardia, coagulopathy, 
nausea, capillary leak, and multi-organ dysfunction. The reported incidence of CRS 
after CAR T-cell therapy ranges from 50% to 100%, with 13% to 48% of patients 
experiencing the severe or life-threatening form. Serum levels of inflammatory cytokines 
are elevated, particularly interleukin-6 (IL-6). The severity of symptoms may correlate 
with the serum cytokine concentrations and the duration of exposure to the inflammatory 
cytokines.
On August 30, 2017, the U.S. Food and Drug Administration approved tocilizumab 
(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 30kg and 12 mg/kg for body weight 30 kg.  Up to three additional 
doses may be given if no improvement of sign/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 for patients treated 
with TCZ who developed CRS after treatment with tisagenlecleucel (Kymriah) or 
axicabtagene ciloleucel (Yescarta) in prospective clinical trials, (Le et al. 2018). Thirty-
one out of the 45 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 of TCZ (maximum up to two doses) and without use of additional treatment other 


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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 among subgroups such as 
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 a 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 at least 8 hours apart in patients with CRS.
TCZ is also approved for CAR-T 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 of an initial 21-patient retrospective study in which 
patients with severe or critical COVID-19 pneumonia were treated with TCZ (Xu et al. 
2020), an investigator-sponsored randomized, controlled trial (n = 188) has been
initiated in the same population in China, testing the same TCZ dose regimen and is 
currently ongoing, with approximately 70 patients enrolled.  At present, the 21-patient 
publication (Xu et al. 2020) is the only published clinical data the Sponsor is aware of 
regarding the use of TCZ in the treatment of COVID-19 pneumonia.  
On 3 March 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.  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%, PaO2/FiO2 ratio (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]) 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 
(MOD) or failure (MOF); this occurred in 5% of cases (Wu et al. 2020).  


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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 IV (which equates to 
between 48 mg/kg based on the body weight range of the Chinese adult population), 
with the maximum single dose no more than 800 mg. If clinical signs/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 TB, bacterial, or fungal.  
Results from 21 Patients Treated with Tocilizumab in China
In February 2020, twenty-one patients with severe or critical COVID-19 pneumonia were 
treated with TCZ IV (400 mg) plus standard of care. The average age of the patients 
was 56.8 16.5 years, ranging from 25 to 88 years. Seventeen patients (81.0%) were 
assessed as severe and four (19.0%) as critical.  Most patients (85%) presented with 
lymphopenia.  C-reactive protein (CRP) levels were increased in all 20 patients (mean, 
75.06 66.80 mg/L).  The median procalcitonin (PCT) value was 0.33 0.78 ng/mL, and 
only two of 20 patients (10.0%) presented with an abnormal value.  Mean IL-6 level 
before TCZ was 132.38 278.54 pg/mL (normal 7 pg/mL).
Standard of care consisted of lopinavir, methylprednisolone, other symptom relievers,
and oxygen therapy as recommended by the Diagnosis and Treatment Protocol for 
Novel Coronavirus Pneumonia (Sixth Edition). All 21 patients had received routine 
standard of care treatment for a week before deteriorating with sustained fever, 
hypoxemia, and chest CT image worsening. 
Eighteen patients (85.7%) received TCZ once, and three patients (14.3%) had a second 
dose due to 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 one patient needed no oxygen 
therapy.  CT scans showed significant remission of opacities in both lungs in 19/20 
patients (90.5%) after treatment with TCZ.  The percentage of lymphocytes in peripheral 
blood, which was decreased in 85.0% of patients (17/20) before treatment (mean, 
15.528.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after 
treatment.  Abnormally elevated CRP decreased significantly in 84.2% patients (16/19).  
No adverse drug reactions and no subsequent pulmonary infections were reported.  
Nineteen patients (90.5%) were discharged at the time of the report, including two critical 
patients.  There were no deaths among the 21 treated patients.
The study authors concluded that TCZ is an effective treatment for patients with severe 
COVID-19 (Xu et al. 2020). 
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
There are currently no drugs licensed for the treatment of patients with COVID-19. 
Given the results of studies outlined above, TCZ, along with standard of care (SOC) 


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treatment, could 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. Therefore, a placebo-
controlled study in combination with SOC to assess safety and efficacy of TCZ in 
hospitalized patients with severe COVID-19 pneumonia is justified to address the high 
unmet need and burden of disease in this severely ill population. 
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics 
of TCZ compared with a matching placebo in combination with SOC in hospitalized 
patients with severe COVID-19 pneumonia.  Specific objectives and corresponding 
endpoints for the study are outlined below.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of TCZ compared 
with placebo in combination with SOC for the treatment of severe COVID-19 pneumonia 
on the basis of the following endpoint:

Clinical status assessed using a 7-category ordinal scale at Day 28 
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objective for this study is to evaluate the efficacy of TCZ 
compared with placebo in combination with SOC for the treatment of severe COVID-19 
pneumonia on the basis of the following endpoints:

Time to clinical improvement (TTCI) defined as a National Early Warning Score 2 
(NEWS2) 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 

Incidence of mechanical ventilation

Ventilator-free days to Day 28

Incidence of intensive care unit (ICU) stay 

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 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 
2L supplemental oxygen)


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
Time to recovery, defined as discharged or “ready for discharge” (as evidenced by 
normal body temperature and respiratory rate, and stable oxygen saturation on 
ambient air or 2L supplemental oxygen); OR, in a non-ICU hospital ward (or 
“ready for hospital ward”) not requiring supplemental oxygen

Duration of supplemental oxygen
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of TCZ 
compared with placebo in combination with SOC for the treatment of severe COVID-19 
pneumonia on the basis of the following endpoints:

Incidence of vasopressor use 

Duration of vasopressor use

Incidence of extracorporeal membrane oxygenation (ECMO)

Duration of ECMO

Organ failure-free days to Day 28
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of TCZ compared with 
placebo in combination with SOC for the treatment of 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 
(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 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
PHARMACODYNAMIC OBJECTIVE
The pharmacodynamic objective for this study is to characterize the pharmacodynamic 
effects of TCZ in patients with COVID-19 pneumonia via longitudinal measures of the 
following analytes relative to baseline:

Serum concentrations of IL-6, sIL-6R, and CRP at specified timepoints 
2.4
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the TCZ PK profile in patients with 
COVID-19 pneumonia on the basis of the following endpoint:

Serum concentration of TCZ at specified timepoints


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2.5
BIOMARKER OBJECTIVE
The exploratory biomarker objectives for this study are to identify and/or evaluate 
biomarkers that could be predictive of response to TCZ (i.e., predictive biomarkers), may 
serve as early surrogates of efficacy, may be associated with progression to a more 
severe disease state (i.e., prognostic biomarkers), may be associated with susceptibility 
to developing adverse events or could lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), could further evidence of TCZ pharmacological 
activity (i.e., pharmacodynamic biomarkers), and overall increase our knowledge and 
understanding of disease pathogenesis and drug safety, on the basis of the following 
endpoint:

Assessments of individual biomarkers in relation to efficacy, safety, exposure (listed 
in Section 4.5.6) and in both blood- and tissue-derived samples
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This 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.  The Sponsor intends to enroll approximately 450 patients that have been 
diagnosed with COVID-19 pneumonia and meet the entry criteria in centers globally.  
Patients must be at least 18 years of age with confirmed SARS-CoV-2 (COVID-19)
infection per WHO criteria, including a positive PCR of any specimen (e.g., respiratory, 
blood, urine, stool, other bodily fluid).  At the time of enrollment, patients must have 
SpO2 93% or PaO2/FiO2 300 mmHg despite being on SOC, which may include anti-
viral treatment, low dose steroids, and supportive care.
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 as soon as possible after screening at a 2:1 ratio to receive 
blinded treatment of either TCZ or a matching placebo, respectively. Study treatment 
must be given in combination with SOC. The randomization will be stratified by 
geographic region (North America and Europe) and mechanical ventilation (yes, no).
The proportion of patients who are on a mechanical ventilator at the time of 
randomization will be capped at no more than 50% of the overall study population.


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Patients assigned to the TCZ arm will receive one infusion of TCZ 8 mg/kg, with a 
maximum dose of 800 mg, and patients assigned to the placebo arm will receive one 
infusion of placebo (see Section 4.3), both in addition to SOC.  
For both arms, if the clinical signs or symptoms worsen or do not improve (reflected by 
sustained fever or at least a one-category worsening on the 7-category ordinal scale of 
clinical status; see Section 4.5.10), one additional infusion of blinded treatment of TCZ or 
placebo can be given, 8–24 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 2 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 investigator will 
record the reasons for screen failure in the screening log in Section 4.5.1.  
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, concomitant therapies, clinical laboratory tests, and 
nasopharyngeal swabs. Please see Appendix 1, Appendix 2, and Appendix 3 for details 
concerning the timing of these assessments.
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. 
Figure 1 presents an overview of the study design.  Schedules of activities are provided 
in Appendix 1, Appendix 2, and Appendix 3.


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Figure 1
Study Schema
IV=intravenous; PBO =placebo; TCZ =tocilizumab.
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 (LPLV) occurs
or the date at which the last data point required for 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 6 months.
Patients with evidence of lung fibrosis will be referred to their regular healthcare provider 
for further follow up.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Tocilizumab Dose and Schedule
At baseline, patients assigned to the TCZ arm will receive one infusion of TCZ 8 mg/kg
IV, with a maximum dose of 800 mg. If the clinical signs or symptoms worsen or do not 
improve (reflected by sustained fever or at least a one-category worsening on the 
7-category ordinal scale of clinical status), one additional infusion of TCZ 8 mg/kg IV can 
be given, 8–24 hours after the initial infusion. 
The TCZ dose regimen chosen in this study for adult patients is consistent with the 
approved TCZ dose for patients experiencing CRS induced by CAR-T cell therapy who 
weigh 30 kg.  Further, based on the off-label experience from China (one additional 
dose if fever is not improved within 12 hours) and the fact that up to three additional 


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infusions of TCZ (with at least 8 hours in between infusions) are allowed for CAR-T 
induced CRS, the proposed additional one infusion if clinical signs/symptoms worsen or 
do not improve is justified. 
Patients will be followed-up for a period of 60 days from randomization. This period is 
supported by historical data from studies performed in healthy subjects and patients with 
RA (study LRO300 and LRO301) where the mean apparent half-life was determined by 
non-compartmental analysis and ranged from 7 to 8 days following a single dose of 10 
mg/kg IV or multiple doses of 8 mg/kg IV Q4W. Moreover, modeling of free sIL6R levels 
over time, as the principal marker of target engagement, showed that soluble receptors 
returned to their maximum level after 4 weeks following a single administration of 8 
mg/kg IV, demonstrating the absence of drug binding and therefore of drug effect after 4 
weeks (Gibiansky and Frey 2012).
3.3.2
Rationale for Patient Population
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 due to more severe disease.  A study of 138 hospitalized patients with 
COVID-19 published on 7 February 2020 found that 26% of patients admitted to hospital 
required transfer to the intensive care unit (ICU) and 4.3% died; however, given that a 
number of patients were still hospitalized at the time of this report, this number may be 
an underestimate (Wang et al. 2020).  A previous study had found that out of 41 
admitted hospital patients, 13 (32%) were admitted to an ICU and six (15%) died (Huang 
et al. 2020). A more recent study with 1099 patients indicated that 16% of patients 
developed a severe form of disease, 5% were admitted to an ICU, 2.3% underwent 
invasive mechanical ventilation, and 1.4% died (Guan et al. 2020).
Given the significant unmet need in patients hospitalized with severe COVID-19, and 
based on the emerging evidence for TCZ use in patients with COVID-19 pneumonia, this 
study is designed to evaluate the efficacy and safety of TCZ in this population.  Morbidity 
and mortality are particularly high for elderly patients and those with comorbidities. This 
study will include both these groups, with no upper age limit.  
3.3.3
Rationale for Control Group
The study will compare the efficacy and safety of TCZ IV compared with matching 
placebo in combination with SOC. Despite the lack of targeted treatments for COVID-19, 
SOC for patients with severe COVID-19 pneumonia generally includes supportive care
and may include available anti-viral agents and low-dose corticosteroids as dictated by 
local treatment guidelines. Therefore, SOC plus placebo treatment is appropriate as a 
control in this study. 


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3.3.4
Rationale for Biomarker Assessments
COVID-19 infection is a heterogeneous disease, and patients with severe COVID-19 
have shown various levels of IL-6 pathway activation (Xu et al. 2020). Therefore, all 
patients may not be equally likely to benefit from treatment with TCZ.  Pharmacodynamic
biomarkers will be assessed to demonstrate evidence of biologic 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 identify those patients who are most likely to respond to TCZ, to 
characterize TCZ mechanism of action, to provide further evidence of TCZ efficacy, and 
to understand progression of COVID-19.
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study aims to enroll approximately 450 hospitalized patients with severe COVID-19
pneumonia.  
4.1.1
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 legal/authorized 
representative

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Hospitalized with COVID-19 pneumonia confirmed per a positive PCR of any 
specimen (e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by 
chest X-ray or CT scan 

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 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 study drug.  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 


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(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 study drug 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 COVID-19) 

In the opinion of the investigator, progression to death is imminent and inevitable 
within the next 24 hours, irrespective of the provision of treatments

Have received oral anti-rejection or immunomodulatory drugs (including TCZ) within
the past 3 months

Participating in other drug clinical trials (participation in COVID-19 anti-viral trials 
may be permitted if approved by Medical Monitor)

ALT or AST 10 x ULN detected within 24 hours at screening (according to local 
laboratory reference ranges)

ANC <1000/L at screening (according to local laboratory reference ranges)


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
Platelet count 50,000/L at screening (according to local laboratory reference 
ranges)

Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination

Treatment with an investigational drug within 5 half-lives or 30 days (whichever is 
longer) of randomization (investigational COVID-19 antivirals may be permitted if 
approved by 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
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1
Treatment Assignment
This is a randomized, double-blind, placebo-controlled study.  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:  TCZ in combination 
with SOC or placebo in combination with SOC.  Randomization will occur in a 2:1 ratio
through use of a permuted-block randomization method to ensure a balanced 
assignment to each treatment arm.  The randomization will be stratified by geographic 
region (North America and Europe) and mechanical ventilation (yes, no). The proportion
of patients who are on a mechanical ventilator at the time of randomization will be 
capped at no more than 50% of the overall study population. 
4.2.2
Blinding
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial. These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and Data Monitoring Committee (DMC)
members.
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK results for these patients are 
generally not needed for the safe conduct or proper interpretation of the study data.  
Laboratories responsible for performing study drug PK assays will be unblinded to 
patient treatment assignments to identify appropriate samples for analysis.  PK samples 
from patients assigned to the comparator arm will not be analyzed for study drug PK 
concentration except by request (e.g. to evaluate a possible error in dosing).  In addition, 
Roche monitors, project statisticians, and the project team will be blinded from PK and 


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PD results (including IL-6, sIL-6R, and CRP) until the primary analysis. Study centers 
may be unblinded after the final study results are reported.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMP) for this study are tocilizumab IV and its 
matching placebo as the comparator. 
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
Tocilizumab and Placebo
TCZ/placebo 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/placebo).  An 
appropriate number of vials (depending on the patient’s bodyweight) of TCZ/placebo 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
The treatment regimens are summarized in Section 3.1.
4.3.2.1
Tocilizumab and Placebo
TCZ/placebo will be administered by IV infusion at doses of 8 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 (see Appendix 1).  
One additional infusion of blinded treatment of TCZ or placebo can be given 8–24 hours 
after the initial infusion.


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TCZ/placebo 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. 
The TCZ/placebo vials will be stored at a temperature of 2C–8C. The infusion bag of 
TCZ/placebo should be diluted to 100 ml infusion bag using aseptic technique.  The fully 
diluted TCZ/placebo solutions for infusion using 0.9% Sodium Chloride Injection, USP 
may be stored at 2to 8C (36to 46F) or at room temperature for up to 24 hours and 
should be protected from light.  
If stored at 2to 8C (36to 46F), the infusion bag should be allowed to return to room 
temperature before administration. The 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 to 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 medication to flush the remaining study 
drug through the intravenous set.
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/placebo) 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/placebo, and only authorized staff 
may supply or administer TCZ/placebo.


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TCZ/placebo 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 IMPs 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 TCZ/placebo Investigator's Brochure for 
information on IMP handling, including preparation and 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 is 
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 eCRF.
4.4.1
Permitted Therapy 
All patients will receive standard of care per local practice for the treatment of COVID-19 
pneumonia.  The standard of care 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. The recommended maximum dose of chloroquine is 400 mg twice a day.
Clinical management guidelines from WHO recommend against the use of 
corticosteroids in patients with COVID-19 pneumonia. However, country- and 
region-specific guidelines recommend considering corticosteroids in some COVID-19 
patients.  This protocol allows the use of low-dose steroids as part of local SOC. If 


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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 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, 
cyclosporin, 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/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 the 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 assessments).
1. Efficacy assessments:  clinical status, clinical signs and symptoms, oxygen 
saturation
2. Safety assessments:  vital signs, review of adverse events, concomitant 
medications
3. Laboratory samples:  on days when study drug is administered, all samples 
(including  predose PK, safety and biomarkers) must be taken within 4 hours prior 
to study drug treatment, except for postdose samples for PK analyses, which will be 
obtained after study drug treatment.  
4. IV infusion of TCZ/placebo (only at baseline and an additional dose if needed)
5. Safety assessments; vital signs post TCZ (if applicable)
Schedules of assessments are found in Appendix 1, Appendix 2, and Appendix 3.
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, while the Day 60 visit 
should be conducted onsite. 
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). In the 
pandemic situation where access to hospitals is limited, if allowed, verbal consent can 
be obtained from the patient’s legally authorized representative and must be 
documented by the investigator or the authorized designee.  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.


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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 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, 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.
In addition, patient body weight will be measured at the timepoints specified in the 
schedule of activities (see Appendix 1, Appendix 2, and Appendix 3). If it is not feasible 
to weigh bed-bound patients, historical body weight may be used.
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 (L/min) and/or fraction of inspired oxygen (FiO2) should be 
recorded. 
In order to allow assessment of the NEWS2 score (see section 4.5.5), 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 the hospitalization during the 
study. This is to ensure that the measurements reflect the patient’s condition over the 
entire study day, where 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 


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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.
These should be recorded at the same time points as the vital sign measurements (see 
Section 4.5.4 and Appendix 1, Appendix 2, and Appendix 3).
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 in the appropriate eCRF. 
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be measured by 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 NK cells; if the test is available at the site)

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, 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.

SARS-CoV-2 (COVID-19) PCR (screening): nasopharyngeal swab, BAL, or other 
respiratory specimen, blood, urine, stool, other bodily fluid
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


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
Serum samples for pharmacodynamic 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)

Whole blood PAXgeneRNA for RNA sequencing or QPCR

Cryopreserved PBMCs for high dimensional cytometry analysis (for sites capable of 
sample collection)
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/mutation analysis.
In countries where acceptable, 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, PBMCs), blood PAXgene RNA, and tissue-derived samples 
(nasopharyngeal swabs and BAL, if applicable) collected for pharmacodynamic
analysis and biomarker research will be destroyed no later than 15 years after the 
final Clinical Study Report has been completed
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 


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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 or matching 
placebo.  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 before dose administration.  Dosing will occur only if the 
clinical assessment and local laboratory liver chemistry panel values are acceptable.
4.5.8
Chest X-Rays 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 per 
the schedule of assessments.
Chest X-ray/CT scan findings should be recorded on the appropriate eCRF.  If additional 
chest X-rays/CT scans are taken per local practice, this information should be provided 
in 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 per 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 daily every morning (between 8 am and 12 pm) 
while 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 2L 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., due to 
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 non-clinical considerations. 
Normal body temperature is defined as oral, rectal, axillary, temporal, or tympanic 
temperature 36.138.0C.  Normal respiratory rate is defined as 1220 breaths per 
minute. 


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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

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 information on patients lost to follow up but have 
not withdrawn consent.  The primary reason for withdrawal 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.


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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. 
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 post-marketing 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 12 doses of 
TCZ.  For a complete list of all identified or potential risks of TCZ therapy, please refer to 
the current version of the TCZ 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.  


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Stevens-Johnson syndrome has been reported during treatment with TCZ in the 
post-marketing 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
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 standard of care 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 with 
increased risk of infection, such as a history of recurring infections or with underlying 
conditions (e.g., diabetes mellitus) which 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.


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5.1.1.4
Hematologic Abnormalities
Decreases in neutrophil counts, platelet counts, and fibrinogen levels have been 
observed following treatment with TCZ for labelled 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.
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 these populations 
are not applicable to this study due to single dose therapy (with possible additional 
infusion) with TCZ or placebo.
Patients who develop elevated liver function tests 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 medicinal products which 
are individually dose adjusted and are metabolized via 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.


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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.
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 5.3.5.9
and 5.3.5.10 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 5.3.5.10)


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
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 National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 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:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6)

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

Malignancies


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
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).  
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 nondirective
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 
occurrence of the event


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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 rechallenge.
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).
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.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.


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
If a severe gastrointestinal 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 
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.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.


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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 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
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
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.
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.
5.3.5.8
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").


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5.3.5.9
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 5.3.5.7).  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.
5.3.5.10
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

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
5.3.5.11
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 


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(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For TCZ (or 
matching placebo), 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 with TCZ (or matching placebo), 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 
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.
5.3.5.12
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 


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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
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
Medical Monitor Contact Information for All Sites
Medical Monitor:
, M.D. 
Mobile Telephone No.:
Alternate Medical Monitor Contact Information for All Sites
Medical Monitor:
, M.D.
Mobile 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. 


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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.
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.  


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5.4.3.2
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. 
5.4.3.3
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.
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.


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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.
A DMC will monitor the incidence of the above-listed anticipated events during the study.  
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
All primary and secondary efficacy outcomes will be analyzed in the modified intent to 
treat (mITT) population.  The mITT population is defined as all patients randomized in 
the study that received any amount of study medication, with patients grouped according 
to the treatment assignment at randomization.


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Safety analyses will be performed on the safety evaluable population, which consists of 
all patients who receive any amount of study medication.  In all safety analyses, patients 
will be grouped according to the treatment that the patients actually received rather than 
the treatment assigned at randomization.  
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP). 
6.1
DETERMINATION OF SAMPLE SIZE
The estimated sample size was determined for the primary endpoint of comparison of 
clinical status based on a 7-category ordinal scale at Day 28 using the Van Elteren test. 
The total mITT sample size of 450 with a 2:1 randomization of TCZ to placebo patients 
provides approximately 90% power to detect a difference in distribution between the 
treatment groups of the ordinal scale at Day 28 using a two-sided Van Elteren test at 
the 5% significance level under the following assumptions of the expected probability 
distribution of patients in the placebo arm:
1 (discharge)
2
3
4
5
6
7 (death)
0.58
0.05
0.09
0.09
0.02
0.02
0.15
And, assuming proportional odds with an odds ratio of 2, the expected distribution in the 
TCZ arm would be:
1 (discharge)
2
3
4
5
6
7 (death)
0.734
0.039
0.064
0.058
0.012
0.012
0.081
In addition, this sample size provides approximately 90% power to detect a ratio of 2 
(TCZ to PBO) for the odds of being in a category or a better using a proportional odds 
model with a two-sided p-value at the 5% significance level.
Assuming proportional odds and the given distribution of the placebo group, the smallest 
odds ratio that could be statistically significant would be approximately 1.5. 
This sample size also provides approximately 90% power to detect a 10% absolute 
difference in mortality rate under the assumption of a 15% mortality rate in the placebo 
group.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who are randomized, enroll, discontinue, or complete the study 
will be summarized.  Reasons for premature study discontinuation will be listed and
summarized. 


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Eligibility criteria and other major protocol deviations will be listed and summarized by 
treatment group.
6.3
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, 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 and may, in addition, be presented for the safety 
population.
Medical history data, including surgery and procedures, and baseline conditions, will be
summarized descriptively by treatment group using the safety population.
Previous and concomitant treatments will be summarized descriptively by treatment 
group.
Exposure to study drug will be summarized, including number of doses. A listing of 
patients by treatment group, detailing dosing of study drug will be prepared.
6.4
EFFICACY ANALYSES
All efficacy analyses will use the mITT population.
Sensitivity analyses to evaluate the robustness of results to the primary analysis
methods (e.g., handling of dropouts) may be conducted and will be described in the 
statistical analysis plan.  
Descriptive subgroup analyses to evaluate the consistency of results across
pre-specified subgroups may also be conducted.  
Full details of adjustments to significance levels for hypothesis tests resulting from 
efficacy interims; and for multiplicity and/or sequential order of analyses will be 
predefined in the statistical analysis plan.
6.4.1
Primary Efficacy Endpoint
The primary efficacy objective for this study is to evaluate the efficacy of TCZ plus SOC
compared with placebo plus SOC using the following endpoint:

Clinical status assessed using a 7-category ordinal scale at Day 28 


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Assessment of patient status using an ordinal scale will be recorded at baseline and 
once daily in the morning (between 8 am and 12 pm) while 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 2L 
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
The estimand is the difference in distributions between TCZ plus SOC and placebo plus 
SOC, which will be tested using a non-parametric method, the Van Elteren test, 
including the stratification factors at randomization (region [North America, Europe] 
and mechanical ventilation [yes, no]). The median ordinal scale result for each 
treatment group and the corresponding 95% CI for the median will be presented along 
with the Van Elteren p-value, as well as the difference in medians and a 95% CI for the 
difference. 
Further details of the primary endpoint analysis will be included in the SAP.
As an additional analysis, the clinical status according to the 7-category ordinal scale 
will be compared between the TCZ group and the placebo group at Day 28, using a 
proportional odds model accounting for stratification factors at randomization in the 
model (region [North America, Europe] and mechanical ventilation [yes, no]).  The 
odds ratio, p-value, and 95% confidence interval will be presented.
For patients who withdraw before Day 28, their last post baseline ordinal category prior 
to withdrawal will be used in the analysis. Any other missing data handling rules for the 
primary endpoint will be specified in the SAP.
6.4.2
Secondary Efficacy Endpoints
Time to event secondary endpoints will be compared between the TCZ group and the 
placebo group using the stratified log-rank test with geographic region (North America,


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Europe) and mechanical ventilation (yes, no) included as the stratification factors.  The 
Kaplan-Meier plot, median time to response, and their 95% CIs, and a p-value will be 
presented. 

Time to clinical improvement (TTCI)
Defined as time from first dose of study drug to NEWS2 of ≤2 maintained for 24 
hours 

Time to improvement in ordinal clinical status (key secondary endpoint)
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

Time to clinical failure 
Defined as the time to first occurrence on study of 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.

Time to hospital discharge or “ready for discharge” (key secondary endpoint)
“Ready for discharge” defined as normal body temperature and respiratory rate, and 
stable oxygen saturation on ambient air or 2L supplemental oxygen

Time to recovery
Defined as discharged or “ready for discharge” (as evidenced by normal body 
temperature and respiratory rate, and stable oxygen saturation on ambient air or 
2L supplemental oxygen); OR, in a non-ICU hospital ward (or “ready for 
hospital ward”) not requiring supplemental oxygen
Secondary efficacy incidence and rate endpoints will be analyzed using the Cochran-
Mantel-Haenszel test statistic adjusted by the stratification factors at baseline 
geographic region (North America, Europe) and mechanical ventilation (yes, no), unless 
stated otherwise. The weighted difference in proportions for the treatment group 
comparison will be presented, together with a 95% CI using the extended Mantel-
Haenszel method.  

Incidence of mechanical ventilation by Day 28

Incidence of intensive care unit (ICU) stay by Day 28

Difference in mortality rate at Day 28 (key secondary endpoint)
In addition, mortality rates at Days 7, 14, 21, and 60 will be summarized
descriptively.
Comparison of clinical status according to the 7-category ordinal scale (as detailed for 
the primary endpoint at Day 28) will also be analyzed at Day 14 (key secondary 
endpoint).
The NEWS2 score and the ordinal clinical status will be summarized descriptively by 
visit.


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Other secondary endpoints include:

Ventilator-free days to Day 28 (key secondary endpoint)

Duration of ICU stay

Duration of supplemental O2
Duration endpoints will be summarized descriptively using the medians, with 95% CIs for 
the medians by treatment group.
6.4.3
Exploratory Efficacy Endpoints
Incidence of vasopressor use and incidence of extracorporeal membrane oxygenation 
(ECMO) will be summarized descriptively.
Duration of vasopressor use and ECMO will be summarized using the median along with 
95 % CIs for the median by treatment group.
Organ failure-free days to Day 28 will be summarized descriptively using the median, 
with 95% CI for the medians by treatment group.
Organ failure is defined as present on any date when the most abnormal vital 
signs/abnormal lab value meets the definition of clinically significant organ failure 
according to the Brussels Organ Failure Table (Vincent 2006). Cardiovascular, 
pulmonary and central nervous system function will be assessed through blood pressure 
and requirement for pressors (instead of responsiveness to fluids), PaO2:FiO2 (or 
SpO2:FiO2 if arterial blood gases were not measured) ratio and the alert, verbal, pain, 
unresponsive scale (AVPU; instead of Glasgow Coma Scale), respectively. Renal, 
hepatic and coagulation parameters will be assessed via blood tests in order that the 
presence of clinically significant organ failure can be determined. Any day that a patient 
is alive and free of all 5 organ failures (pulmonary, cardiovascular, renal, hepatic, central 
nervous system) will be considered organ failure-free days. Days without organ failure 
will be summarized through Day 28 during hospitalization.
6.5
SAFETY ANALYSES
Safety assessments will be performed on the safety evaluable population, which 
consists of all patients who receive any amount of study medication.  In all safety 
analyses, patients will be grouped according to the treatment that the patients actually 
received 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 MedDRA thesaurus terms, and 
adverse event severity will be graded according to NCI CTCAE v5.0 scale


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The proportion of patients with any post-treatment infection will be summarized at time 
points 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.
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 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.
SARS-CoV-2 viral load over time, as collected by nasopharyngeal swab and BAL 
samples (if applicable) will be summarized descriptively by time point and treatment 
group.
Time to reverse-transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 virus 
negativity will be analyzed using similar methods to the other time to analyses.
6.6
PHARMACODYNAMIC ANALYSES
The pharmacodynamic outcome measures for this study are serum IL-6, sIL-6R, and 
CRP levels at baseline and at specified time points after initiation of study drug.  Data for 
all pharmacodynamic biomarkers will be presented using descriptive summary statistics,
including mean, median, range, standard deviation, and coefficient of variation.
6.7
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of patients with sufficient data to enable 
estimation of key parameters (e.g., area under the 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 pre-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 total exposure (AUC), Cmax, total clearance, volume of distribution.  Estimates 
for these parameters will be tabulated and summarized (mean, standard deviation, 


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co-efficient of variation, median, minimum, and maximum).  Inter-patient variability will 
be evaluated.
Additional PK analyses will be conducted as appropriate. The PK parameters derived 
from these analyses might be used for exploratory graphical analyses of the 
pharmacodynamic parameters.
These analyses will be reported separately in a stand-alone report. 
6.8
BIOMARKER ANALYSES
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
PLANNED INTERIM ANALYSES
Up to three interim looks for efficacy will be carried out on the data with mortality rate at 
28 days (secondary endpoint) evaluated for interim efficacy analyses.  The interim looks 
will occur after roughly 111, 222, and 333 patients are enrolled, but all interims are 
subject to change depending on enrollment. If the sample size is increased during the 
study, the remaining efficacy interims will be performed at similar proportions of 
information to the original planned efficacy interim analyses.
The first efficacy interim analysis will be conducted when approximately 111 patients (74
TCZ and 37 placebo) have reached the 28-day follow-up time point and will be based on 
the mortality rate at 28 days (secondary endpoint).  If the results of one of the interim 
analyses meets the pre-specified criteria for efficacy, further enrollment in the placebo 
arm will be discontinued and all enrolled patients will receive open-label TCZ.  At this 
point, efficacy will be declared. If the study is at least 90% enrolled within 5 weeks 
(28 days follow up plus 1 week to perform the analysis) of the 111th patient being 
enrolled, then no interim analyses will be conducted.
If there is a potential for further recruitment into the placebo arm to be stopped for 
positive efficacy because of the interim analysis, the type I error rate will be controlled to 
ensure statistical validity is maintained.  Specifically, the Lan-DeMets -spending 
function that approximates the O'Brien-Fleming boundary will be applied to determine 
the critical value for stopping for positive efficacy at the interim analysis (DeMets and 
Lan 1994). Interim analyses for efficacy will use the Fisher’s exact test for difference in 
proportions for mortality at 28 days and will utilize an O’Brien-Fleming alpha-spending 
function. The efficacy boundaries for the z-scores at the four looks (three interim looks 
and final analysis) are 4.364, 2.986, 2.377, and 2.011. 
The critical value at the final analysis will be adjusted accordingly to maintain the 
protocol-specified overall type I error rate, per standard Lan-DeMets methodology.


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The study management team will remain blinded unless the results meet the efficacy 
criteria (boundary is crossed). The interim efficacy analyses will be produced by a 
statistical programmer and statistician independent of the study management team and 
will reviewed by a Data Monitoring Committee (DMC). 
Full statistical details of the planned interim analyses, along with the rationale and timing 
will be documented in an interim statistical analysis plan, which will be made available to 
the relevant health authorities before the data snapshot for the first interim.
A Data Monitoring Committee will also evaluate safety according to policies and 
procedures detailed in a DMC Charter. Regular safety reviews will begin after 
approximately 15 patients (10 TCZ, 5 placebo) have been enrolled and reached 14-day 
follow-up.  Early stopping criteria based on compelling efficacy or an imbalance in 
adverse events will be detailed in the DMC charter.  The safety interim analyses will also 
be conducted by a statistical programmer and statistician independent from the study 
management team and will be reviewed by the DMC.  Interactions between the DMC 
and Sponsor will be carried out as specified in the DMC Charter.
The Data Monitoring Committee will initially consist of Sponsor representatives not 
involved in any operational aspects of the study before transitioning to a fully 
independent data monitoring committee (iDMC) when feasible.
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 
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.


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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
Due to 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 into 
the eCRFs by authorized site personnel are accurate and complete. Sites will be asked 
to implement a QC step of a second person reviewing the data entry in the eCRF 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, patient-reported outcomes, 
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.
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 into 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.


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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.
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 


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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, HCP 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 
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.
For sites in the United States, 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 


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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 (national or 
regional) 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 9.6).
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. 
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 9.6).


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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, which may include data on genomic variants, 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).
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.  Prior 


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to study initiation, 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 prior to study initiation.  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.
Approximately 60 sites globally will participate to enroll approximately 450 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.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
A DMC will be employed to monitor and evaluate patient safety throughout the study.  
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 


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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.
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.
REFERENCES
Demets DL, Lan KG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:134152.
Gibiansky L and Frey N. Linking interleukin-6 receptor blockade with tocilizumab and its 
hematological effects using a modeling approach. J Pharmacokinet Pharmacodyn 
2012;39:516.
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]
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.
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. The Oncologist 2018;23:943–947.
Vincent JL. Organ dysfunction in patients with severe sepsis. Surg Infect 2006;7:s69.
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 
novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020. 
doi:10.1001/jama.2020.1585
[WHO] World Health Organization. Coronavirus disease (COVID-19) situation reports 
[Resource on the internet]. 2020a [updated 12 April 2020; cited 12 April 2020]. 
Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-
2019/situation-reports
[WHO] World Health Organization. Clinical management of severe acute respiratory 
infection when novel coronavirus (nCoV) infection is suspected [Resource on the 
internet]. 2020b [updated 13 March 2020;  cited 12 April 2020]. Available from: 
https://www.who.int/publications-detail/clinical-management-of-severe-acute-
respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus 
disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases 
from the Chinese Center for Disease Control and Prevention. JAMA 2020. 
doi:10.1001/jama.2020.2648.
Xu X, Han M, Li, T, et al. Effective treatment of severe COVID-19 patients with 
tocilizumab. Proc Natl Acad Sci USA 2020; 117:10970–10975.


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Appendix 1
Schedule of Activities:  Days 1 and 2
Screening a, b
Baseline
Study Day
2 to 0
1
2
Time Post Initial Treatment
(Assessment Window)
0
Pre-dose
(4 hrs)
15 min
After end of 
infusion
(1 hr)
24 hrs
(4 hrs)
36 hrs
(4 hrs)
Informed consent
x
Inclusion/exclusion criteria
x
x
Demographic data
x
Randomization
x
Medical history
x
Complete physical examination c
x
Weight
x
COVID-19 diagnosis d
x
Chest X-ray/CT scan e
x
ECG
x
Pregnancy test f
x
PaO2/FiO2 g
x
  Optional  
SpO2 h
x
x
x
x
x
Vital signs h
x
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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Screening a, b
Baseline
Study Day
2 to 0
1
2
Time Post Initial Treatment
(Assessment Window)
0
Pre-dose
(4 hrs)
15 min
After end of 
infusion
(1 hr)
24 hrs
(4 hrs)
36 hrs
(4 hrs)
Hematology l
x
x
x
Chemistry m
x
x
x
Study drug administration n
x
Central Labs
Serum PD (CRP, IL-6, sIL-6R)
x o
x o
x
x
Serum PK p
x q
x q
x
x
Serum sample 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
Whole blood in PAXgenetubes for RNA 
analyses t
x
CRP=c-reactive protein; CT=computed tomography; ECG =electrocardiogram; eCRF =electronic case report form; NCI CTCAE=National Cancer 
Institute Common Terminology Criteria for Adverse Events v.5.0; NEWS2=National Early Warning Score; PaO2/FiO2 = arterial oxygen partial 
pressure/fraction of inspired oxygen; PBMCs =peripheral blood mononuclear cells; PK =pharmacokinetic; PRO-CTCAE=NCI Patient-Reported 
Outcomes Common Terminology Criteria for Adverse Events; SpO2 =peripheral capillary oxygen saturation.
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.  


Appendix 1: Schedule of Activities:  Days 1 and 2 (Cont.)
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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/CT scans are taken 
per local practice during the study, this information should be provided in 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 on Day 1/Visit 1 then again daily every morning (between 
8 am and 12 pm) 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).
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 NK cells; if the test is available at the site).
m 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.


Appendix 1: Schedule of Activities:  Days 1 and 2 (Cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
80/Protocol WA42380, Version 3
n Study drug should be administered after collection of all samples for pharmacodynamic and exploratory biomarker analyses.  The initial study 
drug infusion should be given within 4 hours of randomization.  If the clinical signs or symptoms worsen or do not improve (reflected by sustained 
fever or at least a one-category worsening on the 7-category ordinal scale of clinical status), one additional infusion of blinded treatment of TCZ 
or placebo can be given, 8–24 hours after the initial infusion.
o 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, on 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, on the opposite arm as the infusion.
p 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, on the opposite arm as the 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, 
on the opposite arm as the 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 where 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 first draw of blood should not be for PAXgenetubes to avoid contact with RNA preservation reagent inside the tube.


Tocilizumab—F. Hoffmann-La Roche Ltd
81/Protocol WA42380, Version 3
Appendix 2
Schedule of Activities:  Days 328
Days 328 a
Study 
Completion/ 
Discontinuation
Study Day
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/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 h
x
x
x
x
x
x
x
Central Labs
Serum PD (CRP, IL-6, 
sIL-6R)
x
x
x
x
x
x
Serum PK
x
x
x
x
x
Serum sample 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
82/Protocol WA42380, Version 3
Days 328 a
Study 
Completion/ 
Discontinuation
Study Day
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
Whole blood in PAXgene
tubes for RNA analyses k
x
x
x
x
BAL=bronchoalveolar lavage; CRP=c-reactive protein; CT =computed tomography; ECG =electrocardiogram; eCRF =electronic case report form; 
NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0; PaO2/FiO2 = arterial oxygen partial 
pressure/fraction of inspired oxygen; PBMCs =peripheral blood mononuclear cells; PK =pharmacokinetic; PRO-CTCAE=NCI Patient-Reported 
Outcomes Common Terminology Criteria for Adverse Events; SpO2 =peripheral capillary oxygen saturation..
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 a 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 on Day 1/Visit 1 then again daily every morning (between 
8 am and 12 pm) 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.


Appendix 2: Schedule of Activities: Days 328 (Cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
83/Protocol WA42380, Version 3
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 NK 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 where 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 first draw of blood should not be for PAXgenetubes to avoid contact with RNA preservation reagent inside the tube.


Tocilizumab—F. Hoffmann-La Roche Ltd
84/Protocol WA42380, Version 3
Appendix 3
Schedule of Activities:  After Day 28
Study Completion
Study Day
(Assessment Window)
35 a
(3 days)
45 a
(3 days)
60
(3 days)
Chest X-ray/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 h
x
x
x
Central Labs
Serum PD (CRP, IL-6, sIL-6R)
x
x
Serum PK
x
x
Serum sample for exploratory biomarkers
x
x
Serum SARS-Cov-2 antibody titer
x
CRP=c-reactive protein; CT=computed tomography; PK=pharmacokinetic; SpO2=peripheral capillary oxygen saturation.
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 a Day 60 Study Completion visit.


Appendix 3: Schedule of Activities:  After Days 28 (Cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
85/Protocol WA42380, Version 3
b Patients who remain in hospital will have viral load assessed by nasopharyngeal swabs; these will be done if there is evidence of on-going 
infection.
c For patients who remain in 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 on Day 1/Visit 1 then again daily every morning (between 
8 am and 12 pm) 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 NK 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 labs will not be performed if follow-up visits are conducted by telephone.


Tocilizumab—F. Hoffmann-La Roche Ltd
86/Protocol WA42380, Version 3
Appendix 4
National Early Warning Score 2 (NEWS2)
SpO2=oxygen saturation. 
The oxygen saturation 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 [COPD]).  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 Score 2 (NEWS2) (cont.)
Tocilizumab—F. Hoffmann-La Roche Ltd
87/Protocol WA42380, Version 3
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 in the appropriate eCRF.
Example Case Calculation:
An 82-year-old lady 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 min)
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 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study 
to Evaluate the Safety and Efficacy of Tocilizumab in Patients With 
Severe COVID-19 Pneumonia 
NCT Number: NCT04320615 
Document Date: SAP Version 3: 16-July-2020 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT 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 WA42380
STATISTICAL ANALYSIS PLAN
TITLE:
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
TOCILIZUMAB IN PATIENTS WITH SEVERE COVID 19 
PNEUMONIA
PROTOCOL NUMBER:
WA42380
STUDY DRUG:
Tocilizumab (RO4877533)
VERSION NUMBER:
3
IND NUMBER:
148225
EUDRACT NUMBER:
2020-001154-22
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
DATE FINAL:
Version 1: 24 April 2020
DATES AMENDED
Version 2: 26 May 2020
Version 3: See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
16-Jul-2020 16:46:46
Company Signatory


Tocilizumab—F. Hoffmann-La Roche Ltd.
2/Statistical Analysis Plan WA42380
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
This Statistical Analysis Plan WA42380 Version 3 was amended from Version 2 as follows:

Time to event endpoints were changed from “time from randomization” to “time from first 
dose of study drug”

The Type I error control section was updated to specify a hierarchy for testing of the 
primary endpoint followed by testing the difference in mortality

Cumulative Incidence Function plots were specified for time to ‘improvement’ end points

The censoring rules for the time to event endpoints were updated

Derivation of organ failure-free days was clarified

Laboratory ranges were clarified

‘Other’ was removed from the stratification by region as only patients from Europe and 
North America were randomized.

The synopsis appended from the protocol was updated to be consistent with protocol 
version 3.

A subgroup analysis of the primary endpoint by mechanical ventilation status (as 
stratified) was added to the primary analysis section
Additional minor changes have been made to improve clarity and consistency.
This Statistical Analysis Plan WA42380 Version 2 was amended from Version 1 as follows:

The sample size was amended to 450 patients based on powering the study at 90%

A new secondary endpoint was added ‘Time to Recovery’

Time to discharge or “ready for discharge” was elevated to one of the key secondary 
endpoints

The censoring rules for deaths were changed to right censoring for time to event 
endpoints, other than for time to clinical failure

The derivation of vent-free days was modified so that patients that have died are 
assigned zero vent-free days.

The list of Adverse Events of Special Interest was modified
Additional minor changes have been made to improve clarity and consistency.


Tocilizumab—F. Hoffmann-La Roche Ltd.
3/Statistical Analysis Plan WA42380
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 8
2.
STUDY DESIGN........................................................................................... 8
2.1
Protocol Synopsis.................................................................. 10
2.2
Endpoints............................................................................... 10
2.2.1
Primary Efficacy Endpoints.................................................... 10
2.2.2
Secondary Efficacy Endpoints............................................... 10
2.2.2.1
Assessments Specific to National Early Warning Score 
2 ............................................................................................ 11
2.2.3
Exploratory Efficacy Endpoints.............................................. 11
2.2.4
Pharmacodynamic Efficacy Endpoints................................... 11
2.2.5
Biomarkers ............................................................................ 11
2.2.6
Safety Endpoints ................................................................... 12
2.3
Determination of Sample Size ............................................... 12
2.4
Analysis Timing ..................................................................... 13
3.
STUDY CONDUCT..................................................................................... 13
3.1
Randomization, Stratification and Blinding ............................ 14
3.2
Data Monitoring ..................................................................... 15
4.
STATISTICAL METHODS .......................................................................... 15
4.1
Analysis Populations ............................................................. 16
4.1.1
mITT Population .................................................................... 16
4.1.2
Safety Population .................................................................. 16
4.2
Analysis of Study Conduct..................................................... 16
4.3
Analysis of Treatment Group Comparability .......................... 16
4.3.1
Demographics ....................................................................... 17
4.3.2
Disease Characteristics......................................................... 17
4.3.3
Medical history....................................................................... 18
4.3.4
Surgeries and Procedures..................................................... 18
4.3.5
Previous and Concomitant Medications................................. 18
4.4
Visit Labels ............................................................................ 18
4.5
Efficacy Analysis.................................................................... 20


Tocilizumab—F. Hoffmann-La Roche Ltd.
4/Statistical Analysis Plan WA42380
4.5.1
Primary Efficacy Endpoint...................................................... 21
4.5.2
Controlling for Type I Error .................................................... 22
4.5.3
Secondary Endpoints ............................................................ 23
4.5.3.1
Time to Event Analyses......................................................... 23
4.5.3.2
Incidence endpoints............................................................... 27
4.5.3.3
Duration endpoints ................................................................ 28
4.5.4
Exploratory Efficacy Endpoints.............................................. 30
4.5.5
Subgroup Analyses ............................................................... 30
4.6
Pharmacodynamic Analyses ................................................. 31
4.7
Safety Analyses..................................................................... 31
4.7.1
Exposure of Study Medication............................................... 32
4.7.2
Adverse Events ..................................................................... 32
4.7.3
Laboratory Data..................................................................... 33
4.7.4
Vital Signs.............................................................................. 34
4.7.5
Other Safety Endpoints.......................................................... 34
4.8
Interim Analyses .................................................................... 35
5.
REFERENCES ........................................................................................... 37


Tocilizumab—F. Hoffmann-La Roche Ltd.
5/Statistical Analysis Plan WA42380
LIST OF TABLES
Table 1
Distribution of Ordinal Scale in the Placebo Group..................... 13
Table 2
Distribution of the Ordinal scale in the Tocilizumab Group ......... 13
Table 3
Time Windows for Assigning Assessment Study Days to Study 
Visits Labels for Deaths and Discharge ...................................... 19
Table 4
Time Windows for Assigning Assessment Study Days to Study 
Visits for PD parameters ............................................................. 20
Table 5
Time to clinical improvement and Censoring .............................. 24
Table 6
Time to improvement in Ordinal Clinical Status and Censoring .. 25
Table 7
Time to Recovery and censoring ................................................ 25
Table 8
Time to hospital discharge or “ready for discharge” and censoring.
.................................................................................................... 26
Table 9
Time to Clinical Failure and censoring........................................ 27
LIST OF FIGURES
Figure 1
Study WA42380 Schema.............................................................. 9
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 38
Appendix 2
Schedule of Activities:  Days 1 and 2.......................................... 45
Appendix 3
Schedule of Activities:  Days 328.............................................. 49
Appendix 4
Schedule of Activities:  After Day 28........................................... 52
Appendix 5
National Early Warning Score 2 (NEWS2).................................. 54
Appendix 6
Cochran-Mantel-Haenszel Test .................................................. 56


Tocilizumab—F. Hoffmann-La Roche Ltd.
6/Statistical Analysis Plan WA42380
GLOSSARY OF ABBREVIATIONS
AE
adverse event
AEGT
adverse event grouped term
AESI
adverse event of special interest
BAL
bronchoalveolar lavage
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus 2019/ SARS-CoV-2
CRP
C-reactive protein
DMC
data monitoring committee
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic Case Report Form
ICU
intensive care unit
IL-6
interleukin 6
iDMC
independent data monitoring committee
ISAP
interim statistical analysis plan
IxRS
interactive voice or web-based response system
LPLV
last patient last visit
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
PaO2/FiO2
Ratio between the blood pressure of the oxygen 
(partial pressure of oxygen, PaO2) and the
percentage of oxygen supplied (fraction of inspired 
oxygen, FiO2)
PBO
placebo
PCR
polymerase chain reaction
PD
phamacodynamic
PK
pharmacokinetic
PT
preferred term
RT-PCR
reverse-transcriptase polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
sIL-6R
soluble interleukin-6 receptor
SMQ
Standard MedDRA Query


Tocilizumab—F. Hoffmann-La Roche Ltd.
7/Statistical Analysis Plan WA42380
SMT
study management team
SOC
SoC
standard of care / system organ class
scientific oversight committee
SpO2
blood oxygen saturation
TB
tuberculosis
TCZ
TLR
tocilizumab
top line report
TTCI
time to clinical improvement
VFDs
ventilator-free days 
WHO
World Health Organisation


Tocilizumab—F. Hoffmann-La Roche Ltd.
8/Statistical Analysis Plan WA42380
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 WA42380. Any 
analyses of biomarkers will be covered by a separate analysis plan. Analyses of 
pharmacokinetic data will be covered by a separate analysis plan.
There are currently no drugs licensed for the treatment of patients with SARS-CoV-2 
(COVID-19).  Based on the results from an initial 21-patient retrospective observational 
study, in which patients with severe or critical COVID-19 pneumonia were treated with 
tocilizumab (TCZ) off-label (Xu et al. 2020), TCZ, 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.  Extensive safety data have previously been generated 
on the use of TCZ in other indications. Therefore, a randomized placebo-controlled study 
in combination with SOC to assess safety and efficacy of TCZ in hospitalized patients 
with severe COVID-19 pneumonia is justified to address the high unmet need and 
burden of disease in this severely ill population.
2.
STUDY DESIGN
Study WA42380 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 (PBO) in combination with SOC in hospitalized adult patients with 
severe COVID-19 pneumonia.  The Sponsor intends to enroll approximately 450 patients 
that diagnosed with COVID-19 pneumonia that meet the entry criteria in centers globally.
Patients must be at least 18 years of age with confirmed SARS-CoV-2 (COVID-19)
infection per WHO criteria, including a positive polymerase chain reaction (PCR) of any 
specimen (e.g., respiratory, blood, urine, stool, other bodily fluid).  At the time of 
enrollment, patients must have blood oxygen saturation (SpO2) ≤93% or PaO2/FiO2 (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] <300 mmHg 
despite being on SOC, which may include anti-viral treatment, low dose steroids, and 
supportive care.
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 2:1 ratio to receive blinded treatment of either TCZ or a 
matching placebo, respectively.  Study treatment will be given in combination with SOC
per local practice.  The randomization will be stratified by geographic region (North 


Tocilizumab—F. Hoffmann-La Roche Ltd.
9/Statistical Analysis Plan WA42380
America, Europe) and mechanical ventilation (yes, no). The proportion of patients on a 
mechanical ventilator will be capped at no more than 50% of the overall study
population.
Patients assigned to the TCZ arm will receive one infusion of TCZ 8 mg/kg, with a 
maximum dose of 800 mg, and patients assigned to the placebo arm will receive one 
infusion of placebo, both in addition to SOC.  
For both arms, if the clinical signs or symptoms worsen or do not improve (reflected by 
sustained fever or at least a one-category worsening on the 7-category ordinal scale), 
one additional infusion of blinded treatment of TCZ or placebo can be given, 8–24 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.  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, 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.
Figure 1 presents an overview of the study design. The Schedule of Assessments is 
provided in Appendix 2, Appendix 3 and Appendix 4.
Figure 1
Study WA42380 Schema 
IV=intravenous; PBO =placebo; TCZ=tocilizumab.


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2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2, Appendix 3 and Appendix 4.
2.2
ENDPOINTS
This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics 
of TCZ compared with a matching placebo in combination with SOC in hospitalized 
patients with severe COVID-19 pneumonia. Specific objectives and corresponding 
endpoints for the study are outlined below.
2.2.1
Primary Efficacy Endpoints
The primary efficacy objective for this study is to evaluate the efficacy of TCZ compared 
with placebo in combination with SOC for the treatment of severe COVID-19 pneumonia 
on the basis of the following endpoint:

Clinical status assessed using a 7-category ordinal scale at Day 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 ≤ 2L 
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
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
2.2.2
Secondary Efficacy Endpoints

Time to clinical improvement (TTCI) defined as a National Early Warning Score 2 
(NEWS2) 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 

Incidence of mechanical ventilation

Ventilator-free days to Day 28

Incidence of intensive care unit (ICU) stay 


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
Duration of ICU stay

Clinical status assessed using a 7-category ordinal scale at Day 14

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 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 
≤2L supplemental oxygen)

Time to recovery defined as hospital discharge or “ready for discharge” (as 
evidenced by normal body temperature and respiratory rate, and stable oxygen 
saturation on ambient air or ≤2L supplemental oxygen), or Non-ICU hospital ward 
(or “ready for hospital ward”) not requiring supplemental oxygen

Duration of supplemental oxygen
2.2.2.1
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”, which can include other 
forms of ventilation to maintain oxygen saturation (see Appendix 5).  
NEWS2 values will be calculated by the Sponsor based on vital sign parameters and 
NEWS2 related assessments recorded by the investigator in the appropriate electronic 
Case Report Form (eCRF).
2.2.3
Exploratory Efficacy Endpoints

Incidence of vasopressor use 

Duration of vasopressor use

Incidence of extracorporeal membrane oxygenation (ECMO)

Duration of ECMO

Organ failure-free days
2.2.4
Pharmacodynamic Efficacy Endpoints

Serum concentrations of interleukin 6 (IL-6), soluble interleukin-6 receptor (sIL-6R), 
ferritin, and C-reactive protein (CRP) at specified time points as shown in the 
schedule of assessments (see Appendix 2, Appendix 3 and Appendix 4).
2.2.5
Biomarkers
The exploratory biomarker objectives for this study are to identify and/or evaluate 
biomarkers that could be predictive of response to TCZ (i.e., predictive biomarkers), may 
serve as early surrogates of efficacy, may be associated with progression to a more 


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severe disease state (i.e., prognostic biomarkers), may be associated with susceptibility 
to developing AEs or could lead to improved adverse event (AE) monitoring or 
investigation (i.e., safety biomarkers), could further evidence of TCZ pharmacological 
activity (i.e., pharmacodynamic 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, safety, exposure
(listed in Section “Laboratory, Biomarker, and Other Biological Samples” of the
protocol) and in both blood- and tissue-derived samples will be defined in a separate
SAP.
2.2.6
Safety Endpoints

Incidence and severity of AEs, with severity determined according to National
Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) v5.0

COVID-19 (SARS-CoV-2) 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 estimated sample size was determined for the primary endpoint of comparison of 
clinical status based on a 7-category ordinal scale at Week 4 using the Van Elteren test.
Table 1 shows the assumed distribution of the ordinal scale in the PBO plus SOC group. 
Table 2 shows the expected distribution in the TCZ plus SOC group with an odds ratio of 
2 (assuming proportional odds). Under these assumptions, the total modified intent to 
treat (mITT) sample size of 450 with a 2:1 randomization of TCZ to placebo patients 
provides approximately 90% power to detect a difference in distribution between the 
treatment groups of the ordinal scale at Week 4 using a two-sided Van Elteren test at the 
5% significance level.
In addition this sample size provides approximately 90% power to detect a ratio of 2 
(TCZ to PBO) for the odds of being in a category or a better category under the
assumptions of the expected probability distribution of patients in the placebo arm in 
Table 1, using a proportional odds model with a two-sided p-value at the 5% 
significance level.
Assuming proportional odds and the given distribution of the placebo group, the smallest 
odds ratio that could be statistically significant would be approximately 1.5. 


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This sample size also provides approximately 90% power to detect a 10% absolute 
difference in mortality rate under the assumption of a 15% mortality rate in the placebo 
group.
Table 1
Distribution of Ordinal Scale in the Placebo Group
1 
(discharge)
2
3
4
5
6
7 (death)
0.58
0.05
0.09
0.09
0.02
0.02
0.15
Assuming proportional odds the expected distribution in the TCZ arm with an odds ratio 
of 2 would be:
Table 2
Distribution of the Ordinal scale in the Tocilizumab Group
1 
(discharge)
2
3
4
5
6
7 (death)
0.734
0.039
0.064
0.058
0.012
0.012
0.081
2.4
ANALYSIS TIMING
Up to three interim looks for efficacy prior to the primary analysis will be carried out on 
the data with mortality rate at 4 Weeks (secondary endpoint) evaluated for interim 
efficacy analyses.  The interim looks will occur after roughly 111, 222 and 333 patients 
have been enrolled and have reached the Day 28 follow-up time point, but all interims 
are subject to change depending on the enrollment rate. For additional information about 
interim analyses, refer to Section 4.8.
If efficacy is declared based on an interim analysis of mortality, the data will be cleaned, 
a snapshot taken and the data in the snapshot will be reported. There will then be a final 
snapshot when all patients either reach Day 60, or have withdrawn. 
If the study does not meet the efficacy criteria at one of the interim looks, or the efficacy 
interim is not performed, no reports for interim data, other than for the data monitoring 
committee (DMC), will be prepared; a snapshot of the data will be taken and the primary 
analysis will occur when the last patient either has withdrawn or completed the Day 28 
visit. A clinical study report (CSR) and/or a top line report (TLR) based on the analyses 
from this snapshot will be produced.
There will be an additional analysis on the final data when all patients have either 
reached Day 60 or withdrawn. Analyses from the first reporting event, restricted to data 
up to Day 28 (Week 4), will not be updated based on the final snapshot.
3.
STUDY CONDUCT
The plan is to enroll approximately 450 patients that have been diagnosed with COVID-
19 pneumonia and meet the entry criteria in centers globally.  Patients will be 


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randomized at a 2:1 ratio to receive blinded treatment of either TCZ or a matching 
placebo, respectively.  Study treatment must be given in combination with standard of 
care. For both arms, if the clinical signs or symptoms worsen or do not improve, one 
additional infusion of blinded treatment of TCZ or placebo can be given, 8–24 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 2:1 ratio to receive 
blinded treatment of either TCZ or a matching placebo, respectively.  Study treatment 
must be given in combination with SOC.  The randomization will be stratified by 
geographic region (North America, Europe) and mechanical ventilation (yes, no); and will 
occur through use of a permuted-block randomization method to ensure a balanced 
assignment to each treatment arm. The proportion of patients who are on a mechanical 
ventilator at the time of randomization will be capped at no more than 50% of the overall 
study population.
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial. These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, interactive voice or web-based response system (IxRS) service 
provider, and Data Monitoring Committee (DMC) members and statistical programming 
analysts working with the DMC.
While pharmacokinetic (PK) samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK results for these 
patients are generally not needed for the safe conduct or proper interpretation of the 


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study data.  Laboratories responsible for performing study drug PK assays will be 
unblinded to patient treatment assignments to identify appropriate samples for analysis.  
PK samples from patients assigned to the comparator arm will not be analyzed for study 
drug PK concentration except by request (e.g., to evaluate a possible error in dosing).  
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event [SAE] for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken
except in emergency situations.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
that are considered by the investigator or Sponsor to be related to study drug.  The 
patient may continue to receive treatment, and the investigator, patient, and Sponsor 
personnel, with the exception of the Drug Safety representative and personnel who must 
have access to patient treatment assignments to fulfill their roles (as defined above), will 
remain blinded to treatment assignment.
3.2
DATA MONITORING
A DMC will monitor the incidence of all SAEs, adverse events of special interest (AESI) 
and any anticipated events during the study.  
The DMC will also evaluate safety according to policies and procedures detailed in a 
DMC Charter. Regular safety reviews will begin after approximately 15 patients (10 
TCZ, 5 placebo) have been enrolled and reached 14-day follow-up.  Early stopping 
criteria will be detailed in the DMC charter and a separate interim statistical analysis plan 
(ISAP). Further details of efficacy interims are provided in Section 4.8. Interim analyses 
will be conducted by a statistical programmer independent from the study management 
team and will be reviewed by the DMC.  Interactions between the DMC and Sponsor will 
be carried out as specified in the DMC Charter.
The Data Monitoring Committee will initially consist of Sponsor representatives not 
directly involved in the study management team (SMT) and a scientific oversight 
committee (SoC) of external experts (responsibilities and operating principles of the 
DMC are described in a charter, the Internal Monitoring Committee and Scientific 
Oversight Committee Agreement). If feasible during study conduct the DMC 
responsibilities may transition to a fully independent data monitoring committee (iDMC).
4.
STATISTICAL METHODS
All primary and secondary efficacy endpoints will be analyzed in the mITT population, 
with patients grouped according to the treatment assignment at randomization.


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In all safety and pharmacodynamic analyses patients will be grouped according to the 
treatment that the patients actually received rather than the treatment assigned at 
randomization.
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 pharmacodynamic 
(PD) data will be based on the safety population.
4.1.1
mITT Population
The mITT population is defined as all patients randomized in the study that received any 
amount of study medication, 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 medication.
In all safety and pharmacodynamic analyses, patients will be grouped according to the 
treatment that the patients first received rather than the treatment assigned at 
randomization. 
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients enrolled, discontinued, or who complete the study will be 
summarized to week 4 and to the end of the study.  Reasons for premature study 
discontinuation will be listed and summarized to Week 4; and additionally to 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.
Eligibility criteria and other major protocol deviations will be listed and summarized by 
treatment group.
A listing by treatment group and patient of missed assessments for the primary endpoint 
will be produced through to Day 28, including study day of missed assessment, study 
day of discharge and /or death, if any. 
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 
country and 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 


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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 and may, in addition, be presented 
for the safety population.
4.3.1
Demographics

Sex

Age

Weight

Race

Ethnicity

Geographic region

Female fertility status
4.3.2
Disease Characteristics

Smoking history (Never, Current, Former)
o
Former/current user: number of years subject smoked (years), Nicotine 
exposure in pack years 
o
e-cigarettes use (Yes/No)

NEWS2 

Ordinal scale for clinical status 

IL-6

CRP

Ferritin

sIL-6R

Mechanical ventilation 

Steroid use at Day 1 (to be derived from concomitant medication)

Anti-viral treatment at Day 1 (to be derived from concomitant medication)

Symptoms at time of COVID 19 diagnosis
o
Fever
o
Cough
o
Shortness of breath
o
gastrointestinal symptoms (e.g. diarrhea, nausea, loss of appetite)
o
Headache
o
Fatigue
o
Other

Number of days from first COVID-19 symptom at baseline


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
COVID-19 diagnosis based on PCR of specimen type

Number of days from COVID-19 diagnosis at baseline

Specimen type at screening

PCR result (Negative, positive)

Quantitative PCR result (viral load)
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.
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 treatments with the indication given as ‘COVID-19’. 
Previous and concomitant treatments will be listed, with treatments for COVID-19 listed 
separately.
A summary of patients requiring supplemental oxygen post-discharge will be provided. 
This will be based on “home oxygen” being recorded on the Concomitant Medication 
page of the eCRF.
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, discharge and ICU stay; 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. Deaths confirmed by 
public record are also captured in the eCRF, which may not have been captured as AEs 
for patients withdrawn from the study. These events will also be incorporated into the 
windowing for death.


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Table 3
Time Windows for Assigning Assessment Study Days to Study 
Visits Labels for Deaths and Discharge
Scheduled study day
Efficacy time window
1* (Baseline)
1
7 (Week 1)
     1 to 7
14 (Week 2)
>7 to 14
21 (Week 3)
> 14 to ≤ 21
28 (Week 4)
> 21 to ≤28
35 (Week 5)
> 28 to ≤ 35
45
> 35 to ≤ 45
60
> 45 to ≤ 67
*Study day 1 is the first day of study drug
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 parameters (CRP, IL-6, sIL-6R) is shown below.


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Table 4
Time Windows for Assigning Assessment Study Days to Study 
Visits for PD parameters
Scheduled study day
aEfficacy time window
1 (Baseline)
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 45
> 38 to ≤ 52
Day 60
> 52 to ≤ 67
a 
From Week 1 onwards use value nearest to scheduled study day.
Where there is more than one efficacy assessment within a time window, then the 
nearest non-missing assessment will be assigned to that visit. If two or more 
assessments are equidistant from the scheduled time point, then the latest assessment 
will be used for efficacy (other than death or discharge where the assessment prior to 
the visit week will be used as described previously). 
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.
4.5
EFFICACY ANALYSIS
All efficacy analyses will use the mITT population. 
Sensitivity analyses to evaluate the robustness of results to the primary 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 pre-
specified subgroups may also be conducted as specified in Section 4.5.5.


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4.5.1
Primary Efficacy Endpoint
The primary efficacy objective for this study is to evaluate the efficacy of TCZ plus SOC, 
compared with placebo plus SOC using the following endpoint:

Clinical status assessed using a 7-category ordinal scale at Week 4
Assessment of patient status using this ordinal scale will be recorded at baseline and 
once daily in the morning (between 8 am and 12 pm) while hospitalized.
The primary estimand attributes are:
–
Population: Patients with severe COVID-19 pneumonia as per the 
inclusion/exclusion criteria specified in the protocol (mITT)
–
Primary endpoint: Clinical status at Week 4
–
Treatments: TCZ plus SOC versus Placebo plus SOC
–
Intercurrent events: Events leading to study withdrawal
–
Handling of intercurrent events: last observed post-baseline value (except if the 
patient has been discharged [without re-admittance] or has died up to and including
Day 28, then the death or discharge will override the Week 4 value or be imputed for 
a missing Week 4 value).
–
Summary measure: medians (95% CI) PBO plus SOC  and TCZ plus SOC
Intercurrent events are those that occur after treatment initiation and either preclude
observation of the variable or affect its interpretation. For patients who withdraw before 
Week 4, 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.  
The estimand is the difference in distributions between Tocilizumab plus SOC and 
Placebo plus SOC which will be tested using a non-parametric method, the Van Elteren 
test, including the stratification factors at randomization (region [North America, Europe] 
and mechanical ventilation [yes, no]). The median ordinal scale result for each treatment 
group and the corresponding 95% CI for the median will be presented along with the 
Van Elteren P-value, as well as the difference in medians and a 95% CI for the 
difference.
Additionally, for patients that withdraw prior to Week 4 on the TCZ arm, the 50th 
percentile of the TCZ data will be imputed from those that complete the study to Week 4
(deaths and discharges are included as completing to Week 4), and on the placebo arm 
the 50th percentile will be imputed from the placebo data.
For patients that withdraw prior to Week 4 on the TCZ arm the 75th percentile will be 
imputed from those that complete the study to Week 4 (deaths and discharges are 
included as completing to Week 4), and on the placebo arm the 25th percentile will be 
imputed from the placebo data.


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In addition, the clinical status according to the 7-category ordinal scale will be compared 
between the TCZ group and the placebo group at Week 4, using a proportional odds 
model accounting for stratification factors at randomization in the model (region [North 
America, Europe] and mechanical ventilation [yes, no] using the mITT population. The 
odds ratio, p-value, and 95% confidence interval will be presented.  
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. 
In addition to imputing the ordinal scale at Week 4 with an earlier death or discharge 
(without re-admittance), captured from ordinal scale or other sources, this imputation 
rule will also be followed at earlier time points, including the day of death or discharge. 
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 a 
patient is re-admitted then the ordinal scale data from the point of re-admittance will be 
used. The ordinal scale will be summarized by Week and treatment showing n and 
percentage in each category, as well as missing data. Comparison of clinical status 
according to the 7-category ordinal scale (detailed for the primary endpoint at Week 4) 
will be analyzed using a proportional odds model at additional time points including but 
not limited to Week 2.
Stacked bar charts of the ordinal scale will be produced by treatment group, the bars will 
total to 100% and the categories, including ‘missing’, will be shown. At Week 4, a side by 
side comparison of the treatment groups by stacked bar chart will be shown.
The primary endpoint will be analysed by the mechanical ventilation status as 
randomized, as it is considered that this stratification factor may be predictive for 
response to tocilizumab treatment. The clinical status assessed using a 7-category 
ordinal scale at Week 4 will be tested in the subgroups split by mechanical ventilation 
status (yes, no) as stratified using the Van Elteren test for each subgroup. The 
subgroups will also be analysed using the proportional odds model as specified for the 
primary endpoint.
4.5.2
Controlling for Type I Error
The following are key secondary endpoints for the study:

Difference in Mortality at Week 4

Ventilator-free days at Week 4

Time to improvement of at least 2 categories relative to baseline on a 7-category 
ordinal scale of clinical status to Week 4

Time to hospital discharge or “ready for discharge”


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
Clinical status assessed using a 7-category ordinal scale at Week 2
The primary endpoint (the difference in distributions in clinical status between 
Tocilizumab plus SOC and Placebo plus SOC at Week 4; Van Elteren test) will be tested 
at a two-sided 5% significance level. If the primary endpoint is statistically significant the 
difference in mortality at Week 4 will then be tested at 0.05 (two-sided Cochran-Mantel-
Haenszel test). There will be no further multiplicity adjustment for the additional four key 
secondary endpoints.
A treatment effect may be observed in a key secondary endpoint that may not meet 
nominal statistical significance, but may still be considered clinically meaningful.
Therefore all five of the key secondary endpoints will be tested in addition to the primary 
endpoint in order to help inform prescribers by potentially providing this information in 
the label if clinically meaningful.
4.5.3
Secondary Endpoints
4.5.3.1
Time to Event Analyses
Time to event secondary endpoints will be compared between the TCZ group and the 
placebo group using the stratified log-rank test with geographic region (North America, 
Europe) and mechanical ventilation (yes, no) included as the stratification factors at Day 
28 using the mITT population.  The Kaplan-Meier plot, median time to response, and 
their 95% CIs, and a p-value will be presented. In addition, the treatment groups will be 
compared descriptively using a Cox proportional hazards model adjusting for the 
stratification factor applied at randomization. Hazard ratios and a 95% CI will be 
produced.
For time to event endpoints, other than time to clinical failure, deaths will be right 
censored (at Day 28). Consequently, for these endpoints, participants censored on Day 
28 reflect two different states, death and failure to meet the improvement outcome 
criterion. Therefore, it is important to understand the efficacy outcome in the context of 
the number and timing of deaths by treatment arm. Cumulative incidence function plots 
for both death and the event of interest will be produced using the non-parametric 
Aalen–Johansen estimator.
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 they are 
discharged later in the study (without re-admittance within 12 hours), then the later time 
of discharge will be used.


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Time to event endpoints include:

Time to clinical improvement in hours
Defined as time from first dose of study drug to NEWS2 of ≤2 maintained for 24 hours 
The estimand is the difference in distributions between Tocilizumab plus SOC and 
Placebo plus SOC using the log rank test as described above.
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 5 below.
Patients who have a score of ≤2 at baseline will be analysed in the same way as 
patients with a score that is >2 at baseline.
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 assessments with a score of ≤2 covering a span 
of at least 21.5 hours will be required to meet the criterion, 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). 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 5
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
Yes
Day 28
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 
Week 4 time window
Other time to event endpoints include: 

Time to improvement in ordinal clinical status (days)


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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. For patients in category 2 at 
baseline, discharge or “ready for discharge” will be considered as meeting the threshold. 
For patients that 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 6 below.
Table 6
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 
Yes
Day 28
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 Week 4 time window

Time from first dose of study drug to Recovery (days)
Defined as discharged or ready for discharge {normal body temperature and respiratory 
rate, and stable oxygen saturation on ambient air or ≤2L supplemental oxygen} (ordinal 
scale category one), or Non-ICU hospital ward {or “ready for hospital ward”} not 
requiring supplemental oxygen (ordinal scale category 2). Patients that are in category 2 
at baseline will need to achieve category 1 to meet the endpoint of recovery.
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 7 below.
Table 7
Time to Recovery 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 Recovery
Yes
Day 28
Discontinuation or lost to follow up for any 
reason prior to recovery criterion met
Yes
last Ordinal scale assessment
Not recovered
Yes
last Ordinal scale assessment 
within Week 4 time window


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
Time from first dose of study drug to hospital discharge or “ready for discharge” 
(days)
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 8 below.
Table 8
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
Yes
Day 28
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 Week 4 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 (as collected in the Vital Signs & Oxygen Saturation eCRF), ICU 
admission or withdrawal (discontinuation from study) prior to discharge, whichever 
occurs first. For patients entering the study already in ICU or on mechanical ventilation
(as collected in the Vital Signs & Oxygen Saturation eCRF), clinical failure is defined as 
a one-category worsening on the ordinal scale, withdrawal or death. Withdrawals not 
during hospitalization will not be considered as having met clinical failure and data will 
be censored at the last vital sign assessment, unless a later death is recorded in which 
case they will have met the event upon 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 9 below.


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Table 9
Time to Clinical Failure and censoring
Event
Censor
Date and Time
Hospital discharge not followed by death or 
readmittance
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 failure 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 Week 4 time 
window
The NEWS2 score and clinical failure status as defined above will be summarized
descriptively by visit.
Sensitivity analyses may be performed considering death as a competitive event (other 
than for the clinical failure endpoint), using a competing risk model if there is an 
imbalance between groups in deaths and reason attributed.
4.5.3.2
Incidence endpoints
Secondary efficacy incidence endpoints will be analyzed using the Cochran-Mantel-
Haenszel test statistic adjusted by the stratification factors at baseline geographic region 
(North America, Europe) and mechanical ventilation (yes, no) using the mITT population, 
unless stated otherwise.  The weighted difference in proportions for the treatment group 
comparison will be presented with a p-value, together with a 95% CI (see Appendix 6).

Incidence of mechanical ventilation (as collected in the Vital Signs & Oxygen 
Saturation eCRF) by Week 4 (mechanical ventilation refers to invasive mechanical 
ventilation only, and/or ECMO).

Incidence of ICU stay by Week 4
For incidence of mechanical ventilation or incidence of intensive care stay by Week 4 for 
patients that have withdrawn or died prior to Week 4, 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 Week 4 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 readmitted to hospital within 12 hours, 
or the patient dies by Week 4.


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In addition to the analyses based on the mITT, incidence of ICU stay and mechanical 
ventilation will also be analyzed excluding those patients that were in ICU/mechanically 
ventilated (according to the stratification), respectively, at baseline.
The number and proportion of patients requiring mechanical ventilation or an ICU stay
will be summarized descriptively by study week.

Difference in mortality at Week 4
The difference in proportion of patients that have died by Day 28 will be compared using 
the CMH test as described above. All deaths post discontinuation and discharge will be 
included in this analysis.
Deaths occurring between each visit, and cumulative deaths by visit will be summarized 
descriptively to Day 60.  
4.5.3.3
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.
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 
remainder of days to Week 4 were not VFDs. For patients not using invasive mechanical 
ventilation at point of withdrawal it will be assumed the period from withdrawal to Week 4 
are VFDs. For patients that are discharged, days from discharge to Day 28 will be 
counted as VFDs. If ventilator data is missing for patients that have not withdrawn, died 
or discharged, then the last observation post-baseline will be carried forward until the 
next observation. 
VFDs will be analysed using the Van Elteren test, including the stratification factors at 
randomization (region [North America, Europe] and mechanical ventilation [yes, no]). 
The median VFDs for each treatment group and the corresponding 95% CI for the 
median will be presented along with the Van Elteren P-value, as well as the difference in 
medians and a 95% CI for the difference. A cumulative distribution plot of VFDs will be 
produced.


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VFDs will also be summarized descriptively using the medians, along 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

Duration of supplemental O2 (days)
Duration of supplemental O2 (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 Week 4. Patients without any supplemental O2 use 
will assigned a duration of zero days. For missing data, the last observation post-
baseline will be carried forward until either the next observation or the point of 
withdrawal/discharge. For patients withdrawn early from the study but not discharged, if 
the patients were on supplemental oxygen at the point of withdrawal it will be assumed 
that the remainder of days to Week 4 were on supplemental oxygen. For patients not 
using supplemental oxygen at point of withdrawal it will be assumed supplemental 
oxygen is not required to Week 4. 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 on the Concomitant Medications eCRF during follow up visits, in 
which case all days from the day after discharge to the end date from the Concomitant 
Medication eCRF will be classed as days with supplemental oxygen). Duration of 
supplemental oxygen use will be 28 days if a patient dies on or prior to Day 28.
Days of supplemental O2 use will be analyzed and summarized descriptively in a similar 
method to VFDs. 

Duration of ICU stay (days)
Duration of ICU stay (days) will be calculated as the sum of the number of hours spent in
ICU up to and including Week 4 divided by 24, based on the admission and discharge 
date times from the ICU stay information log; (ICU discharge datetime – ICU admission 
datetime)/24. Multiple periods of ICU stay will be summed. Patients without any ICU 
stays will be assigned a duration of zero days.
Partial admission and discharge times may be imputed based on available data, 
following a conservative approach. For patients that are discharged, any ongoing ICU 
stays without an end date will be imputed from 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 Week 4 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 
Week 4. Patients that die on or prior to Day 28 will be assigned a duration from the first 
dose of study drug to Day 28 23:59:59.
Days of ICU stay will be analyzed and summarized descriptively in a similar method to 
VFDs.


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4.5.4
Exploratory Efficacy Endpoints
Incidence of vasopressor use (from concomitant medication records) and incidence of 
extracorporeal membrane oxygenation (ECMO) by Week 4 (and separately to Day 60) 
will be summarized descriptively.
Duration of vasopressor use (days) and ECMO (days) to Week 4 will be summarized 
using the median along with 95 % CIs for the median by treatment group. ECMO use is 
collected daily and the number of days of ECMO use will be totaled. Vasopressor 
duration will use start and stop dates from the concomitant medication records.  A 
concomitant medication record that is ongoing at Week 4 will use the upper bound of the 
Week 4 time window as the end date for the duration. 
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 organ 
failure is defined as either systolic BP ≤ 90 mmHg or the need for vasopressor. Renal, 
hepatic and coagulation parameters will be assessed via blood tests in order that the 
presence of clinically significant organ failure can be determined. Renal failure is defined 
as creatinine ≥ 2 mg/dl, hepatic failure is defined as bilirubin ≥ 2 mg/dl and coagulation 
failure is defined as a platelet count of ≤ 80 ×10³/mm³. 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 no data for a particular organ, the last observation post-
baseline will be carried forward until the next observation or discharge. Any day that a 
patient is alive and free of all 4 organ failures (cardiovascular, renal, hepatic,
coagulation) will be considered an organ failure-free day. 
If a patient dies on or before Day 28, they will be assigned a value of zero organ failure-
free days in the overall summary of organ failure-free days. For patients that are 
discharged, days from discharge to Day 28 will be counted as organ failure-free days, 
unless they are readmitted in which case the available data will be used.
4.5.5
Subgroup Analyses
A subgroup analysis of the Clinical status assessed using a 7-category ordinal scale at 
Week 4 by mechanical ventilation status (yes, no) as stratified will be performed using 
the Van Elteren test for each subgroup. In addition, a stacked barchart at Day 28, a 
summary of clinical status at Day 28 and a summary of clinical status over time will be 
produced by mechanical ventilation status (yes, no) at baseline.   
In addition, the clinical status according to the 7-category ordinal scale will be compared 
between the TCZ group and the placebo group at Week 4 by mechanical ventilation 
status (yes, no) as stratified, using a proportional odds model accounting for stratification 


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factors at randomization in the model (region [North America, Europe]) using the mITT 
population. The odds ratio, p-value, and 95% confidence interval will be presented.  
The odds ratio for mortality for TCZ versus PBO 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 gender, race, age (18-64 years, 65-84 
years, 85 years and over), region, mechanical ventilation (as stratified) and ordinal 
clinical status (categories 1 to 3, vs categories 4 and 5) will be determined. Other 
subgroup analyses may also be performed. If necessary, where there are small 
subgroups, categories may be collapsed as appropriate to enable analysis, such as for 
subgroup analysis by race.
4.6
PHARMACODYNAMIC ANALYSES
The PD analysis population will be identical to the safety population. 
Summary tables for serum concentration of IL-6, sIL-6R, CRP and ferritin (mean, 
standard deviation, median, minimum, and maximum) will be produced by visit/ time 
point and treatment arm.
Individual patient data and descriptive statistics (i.e. median and interquartile range) will 
be plotted by visit/ time point for each treatment arm.
4.7
SAFETY ANALYSES
Safety assessments will be performed on the safety population.  In all safety analyses, 
patients will be grouped according to the treatment that the patients first 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 time point 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 reverse-transcriptase polymerase chain reaction (RT-PCR) COVID-19 virus 
negativity will be analyzed using similar methods to the other time to event analyses.
There will be an additional analysis limited to patients positive at baseline based on 
central laboratory results.


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4.7.1
Exposure of Study Medication
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. If after unblinding a patient has 
received study drug from more than one treatment group, then the actual dose of TCZ 
would be calculated from the proportion of TCZ kits received. For example, if a patient 
received 1 kit of TCZ and 3 kits of PBO then the actual dose of TCZ would be calculated 
as ¼ of the total recorded dose.
4.7.2
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 
trial treatment.  Only where the most extreme intensity is greater than the initial intensity 
(or if most extreme intensity is not missing and initial intensity 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 study 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 arms.
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:

serious adverse events

adverse events leading to withdrawal of study drug

adverse events leading to discontinuation from the study

adverse events leading to death

hypersensitivity adverse events (adverse events occurring during or within 24 hours 
of the end of an infusion that are deemed “related” to study treatment) 


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Adverse events of special interest will be defined using SOC, published Standard 
MedDRA Queries (SMQs) or AE 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)

Anaphylactic reaction events (utilizing Roche Standard AEGT Basket according to 
Sampson’s criteria) [Sampson et al. 2006] occurring during or within 24 hours of the 
end of tocilizumab infusion; and a separate summary using the Anaphylactic 
Reaction SMQ Narrow for events occurring during or within 24 hours of the end of
tocilizumab infusion)

Gastrointestinal perforations (Gastrointestinal perforation SMQ Wide)

Bleeding events (Hemorrhages SMQ Wide)

Demyelinating events (Demyelination SMQ Narrow)
Summaries and listings of malignancies and gastrointestinal perforations that were 
confirmed by medical review will be provided. 
A glossary showing the mapping of investigator verbatim terms to preferred terms 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 preferred terms that comprise the SMQ 
will be produced. 
Listings of AEs and SAEs will be produced. Adverse events of special interest will also 
be listed.
AEs and SAEs will summarized by age category (18-64 years, 65-84 years, 85 years 
and over).
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.
4.7.3
Laboratory Data
Laboratory data will use ranges from local laboratories and laboratory values will be 
converted to Système International units.


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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 CTC grade for hematology and
hepatic lab 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, Low).
A listing of all pregnancies will be presented.
4.7.4
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.
For patients requiring supplemental oxygen, summary statistics on absolute values of 
the oxygen flow rate (L/min) and/or fraction of inspired oxygen (FiO2) will be produced 
by visit/ time point 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 [CPAP], bi-level positive airway pressure 
[BiPAP], 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 scans and ECGs (as a separate listing) with 
clinically significant abnormalities will be produced. 
4.7.5
Other Safety Endpoints
SARS-CoV-2 viral load over time, as collected by nasopharyngeal swab and BAL 
samples (if applicable) will be summarized descriptively by time point and treatment 
group.


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Time to reverse-transcriptase polymerase chain reaction (RT-PCR) COVID-19 virus 
negativity will be analyzed using similar methods to the other time to analyses.
4.8
INTERIM ANALYSES
Up to three efficacy interim analyses will be carried out on the data with mortality rate at 
28 days (secondary endpoint) evaluated for efficacy.  The interim looks will occur after 
roughly 111, 222and 333, patients are enrolled and have reached 28 days follow up, but 
all interims are subject to change depending on the enrollment rate. 
The first efficacy interim analysis will be conducted when approximately 111 patients (74
TCZ and 37 placebo) have reached the 28-day follow-up time point and will be based on 
the mortality rate at 28 days (secondary endpoint).  Up to two further interim efficacy 
analyses will occur after roughly 222 and 333 patients have reached the 28-day follow-
up time point.  If the results of one of the interim analyses meets the pre-specified 
criteria for efficacy, further enrollment in the placebo arm will be discontinued and all 
enrolled patients will be eligible receive open-label TCZ.  At this point, efficacy will be 
declared. Recruitment into the TCZ arm will continue until 300 patients have been 
enrolled.
The type I error rate will be controlled to ensure statistical validity is maintained.  
Specifically, the Lan-DeMets -spending function that approximates the O'Brien-Fleming 
boundary will be applied to determine the critical value for stopping for positive efficacy 
at the interim analysis (DeMets and Lan 1994).  Interim analyses for efficacy will use the 
Fisher’s exact test for difference in proportions for mortality at 28 days and will utilize an 
O’Brien-Fleming alpha-spending function.  The efficacy boundaries for the z-scores at 
the four looks (three interim analyses and primary analysis) are 4.364, 2.986, 2.377 and 
2.011.  The one-sided local significance levels at the three efficacy interim analyses are 
0.000006392, 0.001415 and 0.008718.
Additional information regarding the efficacy interim analyses is detailed in the interim 
SAP. The critical value at the final analysis will be adjusted accordingly to maintain the 
protocol-specified overall type I error rate, per standard Lan-DeMets methodology.
The study management team will remain blinded unless the results meet the efficacy 
criteria (boundary is crossed). The Interim efficacy analyses will be produced by a 
statistical programmer and statistician independent of the study management team and 
will be reviewed by a DMC. 
Full statistical details of the planned interim analyses, along with the rationale and timing 
will be documented in an interim statistical analysis plan, which will be made available to 
the relevant health authorities before the data snapshot for the first interim.
A DMC will also evaluate safety according to policies and procedures detailed in a DMC 
Charter.  Regular safety reviews will begin after approximately 15 patients (10 TCZ, 


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5 placebo) have been enrolled and reached 14-day follow-up.  Early stopping criteria 
based on compelling efficacy or an imbalance in adverse events will be detailed in the 
DMC charter.  The safety interim analyses will also be conducted by a statistical 
programmer and statistician independent from the study management team and will be 
reviewed by the DMC.  Interactions between the DMC and Sponsor will be carried out as 
specified in the DMC Charter.
The Data Monitoring Committee will initially consist of Sponsor representatives not 
directly involved in the SMT. If feasible during study conduct, the responsibilities may 
transition to a fully independent DMC (iDMC). 


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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
DeMets DL, Lan KG. Interim analysis: the alpha spending function approach. Stat Med. 
1994;13:1341−52.
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]. http://www.chinaxiv.org/abs/202003.00026
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. 


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Appendix 1 Protocol Synopsis
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF TOCILIZUMAB IN PATIENTS WITH SEVERE 
COVID-19 PNEUMONIA
PROTOCOL NUMBER:
WA42380
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001154-22
IND NUMBER:
148225
IND NUMBER:
NCT04320615
TEST PRODUCT:
Tocilizumab (RO4877533)
PHASE:
Phase III
INDICATION:
Severe COVID-19 pneumonia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of 
tocilizumab (TCZ) compared with a matching placebo in combination with standard of care 
(SOC) in hospitalized patients with severe COVID-19 pneumonia.  Specific objectives and 
corresponding endpoints for the study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of TCZ compared with 
placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the
basis of the following endpoint:

Clinical status assessed using a 7-category ordinal scale at Day 28 
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of TCZ compared with 
placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the 
basis of the following endpoints:

Time to clinical improvement (TTCI) defined as a National Early Warning Score 2 (NEWS2) 
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 

Incidence of mechanical ventilation

Ventilator-free days to Day 28

Incidence of intensive care unit (ICU) stay 

Duration of ICU stay


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
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 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 2L 
supplemental oxygen)

Time to recovery, defined as discharged or “ready for discharge” (as evidenced by normal 
body temperature and respiratory rate, and stable oxygen saturation on ambient air or 
2L supplemental oxygen); OR, in a non-ICU hospital ward (or “ready for hospital 
ward”) not requiring supplemental oxygen

Duration of supplemental oxygen
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of TCZ compared with 
placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the 
basis of the following endpoints:

Incidence of vasopressor use 

Duration of vasopressor use

Incidence of extracorporeal membrane oxygenation (ECMO)

Duration of ECMO

Organ failure-free days to Day 28
Safety Objective
The safety objective for this study is to evaluate the safety of TCZ compared with placebo in 
combination with SOC for the treatment of 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 (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 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
Pharmacodynamic Objective
The pharmacodynamic objective for this study is to characterize the pharmacodynamic effects 
of TCZ in patients with COVID-19 pneumonia via longitudinal measures of the following 
analytes relative to baseline

Serum concentrations of IL-6, sIL-6R, and CRP at specified timepoints 
Pharmacokinetic Objective
The PK objective for this study is to characterize the TCZ PK profile in patients with COVID-19 
pneumonia on the basis of the following endpoint:

Serum concentration of TCZ at specified timepoints
Biomarker Objective
The exploratory biomarker objectives for this study are to identify and/or evaluate biomarkers 
that could be predictive of response to TCZ (i.e., predictive biomarkers), may serve as early 
surrogates of efficacy, may be associated with progression to a more severe disease state 


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(i.e., prognostic biomarkers), may be associated with susceptibility to developing adverse 
events or could lead to improved adverse event monitoring or investigation (i.e., safety 
biomarkers), could further evidence of TCZ pharmacological activity (i.e., pharmacodynamic 
biomarkers), and overall increase our knowledge and understanding of disease pathogenesis 
and drug safety, on the basis of the following endpoint:

Assessments of individual biomarkers in relation to efficacy, safety, exposure and in both 
blood- and tissue-derived samples
STUDY DESIGN
Description of the Study
This 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.  The 
Sponsor intends to enroll approximately 450 patients that have been diagnosed with COVID-19 
pneumonia and meet the entry criteria in centers globally.  
Patients must be at least 18 years of age with confirmed SARS-CoV-2 (COVID-19) infection per 
WHO criteria, including a positive PCR of any specimen (e.g., respiratory, blood, urine, stool, 
other bodily fluid).  At the time of enrollment, patients must have SpO2 93% or PaO2/FiO2
300 mmHg despite being on SOC, which may include anti-viral treatment, low dose steroids, 
and supportive care.
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 as soon as possible after screening at a 2:1 ratio to receive blinded 
treatment of either TCZ or a matching placebo, respectively.  Study treatment must be given in 
combination with SOC.  The randomization will be stratified by geographic region (North 
America and Europe) and mechanical ventilation (yes, no).  The proportion of patients who are 
on a mechanical ventilator at the time of randomization will be capped at no more than 50% of 
the overall study population.
Patients assigned to the TCZ arm will receive one infusion of TCZ 8 mg/kg, with a maximum 
dose of 800 mg, and patients assigned to the placebo arm will receive one infusion of placebo, 
both in addition to SOC.  
For both arms, if the clinical signs or symptoms worsen or do not improve (reflected by 
sustained fever or at least a one-category worsening on the 7-category ordinal scale of clinical 
status), one additional infusion of blinded treatment of TCZ or placebo can be given, 8–24 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 2 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: physical examination, vital signs, 
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 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. 


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Number of Patients
This study aims to enroll approximately 450 hospitalized patients with severe COVID-19 
pneumonia.
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 legal/authorized representative

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Hospitalized with COVID-19 pneumonia confirmed per a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT 
scan 

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 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 study drug.  
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 study drug 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


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
Active TB infection 

Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) 

In the opinion of the investigator, progression to death is imminent and inevitable within the 
next 24 hours, irrespective of the provision of treatments

Have received oral anti-rejection or immunomodulatory drugs (including TCZ) with the past 
3 months

Participating in other drug clinical trials (participation in COVID-19 anti-viral trials may be 
permitted if approved by Medical Monitor)

ALT or AST 10 x ULN detected within 24 hours at screening (according to local laboratory 
reference ranges)

ANC 1000/L at screening (according to local laboratory reference ranges)

Platelet count 50,000/L at screening (according to local laboratory reference ranges)

Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination

Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of 
randomization (investigational COVID-19 antivirals 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 (LPLV) occurs or the 
date at which the last data point required for 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 6 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
Patients assigned to the active arm will receive one or two doses of tocilizumab (TCZ) via IV 
infusion at a dose of 8 mg/kg IV to a maximum of 800 mg per dose.  
Comparator
Patients assigned to the comparator arm will receive one or two doses of placebo via IV.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of TCZ plus standard of 
care, compared with placebo plus standard of care using the following endpoint:

Clinical status assessed using a 7-category ordinal scale at Day 28 
Assessment of patient status using an ordinal scale will be recorded at baseline and daily in the 
morning (between 8 am and 12 pm) while 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 2L 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 


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6.
ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g., 
vasopressors, renal replacement therapy)
7.
Death
The estimand is the difference in distributions between TCZ plus SOC and placebo plus SOC,
which will be tested using a non-parametric method, the Van Elteren test, including the 
stratification factors at randomization (region [North America, Europe] and mechanical 
ventilation [yes, no]).  The median ordinal scale result for each treatment group and the 
corresponding 95% CI for the median will be presented along with the Van Elteren p-value, 
as well as the difference in medians and a 95% CI for the difference.
Further details of the primary endpoint analysis will be included in the SAP.
As an additional analysis, the clinical status according to the 7-category ordinal scale will be  
compared between the TCZ group and the placebo group at Day 28, using a proportional odds 
model accounting for stratification factors at randomization in the model (region [North 
America, Europe] and mechanical ventilation [yes, no]).  The odds ratio, p-value, and 95% 
confidence interval will be presented.
For patients who withdraw before Day 28, their last post baseline ordinal category prior to 
withdrawal will be used in the analysis.  Any other missing data handling rules for the primary 
endpoint will be specified in the SAP.
Determination of Sample Size  
The estimated sample size was determined for the primary endpoint of comparison of clinical 
status based on a 7-category ordinal scale at Day 28 using the Van Elteren test. 
The total mITT sample size of 450 with a 2:1 randomization of TCZ to placebo patients provides 
approximately 90% power to detect a difference in distribution between the treatment groups 
of the ordinal scale at Day 28 using a two-sided Van Elteren test at the 5% significance level 
under the following assumptions of the expected probability distribution of patients in the 
placebo arm:
1 (discharge)
2
3
4
5
6
7 (death)
0.58
0.05
0.09
0.09
0.02
0.02
0.15
And, assuming proportional odds with an odds ratio of 2, the expected distribution in the TCZ 
arm with would be:
1 (discharge)
2
3
4
5
6
7 (death)
0.734
0.039
0.064
0.058
0.012
0.012
0.081
In addition, this sample size provides approximately 90% power to detect a ratio of 2 (TCZ to 
PBO) for the odds of being in a category or a better using a proportional odds model with a 
two-sided p-value at the 5% significance level.
Assuming proportional odds and the given distribution of the placebo group, the smallest odds 
ratio that could be statistically significant would be approximately 1.5.
This sample size also provides approximately 90% power to detect a 10% absolute difference 
in mortality rate under the assumption of a 15% mortality rate in the placebo group.
Planned Interim Analyses
Up to three interim looks for efficacy will be carried out on the data with mortality rate at 28 days 
(secondary endpoint) evaluated for interim efficacy analyses.  The interim looks will occur after 
roughly 111, 222, and 333 patients are enrolled, but all interims are subject to change 
depending on enrollment.  If the sample size is increased during the study, the remaining 
efficacy interims will be performed at similar proportions of information to the original planned 
efficacy interim analyses.
The first efficacy interim analysis will be conducted when approximately 111 patients (74 TCZ 
and 37 placebo) have reached the 28-day follow-up time point and will be based on the 
mortality rate at 28 days (secondary endpoint).  If the results of one of the interim analyses 
meets the pre-specified criteria for efficacy, further enrollment in the placebo arm will be 
discontinued and all enrolled patients will receive open-label TCZ.  At this point, efficacy will be 


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declared.  If the study is at least 90% enrolled within 5 weeks (28 days follow up plus 1 week 
to perform the analysis) of the 111th patient being enrolled, then no interim analyses will be 
conducted.
If there is a potential for further recruitment into the placebo arm to be stopped for positive 
efficacy because of the interim analysis, the type I error rate will be controlled to ensure 
statistical validity is maintained.  Specifically, the Lan-DeMets -spending function that 
approximates the O’Brien-Fleming boundary will be applied to determine the critical value for 
stopping for positive efficacy at the interim analysis (DeMets and Lan 1994).  Interim analyses 
for efficacy will use the Fisher’s exact test for difference in proportions and will utilize an 
O’Brien-Fleming alpha-spending function.  The efficacy boundaries for the z-scores at the four 
looks (three interim looks and final analysis) are 4.364, 2.986, 2.377, and 2.011.  
The critical value at the final analysis will be adjusted accordingly to maintain the protocol-
specified overall type I error rate, per standard Lan-DeMets methodology.
The study management team will remain blinded unless the results meet the efficacy criteria. 
The interim efficacy analyses will be produced by a statistical programmer independent of the 
study management team and will reviewed by a Data Monitoring Committee (DMC). 
Full statistical details of the planned interim analyses, along with the rationale and timing will be 
documented in an interim statistical analysis plan, which will be made available to the relevant 
health authorities before the data snapshot for the first interim.
A Data Monitoring Committee will also evaluate safety according to policies and procedures 
detailed in a DMC Charter.  Regular safety reviews will begin after approximately 15 patients 
(10 TCZ, 5 placebo) have been enrolled and reached 14-day follow-up.  Early stopping criteria 
based on compelling efficacy or an imbalance in adverse events will be detailed in the DMC 
charter.  The safety interim analyses will also be conducted by a statistical programmer 
independent from the study management team and will be reviewed by the DMC.  Interactions 
between the DMC and Sponsor will be carried out as specified in the DMC Charter.
The Data Monitoring Committee may initially consist of Sponsor representatives not involved in 
any operational aspects of the study before transitioning to a fully independent data monitoring 
committee (iDMC) when feasible. 


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Appendix 2 Schedule of Activities:  Days 1 and 2
Screening a, b
Baseline
Study Day
2 to 0
1
2
Time Post Initial Treatment
(Assessment Window)
0
Pre-dose
(4 hrs)
15 min
After end of 
infusion
(1 hr)
24 hrs
(4 hrs)
36 hrs
(4 hrs)
Informed consent
x
Inclusion/exclusion criteria
x
x
Demographic data
x
Randomization
x
Medical history
x
Complete physical examination c
x
Weight
x
COVID-19 diagnosis d
x
Chest X-ray/CT scan e
x
ECG
x
Pregnancy test f
x
PaO2/FiO2 g
x
  Optional  
SpO2 h
x
x
x
x
x
Vital signs h
x
x
x
x
x
Ordinal scoring i
x
x
Adverse events j
x
x
Concomitant medications k
x
x
Hematology l
x 
x
x
Chemistry m
x
x
x


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Appendix 2 Schedule of Activities:  Days 1 and 2 (cont.)
Screening a, b
Baseline
Study Day
2 to 0
1
2
Time Post Initial Treatment
(Assessment Window)
0
Pre-dose
(4 hrs)
15 min
After end of 
infusion
(1 hr)
24 hrs
(4 hrs)
36 hrs
(4 hrs)
Study drug administration n
x
Central Labs
Serum PD (CRP, IL-6, sIL-6R)
x o
x o
x
x
Serum PK p
x q
x q
x
x
Serum sample 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
Whole blood in PAXgenetubes for RNA 
analyses t
x
CRP=c-reactive protein; CT=computed tomography; ECG =electrocardiogram; eCRF =electronic case report form; NCI CTCAE=National Cancer 
Institute Common Terminology Criteria for Adverse Events v.5.0; NEWS2=National Early Warning Score; PaO2/FiO2 = arterial oxygen partial 
pressure/fraction of inspired oxygen; PBMCs =peripheral blood mononuclear cells; PK =pharmacokinetic; PRO-CTCAE=NCI Patient-Reported 
Outcomes Common Terminology Criteria for Adverse Events; SpO2 =peripheral capillary oxygen saturation.
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.  
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. 


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Appendix 2 Schedule of Activities:  Days 1 and 2 (cont.)
e Screening chest X-ray or CT scans should be performed within 48 hours prior to randomization.  If additional chest X-rays/CT scans are 
taken per local practice during the study, this information should be provided in 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 on Day 1/Visit 1 then again daily every morning (between 
8 am and 12 pm) 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.
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 NK cells; if the test is available at the site).
m 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.
n Study drug should be administered after collection of all samples for pharmacodynamic and exploratory biomarker analyses.  The initial study 
drug infusion should be given within 4 hours of randomization.  If the clinical signs or symptoms worsen or do not improve (reflected by 
sustained fever or at least a one-category worsening on the 7-category ordinal scale of clinical status), one additional infusion of blinded 
treatment of TCZ or placebo can be given, 8–24 hours after the initial infusion.
o 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, on 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, on the opposite arm as the infusion.
p 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, on the opposite arm as the infusion.


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Appendix 2 Schedule of Activities:  Days 1 and 2 (cont.)
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, on the opposite arm as the 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 where 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 first draw of blood should not be for PAXgenetubes to avoid contact with RNA preservation reagent inside the tube.


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Appendix 3 Schedule of Activities:  Days 328
Days 328 a
Study 
Completion/ 
Discontinuati
on
Study Day
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/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 h
x
x
x
x
x
x
x
Central Labs
Serum PD (CRP, IL-6, 
sIL-6R)
x
x
x
x
x
x
Serum PK
x
x
x
x
x
Serum sample 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


Tocilizumab—F. Hoffmann-La Roche Ltd.
50/Statistical Analysis Plan WA42380
Appendix 3 Schedule of Activities:  Days 328 (cont.)
Days 328 a
Study 
Completion/ 
Discontinuati
on
Study Day
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
Cryopreserved PBMCs j
x
x
x
x
x
x
Whole blood in 
PAXgene
tubes for RNA analyses k
x
x
x
x
BAL=bronchoalveolar lavage; CRP=c-reactive protein; CT =computed tomography; ECG =electrocardiogram; eCRF =electronic case 
report form; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0; PaO2/FiO2 = arterial oxygen 
partial pressure/fraction of inspired oxygen; PBMCs =peripheral blood mononuclear cells; PK =pharmacokinetic; PRO-CTCAE =NCI 
Patient-Reported Outcomes Common Terminology Criteria for Adverse Events; SpO2=peripheral capillary oxygen saturation..
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 a 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 on Day 1/Visit 1 then again daily every morning 
(between 8 am and 12 pm) 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.


Tocilizumab—F. Hoffmann-La Roche Ltd.
51/Statistical Analysis Plan WA42380
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 NK 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 where 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 first draw of blood should not be for PAXgenetubes to avoid contact with RNA preservation reagent inside the tube.


Tocilizumab—F. Hoffmann-La Roche Ltd.
52/Statistical Analysis Plan WA42380
Appendix 4 Schedule of Activities:  After Day 28
Study Completion
Study Day
(Assessment Window)
35 a
(3 days)
45 a
(3 days)
60
(3 days)
Chest X-ray/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 h
x
x
x
Central Labs
Serum PD (CRP, IL-6, sIL-6R)
x
x
Serum PK
x
x
Serum sample for exploratory biomarkers
x
x
Serum SARS-Cov-2 antibody titer
x
CRP=c-reactive protein; CT=computed tomography; PK=pharmacokinetic; SpO2=peripheral capillary 
oxygen saturation.
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 a 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 on-going infection.
c For patients who remain in 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.


Tocilizumab—F. Hoffmann-La Roche Ltd.
53/Statistical Analysis Plan WA42380
Appendix 4 Schedule of Activities:  After Day 28 (cont.)
d Assessment of clinical status using the ordinal scale should be recorded at baseline on Day 1/Visit 1 
then again daily every morning (between 8 am and 12 pm) 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.
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 NK 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 labs will not be performed if follow-up visits are conducted by 
telephone.


Tocilizumab—F. Hoffmann-La Roche Ltd.
54/Statistical Analysis Plan WA42380
Appendix 5 National Early Warning Score 2 (NEWS2)
SpO2=oxygen saturation. 
The oxygen saturation 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 [COPD]).  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.


Tocilizumab—F. Hoffmann-La Roche Ltd.
55/Statistical Analysis Plan WA42380
Appendix 5 National Early Warning Score 2 (NEWS2) (cont.)
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 in the appropriate eCRF.
Example Case Calculation:
An 82-year-old lady 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 min)
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.
56/Statistical Analysis Plan WA42380
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% 
confidence interval 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.
57/Statistical Analysis Plan WA42380
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

