Clinical trial NCT04372186
Conditions: COVID-19 Pneumonia
Sponsor: Genentech, Inc.
Start date: 2020-05-14; Completion date: 2020-09-22
Enrollment: 377 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study (EMPACTA) will a) evaluate the efficacy and safety of tocilizumab (TCZ) compared with a placebo in combination with standard of care (SOC) in hospitalized participants with COVID-19 pneumonia, and b) include an optional long-term extension for eligible participants to explore the long-term sequelae of resolved COVID-19 pneumonia.

Detailed description:

Arms: arm 1: Participants will receive one intravenous (IV) infusion of placebo, in addition to SOC. Up to one additional infusion may be given. arm 2: Participants will receive one IV infusion of TCZ in addition to SOC. Up to one additional infusion may be given.
Interventions: intervention 1: Placebo intervention 2: Tocilizumab
Intervention descriptions: intervention 1: Participants will receive one dose of IV placebo matched to TCZ. Up to one additional dose may be given. intervention 2: Participants will receive one IV infusion of TCZ 8 mg/kg, with a maximum dose of 800 mg. Up to one additional dose may be given.

Protocol documents:
Prot_000.pdf: 
Clinical Study Report: tocilizumab - Genentech, Inc.
Protocol ML42528     Report Number 1104869
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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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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—Genentech, Inc.
Protocol ML42528, Version 3
PROTOCOL
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
TOCILIZUMAB IN HOSPITALIZED PATIENTS WITH 
COVID-19 PNEUMONIA
PROTOCOL NUMBER:
ML42528
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001154-22
IND NUMBER:
148225
NCT NUMBER:
NCT04372186
TEST PRODUCT:
Tocilizumab (RO4877533)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
See electronic date stamp below
 
15-Aug-2020 00:02:50
Title
Approver's Name
Date and Time (UTC)


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PROTOCOL HISTORY
Protocol
Version
Date Final
1
29 April 2020
2
02 June 2020


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PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol ML42528 has been amended to add an optional long-term follow-up substudy.  
There is limited evidence on the long-term effects of COVID-19 infection.  This is due to 
the recent onset of the pandemic and, therefore, there has not been an opportunity to 
study patients who have recovered from the infection.  Therefore, the purpose of this 
optional substudy will be to follow patients who participated in Study ML42528 or other 
Genentech/Roche sponsored study that evaluates patients with COVID-19 associated 
pneumonia (i.e., Studies WA42380 [COVACTA], WA42511 [REMDACTA], or CA42481 
[MARIPOSA]) for approximately 12 months after completing or discontinuing from one of 
these studies.  This is in order to understand the long-term sequelae of resolved 
COVID-19 associated pneumonia. Changes to the protocol are summarized below:

The Medical Monitor for the substudy and their contact information were added 
(Section 5.4.1).

An appendix was added that details the conduct and procedures for the substudy 
(Appendix 3).
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 .......................................................................................... 18
1.1
Background on COVID-19 Pneumonia.................................. 18
1.2
Background on Tocilizumab .................................................. 18
1.3
Tocilizumab Treatment in Cytokine-Release 
Syndrome of CAR-T therapy ................................................. 19
1.4
Real World Experience with Tocilizumab in 
COVID-19 Pneumonia........................................................... 20
1.5
Study Rationale and Benefit-Risk Assessment...................... 23
2.
OBJECTIVES AND ENDPOINTS ............................................................... 23
2.1
Efficacy Objectives ................................................................ 23
2.1.1
Primary Efficacy Objective..................................................... 23
2.1.2
Secondary Efficacy Objectives .............................................. 23
2.1.3
Exploratory Efficacy Objectives ............................................. 24
2.2
Safety Objective .................................................................... 24
3.
STUDY DESIGN......................................................................................... 24
3.1
Description of the Study......................................................... 24
3.2
End of Study and Length of Study......................................... 26
3.3
Rationale for Study Design.................................................... 26
3.3.1
Rationale for Tocilizumab Dose and Schedule...................... 26
3.3.2
Rationale for Patient Population ............................................ 27
3.3.3
Rationale for Control Group................................................... 27
4.
MATERIALS AND METHODS .................................................................... 28
4.1
Patients.................................................................................. 28
4.1.1
Inclusion Criteria.................................................................... 28
4.1.2
Exclusion Criteria................................................................... 29
4.2
Method of Treatment Assignment and Blinding..................... 30
4.2.1
Treatment Assignment........................................................... 30
4.2.2
Blinding.................................................................................. 30


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4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 31
4.3.1
Study Treatment Formulation and Packaging........................ 31
4.3.1.1
Tocilizumab and Placebo....................................................... 31
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 31
4.3.2.1
Tocilizumab and Placebo....................................................... 31
4.3.3
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 32
4.3.4
Continued Access to Tocilizumab.......................................... 33
4.4
Concomitant Therapy ............................................................ 33
4.4.1
Permitted Therapy................................................................. 33
4.4.2
Cautionary Therapy ............................................................... 34
4.4.2.1
Medications Given with Precaution due to Effects 
Related to CYP Enzymes ...................................................... 34
4.4.2.2
Herbal Therapies................................................................... 34
4.4.3
Prohibited Therapy ................................................................ 34
4.5
Study Assessments ............................................................... 35
4.5.1
Informed Consent Forms and Screening Log........................ 35
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 36
4.5.3
Physical Examinations........................................................... 36
4.5.4
Vital Signs and Oxygen Saturation........................................ 36
4.5.5
Ventilation Requirement ........................................................ 37
4.5.6
Laboratory and Other Biological Samples ............................. 37
4.5.7
Liver Function Monitoring ...................................................... 37
4.5.8
Chest X-Rays and CT Scans................................................. 37
4.5.9
Electrocardiograms................................................................ 38
4.5.10
Ordinal Scale Determination.................................................. 38
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 39
4.6.1
Study Treatment Discontinuation........................................... 39
4.6.2
Patient Discontinuation from the Study.................................. 39
4.6.3
Study Discontinuation............................................................ 40
4.6.4
Site Discontinuation............................................................... 40


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5.
ASSESSMENT OF SAFETY....................................................................... 40
5.1
Safety Plan ............................................................................ 40
5.1.1
Risks Associated with Tocilizumab........................................ 41
5.1.1.1
Hypersensitivity Reactions, Including 
Anaphylaxis ........................................................................... 41
5.1.1.2
Serious Infections and Opportunistic Infections..................... 41
5.1.1.3
Gastrointestinal Perforations ................................................. 42
5.1.1.4
Hematologic Abnormalities.................................................... 42
5.1.1.5
Demyelinating Disorders........................................................ 42
5.1.1.6
Elevated Liver Enzymes ........................................................ 42
5.1.1.7
CYP450 Enzyme Normalization ............................................ 43
5.2
Safety Parameters and Definitions ........................................ 43
5.2.1
Adverse Events ..................................................................... 43
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 44
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 44
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 45
5.3.1
Adverse Event Reporting Period ........................................... 45
5.3.2
Eliciting Adverse Event Information....................................... 46
5.3.3
Assessment of Severity of Adverse Events ........................... 46
5.3.4
Assessment of Causality of Adverse Events ......................... 46
5.3.5
Procedures for Recording Adverse Events............................ 47
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 47
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 48
5.3.5.3
Persistent or Recurrent Adverse Events................................ 48
5.3.5.4
Abnormal Laboratory Values ................................................. 48
5.3.5.5
Abnormal Vital Sign Values ................................................... 49
5.3.5.6
Abnormal Liver Function Tests.............................................. 50
5.3.5.7
Deaths ................................................................................... 50
5.3.5.8
Preexisting Medical Conditions.............................................. 51
5.3.5.9
Lack of Efficacy or Worsening of COVID-19 
Pneumonia ............................................................................ 51


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5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 51
5.3.5.11
Cases of Accidental Overdose or Medication 
Error....................................................................................... 52
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 53
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 53
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 54
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 54
5.4.2.2
Events That Occur after Study Drug Initiation........................ 54
5.4.3
Reporting Requirements for Pregnancies.............................. 54
5.4.3.1
Pregnancies in Female Patients............................................ 54
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 55
5.4.3.3
Abortions ............................................................................... 55
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 55
5.5
Follow-Up of Patients after Adverse Events .......................... 56
5.5.1
Investigator Follow-Up........................................................... 56
5.5.2
Sponsor Follow-Up ................................................................ 56
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 56
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 56
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 57
6.1
Determination of Sample Size ............................................... 57
6.2
Summaries of Conduct of Study............................................ 58
6.3
Treatment Group Comparability ............................................ 58
6.4
Efficacy Analyses .................................................................. 58
6.4.1
Primary Efficacy Endpoint...................................................... 58
6.4.2
Secondary Efficacy Endpoints............................................... 59
6.4.3
Exploratory Efficacy Endpoints.............................................. 60
6.5
Interim Analyses .................................................................... 60
6.6
Safety Analyses..................................................................... 60


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7.
DATA COLLECTION AND MANAGEMENT ............................................... 61
7.1
Data Quality Assurance......................................................... 61
7.2
Electronic Case Report Forms............................................... 61
7.3
Source Data Documentation.................................................. 61
7.4
Use of Computerized Systems .............................................. 62
7.5
Retention of Records............................................................. 62
8.
ETHICAL CONSIDERATIONS.................................................................... 63
8.1
Compliance with Laws and Regulations ................................ 63
8.2
Informed Consent.................................................................. 63
8.3
Institutional Review Board or Ethics Committee.................... 64
8.4
Confidentiality........................................................................ 65
8.5
Financial Disclosure .............................................................. 65
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 66
9.1
Study Documentation ............................................................ 66
9.2
Protocol Deviations................................................................ 66
9.3
Management of Study Quality ............................................... 66
9.4
Site Inspections ..................................................................... 66
9.5
Administrative Structure......................................................... 66
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 67
9.7
Protocol Amendments ........................................................... 68
10. REFERENCES ........................................................................................... 69
LIST OF TABLES
Table 1
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 46
Table 2
Causal Attribution Guidance ....................................................... 47
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 26


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LIST OF APPENDICES
Appendix 1
Schedule of Activities:  Days 1 and 2......................................... 71
Appendix 2
Schedule of Activities:  Day 3Study Completion ...................... 74
Appendix 3
Long-Term, Follow-Up Substudy of Patients with COVID-19 
Associated Pneumonia Who Participated in a 
Genentech/Roche Sponsored Study That Evaluates Patients 
with COVID-19 Associated Pneumonia ...................................... 76


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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 HOSPITALIZED PATIENTS WITH 
COVID-19 PNEUMONIA
PROTOCOL NUMBER:
ML42528
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001154-22
IND NUMBER:
148225
NCT NUMBER:
NCT04372186
TEST PRODUCT:
Tocilizumab (RO4877533)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
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.


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PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF TOCILIZUMAB IN HOSPITALIZED PATIENTS WITH 
COVID-19 PNEUMONIA
PROTOCOL NUMBER:
ML42528
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001154-22
IND NUMBER:
148225
NCT NUMBER:
NCT04372186
TEST PRODUCT:
Tocilizumab (RO4877533)
PHASE:
Phase III
INDICATION:
COVID-19 pneumonia
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the efficacy and safety of tocilizumab (TCZ) compared with a placebo in 
combination with SOC in hospitalized patients with COVID-19 pneumonia.  To enhance the 
understanding of the clinical profile of tocilizumab for patients who belong to high-risk and 
minority populations, an emphasis will be placed on including minority-enrolling sites.  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 standard of care (SOC) for the treatment of COVID-19 pneumonia 
on the basis of the following endpoint:

Cumulative proportion of patients with death or requiring mechanical ventilation by 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 COVID-19 pneumonia on the basis of the 
following endpoints:

Time to improvement of at least 2 categories relative to baseline on a 7-category ordinal 
scale of clinical status 

Time to clinical failure, defined as the time to death, mechanical ventilation, intensive care 
unit (ICU) admission, or withdrawal (whichever occurs first)

Mortality rate by Day 28

Time to hospital discharge or “ready for discharge” (e.g., awaiting social disposition) as 
evidenced by, for example, normal body temperature and respiratory rate, and stable 
oxygen saturation on ambient air or 2L supplemental oxygen


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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 COVID-19 pneumonia on the basis of the 
following endpoints:

Change from baseline in inflammatory markers levels (high sensitivity C-reactive protein
[hs-CRP]/C-reactive protein [CRP], D-dimer, and ferritin) over time

Cumulative proportion of patients requiring CPAP or BIPAP by 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 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

Incidence of any post-treatment bacterial and/or fungal infection

Incidence of any post-treatment acute kidney injury (defined by 50% increase of creatinine 
from baseline)
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 placebo in combination 
with SOC in hospitalized adult patients with COVID-19.  The Sponsor intends to enroll 
approximately 379 patients that have been diagnosed with COVID-19 pneumonia and meet the 
entry criteria.  
Patients must be at least 18 years of age with confirmed SARS-CoV-2 (COVID-19) infection per 
World Health Organization (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 SpO2 94% on ambient air and be on SOC, which may include 
anti-viral treatment, low dose systemic corticosteroids, 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 and well-controlled HIV) will be excluded from the study.  
Patients will be screened and randomized within 96 hours of hospital admission.  Patients will 
be randomized at a 2:1 ratio to receive blinded treatment of either TCZ or placebo, respectively.  
Study treatment must be given within approximately 4 hours after randomization.  TCZ and 
placebo will be given in combination with SOC.
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.  
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.  Note:  Pre-dose assessments must be repeated and reviewed before an additional 
infusion of blinded treatment of TCZ or placebo is administered.
Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity within 96 hours of hospital admission (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.  
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, and clinical laboratory tests.  


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Patients will be followed up for a total of 60 days after first dose of study medication.  
If patients are discharged from the hospital prior to Day 28 or discontinue the study, the Study 
Completion/Discontinuation assessments are to be conducted prior to discharge or at 
discontinuation from the study.  In addition, if patients are discharged from the hospital prior to 
Day 28, follow-up visits should occur weekly, or more often if clinically relevant, through Day 28 
to assess mortality and adverse events.  Follow-up visits may be conducted by onsite clinic 
visits, telephone calls, or home visits.  After Day 28, all patients should have a follow-up visit on 
approximately Day 60 which may be conducted as an onsite clinic visit, telephone call, or home 
visit for discharged patients.
During the study, standard supportive care will be given according to clinical practice.  After 
study completion, patients should be referred to their regular healthcare provider based on their 
doctor’s decision and as part of standard of care.
Number of Patients
This study aims to enroll approximately 379 hospitalized patients with COVID-19 pneumonia.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Documented informed consent 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 providing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Hospitalized 

COVID-19 pneumonia confirmed per a positive PCR of any specimen (e.g., respiratory, 
blood, urine, stool, other bodily fluid) and radiographic imaging (CT scan or chest X-ray) 

Able to complete screening within 96 hours of hospital admission

Blood oxygen saturation (SpO2) 94% while on ambient air
If a patient is on supplemental oxygen with SpO2 94%, but desaturation to 94% 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).  
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:


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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

Require CPAP, BIPAP, or mechanical ventilation

Active TB infection or last TB infection within 1 month of randomization

Suspected active bacterial, fungal, viral, or other infection (besides COVID-19 and 
well-controlled HIV) 

In the opinion of the investigator, progression to death is imminent and inevitable within the 
next 24 hours, irrespective of the provision of treatments

Immunocompromised (besides well-controlled HIV) or on immunosuppressive therapy 
(except for steroids for COVID), advanced cancer

Have received oral anti-rejection or immunomodulatory drugs (including TCZ) within the 
past 3 months

Participating in another IL-6 antagonist clinical trial or other drug clinical trials (participation 
in COVID-19 anti-viral trials may be permitted if approved by Medical Monitor)

ALT or AST 5 x upper limit of normal (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 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

Any history of diverticulitis or gastrointestinal perforation 
The use of remdesivir, hydroxychloroquine, chloroquine, and convalescent plasma, is not an 
exclusion to participation in this trial, and is left to the discretion of the primary medical team. 
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 8 months.


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Investigational Medicinal Products
Test Product (Investigational Drug)
Patients assigned to the active arm will receive one or two doses of tocilizumab (TCZ) via 
intravenous (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 infusion.
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:

Cumulative proportion of patients with death or requiring mechanical ventilation by Day 28
Time to death or the first utilization of mechanical ventilation after randomization will be 
compared between the TCZ group and the placebo group using the stratified log-rank test with 
age group (age 60, age 60 years) as the stratification factor.  The cumulative proportion of 
patients with death or requiring mechanical ventilation at Day 28 will be estimated using the 
Kaplan-Meier method.  
Details of the primary endpoint analysis will be included in the Statistical Analysis Plan (SAP).
Determination of Sample Size  
The estimated sample size was determined based on the time from randomization to the first 
utilization of mechanical ventilation by Day 28. 
The total modified intent-to-treat (mITT) sample size of 379 patients with a 2:1 randomization of 
TCZ (n253) to placebo (n126) provides approximately 80% power using a Logrank test to 
detect a 15% difference between treatment groups in time to death or mechanical ventilation by 
Day 28 under the following assumptions:  cumulative survival (i.e., alive and not requiring 
mechanical ventilation) rates of 75% in the TCZ group and 60% in placebo group, with 28-day 
follow-up, using a two-sided 5% alpha, and 10% dropout rate in each arm.  Sample size 
re-estimation may be considered during the study based on updated assumptions of the 
treatment effect.
Planned Interim Analyses
An Internal Monitoring Committee (IMC) will evaluate safety according to procedures and 
guidelines detailed in the IMC agreement.  The IMC will consist of Sponsor representatives who 
will not be blinded to study data.  Details of the safety reviews will be provided in the SAP.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ARDS
acute respiratory distress syndrome
BIPAP
bilevel positive airway pressure
CAR
chimeric antigen receptor
CDC
Centers for Disease Control
CoV
coronaviruses
CPAP
continuous positive airway pressure
CRP
C-reactive protein
CRS
cytokine-release syndrome
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP450
cytochrome P450
EC
Ethics Committee
eCRF
electronic Case Report Form
ECMO
extracorporeal membrane oxygenation
EDC
electronic data capture
FDA
Food and Drug Administration
FiO2
fraction of inspired oxygen
GCA
giant cell arteritis
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
hs-CRP
high sensitivity C-reactive protein
ICH
International Council for Harmonisation
ICU
intensive care unit
IL-6
interleukin 6
IL-6R
interleukin-6 receptor
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LPLV
last patient, last visit
IV
intravenous
MERS-CoV
Middle East respiratory syndrome
MOD
multiple organ dysfunction
MOF
multi-organ failure
mITT
modified intent-to-treat


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Abbreviation
Definition
NCI
National Cancer Institute
PaO2
partial pressure of oxygen
PCR
polymerase chain reaction
PCT
procalcitonin
pJIA
polyarticular juvenile idiopathic arthritis
PK
pharmacokinetic
PY
patient years
RA
rheumatoid arthritis
RT-PCR
real time polymerase chain reaction
SAP
Statistical Analysis Plan
SARS-CoV
severe acute respiratory syndrome
SC
subcutaneous
sJIA
systemic juvenile idiopathic arthritis
sIL-6R
soluble IL-6R
SOC
standard of care
SpO2
blood oxygen saturation
SSc
systemic sclerosis
TAK
Takayasu arteritis
TB
tuberculosis
TCZ
tocilizumab
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).
Cohort studies of ethnically homogeneous patients in China indicate that male gender, 
and comorbidities such as diabetes, hypertension, and cardiovascular disease 
predispose to increased risk of infection and morbidity (Li et al. 2020). The U.S. Centers 
for Disease Control (CDC) published hospitalization rates and characteristics of patients 
with COVID-19 suggest minority patients may be disproportionately affected by 
COVID-19, potentially due to increased frequency of underlying conditions (Garg 2020).
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 


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metabolism; lipid metabolism; hepatoprotection; and fibrosis.  Elevated tissue and serum 
levels of IL-6 have been implicated in the disease pathology of several inflammatory and 
autoimmune disorders including rheumatoid arthritis (RA), Castleman disease, systemic 
juvenile idiopathic arthritis (sJIA), polyarticular juvenile idiopathic arthritis (pJIA), giant 
cell arteritis (GCA), Takayasu arteritis (TAK), systemic sclerosis (SSc), and 
cytokine-release syndrome (CRS). Inhibition of the biological activity of IL-6 or IL-6R 
has been effective in the treatment of these disorders, including chimeric antigen 
receptor (CAR) T-cell induced CRS, for which treatment with TCZ has been approved in 
many countries. 
TCZ has intravenous (IV) and subcutaneous (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.  
 
 
 
 
 
 
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 30 kg 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.  


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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 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 (Submitted, 
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) and case reports of individual patients include the limited
available published clinical data the Sponsor is aware of regarding the use of TCZ in the 
treatment of COVID-19 pneumonia.  


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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).  
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 


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(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 (Submitted, Xu et al. 2020). 
Results from Individual Case Reports
Michot et al. (2020) reported a 42-year-old with history of renal cell carcinoma 
hospitalized for COVID-19 pneumonia and treated with 5 days of lopinavir-ritonavir 
treated and 2 doses of tocilizumab (8 mg/kg IV) following rapid respiratory 
decompensation. The patient experienced clinical improvement with discontinuation of 
supplemental oxygen 4 days later and fully recovered. No adverse drug reactions were 
reported.  
Ferrey et al. (2020) reported a 56-year-old with end stage renal disease hospitalized for 
bilateral interstitial pneumonia secondary to COVID-19 who developed acute respiratory 
distress syndrome. The patient was treated with hydroxychloroquine, tocilizumab, and 
broad spectrum antibiotics along with supportive care. At the time of publication, the 
patient remained in critical condition without report of adverse drug reactions. 
Cellina et al. (2020) reported a 64 year old male with confirmed COVID-19 infection and 
dyspnea who had favorable changes in computed tomography (CT) results following 
2 doses of tocilizumab (8 mg/kg) 12 hours apart. The patient’s clinical condition 
improved and was able to be weaned off the ventilator. No adverse drug reactions were 
reported.
Results from Patients in Special Populations
De Luna et al. (2020) reported a 45-year-old male with sickle cell disease who 
developed rapid and severe COVID-19 pneumonia. He was treated with 
amoxicillin-clavulanic acid and hydroxychloroquine but clinical condition continued to 
deteriorate with increased oxygen requirement. He was treated with 1 dose of 
tocilizumab (8 mg/kg) and was reported to have clear improvement in general condition. 
The patient was discharged 2 days later. No adverse drug reactions were reported. 
Zhang et al. (2020) reported a 60-year-old male with multiple myeloma in Wuhan, China 
who developed shortness of breath and was started on methylprednisolone. CT chest
was positive for ground glass opacities and RT-PCR confirmed COVID-19 infection.  He 
was treated with umifenovir without clinical improvement. Clinical improvement noted 


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following 1 dose of tocilizumab (8 mg/kg) with gradual decline in IL-6. The patient was 
later discharged from the hospital. No adverse drug reactions were reported.
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) 
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 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 and safety of TCZ compared with a placebo in 
combination with SOC in hospitalized patients with COVID-19 pneumonia. To enhance 
the understanding of the clinical profile of tocilizumab for patients who belong to high-risk 
and minority populations, an emphasis will be placed on including minority-enrolling sites.
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 COVID-19 pneumonia on the 
basis of the following endpoint:

Cumulative proportion of patients with death or requiring mechanical ventilation by
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 COVID-19 
pneumonia on the basis of the following endpoints:

Time to improvement of at least 2 categories relative to baseline on a 7-category 
ordinal scale of clinical status 

Time to clinical failure, defined as the time to death, mechanical ventilation, ICU 
admission, or withdrawal (whichever occurs first)

Mortality rate by Day 28

Time to hospital discharge or “ready for discharge” (e.g., awaiting social disposition)
as evidenced by, for example, normal body temperature and respiratory rate, and 
stable oxygen saturation on ambient air or 2L supplemental oxygen


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2.1.3
Exploratory Efficacy Objectives
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 COVID-19 
pneumonia on the basis of the following endpoints:

Change from baseline in inflammatory markers levels (hs-CRP/CRP, D-dimer, and 
ferritin) over time

Cumulative proportion of patients requiring CPAP or BIPAP by 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 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

Incidence of any post-treatment bacterial and/or fungal infection

Incidence of any post-treatment acute kidney injury (defined by 50% increase of 
creatinine from baseline)
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 placebo 
in combination with SOC in hospitalized adult patients with COVID-19.  The Sponsor 
intends to enroll approximately 379 patients that have been diagnosed with COVID-19 
pneumonia and meet the entry criteria.  
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 94% on ambient air and be on SOC, which may include anti-viral treatment, low 
dose systemic corticosteroids, 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 and 
well-controlled HIV) will be excluded from the study.  
Patients will be screened and randomized within 96 hours of hospital admission.  
Patients will be randomized at a 2:1 ratio to receive blinded treatment of either TCZ or 


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placebo, respectively. Study treatment must be given within approximately 4 hours after
randomization.  TCZ and placebo will be given in combination with SOC.
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.  
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.  Note:  Pre-dose assessments must be repeated and reviewed 
before an additional infusion of blinded treatment of TCZ or placebo is administered.
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity within 96 hours of hospital admission (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, and clinical laboratory tests. 
Please see Appendix 1 and Appendix 2 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 the hospital prior to Day 28 or discontinue the study, the 
Study Completion/Discontinuation assessments are to be conducted prior to discharge
or at discontinuation from the study.  In addition, if patients are discharged from the 
hospital prior to Day 28, follow-up visits should occur weekly, or more often if clinically 
relevant, through Day 28 to assess mortality and adverse events.  Follow-up visits may 
be conducted by onsite clinic visits, telephone calls, or home visits.  After Day 28, all 
patients should have a follow-up visit on approximately Day 60 which may be conducted 
as an onsite clinic visit, telephone call, or home visit for discharged patients.
During the study, standard supportive care will be given according to clinical practice. 
After study completion, patients should be referred to their regular healthcare provider 
based on their doctor’s decision and as part of standard of care.
Figure 1 presents an overview of the study design.  Schedules of activities are provided 
in Appendix 1 and Appendix 2.




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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 hospitalized high-risk and/or minority patient 
populations with COVID-19 pneumonia, 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 placebo in 
combination with SOC. Despite the lack of targeted treatments for COVID-19, SOC for 
patients with COVID-19 pneumonia generally includes supportive care and may include 
available anti-viral agents and low-dose systemic corticosteroids as dictated by local 
treatment guidelines. Therefore, SOC plus placebo treatment is appropriate as a control
in this study. 


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4.
MATERIALS AND METHODS
4.1
PATIENTS
This study aims to enroll approximately 379 hospitalized patients with COVID-19
pneumonia.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Documented informed consent 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 providing informed consent

Ability to comply with the study protocol, in the investigator's judgment

Hospitalized 

COVID-19 pneumonia confirmed per a positive PCR of any specimen
(e.g., respiratory, blood, urine, stool, other bodily fluid) and radiographic imaging 
(CT scan or chest X-ray)

Able to complete screening within 96 hours of hospital admission

SpO2 94% while on ambient air
If a patient is on supplemental oxygen with SpO2 94%, but desaturation to 94%
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).  
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.  


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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

Require CPAP, BIPAP, or mechanical ventilation

Active TB infection or last TB infection within 1 month of randomization

Suspected active bacterial, fungal, viral, or other infection (besides COVID-19 and 
well-controlled HIV) 

In the opinion of the investigator, progression to death is imminent and inevitable 
within the next 24 hours, irrespective of the provision of treatments

Immunocompromised (besides well-controlled HIV) or on immunosuppressive 
therapy (except for steroids for COVID), advanced cancer

Have received oral anti-rejection or immunomodulatory drugs (including TCZ) within
the past 3 months

Participating in another IL-6 antagonist clinical trial or other drug clinical trials 
(participation in COVID-19 anti-viral trials may be permitted if approved by Medical 
Monitor)

ALT or AST 5 x upper limit of normal (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


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
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

Any history of diverticulitis or GI perforation 
The use of remdesivir, hydroxychloroquine, chloroquine, and convalescent plasma, is 
not an exclusion to participation in this trial, and is left to the discretion of the primary 
medical team. 
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 age 
(i.e., 60 and 60 years of age).  
4.2.2
Blinding
Study site personnel and patients will be blinded to treatment assignment during the 
study, with the exception of the study pharmacist.  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 and 
members of the internal Monitoring Committee (IMC). These roles include the 
unblinding group responsible, clinical supply chain managers, sample handling staff,
operational assay group personnel, IxRS service provider, and IMC members.
Genentech monitors, project statisticians, and the project team will be blinded from study
results, with the exception of the IMC members. 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 
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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 
placebo as the comparator. 
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
Tocilizumab and Placebo
TCZ will be supplied by the Sponsor as a sterile IV injection for reconstitution in 20-mL 
glass vials with a 10 mL fill (200 mg/10 mL of TCZ) or with a 20 mL fill (400 mg / 20 mL 
of TCZ).  An appropriate number of vials (depending on the patient’s body weight) of 
TCZ will be assigned to each patient for the infusion.  The amount of solution that is 
withdrawn from each vial will depend on the patient’s allocated dose.  For information on 
the formulation and handling of TCZ, see the TCZ pharmacy manual and Tocilizumab 
Investigator's Brochure.
Placebo will be supplied by the investigative site in the form of a 0.9% sodium chloride 
(normal saline) bag. Placebo is not supplied by the Sponsor; please refer to the 
pharmacy manual for instructions on the preparation of the placebo.
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.
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. 


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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/placebo 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.
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 


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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 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 systemic 
corticosteroids, and supportive care.
Chloroquine or hydroxychloroquine 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 
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 


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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

Open-label tocilizumab

Bone marrow transplantation with total lymphoid irradiation during the study

Plasmapheresis or extracorporeal photopheresis during the study

Immunization with a live or attenuated vaccine for the duration of the patient’s study 
participation.


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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 safety) must be taken within 4 hours prior to 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 and Appendix 2.
If patients are discharged from the hospital prior to Day 28 or discontinue the study, the 
Study Completion/Discontinuation assessments are to be conducted prior to discharge
or at discontinuation from the study.  In addition, if patients are discharged from the 
hospital prior to Day 28, follow-up visits should occur weekly, or more often if clinically 
relevant, through Day 28 to assess mortality and adverse events.  Follow-up visits may 
be conducted by onsite clinic visits, telephone calls, or home visits.  After Day 28, all 
patients should have a follow-up visit on approximately Day 60 which may be conducted 
as an onsite clinic visit, telephone call, or home visit for discharged patients.
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.  Physical examination, blood tests, and other 
assessments conducted after arrival at the hospital, but before the informed consent is 
signed, can be used as screening assessments. 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, self-reported race/ethnicity, smoking history, 
and patient characteristics.
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,
respiratory, gastrointestinal, and neurologic systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
electronic Case Report Form (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 screening (see Appendix 1). If it is 
not feasible to weigh bed-bound patients, historical body weight may be used.
Physical examination, blood tests, and other assessments conducted after arrival at the 
hospital, but before the informed consent is signed, can be used as screening 
assessments.  
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 FiO2 should be recorded. 
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.


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4.5.5
Ventilation Requirement
Assessment of ventilation usage (non-invasive or mechanical) should be recorded once 
daily with ordinal scale determination based upon the following categories:

No supplemental oxygen 

Supplemental oxygen (nasal cannula, face mask)

Non-invasive ventilation or high-flow oxygen (high-flow nasal cannula, CPAP, BiPAP)

Intubation and mechanical ventilation 
4.5.6
Laboratory 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)

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 bilirubin, ALP, ALT, AST

hs-CRP/CRP, D-dimer (if available locally), 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 or other 
respiratory specimen, blood, urine, stool, other bodily fluid
4.5.7
Liver Function Monitoring
Patients should be assessed for liver function prior to each dose of TCZ or 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 Scans
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.


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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.  
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 approximately 
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 extracorporeal membrane oxygenation (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. 
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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. 
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


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
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.
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 


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nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events and laboratory abnormalities, including criteria for 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.  
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 
hs-CRP/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 


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neutropenic patients (ANC 1000/L) undergo weekly surveillance blood cultures during 
the study.
If a patient develops a serious infection, administration of TCZ should be discontinued.
5.1.1.3
Gastrointestinal Perforations
Symptomatic diverticulosis, diverticulitis, or chronic ulcerative lower GI disease, such as 
Crohn disease, ulcerative colitis, or other chronic lower GI conditions, might predispose 
patients to GI perforations. Timely diagnosis and appropriate treatment may reduce the 
potential for complications of diverticular disease and thus reduce the risk of GI 
perforations.  
Discontinuation of TCZ is required for patients who develop GI perforations.
5.1.1.4
Hematologic Abnormalities
Decreases in neutrophil counts, platelet counts, and fibrinogen levels have been 
observed following treatment with TCZ for 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.


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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.
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 
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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)

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


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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

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.


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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.
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"


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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
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 


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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.

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


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
Results in a change in study treatment (e.g., 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.
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., 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.


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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
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.


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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").
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


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




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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 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
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
60 days after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).


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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.
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.


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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.
An IMC 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 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.
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 based on the time from randomization to the 
first utilization of mechanical ventilation by Day 28. 
The total mITT sample size of 379 patients with a 2:1 randomization of TCZ (n253) to 
placebo (n126) provides approximately 80% power using a Logrank test to detect a 15% 
difference between treatment groups in time to death or mechanical ventilation by Day 
28 under the following assumptions:  cumulative survival (i.e., alive and not requiring 
mechanical ventilation) rates of 75% in the TCZ group and 60% in placebo group, with 
28-day follow-up, using a two-sided 5% alpha, and 10% dropout rate in each arm.


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Sample size re-estimation may be considered during the study based on updated 
assumptions of the treatment effect.
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. 
Eligibility criteria and other major protocol deviations will be listed and summarized by 
treatment group.
6.3
TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics 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.
Descriptive subgroup analyses to evaluate the consistency of results across
pre-specified subgroups may also be conducted.  
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:

Cumulative proportion of patients with death or requiring mechanical ventilation by 
Day 28
Time to death or the first utilization of mechanical ventilation after randomization will be 
compared between the TCZ group and the placebo group using the stratified log-rank 
test with age group (age 60, age 60 years) as the stratification factor.  The cumulative 
proportion of patients with death or requiring mechanical ventilation at Day 28 will be 
estimated using the Kaplan-Meier method. 


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Details of the primary endpoint analysis will be included 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.  The Kaplan-Meier plot, median time to 
response, and their 95% CIs, and a p-value will be presented. 

Time to improvement in ordinal clinical status
Defined as time from randomization to the time when at least a 2-category 
improvement in the 7-category ordinal scale is observed. Assessment of patient 
status using an ordinal scale will be recorded at baseline and once daily in the 
morning (between approximately 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

Time to clinical failure 
Defined as the time to first occurrence on study of death, mechanical ventilation,
ICU admission, or withdrawal, whichever occurs first.

Mortality rate at Day 28
Difference in mortality rate at Day 28 will be compared using the 
Cochran-Mantel-Haenszel test statistic stratified by age group (age 60, age 
60 years).  The difference in proportions and its 95% CI for the treatment group 
comparison will be presented.

Time to hospital discharge or “ready for discharge” 
“Ready for discharge” defined as normal body temperature and respiratory rate, 
and stable oxygen saturation on ambient air or 2L supplemental oxygen.
Comparison of clinical status according to the 7-category ordinal scale may also be 
analyzed using a proportional odds model at Day 28.


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6.4.3
Exploratory Efficacy Endpoints
Inflammatory markers, hs-CRP/CRP, D-dimer, and ferritin, will be summarized 
descriptively using means, standard deviations, medians, and ranges.  Absolute value 
and change from baseline will be provided over time by treatment group.
The time to first requiring CPAP or BIPAP after randomization will be analyzed by the 
Kaplan Meier analysis, with the cumulative proportion of patients requiring CPAP or 
BIPAP estimated at Day 28.
Additional exploratory efficacy endpoints may be explored and details will be provided in 
the SAP.
6.5
INTERIM ANALYSES
An IMC will evaluate safety according to procedures and guidelines detailed in the IMC 
agreement. The IMC will consist of Sponsor representatives who will not be blinded to 
study data. Details of the safety reviews will be provided in the SAP.
6.6
SAFETY ANALYSES
Safety assessments will be performed on the safety evaluable population, which 
consists of all patients who receive any amount of study 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
The proportion of patients with any post-treatment bacterial and/or fungal infection and 
acute kidney injury will be summarized, respectively.
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 
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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.
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.  
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
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.


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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.
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.


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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. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies
conducted in the European Union or European Economic Area will comply with the E.U.
Clinical Trial Directive (2001/20/EC) and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative or where allowed, 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.


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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 
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 


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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).
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).


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
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 Genentech, Inc.  The Sponsor will provide 
clinical operations management, data management, and medical monitoring.


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Approximately 40 sites will participate to enroll approximately 379 patients.  Enrollment 
will occur through an IxRS.  Target enrollment may be changed if a sample size 
re-estimation is performed (see Section 6.1).
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected either from local laboratories or from The Roche Integrated Global 
Textbook Ranges, as appropriate.
An IMC 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 
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 


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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
Cellina M, Orsi M, Bombaci F, et al. Favorable changes of CT findings in a patient with 
COVID-19 pneumonia after treatment with tocilizumab. Diagnostic and 
Interventional Imaging. 2020 Mar 31. 
De Luna G, Habibi A, Deux JF, Colard M, d'Alexandry DO, Schlemmer F, Joher N, 
Kassasseya C, Pawlotsky JM, Ourghanlian C, Michel M. Rapid and Severe 
COVID-19 Pneumonia with Severe Acute Chest Syndrome in a Sickle Cell Patient 
Successfully Treated with Tocilizumab. Am J Hematol. 2020 Apr 13.
Ferrey AJ, Choi G, Hanna RM, et al. A Case of Novel Coronavirus Disease 19 in a 
Chronic Hemodialysis Patient Presenting with Gastroenteritis and Developing 
Severe Pulmonary Disease. Am J Nephrol. 2020:16.
Garg S. Hospitalization rates and characteristics of patients hospitalized with 
laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 states, 
March-1-30, 2020. MMWR. Morbidity and Mortality Weekly Report. 2020;69.
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. [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.
Li B, Yang J, Zhao F, et al. Prevalence and impact of cardiovascular metabolic diseases 
on COVID-19 in China. Clin Res Cardiol. 2020:18.
Michot JM, Albiges L, Chaput N, et al. Tocilizumab, an anti-IL6 receptor antibody, to 
treat COVID-19-related respiratory failure: a case report. Ann Oncol. 2020 Apr 2.
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. 
[WHO] World Health Organization. Coronavirus disease (COVID-19) situation reports 
[Resource on the internet]. 2020a [updated 12 April 2020a; cited 12 April 2020]. 
Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-
2019/situation-reports


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[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 2020b; 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. 
Xu X, Han M, Li, T, et al. Effective treatment of severe COVID-19 patients with 
tocilizumab. ChinaXiv preprint. [Resource on the internet]. 2020 [updated 5 March 
2020;  cited 17 March 2020]. Available from:
http://www.chinaxiv.org/abs/202003.00026
Zhang X, Song K, Tong F, et al. First case of COVID-19 in a patient with multiple 
myeloma successfully treated with tocilizumab. Blood Adv. 2020;4(7):1307-10.


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


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Screening a, b
Baseline
Study Day
4 to 0
1
2
Time Post Initial Treatment
(Assessment Window)
0 min
Pre-dose
(approx. 4 hrs)
15 min
After end of infusion
(approx. 1 hr)
24 hrs
(12 hrs)
Chemistry d, n
x 
x
hs-CRP/CRP, D-dimer (if available via local laboratory), and ferritin d
x
Study drug administration o
x
ALPalkaline phosphatase; CRPC-reactive protein; CTcomputed tomography; ECGelectrocardiogram; eCRFelectronic case report form;
hr(s)hour(s); hs-CRPhigh sensitivity C-reactive protein; minminutes; NCI CTCAENational Cancer Institute Common Terminology Criteria for 
Adverse Events v.5.0; PaO2/FiO2arterial oxygen partial pressure/fraction of inspired oxygen; SpO2peripheral capillary oxygen saturation; 
TCZtocilizumab.
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  
a Results from standard-of-care tests or examinations performed prior to obtaining informed consent and within 96 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, respiratory, gastrointestinal, 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 Physical examination, blood tests, and other assessments conducted after arrival at the hospital, but before the informed consent is signed, can 
be used as screening assessments.
e COVID-19 test (SARS-CoV2 PCR) to confirm diagnosis should be performed at or before screening (if testing is conducted before screening, 
documentation must be available). 
f
Screening chest X-ray or CT scans should be performed within 96 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. 
g 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.


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h If arterial blood gases are measured.
i
All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body temperature) and oxygen 
saturation should be recorded together once daily while the patient remains hospitalized. If measured more than once daily, 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.  
j Assessment of clinical status using the ordinal scale, which includes change in ventilation usage (non-invasive or mechanical), should be 
recorded at baseline on Day 1 then again daily every morning (between approximately 8 am and 12 pm) for patients who remain hospitalized.
k 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).
l
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.
m Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).
n Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total bilirubin, ALP, ALT, and AST.
o The initial study drug infusion should be given within approximately 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.  Note:  Pre-dose assessments must be 
repeated and reviewed before an additional infusion of blinded treatment of TCZ or placebo is administered.


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Appendix 2
Schedule of Activities:  Day 3Study Completion
Days 328 a
Study 
Completion/ 
Discontinuation i
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 i
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
Concomitant medications f
x
Hematology g
x
x
Chemistry h
x
x
hs-CRP/CRP, D-dimer (if 
available via local 
laboratory), and ferritin
x
x
ALPalkaline phosphatase; CRPC-reactive protein; CTcomputed tomography; ECGelectrocardiogram; eCRFelectronic case report form; hs-
CRPhigh sensitivity C-reactive protein; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events v.5.0; 
PaO2/FiO2arterial oxygen partial pressure/fraction of inspired oxygen; SpO2peripheral capillary oxygen saturation.
a If patients are discharged from the hospital prior to Day 28, follow-up visits should occur weekly, or more often if clinically relevant, through 
Day 28 to assess mortality and adverse events. Follow-up visits may be conducted by onsite clinic visits, telephone calls, or home visits.  
b All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body temperature) and oxygen 
saturation should be recorded together once daily while the patient remains hospitalized.  If measured more than once daily, 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.  
c If arterial blood gases are measured.
d Assessment of clinical status using the ordinal scale should be recorded at baseline on Day 1 then again daily for patients who remain 
hospitalized.


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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).
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 bilirubin, ALP, ALT, and AST.
i
If patients are discharged from the hospital prior to Day 28 or discontinue the study, the Study Completion/Discontinuation assessments are to 
be conducted prior to discharge or at discontinuation from the study.  In addition, if patients are discharged from the hospital prior to Day 28,
follow-up visits should occur weekly, or more often if clinically relevant, through Day 28 to assess mortality and adverse events.  The Day 60 
follow up may be conducted by an onsite clinic visit, telephone call, or home visit for discharged patients.  Day 60 follow up is required to collect 
adverse events only.


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Appendix 3
Long-Term, Follow-Up Substudy of Patients with COVID-19 
Associated Pneumonia Who Participated in a Genentech/Roche 
Sponsored Study That Evaluates Patients with COVID-19 
Associated Pneumonia
RATIONALE FOR THE SUBSTUDY ............................................................. 78
OBJECTIVES AND ENDPOINTS .................................................................. 78
SUBSTUDY DESIGN ..................................................................................... 79
Description of the Substudy ..................................................................... 79
End of Substudy and Length of Substudy ................................................. 80
Rationale for Biomarker Assessments........................................................ 80
MATERIALS AND METHODS...................................................................... 80
Patients
............................................................................................ 80
Inclusion Criteria.................................................................................. 81
Exclusion Criteria ................................................................................. 81
Restrictions ............................................................................................ 81
Substudy Assessments.............................................................................. 81
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data....................................................... 81
Physical Examinations .......................................................................... 82
Vital Signs............................................................................................ 82
Pulmonary Function Testing................................................................. 82
In-Home Handheld Spirometry.............................................................. 83
HRCT Scan of the Chest........................................................................ 83
Echocardiogram..................................................................................... 83
Six-Minute Walk Test and Borg Scale (Optional) .................................. 84
Physical Activity and Sleep Pattern Monitoring (Optional) .................. 84
Laboratory, Biomarker, and Other Biological Samples............................ 84
Blood Samples for Genetic Analysis....................................................... 85
Clinical Outcome Assessments .............................................................. 86
Data Collection Methods for Clinical Outcome Assessments.................. 86
Collection of SF-36v2, EQ-5D-5L, and L-IPF-M .............................. 87
Collection of HCRU ......................................................................... 87


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Montreal Cognitive Assessment, 6-Minute Walk Test, 
and Borg Scale ................................................................................. 87
SAFETY PLAN ............................................................................................... 88
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 88
Determination of Sample Size................................................................... 88
Summaries of Conduct of Substudy .......................................................... 88
Summaries of Demographic and Baseline Characteristics .......................... 88
Outcome Analyses.................................................................................... 88
Endpoints ............................................................................................. 89
Safety Analyses ........................................................................................ 89
Adverse Event, Laboratory, and Vital Sign Data ................................... 90
Biomarker Analyses.................................................................................. 90
Patient Reported Outcome Analyses ......................................................... 90
Interim Analysis ...................................................................................... 90
REFERENCES ................................................................................................ 91
APPENDIX A
SCHEDULE OF ACTIVITIES:  OPTIONAL 
SUBSTUDY......................................................................... 93


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RATIONALE FOR THE SUBSTUDY
There is limited evidence on the long-term effects of COVID-19 infection.  This is due 
to the recent onset of the pandemic and, therefore, there has not been an opportunity to 
study patients who have recovered from the infection.  One study from China found 
that 66 out of 70 hospitalized patients had residual disease on final computed 
tomography (CT) scans, with ground glass opacity the most common pattern 
(Wang et al. 2020).  Another study, also from China, suggests this may not apply only 
to critically ill patients.  In addition, there have been reports of cardiovascular injury, 
which may increase the risk for myocardial infarction.  Some neurological sequelae, 
such as numbness, paresthesias, and confusion, have also been reported.  The UK 
National Health Service, in March 2020, predicted that 45% of COVID-19 patients 
who had been hospitalized will need ongoing medical care, 4% will require inpatient 
rehabilitation, and 1% may permanently require acute care.  
The purpose of this substudy will be to follow patients who were hospitalized with 
COVID-19 associated pneumonia, and who participated in a Genentech/Roche 
sponsored study that evaluates patients with COVID-19 associated pneumonia, for 
approximately 12 months after hospital discharge or end of the respective parent study, 
in order to understand the long-term sequela of resolved COVID-19 associated 
pneumonia.
OBJECTIVES AND ENDPOINTS
The long-term outcomes will be assessed based on the following endpoints:

Nature, frequency, and severity of serious adverse events, with severity determined 
according to scale National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5.0 and including the following:
–
Vital status
–
COVID-19 reinfection

Results over time during the substudy follow-up period in the following:
–
Patient reported outcomes including health-related quality of life, cognitive 
function, and respiratory symptoms, as measured by the Short Form 36 
Question Health Survey Version 2 (SF-36v2), Euro-QoL-5D-5-L (EQ-5D-5L), 
Living with Idiopathic Pulmonary Fibrosis Symptoms Questionnaire-Modified 
(L-IPF-M), and Montreal Cognitive Assessment (MoCA)
–
Lung texture analysis of high-resolution computed tomography (HRCT) scan 
of chest 
–
Pulmonary function tests 


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–
Healthcare resource utilization including, but not limited to, hospitalization, 
emergency room visits, urgent care/unscheduled visits, physical therapy, and 
rehabilitation
–
Peripheral blood biomarkers, including circulating markers of inflammation, 
fibrosis, coagulation, or other emerging exploratory markers of disease biology, 
as appropriate
–
Symptom guided nasopharyngeal swab for COVID-19 real time polymerase 
chain reaction (RT-PCR)
–
Six-minute walk test (6MWT) and Borg Scale of Perceived Exertion (optional) 
–
Continuous activity and sleep tracking (optional)

Prevalence and incidence of COVID-19 antibodies

Association between patient reported outcomes and radiologic and/or clinical 
disease outcomes 

Association between peripheral blood biomarkers and long-term disease course or 
other biomarker endpoints

Association between peripheral blood biomarkers with radiologic and/or clinical 
disease outcomes

Change from baseline in targeted clinical laboratory test results 
SUBSTUDY DESIGN
DESCRIPTION OF THE SUBSTUDY
This is a Phase IV, non-treatment, multicenter, follow-up substudy to assess long-term 
outcomes in adult patients who were hospitalized with COVID-19 associated 
pneumonia.  Patients must have participated (i.e., completed or discontinued early) in 
Study ML42528 (EMPACTA) or Studies WA42380 (COVACTA), WA42511 
(REMDACTA), or CA42481 (MARIPOSA) to be eligible for this substudy.  There is no 
study drug or other treatment in this substudy.  
Patients will provide consent to participate prior to the first assessment of this 
substudy (i.e., at the Baseline visit).  This Baseline visit will occur as soon as possible 
after the patient completes Day 60 or discontinues from the respective parent study.  
Substudy visits will occur approximately every 3 months for approximately 12 months 
(i.e., visits at Baseline and 3, 6, 9, and 12 months).  
Throughout the substudy, patients will conduct weekly home forced vital 
capacity/forced expiratory volume in the first second (FVC/FEV1) monitoring using 
handheld spirometry.  Data stored in the handheld spirometry device will be uploaded 
via an iPhone.  The handheld spirometry device and iPhone will be provided by the 
Sponsor.  In addition, patients will be invited to use an optional wearable device (e.g., 
Apple Watch), provided by the Sponsor, on a continuous basis to capture daily activity 


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and sleep patterns for the duration of the substudy.  Data stored in the wearable 
device will be uploaded via the iPhone.  At the end of this substudy, patients will be 
required to return the handheld spirometry device and iPhone, but not the wearable 
device.  
END OF SUBSTUDY AND LENGTH OF SUBSTUDY
The end of this substudy is defined as the date when the last patient last visit (LPLV) 
occurs or the date at which the last data point required for statistical analysis is 
received from the last patient on the substudy, whichever occurs later.  The end of the 
substudy is expected to occur 12 months after the last patient on the substudy is 
enrolled.
In addition, the Sponsor may decide to terminate the substudy at any time.
The total length of the substudy, from enrollment of the first patient to the end of the 
substudy, is expected to be approximately 18 months.
RATIONALE FOR BIOMARKER ASSESSMENTS
COVID-19 is a heterogeneous disease, where temporal changes in lung abnormalities 
and other manifestations have been shown to vary for patients with severe COVID-19 
pneumonia (Shi et al. 2020; Wang et al. 2020).  Therefore, not all patients may be 
equally likely to recover after discharge from hospital.  The exploratory biomarkers are 
collected in this substudy during the recovery phase and may aid target discovery 
and/or allow for identification of future patients at higher risk of sustained or worse 
outcomes to COVID-19.  Blood biomarkers will include, but are not limited to, those 
with previous associations to wound healing/fibrotic remodeling of the lung in other 
types of fibrotic lung disease (e.g., idiopathic pulmonary fibrosis [IPF], systemic 
sclerosis [SSc], and acute respiratory distress syndrome [ARDS]) such as CCL18, 
sRAGE, rs35705950 SNP of the MUC5B promoter and short telomeres, to explore their 
associations to persistent lung anomalies induced by COVID-19 (Dressen et al. 2018; 
Neighbors et al. 2018).  Biomarkers for non-lung related outcomes may also be 
measured to understand the progression of COVID-19.
MATERIALS AND METHODS 
PATIENTS
Approximately 300 patients who were hospitalized with COVID-19 associated 
pneumonia will be enrolled in this substudy.


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Inclusion Criteria
Patients must meet the following criteria for substudy entry:

Informed consent 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 providing informed consent

Ability to comply with the substudy procedures, in the investigator's judgment

Participated in Study ML42528 (EMPACTA) or Studies WA42380 (COVACTA), 
WA42511 (REMDACTA), or CA42481 (MARIPOSA) (Note:  Includes patients 
who completed or discontinued early from one of these studies)
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from substudy entry:

Participation in an interventional study at the time of enrollment or plans to enroll 
in an interventional study during this study

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 substudy 
RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from providing informed consent to the Month 12 visit 
or withdrawal from the substudy.  While there are no restrictions on concomitant 
therapies in this substudy, all such medications should be recorded on the Concomitant 
Medications electronic Case Report Form (eCRF).  There are no food, alcohol, herbal 
therapy, or smoking restrictions during this substudy.
SUBSTUDY ASSESSMENTS
The schedule of activities to be performed during the substudy is provided in 
Appendix A.  All activities should be performed and documented for each patient.  
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, 
and home oxygen use, will be recorded at the Baseline visit.  
In addition, all concomitant medications (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
patient during the substudy will be recorded.  At the time of each follow-up physical


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examination, an interval medical history should be obtained and any changes in 
concomitant medications and allergies should be recorded.
Demographic data will include age, sex, self-reported race/ethnicity, smoking history, 
and patient characteristics.
Physical Examinations
A complete physical examination, performed at the substudy Baseline visit, should 
include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, respiratory, gastrointestinal, and neurologic systems.  Any abnormality 
identified at the Baseline visit should be recorded on the General Medical History and 
Baseline Conditions eCRF.
Limited, symptom-directed physical examinations may be performed at unscheduled 
visits after the Baseline visit, as clinically indicated.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically 
significant abnormalities that meet the criteria for serious adverse events should be 
recorded on the Serious Adverse Event eCRF.
Vital Signs
Vital signs will include measurements collected in the ML42528 main study (see 
Section 4.5.4) plus supine and standing blood pressures to assess for orthostatic 
hypotension.  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. 
Abnormalities observed at baseline will be recorded on the General Medical History and 
Baseline Conditions eCRF.  At subsequent visits, new or worsened clinically significant 
abnormalities will be recorded on the Adverse Event eCRF. 
Pulmonary Function Testing
Forced vital capacity (FVC) is defined as the maximal volume of gas that can be exhaled
following full inhalation by exhaling as forcefully and rapidly as possible.  FVC has 
been an established measure of pulmonary function in patients with IPF for many 
decades (Du Bois et al. 2011).  Longitudinal changes in serial measures of lung volume 
are a widely accepted reflection of disease progression in patients with fibrotic lung 
disease (e.g., IPF) and a commonly used primary endpoint in therapeutic studies.
Patients will undergo the following pulmonary function tests at Baseline and each 
clinic visit that include the following:  

Forced expiratory volume in the first second (FEV1)

FVC


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
FEV1/FVC ratio

Lung volumes (expiratory reserve volume, inspiratory reserve volume,
residual volume, and tidal volume)

Diffusing capacity of the lungs for carbon monoxide (DLCO)

Forced expiratory flow at 25% and 75% of the pulmonary volume (FEF25-75%) 
Patients who are unable to perform or complete the pulmonary function test 
assessments may still participate in the substudy.
In-Home Handheld Spirometry
A hand-held spirometry will be performed according to the manual of operations.  The 
test will be performed while the patient is in a sitting position.
At Baseline, patients will receive a handheld spirometry device, provided by the
Sponsor, and given dedicated instruction on the correct use of the device.  Patients will 
be instructed to perform a spirometry reading once a week at approximately the same 
day and time each week in order to collect FVC/FEV1 data. Monitoring data stored on 
the device will upload via an iPhone, provided by the Sponsor (see the substudy manual 
for details).  The spirometry data will including the following:

FEV1

FVC

FEV1/FVC ratio (calculated)
Patients with functional issues that prevent the use of a handheld spirometry device will be ex-
empted from weekly home FVC/FEV1 monitoring.
High-Resolution Computed Tomography Scan of the Chest
High-resolution computed tomography (HRCT) will be used to gather radiographic 
images of the lung.  This will include images of the entire lung at full inspiration and
at functional residual volume.  The HRCT scan of the chest will be conducted using the 
technical requirements detailed in the publication “Diagnosis of idiopathic pulmonary 
fibrosis: An official ATS/ERS/JRS/ALAT clinical practice guideline” (Raghu et al. 
2018). The scans will be assessed by independent central readers. In addition, the 
scans, interpretations, and digital files are to be forwarded to the Sponsor by the central 
reader laboratory.
Echocardiogram
Echocardiograms will be used in all patients to evaluate the independent prognostic 
value of baseline echocardiographic variables and their interaction with treatment 
allocation and outcome on long-term follow-up.  The echocardiogram obtained at the 
Baseline visit will provide baseline echocardiographic variables to be compared with 
those obtained from the 12-month echocardiogram.  Echocardiographic measurements at


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the Baseline and 12-month visits will include assessments of cardiac structural, 
functional, and hemodynamic parameters.  The protocol for baseline and serial 
echocardiograms will be provided in a substudy manual.  All procedures will be 
performed in accordance with American Society of Echocardiography Guidelines and 
Standards for Good Laboratory Practice (Gottdiener et al. 2004; Douglas et al. 2009; 
Picard et al. 2011).
The echocardiograms will be assessed by independent central readers and the digital 
files and interpretations are to be forwarded to the Sponsor by the central reader 
laboratory. 
Six-Minute Walk Test and Borg Scale (Optional)
The six-minute walk test (6MWT) will be conducted for patients who consent as per the 
study 6MWT Procedural Manual that is based on the 2002 ATS guidelines for the 
Six-Minute Walk Test (ATS Statement 2002).
For safety reasons, all patients should be clinically stable prior to performing any 
study-related 6MWT.  Supplemental oxygen flow rate will be recorded before every 
6MWT.  Heart rate, oxygen saturation (SpO2), and the Borg Category Ratio 10 (CR10) 
Scalewill be recorded immediately before and after the procedure.  The Borg CR10 
Scale is a 1-item assessment that can be used to measure a variety of perceptions and 
experiences (i.e., perceived exertion, chest pain, dyspnea, and fatigue) (Borg and Borg 
2010).  The Borg CR10 Scale ranges from 0 (Nothing at all) to 10 (Absolute 
maximum/Highest possible).  The scale will be used to assess dyspnea and fatigue.
Physical Activity and Sleep Pattern Monitoring (Optional)
Patients who consent to the optional physical and sleep monitoring will be provided 
with a wearable device (e.g., Apple Watch) at Baseline to use on a continuous basis.  
Patients will be provided information concerning the use of the device (e.g., charging, 
waterproof properties, support).  Monitoring data stored on the device will upload to 
the iPhone provided by the Sponsor for the handheld spirometry (see the substudy 
manual for details).
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the site's local laboratory for 
analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 


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BUN or urea, creatinine, total bilirubin, lipids, alkaline phosphatase (ALP), ALT, 
and AST

Symptom guided nasopharyngeal swab for COVID-19 RT-PCR

Other tests:  d-dimer, ferritin, C-reactive protein (CRP), and brain natriuretic 
peptide (BNP)
Samples for the following laboratory tests will be sent to a central laboratory for 
analysis:

Serum samples for exploratory research on biomarkers and biomarker assay 
development

Blood PAXgene/RNA for RNA sequencing or quantitative PCR

SARS-CoV-2 serology testing (samples may be collected and stored until 
availability of central testing)
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 exception:

Serum and blood PAXgene samples collected for biomarker research and biomarker 
assay development will be destroyed no later than 5 years after the final Clinical 
Study Report has been completed.
When a patient withdraws from the substudy, 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 8.2 of the main ML42528 protocol.
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.
Blood Samples for Genetic Analysis
If patients gave a PAXgene blood sample for RNA analysis during their participation 
in the parent Genentech/Roche sponsored study for COVID-19 associated pneumonia, 
these blood samples will be used in this substudy for genetic analysis.  Otherwise, a 
new blood sample will be collected for DNA extraction and genetic analysis.


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The genetic analysis may include, but is not limited to, the following:

Telomere length measurement

Genetic variants associated with wound healing/fibrotic remodeling of the lung in 
other types of fibrotic lung disease (e.g., IPF, SSc, ARDS) such as rs35705950 
SNP of the MUC5B promoter
This may include genome sequencing to investigate genetic variants that are predictive 
of response to the study drug administered in the respective parent study that may be 
associated with any long-term outcomes of COVID-19, that may be associated with 
progression to a more severe disease state or can increase the knowledge and 
understanding of disease biology and drug safety.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS or WES are to be stored up to 5 years after the final 
Clinical Study Report has been completed.  However, the storage period will be in 
accordance with the IRB/EC approved Informed Consent Form and applicable laws (e.g., 
health authority requirements).
Clinical Outcome Assessments
Patient-reported outcome (PRO) instruments and interviewer-assessed outcomes will 
be completed to evaluate the long-term outcomes of patients who were hospitalized for 
COVID-19 associated pneumonia.
PRO data will be collected through use of the following instruments:  SF-36v2, 
EQ-5D-5L, and the L-IPF-M.  The MoCA and HCRU information will be 
interviewer-assessed and collected from the patients and recorded in the appropriate 
CRFs.  
Data Collection Methods for Clinical Outcome Assessments
PRO instruments will be self-administered or interviewer-administered (as appropriate) 
at the clinic at specified timepoints during the substudy (see the Schedule of 
Assessments [Appendix A]).  
At the clinic, paper instruments will be administered before the patient receives any 
information on disease status and prior to the performance of non-PRO assessments, 
unless otherwise specified.  Due to the physical nature of the test and the potential for 
impacting the other clinical outcomes assessments, the optional 6MWT and the 
associated Borg Scale questions, should be administered last in this sequence of clinical 
outcome assessments.  The sequence of PRO administration and interviewer 
administered assessments is as follows; for visits where an assessment is not scheduled 


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to be administered, skip to the following instrument in the list:  SF-36v2, EQ-5D-5L; 
L-IPF-M; HCRU; MoCA; and 6MWT.  The 6MWT consists of the following 
components, which are to be conducted in the following order:  Borg scale for dyspnea; 
6MWT; and Borg scales for dyspnea and fatigue.
Collection of SF-36v2, EQ-5D-5L, and L-IPF-M
Patients should be given the following instructions for completing the SF-36, 
EQ-5D-5L, and L-IPF-M instruments at the clinic:  

Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions.

Patients should answer questions to the best of their ability; there are no right or 
wrong answers.

Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments.

Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank.
Collection of Healthcare Research Utilization Data
Sites will complete the eCRF for healthcare resource utilization (HCRU) based on 
patient interview, and if available, known healthcare utilization/visits at the study site.
Montreal Cognitive Assessment, 6-Minute Walk Test, and Borg Scale 
During clinic visits, the MoCA, 6MWT (optional), and Borg Scale (optional) should be 
administered as outlined below:

Patients' health status should not be discussed prior to administration of the 
instruments.

Sites must administer the official version of the instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol.

Sites should allow sufficient time for patients to complete the instruments, 
estimated to be approximately 10 minutes at each specified visit.

Sites should administer the instruments in a private and quiet area with minimal 
distractions and disruptions.

Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers.

Site staff should not interpret or explain questions, but may read questions 
verbatim upon request.

Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments.


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
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank.

The 6MWT is comprised of several components.  The Borg dyspnea PRO is assessed 
before the patient completes the walk test.  After the completion of the walk test, 
the patient is asked to rate their dyspnea once again and then their level of fatigue 
using the Borg scale.
SAFETY PLAN
Any serious adverse events that occur during this substudy, regardless of organ system 
or cause, should be reported as outlined in the main ML42528 study protocol.  This 
includes serious adverse events associated with substudy procedures.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
DETERMINATION OF SAMPLE SIZE
This substudy is observational in nature and designed for estimation and hypothesis 
generating purposes.  Sample size of approximately 300 patients is based on practical 
rather than statistical considerations.
SUMMARIES OF CONDUCT OF SUBSTUDY
Patient disposition (i.e., number of patients enrolled, discontinued, or completed the 
substudy) will be tabulated descriptively.  Reasons for premature substudy 
discontinuation will be also be summarized.  Enrollment and major protocol deviations 
will be listed as appropriate.
SUMMARIES OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race/ethnicity, and other 
patient characteristics of interest) will be summarized using descriptive statistics, as 
appropriate.  Baseline characteristics will be defined as the characteristics assessed at 
substudy enrollment, such characteristics may be obtained from prior study data.
OUTCOME ANALYSES
The analysis population will consist of all patients enrolled in the substudy.  Long-term 
clinical and patient outcomes will be summarized by descriptive statistics and trends 
over time will be explored.  Outcomes may also be explored by patient characteristics, 
such as, but not limited to, treatment received in the respective parent study, as 
appropriate.


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Endpoints
HRCT chest scan endpoints include:

Proportion of patients with honeycombing

Proportion of patients with traction bronchiectasis/bronchiolectasis

Proportion of patients with ground-glass opacification superimposed on a fine 
reticular pattern
Association of quantitative lung texture analysis with PFTs and biomarkers may be 
explored.  Pulmonary function endpoints include FVC and FEV1.
Echocardiogram endpoints include:

Left ventricular ejection fraction (LVEF)

Proportion of patients with right ventricular systolic function (RVSF) impairment, 
categorized by mild, moderate, severe

Right ventricular systolic pressure (RVSP)

Mean positive airway pressure (PAP)

Proportion of patients with tricuspid valve regurgitation (TR) severity, categorized 
as mild, moderate, or severe
Healthcare resource utilization endpoints include, but are not limited to:

Any and number of hospitalizations

Any and number of emergency room visits

Any and number of urgent care/unscheduled visits

Any physical therapy

Any rehabilitation
Additional optional endpoints may include:

6MWT and Borg Scale

Number of steps per day 

Number of hours of sleep per day
Observed absolute values and changes from baseline will be summarized by means, 
standard deviations, medians, and ranges for continuous endpoints, as appropriate, 
while count and percentages will be tabulated for categorical endpoints by study 
timepoints.  Longitudinal modeling of endpoints may also be explored, as appropriate.
SAFETY ANALYSES
Safety assessments will be performed on all enrolled patients in the substudy. 


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Safety will be assessed through descriptive summaries of serious adverse events (nature, 
frequency, and severity) and vital status.  Serious adverse events will also be listed.  
Pulmonary serious adverse events that are not related to any drug will also be listed.  
Serious adverse events caused by imaging and pulmonary function testing will be 
summarized and listed, as appropriate.
Descriptive summaries of laboratory values and change from baseline throughout the 
substudy will be tabulated. 
Adverse Event, Laboratory, and Vital Sign Data
For selected parameters, the proportion of patients experiencing clinically significant 
changes relative to baseline for this substudy will be summarized by the treatment 
received in the respective parent study. 
The proportion of patients with any infection, including reinfection with COVID-19, 
will be summarized.  The proportion of patients with detectable SARS-CoV-2 antibodies 
will also be summarized by timepoint.
Relevant laboratory and vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature) data will be summarized, with grades identified where 
appropriate.  Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and maximum post-baseline severity grade.  Changes in vital 
sign data will be summarized.  
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, 
data may be analyzed in the context of this substudy and in aggregate with data from 
other studies.  
PATIENT REPORTED OUTCOME ANALYSES
Domain and subscale scores or index scores will be calculated for each PRO 
administered based on the corresponding scoring algorithm as appropriate.  The scores 
and their changes from baseline will be summarized at specified timepoints.  
Associations between the PRO outcomes and radiologic and/or clinical outcomes may 
also be explored as appropriate.
INTERIM ANALYSIS
No interim analysis is planned for this substudy.


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REFERENCES
American Association for Respiratory Care. Clinical practice guideline. Exercise 
testing for evaluation of hypoxemia and/or desaturation. Respir 
Care.1992;37:907912.
ATS Committee on Proficiency Standards for Clinical Pulmonary Function 
Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir
Crit Care Med. 2002;166:111117.
Borg E, Borg G, Larsson K, Letzter M, Sundblad BM. An index for breathlessness and 
leg fatigue. Scand J Med Sci Sports. 2010;20(4):644650.
Douglas PS, DeCara JM, Devereux RB, et al. Echocardiographic imaging in clinical 
trials: American Society of Echocardiography Standards for echocardiography 
core laboratories: endorsed by the American College of Cardiology Foundation. 
J Am Soc Echocardiogr. 2009;22(7):755765.
Du Bois RM, Weycker D, Albera C, et al. Forced vital capacity in patients with 
idiopathic pulmonary fibrosis: test properties and minimal clinically important 
difference. Am J Respir Crit Care Med. 2011;184(12):13821389. 
Dressen A, Abbas AR, Cabanski C, et al. Analysis of protein-altering variants in 
telomerase genes and their association with MUC5B common variant status in 
patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study. 
Lancet Respir Med. 2018;6(8):603614.
Gottdiener JS, Bednarz J, Devereux R, et al. American Society of Echocardiography 
recommendations for use of echocardiography in clinical trials: A report from the 
american society of echocardiography's guidelines and standards committee and 
the task force on echocardiography in clinical trials. J Am Soc Echocardiogr. 
2004;17(10):10861119.
Neighbors M, Cabanski CR, Ramalingam TR, et al. Prognostic and predictive 
biomarkers for patients with idiopathic pulmonary fibrosis treated with 
pirfenidone: post-hoc assessment of the CAPACITY and ASCEND trials. Lancet 
Respir Med. 2018;6(8):615626.
Picard MH, Adams D, Bierig SM, et al. American Society of Echocardiography 
recommendations for quality echocardiography laboratory operations. J Am Soc 
Echocardiogr. 2011;24(1):110.
Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry 
for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J. 
2012;40(6):13241343.


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Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. 
An official ATS/ERS/JRS/ALAT clinical practice guideline. American journal of 
respiratory and critical care medicine. 2018;198(5):e4468.
Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 
pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 
2020;20(4):425434.
Wang Y, Dong C, Hu Y, et al. Temporal changes of CT findings in 90 patients with 
COVID-19 pneumonia: a longitudinal study. Radiology. 2020:200843.


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APPENDIX A
SCHEDULE OF ACTIVITIES:  OPTIONAL SUBSTUDY
Long-Term Follow-Up
Unplanned Visit/
Early Discontinuation
Month
Baseline a
Month 3 b
Month 6 b
Month 9 b
Month  12 b
(Visit Window)
14 days
14 days
14 days
14 days
Informed consent a
x
Medical history & demographics c
x
Vital signs d
x
x
x
x
x
x
Physical examination e
x
x
x
x
x
x
Pulmonary function testing f, g
x
x
x
x
x
x
Home FVC/FEV1 monitoring h
To be conducted weekly
Echocardiogram f, i
x
x
x
HRCT scans of chest f
x
x
x
PROs j
SF-36v2
x
x
x
x
EQ-5D-5L
x
x
L-IPF-M
x
x
x
x
Healthcare resource utilization k
x
x
x
x
x
x
MoCA l
x
x
x
6-minute walk test & Borg Scale (optional) m
x
x
x
Hematology, chemistry, and other laboratory 
tests n
x
x
x
x
x
x
SARS-CoV-2 serology 
x
x
x
x
x
x
Symptom guided COVID-19 RT-PCR 
(nasopharyngeal swab) o
x
x
x
x
x
x
Serum samples for biomarkers
x
x
x
x
x
x


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Protocol ML42528     Report Number 1104869
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Long-Term Follow-Up
Unplanned Visit/
Early Discontinuation
Month
Baseline a
Month 3 b
Month 6 b
Month 9 b
Month  12 b
(Visit Window)
14 days
14 days
14 days
14 days
Blood PAXgene® for RNA p
x
x
x
x
x
x
Blood sample for genetic analyses q
x
Serious adverse events r
x
x
x
x
x
x
Concomitant medications review s
x
x
x
x
x
x
Physical and sleep monitoring (optional) t
Continuous monitoring via wearable device
6MWT 6 minute walk test; ALP alkaline phosphatase; BNP brain natriuretic peptide; CRP C-reactive protein; DLCO diffusing capacity 
of the lungs for carbon monoxide eCRF electronic Case Report Form; EQ-5D-5L Euro-QoL-5D-5-L; FEF25-75% forced expiratory flow at 
25% and 75% of the pulmonary volume; FEV1 forced expiratory volume in the first second; FVC forced vital capacity; HRCT high 
resolution CT scan; L-IPF-M Living with Idiopathic Pulmonary Fibrosis Symptoms Questionnaire-Modified; MoCA Montreal Cognitive 
Assessment; PROs patient reported outcomes; RT-PCR Reverse transcription polymerase chain reaction; SF-36v2 Short Form 36 Question 
Health Survey Version 2; WGS whole genome sequencing.
a Patients will provide consent to participate prior to the first assessment of this substudy (i.e., at the Baseline visit).  Baseline visit will occur 
as soon as possible after the patient completes or discontinues a respective parent study.  
b Sites are encouraged to contact patients remotely (e.g., phone call, text message) between visits to check on the patient and to remind them to 
complete the home assessments. 
c
Demographic data will include age, sex, self-reported race/ethnicity, smoking history, and patient characteristics.
d All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures [supine and standing to assess for 
orthostatic hypotension, and body temperature), and oxygen saturation should be recorded on the eCRF.  
e
A complete physical examination, performed at the Baseline visit and per the investigator’s discretion during the study, includes an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, respiratory, gastrointestinal, and neurologic 
systems.  Any abnormality identified at the Baseline visit should be recorded on the General Medical History and Baseline Conditions eCRF.  
New or worsened clinically significant abnormalities identified during the study that meet the criteria for serious adverse events should be 
reported as serious adverse events.
f
The pulmonary function tests, HRCT scan of the chest, and the echocardiogram may be completed over multiple days; however, assessments 
must be completed within 14 days of scheduled visits.


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g Pulmonary function testing will be conducted at the clinic and include FEV1, FVC, percentage of predicted values for FEV1 and FVC, FEV1 
to FVC ratio, and average expiratory flow during the middle portion of the expiration (FEF25-75%). The percentage of predicted values for 
FEV1 and FVC will be derived from the Global Lung Function Initiative (Quanjer et al. 2012). Lung volumes and DLCO will also be 
obtained.  Each test procedure requires that three valid spirometry maneuvers be performed within 1 hour.  The highest FEV1 and FVC
values from the set of three accepted maneuvers will be recorded.  Other parameters will be taken from the accepted maneuver with the highest 
sum of FEV1 and FVC.  A hard-copy report of the spirometry results will be maintained in the patient's medical record.
h At Baseline, patients will receive a handheld spirometry device, provided by the Sponsor, and given dedicated instruction on the correct use 
of the device.  Patients will be instructed to perform a spirometry reading once a week at approximately the same day and time each week in 
order to collect FVC/FEV1 data.  Monitoring data stored on the device will upload via an iPhone, provided by the Sponsor (see the substudy 
manual for details). Patients with functional issues that prevent the use of a handheld spirometry device will be exempted from this monitoring.
i A complete echocardiogram will be conducted; contrast is allowed, if needed.
j PRO questionnaires (i.e., SF-36v2, EQ-5D-5L, L-PIF-M) will be administered in the clinic and are to be completed by the patient or
administered by an interviewer (i.e., 6MWT, Borg Scale) before the patient receives any information on disease status, prior to the 
performance of non-PRO assessments.  The assessments are to be conducted in the following order, if an assessment is not schedule to be 
administered, skip to the following instrument: SF-36v2, EQ-5D-5L, L-IPF-M, HCRU, MoCA, and 6MWT.
k Healthcare resource utilization including, but not limited to, emergency room visits, urgent care/unscheduled visits, physical therapy, and 
rehabilitation from providing informed consent to the Month 12 visit or withdrawal from the substudy, will be recorded. Patients will be 
asked specifically about the occurrence and/or number of hospitalizations, emergency room visits, or other healthcare utilization at each 
contact.
l The MoCA will be administered in the clinic by an interviewer before the patient receives any information on disease status.
m The 6MWT and Borg Scale are optional and will be performed according to institutional standards. The 6MWT consists of the following
components, which are to be conducted in the following order:  Borg Scale for dyspnea; 6MWT; and Borg Scales for dyspnea and fatigue.
n Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils,
monocytes, lymphocytes, other cells).  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 bilirubin, lipids, ALP, ALT, and AST.
Other tests: d-dimer, ferritin, CRP, and BNP.
o The symptom guided COVID-19 RT-PCR (nasopharyngeal swab) is to be conducted when the investigator determines it is warranted. 
A nasopharyngeal swab may be collected at any visit or unplanned visit.
p The first draw of blood should not be for PAXgene® tubes to avoid contact with RNA preservation reagent inside the tube.
q If the sample is not collected at the Baseline visit for any reason, it may be collected at any later timepoint.
r Only serious adverse events will be collected through the completion of this substudy at Month 12.
s Medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) and
supplemental oxygen used by a patient from providing informed consent to the Month 12 visit or withdrawal from the substudy, will be 
recorded.


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t
Patients who consent to the optional physical and sleep monitoring will be provided with a wearable device (e.g., Apple Watch) at Baseline to 
use on a continuous basis.  Patients will be provided information concerning the use of the device (e.g., charging, waterproof properties, 
support).  Monitoring data stored on the device will upload via an iPhone, provided by the Sponsor (see the substudy manual for details). 

SAP_001.pdf: 
 
Official Title: 
A Randomized, Double-Blind, Placebo-controlled, Multicenter Study 
to Evaluate The Efficacy And Safety of Tocilizumab in Hospitalized 
Patients With Covid-19 Pneumonia 
NCT Number: 
NCT04372186 
Document Date: 
SAP Version 2: 31-August-2020 
 
 




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2/Statistical Analysis Plan ML42528 
 
 
 
Statistical Analysis Plan Update Rationale 
 
The statistical analysis plan ML42528 Version 2 includes the following updates from 
Version 1: 
 
• 
Key secondary endpoints were updated 
 
• 
The Type I error control section was added to specify a hierarchy for testing of 
the primary endpoint followed by testing of the predefined key secondary 
endpoints 
 
• 
Cumulative Incidence Function plots were specified for time to ‘improvement’ 
secondary endpoints 
 
• 
The censoring rules for the time to event endpoints were updated 
 
• 
Derivation of the time to clinical failure endpoint was clarified 
 
• 
Pre-specification of the stratified efficacy analyses to include only the age 
randomization strata 
 
• 
Definition of baseline was added 
 
• 
Additional subgroup analyses for race/ethnicity combined category and elevated 
CRP were added 
 
• 
Appendices 1, 2, and 3 were updated to be consistent with the current protocol 
version 3 
 
Additional minor changes have been made to improve clarity and consistency. 


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3/Statistical Analysis Plan ML42528 
 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 6 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 8 
2.2 
Endpoints ................................................................................. 8 
2.2.1 
Primary Efficacy Endpoint ........................................................ 8 
2.2.2 
Secondary Efficacy Endpoints ................................................. 8 
2.2.3 
Exploratory Efficacy Endpoints ................................................ 8 
2.2.4 
Safety Endpoints...................................................................... 8 
2.3 
Determination of Sample Size ................................................. 8 
2.4 
Analysis Timing ....................................................................... 9 
3. 
STUDY CONDUCT ....................................................................................... 9 
3.1 
Randomization ......................................................................... 9 
3.2 
Data Monitoring ....................................................................... 9 
4. 
STATISTICAL METHODS .......................................................................... 10 
4.1 
Analysis Populations.............................................................. 10 
4.1.1 
mITT Population .................................................................... 10 
4.1.2 
Safety Population................................................................... 10 
4.2 
Data Handling Conventions ................................................... 11 
4.2.1 
Definition of Study Day .......................................................... 11 
4.2.2 
Definition of Baseline ............................................................. 11 
4.3 
Analysis of Study Conduct ..................................................... 11 
4.4 
Analysis of Treatment Group Comparability .......................... 11 
4.4.1 
Demographics and Social Status ........................................... 11 
4.4.2 
Disease Characteristics ......................................................... 12 
4.4.3 
Targeted and General Medical History .................................. 12 
4.4.4 
Surgeries and Procedures ..................................................... 13 
4.4.5 
Previous and Concomitant Medications................................. 13 
4.5 
Efficacy Analysis .................................................................... 13 
4.5.1 
Primary Efficacy Endpoint ...................................................... 13 
4.5.2 
Controlling for Type I Error .................................................... 14 
4.5.3 
Secondary Efficacy Endpoints ............................................... 15 


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4.5.3.1 Key Secondary Efficacy Endpoints ....................................... 15 
4.5.3.2 Other Secondary Efficacy Endpoint ...................................... 19 
4.5.4 
Exploratory Efficacy Endpoints .............................................. 19 
4.5.5 
Subgroup Analyses................................................................ 20 
4.6 
Safety Analyses ..................................................................... 21 
4.6.1 
Exposure of Study Medication ............................................... 21 
4.6.2 
Adverse Events ..................................................................... 21 
4.6.3 
Laboratory Data ..................................................................... 23 
4.6.4 
Oxygen Saturation and Vital Signs ........................................ 23 
4.7 
Interim Analyses .................................................................... 24 
5. 
REFERENCES ........................................................................................... 25 
 
 
 
LIST OF TABLES 
Table 1 
Time to Death or Requiring Mechanical Ventilation and 
Censoring Status ........................................................................ 14 
Table 2 
Time to Hospital Discharge and Censoring Status ...................... 16 
Table 3 
Time to Improvement in Ordinal Clinical Status and 
Censoring Status ........................................................................ 17 
Table 4 
Time to Clinical Failure and Censoring Status ............................ 18 
Table 5 
Time to Requiring CPAP or BIPAP and Censoring Status .......... 20 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................... 7 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ...................................................................... 26 
Appendix 2 
Schedule of Activities:  Days 1 and 2 ......................................... 31 
Appendix 3 
Schedule of Activities:  Day 3−Study Completion....................... 34 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
BIPAP 
bilevel positive airway pressure 
CoV 
coronaviruses 
CPAP 
continuous positive airway pressure 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
electronic Case Report Form 
ECMO 
extracorporeal membrane oxygenation 
FiO2 
fraction of inspired oxygen 
hs-CRP 
high sensitivity C-reactive protein 
ICU 
intensive care unit 
IL-6 
interleukin 6 
IMC 
Internal Monitoring Committee 
IxRS 
interactive voice or web-based response system 
LPLV 
last patient, last visit 
mITT 
modified intent-to-treat 
NCI 
National Cancer Institute 
PaO2 
partial pressure of oxygen 
SARS-CoV 
severe acute respiratory syndrome 
SOC 
standard of care 
SpO2 
blood oxygen saturation 
TB 
tuberculosis 
TCZ 
tocilizumab 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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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 ML42528. 
There are currently no drugs approved for the treatment of patients with SAS-CoV-2 
(COVID-19). Given the results of studies (Xu et al. 2020), tocilizumab (TCZ), along with 
standard of care (SOC) 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 COVID-19 pneumonia is justified 
to address the high unmet need. 
2. 
STUDY DESIGN 
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 placebo 
in combination with SOC in hospitalized adult patients with COVID-19. The Sponsor 
intends to enroll approximately 379 patients that have been diagnosed with COVID-19 
pneumonia and meet the entry criteria. 
 
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<94% on ambient air and be on SOC, which may include anti-viral treatment, low 
dose systemic corticosteroids, 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 and well- 
controlled HIV) will be excluded from the study. 
 
Eligible patients per study eligibility criteria will be randomly allocated in a 2:1 ratio to 
receive double-blind treatment with TCZ or placebo within 96 hours of hospital 
admission. Randomization will be stratified by country and age (≤60 and >60 years). The 
first dose of study drug will be administered within approximately 4 hours after 
randomization along with local SOC. 
 
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. 
 
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), 




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2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1. 
 
2.2 
ENDPOINTS 
2.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
• 
Cumulative proportion of patients with death or requiring mechanical ventilation 
by Day 28 
2.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Time to hospital discharge or “ready for discharge” (e.g., awaiting social 
disposition) up to Day 28 as evidenced by, for example, normal body 
temperature and respiratory rate, and stable oxygen saturation on ambient air or 
≤2L supplemental oxygen 
• Time to improvement in ordinal clinical status up to Day 28 relative to baseline 
based on a 7-category ordinal scale of clinical status 
• Time to clinical failure up to Day 28, defined as the time to death, mechanical 
ventilation, ICU admission, or withdrawal 
• Mortality rate by Day 28 
• 7-category ordinal scale at Day 28 
 
2.2.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are as follows: 
• 
Change from baseline at Day 28/discharge/early dropout in inflammatory 
markers levels (hs-CRP/CRP, D-dimer, and ferritin) 
 
• 
Time to first requiring CPAP or BIPAP 
 
2.2.4 
Safety Endpoints 
The safety endpoints are as follows: 
• 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v5.0 
• 
Incidence of any post-treatment bacterial and/or fungal infection 
• 
Incidence of any post-treatment acute kidney injury (defined by 50% increase of 
creatinine from baseline) 
2.3 
DETERMINATION OF SAMPLE SIZE 
A total of approximately 379 patients will be randomized in this study. Patients will be 
randomly allocated in a 2:1 ratio to receive TCZ and or placebo, in addition to local SOC. 


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The sample size of 379 patients provides approximately 80% power using a logrank test 
to detect a 15% difference between treatment arms in the cumulative proportions of 
patients with death or mechanical ventilation by Day 28 under the following assumptions: 
cumulative survival (i.e., alive and not requiring mechanical ventilation) rates of 75% in 
the TCZ group and 60% in placebo group by Day 28, using a two-sided 5% alpha, and 
10% dropout rate in each arm. Sample size re-estimation may be considered during the 
study based on updated assumptions of the treatment effect. 
2.4 
ANALYSIS TIMING 
No interim efficacy analyses have been planned. Safety data will be reviewed by an 
Internal Monitoring Committee (IMC) during the study. The IMC will consist of Sponsor 
representatives who will not be blinded to study data. The planned safety interim review 
will occur when the first 30 patients have completed the Day 14 study visit. See 
Section 3.2 for further details. 
 
The primary analysis of Day 28 outcomes will occur when the last patient either has 
withdrawn or completed the Day 28 visit. A snapshot of this data will be taken and the 
primary and key secondary efficacy analyses will be performed. 
 
There will be one additional analyses on the final data when all patients have either 
reached Day 60 or withdrawn from study, all data from the study are in the database, 
and the database is locked. 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
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. Randomization will be stratified by country (US, 
Peru, Brazil, Mexico, Kenya, South Africa) and age (≤60 and >60 years). 
3.2 
DATA MONITORING 
An IMC will evaluate safety according to procedures and guidelines detailed in the IMC 
agreement. The IMC will consist of Sponsor representatives who are not members of the 
study management team and will not be blinded to study data. 
 
The first IMC safety review will occur after approximately 30 patients (20 in TCZ and 10 
in PBO) have completed the Day 14 visit. There will be further IMC meetings when 


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approximately half of the targeted number of patients (i.e., n=189) have been enrolled; 
but all interim analyses are subject to change depending on enrollment and as 
appropriate. 
 
The IMC will review unblinded summaries and listings of overall rates of death, serious 
adverse events (SAEs), and all adverse events (AEs) as well as other key safety data. 
All enrolled patients will be included in the interim safety summaries as there may be a 
lag time for obtaining treatment exposure data. 
 
Deaths and serious infections will be reviewed in an expedited manner. The Study 
Medical director, Safety Scientist or IMC Chair may request additional meetings if 
concerns arise. 
 
The unblinded safety summaries will be conducted by the IMC-Statistician and statistical 
programmer independent from the study management team. The list of the planned 
safety summary tables and listings are provided in the IMC agreement. Communications 
and recommendations from the IMC will be carried out as specified in the IMC 
agreement. 
 
4. 
STATISTICAL METHODS 
All primary and secondary efficacy endpoints will be analyzed in the modified intent-to- 
treat (mITT) population, with patients grouped according to the treatment assignment at 
randomization. 
 
In all safety 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 regardless of whether study drug was received). Efficacy analyses will be 
based on the mITT population, if not otherwise specified. Analysis of safety data will be 
based on the safety population. 
4.1.1 
mITT Population 
The mITT population is defined as all randomized patients in the study who 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 received any amount of study 
medication. In all safety analyses, patients will be grouped according to the treatment 
that the patients first actually received rather than the treatment assigned at 
randomization. 


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4.2 
DATA HANDLING CONVENTIONS 
4.2.1 
Definition of Study Day 
Based on the protocol, study treatment must be given within approximately 4 hours after 
randomization. Therefore, the first treatment dose date will be used as Day 1 in all 
analyses. The day immediately following the first treatment dose date is study Day 2 and 
so on. 
 
The detailed analysis windows for inflammatory markers, vital signs, and laboratory data 
will be defined in the specifications of the planned tables, listings, and graphs. 
4.2.2 
Definition of Baseline 
Baseline value is defined as value from Day 1. The last value from screening will be 
used for baseline assessment if there is no baseline value. Pretreatment assessments 
will be used preferentially on study Day 1 for baseline. 
4.3 
ANALYSIS OF STUDY CONDUCT 
The number of patients enrolled, discontinued, or who completed the study up to Day 28 
will be summarized. Reasons for premature study discontinuation will be listed and 
summarized. Listing of randomized patients and listing of investigators will be produced. 
A summary of enrollment by country and investigator name will be produced. 
 
The number of patients discharged from hospital will be summarized over time. 
 
Eligibility criteria deviations and other major protocol deviations will be listed and 
summarized by treatment arm. 
 
Randomized patients excluded from the safety and mITT populations will be 
summarized, including the reason for exclusion by treatment arm. 
4.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics (including, but not limited to, age, sex, self- 
reported race/ethnicity, smoking history) 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 arm based on the 
mITT population; additional summary may be based on the safety population, as 
needed. 
4.4.1 
Demographics and Social Status 
• 
Sex 
• 
Age 
• 
Weight 
• 
BMI 
• 
Race 


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• 
Ethnicity 
• 
Race/Ethnicity Combined [Hispanic or Latino, American Indian or Alaska Native, 
Black or African American, WHITE, Other/unknown] 
• 
Employment status 
• 
Education status 
• 
Primary language 
• 
Living situation (Alone, With Others) 
• 
Smoking history (Never, Current/Former) 
• 
Country group (US, ex-US) 
 
4.4.2 
Disease Characteristics 
• 
Ordinal scale for clinical status 
• 
CRP and hs-CRP 
— Elevated CRP (CRP >50 mg/L or hs-CRP >3 mg/L) 
• 
D-dimer 
• 
Ferritin 
• 
Symptoms at time of COVID 19 diagnosis 
• 
Number of days from first COVID-19 symptom at baseline (to be derived from 
COVID 19 Diagnosis) 
• 
COVID19 diagnosis based on PCR of specimen type 
• 
Number of days from COVID-19 diagnosis at baseline (to be derived from COVID 
19 Diagnosis) 
• 
PCR result (Negative, positive) 
• 
ICU admission status at baseline (yes, no) 
• 
Steroid use (part of previous and concomitant medications), including prior 
(treatment started within 7 days of Day 1) and concurrent treatment (yes, no) 
• 
Antiviral use (part of previous and concomitant medications), including prior 
(treatment started within 7 days of Day 1) and concurrent treatment (yes, no) 
 
4.4.3 
Targeted and General Medical History 
Targeted medical history, including Diabetes, hypertension, hyperlipidemia, asthma, 
COPD, obesity, myocardial infarction, atrial fibrillation, and stroke, will be summarized by 
treatment arm. 
 
General medical history data will be summarized descriptively by treatment arm. 
Summaries of the targeted and general medical history will be provided for the safety 
population. A glossary showing the mapping of investigator verbatim terms to coded 
disease terms will be produced for the general medical history data. 


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4.4.4 
Surgeries and Procedures 
A listing of any previous or ongoing surgeries and procedures will be produced for the 
safety population. 
4.4.5 
Previous and Concomitant Medications 
Previous and concomitant treatments will be summarized descriptively by treatment arm 
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. 
4.5 
EFFICACY ANALYSIS 
All efficacy analyses will be performed on the mITT population with patients grouped 
according to treatment assigned at randomization. 
 
While two-sided unadjusted p-values will be reported, the overall study-level type 1 error 
will be controlled at a two-sided α=0.05 level according to the type 1 error control plan 
detailed in Section 4.5.2. 
 
All efficacy analyses will be stratified by age (≤60 and >60 years). Country group (US, 
Peru, Brazil, Mexico, Kenya, South Africa) will not be included as a stratification variable 
in the efficacy analyses to avoid the likelihood of getting unreliable estimates due to 
small sample size in a particular stratum (there are only 16 patients in the ex-US 
countries and age >60 years stratum, with possibly fewer than 10 patients in one of the 
treatment arms). 
 
Consistent treatment effect in the country group and other prespecified subgroup will be 
evaluated through subgroup analysis specified in Section 4.5.5. 
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: 
• 
Cumulative proportion of patients with death or requiring mechanical ventilation by 
Day 28 
For this endpoint, mechanical ventilation is defined as mechanical invasive ventilation or 
ECMO (extracorporeal membrane oxygen). Any patient, who died prior to requiring 
invasive mechanical ventilation on or prior to Day 28, will be considered as having an 
event for this endpoint. Time to primary endpoint event is defined as time from Day 1 to 
the first occurrence of death or requiring mechanical ventilation by Day 28. The 
cumulative proportions of patients who experienced events by Day 28 will be estimated 
using the Kaplan-Meier methodology and compared between the TCZ group and the 
placebo group using the stratified log-rank test with age group as stratification factor. 


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The cumulative incidence function will be used to estimate and plot the cumulative 
primary efficacy event rates up to Day 28 for each treatment arm. The estimated 
cumulative primary efficacy event rates and their 95% confidence intervals (CIs) at Days 
7, 14, 21 and 28 will be summarized by treatment arm. The median time to event will 
also be provided along with the corresponding 95% CIs by treatment arm. 
 
The stratified Cox proportional hazard model, with age group as stratification factor, will 
be used to estimate the hazard ratio (HR) between the two treatment arms and its 95% 
CI. 
 
The primary efficacy event and the censoring rules are described in Table 1 below. 
Death after Day 28 will not be considered as an event. 
 
Table 1 
Time to Death or Requiring Mechanical Ventilation and Censoring 
Status 
 
Event 
Censor 
Date 
Patient with death or requiring mechanical 
ventilation* recordings on or prior to Day 28 
No 
Earlier of date of death and/or 
first date requiring mechanical 
ventilation 
Patient without death and not requiring 
mechanical ventilation recordings on or prior to 
Day 28; 
If patient with safety follow-up 
Yes 
Earlier of the date of Day 28 and 
the date of last available follow- 
up** 
If patient without safety follow-up 
Yes 
Earlier of the date of Day 28 and 
the date of last available in- 
hospital assessment *** 
* Mechanical ventilation is defined as mechanical invasive ventilation or ECMO per CRF; ** 
Follow-up includes (1) safety follow-up per CRF, (2) 7-ordinal scale assessment in hospital, (3) 
oxygen saturation assessment in hospital; *** In-hospital assessment includes (1) 7-ordinal scale 
assessment in hospital, (2) oxygen saturation assessment in hospital. For patients without any 
oxygen saturation or ordinal scale assessment in-hospital assessment, date is set to Day 1. 
4.5.2 
Controlling for Type I Error 
The primary and key secondary efficacy endpoints will be evaluated in a hierarchical 
manner to control the overall study-wide Type 1 error rate at the 5% significance level. If 
the primary efficacy endpoint reaches statistical significance at the two-sided 5% 
significance level, the following list of key secondary efficacy endpoints will be tested at 
the two-sided 5% significance level in the predefined order below: 
1. Time to hospital discharge or “ready for discharge” up to Day 28 
2. Time to improvement in ordinal clinical status up to Day 28 relative to baseline 
based on a 7-category ordinal scale of clinical status 


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3. Time to clinical failure up to Day 28, defined as the time to death, mechanical 
ventilation, ICU admission, or withdrawal (whichever occurs first) 
4. Mortality rate by Day 28 
Testing of the first secondary endpoint will be gated on the success (significance 
p<0.05) of the primary efficacy endpoint, and testing of subsequent secondary endpoints 
will be gated on the success (significance p<0.05) of the previous secondary endpoint. 
Testing will stop once an endpoint fails to reach statistical significance (p≥0.05). 
Other secondary endpoint and exploratory efficacy endpoints will be tested at the 
nominal two-sided 5% significance level for exploratory purposes without any adjustment 
for multiplicity. 
4.5.3 
Secondary Efficacy Endpoints 
Time to event secondary endpoints will be compared between the TCZ group and the 
placebo group using similar analytic methodologies as the primary efficacy endpoint. 
The Kaplan-Meier approach will be used to estimate and plot survival rates up to Day 28 
for each treatment arm. The median time to event with its 95% CI will be summarized by 
treatment whenever they are estimable. 
 
For the endpoints of time to hospital discharge or “ready for discharge” and time to 
improvement in clinical status, deaths will be right censored (at Day 28). Consequently, 
for these endpoints, patients censored on Day 28 could have two different states, death 
or failure to meet the criterion of improvement outcome. Therefore, it is important to 
understand the efficacy outcome in the context of the number and timing of deaths by 
treatment arm. In addition, in order to evaluate the effect of competing risk of death in 
these endpoints, the cumulative incidence function plots for both death and the event of 
interest will be produced using the non-parametric Aalen–Johansen estimator. 
4.5.3.1 
Key Secondary Efficacy Endpoints 
• 
Time to hospital discharge or “ready for discharge” up to Day 28 
 
This key secondary endpoint is defined as time from Day 1 to hospital discharge or 
“ready for discharge” up to Day 28 based on the 7-category ordinal scale. 
 
Assessment of clinical status using an ordinal scale will be recorded at baseline and 
once daily 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 


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4. 
ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow 
oxygen 
5. 
ICU, requiring intubation and mechanical ventilation 
6. 
ICU, requiring ECMO or mechanical ventilation and additional organ support 
(e.g., vasopressors, renal replacement therapy) 
7. 
Death 
The efficacy event and the censoring rules for this endpoint are described in Table 2. 
 
Table 2 
Time to Hospital Discharge and Censoring Status 
 
Event 
Censor 
Date 
If patient with discharge or “ready for discharge” 
recordings on or prior to Day 28 
No 
Earliest discharge day 
Else if before discharge or “ready for discharge”, 
patient died on or prior to Day 28 
Yes 
Day 28 
Else if patient without discharge or “ready for 
discharge” recordings on or prior to Day 28 
Yes 
Earlier of the date of Day 28 and 
the date of last ordinal scale 
assessment* 
* For patients without any ordinal scale assessment in-hospital assessment, date is set to Day 1. 
 
• 
Time to improvement in clinical status up to Day 28 relative to baseline based on a 
7-category ordinal scale of clinical status 
This secondary endpoint is defined as time from Day 1 to the time when at least a 2- 
category improvement in the 7-category ordinal scale is observed on or prior to Day 28. 
For patients in category 2 at baseline, having a clinical status of category 1 (discharge or 
“ready for discharge”) on or prior to Day 28 will be considered as meeting the threshold. 
 
The event and the censoring rules for this endpoint are described in Table 3 below. 


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Table 3 
Time to Improvement in Ordinal Clinical Status and Censoring Status 
 
Event 
Censor 
Date 
Patient enrolled with scale≥3 
If patient with 2-category improvement in ordinal 
clinical status on or prior to Day 28 (regardless of 
whether the patient die after the improvement) 
No 
First improvement day 
Else if patient died prior to improvement in 
ordinal clinical status 
Yes 
Day 28 
Else if patient without 2-category improvement in 
ordinal clinical status on or prior to Day 28 
Yes 
Earlier of the date of Day 28 and 
the date of last ordinal scale 
assessment* 
Patient enrolled with scale=2 
If patient with 1-category improvement in ordinal 
clinical status on or prior to Day 28 (regardless of 
whether the patient die after the improvement) 
No 
First improvement day 
Else if patient died prior to improvement in 
ordinal clinical status 
Yes 
Day 28 
Else if patient without 1-category improvement in 
ordinal clinical status on or prior to Day 28 
Yes 
Earlier of the date of Day 28 and 
the date of last ordinal scale 
assessment* 
* For patients without any ordinal scale assessment in-hospital assessment, date is set to Day 1. 
 
• 
Time to clinical failure up to Day 28 
This secondary efficacy endpoint is defined as time from Day 1 to first occurrence of 
death, mechanical ventilation (defined same as in primary endpoint), ICU admission, or 
withdrawal from study due to any reason on or prior to Day 28. For patients entering the 
study already in the ICU, time to clinical failure is defined as the first occurrence of, 
death, mechanical ventilation (defined same as in primary endpoint), two-category 
worsening in the 7-category ordinal scale from baseline, or withdrawal from study due to 
any reason on or prior to Day 28. 
 
The event and censoring rules for this endpoint are described in Table 4 below. 


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Table 4 
Time to Clinical Failure and Censoring Status 
 
Event 
Censor 
Date 
No ICU admission prior to first study treatment 
Patient with death, ICU admission, requiring 
mechanical ventilation* recordings, or withdrawal 
from study before discharge on or prior to Day 
28 
No 
Earliest of the death date, first 
ICU admission date, first date 
requiring mechanical ventilation, 
and study withdrawal date 
Patient without death, ICU admission, requiring 
mechanical ventilation recordings, and 
withdrawal from study before discharge on or 
prior to Day 28 
with safety follow-up 
Yes 
Earlier of the date of Day 28 and 
the date of last available follow- 
up** 
without safety follow-up 
Yes 
Earlier of the date of Day 28 and 
the date of last available in- 
hospital assessment *** 
For patients whose ICU admission is prior to first study medication administration 
Patient with death, two-category worsening on 
the ordinal scale, requiring mechanical 
ventilation* recordings or withdrawal from study 
before discharge on or prior to Day 28 
No 
Earliest of the death date, first 
date with two-category 
worsening on the ordinal scale, 
requiring mechanical ventilation* 
recordings, and study withdrawal 
date 
Patient without death, two-category worsening 
on the ordinal scale, requiring mechanical 
ventilation* recordings, and withdrawal from 
study before discharge on or prior to Day 28 
with safety follow-up 
Yes 
Earlier of the date of Day 28 and 
the date of last available follow- 
up** 
without safety follow-up 
Yes 
Earlier of the date of Day 28 and 
the date of last available in- 
hospital assessment *** 
* Mechanical ventilation is defined as mechanical invasive ventilation or ECMO per CRF; ** 
Follow-up includes (1) safety follow-up per CRF, (2) 7-ordinal scale assessment in hospital, (3) 
oxygen saturation assessment in hospital; *** In-hospital assessment includes (1) 7-ordinal scale 
assessment in hospital, (2) oxygen saturation assessment in hospital. For patients without any 
oxygen saturation or ordinal scale assessment in-hospital assessment, date is set to Day 1. 


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• 
Mortality rate at Day 28 
The difference in proportion of patients who have died by Day 28 will be compared 
between the treatment arms using the Cochran-Mantel-Haenszel test adjusted for 
stratification factor age. The adjusted proportion in each treatment arm will be presented 
along with its 95% CI. Adjusted difference in proportions and its associated 95% CI for 
the treatment group comparison will also be presented. Any mortality that occurs 
between Day 1 and Day 28 will be included in the analysis. 
4.5.3.2 
Other Secondary Efficacy Endpoint 
• 
7-category ordinal scale at Day 28 
The patients’ clinical status as assessed by the 7-category ordinal scale at Day 28 will 
be analyzed by comparing the difference in distributions of the ordinal scale between the 
TCZ and placebo groups. Patients with missing ordinal scale status at Day 28 will have 
the value imputed by the last post-baseline available assessment. The Van Elteren test 
will be used, including the stratification factor age for this comparison. The count and 
proportion of patients with scores at each category of the scale at Day 28 will be 
summarized along with the p-value from the Van Elteren test. 
 
In addition, the 7-category ordinal scale at Day 28 will be compared between the TCZ 
and placebo groups using a proportional odds model stratified by age group as a 
sensitivity analysis. The odds ratio, p-value, and 95% CI on the odds ratio will be 
presented. 
4.5.4 
Exploratory Efficacy Endpoints 
• 
Time to first requiring CPAP or BIPAP 
 
Defined as the time from Day 1 to the first documented date of death, requiring CPAP or 
BIPAP, or requiring mechanical ventilation (as defined in primary endpoint). Table 5 
describes the event/censoring rules for the time to requiring CPAP or BIPAP. This 
endpoint will be analyzed using the same methodologies as the primary efficacy 
endpoint. 


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Table 5 
Time to Requiring CPAP or BIPAP and Censoring Status 
 
Event 
Censor 
Date 
Patient with death or requiring CPAP or BIPAP, 
or requiring mechanical ventilation* on or prior to 
Day 28 
No 
Earlier of date of death, and/or 
first date requiring CPAP or 
BIPAP, and/or mechanical 
ventilation 
Patient without death, requiring CPAP or BIPAP, 
and requiring mechanical ventilation recordings 
on or prior to Day 28 
Patient with safety follow-up 
Yes 
Earlier of the date of Day 28 and 
the date of last available follow- 
up** 
Patient without safety follow-up 
Yes 
Earlier of the date of Day 28 and 
the date of last available in- 
hospital assessment *** 
* Mechanical ventilation is defined as mechanical invasive ventilation or ECMO; ** Follow-up 
includes (1) safety follow-up, (2) 7-ordinal scale assessment in hospital, (3) oxygen saturation 
assessment in hospital; *** In-hospital assessment includes (1) 7-ordinal scale assessment in 
hospital, (2) oxygen saturation assessment in hospital. For patients without any oxygen saturation 
or ordinal scale assessment in-hospital assessment, date is set to Day 1. 
 
• 
Change from baseline in inflammatory markers levels (hs-CRP/CRP, D-dimer, and 
ferritin) over time 
CRP and hs-CRP will be summarized separately. Elevated CRP (yes) will be defined as 
CRP >50 mg/L or hs-CRP >3 mg/L. 
The level of inflammatory markers will be summarized descriptively using means, 
standard deviations, medians, and ranges at baseline and post baseline, together with 
the change from baseline values. This summary will be provided for patients with 
observed data, missing data will not be imputed. 
4.5.5 
Subgroup Analyses 
The primary endpoint (cumulative proportion of patients with death or requiring 
mechanical ventilation by Day 28) and the key secondary endpoint (time to hospital 
discharge or “ready for discharge”) will be assessed by the same methodologies as in 
the mITT population for the following subgroups: 
• 
Sex [Male, Female] 
• 
Age [≤60, >60 years] 
• 
Race/Ethnicity Combined [Hispanic or Latino, American Indian or Alaska Native, 
Black or African American, White, Other/unknown] 
• 
Smoking history [Never, Current/Former] 
• 
BMI [<30, >=30] 


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• 
Country group [US, ex-US] 
• 
Steroid use, prior (within 7 days of Day 1) and concurrent [Yes, No] 
• 
Anti-viral treatment use, prior (within 7 days of Day 1) and concurrent [Yes, No] 
• 
Elevated CRP [Yes, No; see definition in Section 4.5.4] 
Summaries of the endpoints listed above will be produced, separately, for each level of 
the subgroup variables and displayed on Forest plots. Small subgroups (e.g., with 
number of patients <30) may be combined to enable meaningful analysis as appropriate. 
4.6 
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. 
4.6.1 
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. 
4.6.2 
Adverse Events 
Medical Dictionary for Regulatory Activities (MedDRA) will be used as the thesaurus for 
AEs and disease codes, and the WHO Drug Global B3 Format dictionary will be used for 
treatments. A glossary of these codes will be produced. 
 
Only treatment-emergent AEs will be summarized. Treatment-emergent events are 
defined as those AEs with observed or imputed onset date on or after the start date of 
study treatment. Only where the most extreme 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. 


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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) 
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) 
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. 


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Listings of AEs and SAEs will be produced. Adverse events of special interest will also 
be listed. 
 
Listings and summary tables for post-treatment acute kidney injury (defined by 50% 
increase of creatinine from baseline) will be produced. 
 
The exposure duration in days on study (exposure duration is the date of the last safety 
assessment or death if present, minus the date of the first dose of TCZ plus one divided 
by 365.25) will be summarized. 
4.6.3 
Laboratory Data 
Summary tables will detail the actual values and changes from baseline of the laboratory 
parameters to post baseline by treatment arm. Arterial blood gases will be summarized 
separately. 
 
Patients with values outside the reference normal ranges will be listed. A listing of all 
pregnancies will be presented. 
 
Inflammatory markers hs-CRP, CRP, D-dimer, and ferritin will be analyzed by the 
methods in Section 4.5.4. 
4.6.4 
Oxygen Saturation and 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. Additionally, a graphical representation of means over time of oxygen 
saturation and temperature (daily to Day 28) will be presented by treatment group. 
 
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. Noninvasive 
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. 


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4.7 
INTERIM ANALYSES 
No interim efficacy analyses have been planned. Safety reviews by the IMC will be 
performed according to the IMC agreement (See Section 3.2). 


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5. 
REFERENCES 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report—Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol 2006; 117:391–7. 
 
Xu X, Han M, Li, T, et al. Effective treatment of severe COVID-19 patients with 
tocilizumab. Submitted manuscript. [Resource on the internet]. 2020 [updated 5 March 
2020; cited 17 March 2020]. Available from: http://www.chinaxiv.org/abs/202003.00026. 


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Appendix 1 
Protocol Synopsis 
 
 
PROTOCOL SYNOPSIS 
 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF TOCILIZUMAB IN HOSPITALIZED PATIENTS WITH 
COVID-19 PNEUMONIA 
PROTOCOL NUMBER: 
ML42528 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-001154-22 
IND NUMBER: 
148225 
 
NCT NUMBER: 
NCT04372186 
 
TEST PRODUCT: 
Tocilizumab (RO4877533) 
 
PHASE: 
Phase III 
 
INDICATION: 
COVID-19 pneumonia 
 
SPONSOR: 
Genentech, Inc. 
Objectives and Endpoints 
This study will evaluate the efficacy and safety of tocilizumab (TCZ) compared with a placebo in 
combination with SOC in hospitalized patients with COVID-19 pneumonia. To enhance the 
understanding of the clinical profile of tocilizumab for patients who belong to high-risk and 
minority populations, an emphasis will be placed on including minority-enrolling sites. 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 standard of care (SOC) for the treatment of COVID-19 pneumonia 
on the basis of the following endpoint: 
• 
Cumulative proportion of patients with death or requiring mechanical ventilation by 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 COVID-19 pneumonia on the basis of the 
following endpoints: 
• 
Time to improvement of at least 2 categories relative to baseline on a 7-category ordinal 
scale of clinical status 
• 
Time to clinical failure, defined as the time to death, mechanical ventilation, intensive care 
unit (ICU) admission, or withdrawal (whichever occurs first) 
• 
Mortality rate by Day 28 
• 
Time to hospital discharge or “ready for discharge” (e.g., awaiting social disposition) as 
evidenced by, for example, normal body temperature and respiratory rate, and stable 
oxygen saturation on ambient air or ≤2L supplemental oxygen 


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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 COVID-19 pneumonia on the basis of the 
following endpoints: 
• 
Change from baseline in inflammatory markers levels (high sensitivity C-reactive protein 
[hs-CRP]/C-reactive protein [CRP], D-dimer, and ferritin) over time 
• 
Cumulative proportion of patients requiring CPAP or BIPAP by 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 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 
• 
Incidence of any post-treatment bacterial and/or fungal infection 
• 
Incidence of any post-treatment acute kidney injury (defined by 50% increase of creatinine 
from baseline) 
 
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 placebo in combination 
with SOC in hospitalized adult patients with COVID-19. The Sponsor intends to enroll 
approximately 379 patients that have been diagnosed with COVID-19 pneumonia and meet the 
entry criteria. 
Patients must be at least 18 years of age with confirmed SARS-CoV-2 (COVID-19) infection per 
World Health Organization (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 SpO2 <94% on ambient air and be on SOC, which may include 
anti-viral treatment, low dose systemic corticosteroids, 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 and well-controlled HIV) will be excluded from the study. 
Patients will be screened and randomized within 96 hours of hospital admission. Patients will 
be randomized at a 2:1 ratio to receive blinded treatment of either TCZ or placebo, respectively. 
Study treatment must be given within approximately 4 hours after randomization. TCZ and 
placebo will be given in combination with SOC. 
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. 
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. Note: Pre-dose assessments must be repeated and reviewed before an additional 
infusion of blinded treatment of TCZ or placebo is administered. 
Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity within 96 hours of hospital admission (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. 


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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, and clinical laboratory tests. 
Patients will be followed up for a total of 60 days after first dose of study medication. 
If patients are discharged from the hospital prior to Day 28 or discontinue the study, the Study 
Completion/Discontinuation assessments are to be conducted prior to discharge or at 
discontinuation from the study. In addition, if patients are discharged from the hospital prior to 
Day 28, follow-up visits should occur weekly, or more often if clinically relevant, through Day 28 
to assess mortality and adverse events. Follow-up visits may be conducted by onsite clinic 
visits, telephone calls, or home visits. After Day 28, all patients should have a follow-up visit on 
approximately Day 60 which may be conducted as an onsite clinic visit, telephone call, or home 
visit for discharged patients. 
During the study, standard supportive care will be given according to clinical practice. After 
study completion, patients should be referred to their regular healthcare provider based on their 
doctor’s decision and as part of standard of care. 
 
Number of Patients 
This study aims to enroll approximately 379 hospitalized patients with COVID-19 pneumonia. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Documented informed consent 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 providing Informed Consent Form 
• 
Ability to comply with the study protocol, in the investigator's judgment 
• 
Hospitalized 
• 
COVID-19 pneumonia confirmed per a positive PCR of any specimen (e.g., respiratory, 
blood, urine, stool, other bodily fluid) and radiographic imaging (CT scan or chest X-ray) 
• 
Able to complete screening within 96 hours of hospital admission 
• 
Blood oxygen saturation (SpO2) <94% while on ambient air 
If a patient is on supplemental oxygen with SpO2 ≥94%, but desaturation to <94% 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). 
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. 


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• 
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 
• 
Require CPAP, BIPAP, or mechanical ventilation 
• 
Active TB infection or last TB infection within 1 month of randomization 
• 
Suspected active bacterial, fungal, viral, or other infection (besides COVID-19 and 
well-controlled HIV) 
• 
In the opinion of the investigator, progression to death is imminent and inevitable within the 
next 24 hours, irrespective of the provision of treatments 
• 
Immunocompromised (besides well-controlled HIV) or on immunosuppressive therapy 
(except for steroids for COVID), advanced cancer 
• 
Have received oral anti-rejection or immunomodulatory drugs (including TCZ) within the 
past 3 months 
• 
Participating in another IL-6 antagonist clinical trial or other drug clinical trials (participation 
in COVID-19 anti-viral trials may be permitted if approved by Medical Monitor) 
• 
ALT or AST >5 x upper limit of normal (ULN) detected within 24 hours at screening 
(according to local laboratory reference ranges) 
• 
ANC <1000/µL at screening (according to local laboratory reference ranges) 
• 
Platelet count <50,000/µL 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 
• 
Any history of diverticulitis or gastrointestinal perforation 
The use of remdesivir, hydroxychloroquine, chloroquine, and convalescent plasma, is not an 
exclusion to participation in this trial, and is left to the discretion of the primary medical team. 
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 8 months. 


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Investigational Medicinal Products 
Test Product (Investigational Drug) 
Patients assigned to the active arm will receive one or two doses of tocilizumab (TCZ) via 
intravenous (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 
infusion. 
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: 
• 
Cumulative proportion of patients with death or requiring mechanical ventilation by Day 28 
 
Time to death or the first utilization of mechanical ventilation after randomization will be 
compared between the TCZ group and the placebo group using the stratified log-rank test with 
age group (age ≤60, age >60 years) as the stratification factor. The cumulative proportion of 
patients with death or requiring mechanical ventilation at Day 28 will be estimated using the 
Kaplan-Meier method. 
Details of the primary endpoint analysis will be included in the Statistical Analysis Plan (SAP). 
Determination of Sample Size 
The estimated sample size was determined based on the time from randomization to the first 
utilization of mechanical ventilation by Day 28. 
The total modified intent-to-treat (mITT) sample size of 379 patients with a 2:1 randomization of 
TCZ (n=253) to placebo (n=126) provides approximately 80% power using a Logrank test to 
detect a 15% difference between treatment groups in time to death or mechanical ventilation by 
Day 28 under the following assumptions: cumulative survival (i.e., alive and not requiring 
mechanical ventilation) rates of 75% in the TCZ group and 60% in placebo group, with 28-day 
follow-up, using a two-sided 5% alpha, and 10% dropout rate in each arm. Sample size 
re-estimation may be considered during the study based on updated assumptions of the 
treatment effect. 
Planned Interim Analyses 
An Internal Monitoring Committee (IMC) will evaluate safety according to procedures and 
guidelines detailed in the IMC agreement. The IMC will consist of Sponsor representatives who 
will not be blinded to study data. Details of the safety reviews will be provided in the SAP. 


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Appendix 2 
Schedule of Activities: Days 1 and 2 
 
Screening a, b 
Baseline 
Study Day 
−4 to 0 
1 
2 
Time Post Initial Treatment 
(Assessment Window) 
0 min 
Pre-dose 
(approx. −4 hrs) 
15 min 
After end of infusion 
(approx. +1 hr) 
24 hrs 
(±12 hrs) 
Informed consent 
x 
Inclusion/exclusion criteria 
x 
x 
Demographic data 
x 
Randomization 
x 
Medical history 
x 
Complete physical examination c, d 
x 
Weight 
x 
COVID-19 diagnosis e 
x 
Chest X-ray/CT scan d, f 
x 
ECG 
x 
Pregnancy test d, g 
x 
PaO2/FiO2 d, h 
x (optional) 
  Optional   
SpO2 d, i 
x 
x 
x 
x 
Vital signs d, i 
x 
x 
x 
x 
Ordinal scoring (including ventilation requirement) j 
x 
x 
Adverse events k 
x 
x 
Concomitant medications l 
x 
x 
Hematology d, m 
x 
x 


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Screening a, b 
Baseline 
Study Day 
−4 to 0 
1 
2 
Time Post Initial Treatment 
(Assessment Window) 
0 min 
Pre-dose 
(approx. −4 hrs) 
15 min 
After end of infusion 
(approx. +1 hr) 
24 hrs 
(±12 hrs) 
Chemistry d, n 
x 
x 
hs-CRP/CRP, D-dimer (if available via local laboratory), and ferritin d 
x 
Study drug administration o 
x 
ALP=alkaline phosphatase; CRP=C-reactive protein; CT=computed tomography; ECG=electrocardiogram; eCRF=electronic case report form; 
hr(s)=hour(s); hs-CRP=high sensitivity C-reactive protein; min=minutes; NCI CTCAE=National Cancer Institute Common Terminology Criteria for 
Adverse Events v.5.0; PaO2/FiO2=arterial oxygen partial pressure/fraction of inspired oxygen; SpO2=peripheral capillary oxygen saturation; 
TCZ=tocilizumab. 
Note: On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a Results from standard-of-care tests or examinations performed prior to obtaining informed consent and within 96 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, respiratory, gastrointestinal, 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 Physical examination, blood tests, and other assessments conducted after arrival at the hospital, but before the informed consent is signed, can 
be used as screening assessments. 
e COVID-19 test (SARS-CoV2 PCR) to confirm diagnosis should be performed at or before screening (if testing is conducted before screening, 
documentation must be available). 
f Screening chest X-ray or CT scans should be performed within 96 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. 
g 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. 
h If arterial blood gases are measured. 


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i All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body temperature) and oxygen 
saturation should be recorded together once daily while the patient remains hospitalized. If measured more than once daily, 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. 
j Assessment of clinical status using the ordinal scale, which includes change in ventilation usage (non-invasive or mechanical), should be 
recorded at baseline on Day 1 then again daily every morning (between approximately 8 am and 12 pm) for patients who remain hospitalized. 
k 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). 
l 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. 
m Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes). 
n Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total bilirubin, ALP, ALT, and AST. 
o The initial study drug infusion should be given within approximately 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. Note: Pre-dose assessments must be 
repeated and reviewed before an additional infusion of blinded treatment of TCZ or placebo is administered. 


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Appendix 3 
Schedule of Activities: Day 3−Study Completion 
 
Days 3−28 a 
Study 
Completion/ 
Discontinuation i 
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 i 
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 
Concomitant medications f 
 
x 
Hematology g 
x 
x 
Chemistry h 
x 
x 
hs-CRP/CRP, D-dimer (if 
available via local 
laboratory), and ferritin 
x 
x 
ALP=alkaline phosphatase; CRP=C-reactive protein; CT=computed tomography; ECG=electrocardiogram; eCRF=electronic case report form; hs- 
CRP=high sensitivity C-reactive protein; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0; 
PaO2/FiO2=arterial oxygen partial pressure/fraction of inspired oxygen; SpO2=peripheral capillary oxygen saturation. 
a If patients are discharged from the hospital prior to Day 28, follow-up visits should occur weekly, or more often if clinically relevant, through 
Day 28 to assess mortality and adverse events. Follow-up visits may be conducted by onsite clinic visits, telephone calls, or home visits. 
b All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body temperature) and oxygen 
saturation should be recorded together once daily while the patient remains hospitalized. If measured more than once daily, 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. 
c If arterial blood gases are measured. 
d Assessment of clinical status using the ordinal scale should be recorded at baseline on Day 1 then again daily for patients who remain 
hospitalized. 


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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). 
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 bilirubin, ALP, ALT, and AST. 
i If patients are discharged from the hospital prior to Day 28 or discontinue the study, the Study Completion/Discontinuation assessments are to 
be conducted prior to discharge or at discontinuation from the study. In addition, if patients are discharged from the hospital prior to Day 28, 
follow-up visits should occur weekly, or more often if clinically relevant, through Day 28 to assess mortality and adverse events. The Day 60 
follow up may be conducted by an onsite clinic visit, telephone call, or home visit for discharged patients. Day 60 follow up is required to collect 
adverse events only.