Clinical trial NCT04409262
Conditions: COVID-19 Pneumonia
Sponsor: Hoffmann-La Roche
Start date: 2020-06-16; Completion date: 2021-03-08
Enrollment: 649 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy and safety of combination therapy with remdesivir plus tocilizumab compared with remdesivir plus placebo in hospitalized patients with COVID-19 pneumonia.

Detailed description:

Arms: arm 1: Participants assigned to the RDV+TCZ arm will receive a 10-day treatment course of RDV, plus one infusion of TCZ on Day 1. arm 2: Participants assigned to the RDV+ placebo arm will receive a 10-day treatment course of RDV, plus one infusion of TCZ-placebo on Day 1.
Interventions: intervention 1: Remdesivir intervention 2: Tocilizumab intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive intravenous (IV) RDV intervention 2: Participants will receive IV TCZ intervention 3: Participants will receive IV placebo matched to TCZ

Protocol documents:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
TocilizumabF. Hoffmann-La Roche Ltd
Protocol WA42511, Version 6
PROTOCOL
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
MULTICENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF REMDESIVIR PLUS 
TOCILIZUMAB COMPARED WITH REMDESIVIR
PLUS PLACEBO IN HOSPITALIZED PATIENTS WITH 
SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
WA42511
VERSION NUMBER:
6
EUDRACT NUMBER:
2020-002275-34
IND NUMBER:
148225
NCT NUMBER:
NCT04409262
TEST PRODUCTS:
Tocilizumab (RO4877533)
Remdesivir
MEDICAL MONITOR:
, M.D., M.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below.
 
22-Feb-2021 00:20:00
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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PROTOCOL HISTORY
Protocol
Version
Date Final
5
10 December 2020
4
21 September 2020
3
1 July 2020
2
21 May 2020
1
27 April 2020


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PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Protocol WA42511 has been amended in response to health authority feedback.
Changes have been made to the planned data analyses and do not affect the Schedule 
of Activities or data collected in the study.  Changes to the protocol are summarized 
below:

The derivation of the primary endpoint was updated (Section 2.1.1).

Two additional secondary endpoints were added (Section 2.1.2):
–
Proportion of patients discharged or “ready for discharge” up to Day 28
–
Proportion of patients who require initiation of mechanical ventilation 
postbaseline or die up to Day 28 and up to Day 60

The definition of the mITT population was clarified as all patients randomized in the 
study who received any amount of tocilizumab/placebo (Section 6.4).

Time to event endpoints were changed from “time from administration of 
tocilizumab/placebo” to “time from randomization” (Sections 2.1.1, 2.1.2, 2.1.3, 6.4.1, 
6.4.2, and 6.4.3). 

Analysis timepoints were defined for all efficacy endpoints (Sections 2.1.1, 2.1.2, 
2.1.3, 6.4.1, 6.4.2, and 6.4.3).

It was clarified that SARS-CoV-2 viral load is not limited to respiratory samples and
will also be analyzed in serum samples (Sections 2.1.3 and 6.4.3).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 20
1.1
Background on COVID-19 Pneumonia.................................. 20
1.2
Background on Remdesivir.................................................... 20
1.3
Experience with Remdesivir in COVID-19 
Pneumonia ............................................................................ 21
1.4
Background on Tocilizumab .................................................. 22
1.5
Tocilizumab Treatment in Cytokine-Release 
Syndrome of CAR T-Cell Therapy......................................... 23
1.6
Experience with Tocilizumab in COVID-19 
Pneumonia ............................................................................ 24
1.7
Study Rationale and BenefitRisk Assessment..................... 26
2.
OBJECTIVES AND ENDPOINTS ............................................................... 26
2.1
Efficacy Objectives ................................................................ 26
2.1.1
Primary Efficacy Objective..................................................... 26
2.1.2
Secondary Efficacy Objective................................................ 26
2.1.3
Exploratory Efficacy Objective............................................... 27
2.2
Safety Objective .................................................................... 28
2.3
Pharmacokinetic Objective .................................................... 28
2.4
Biomarker Objective .............................................................. 28
3.
STUDY DESIGN......................................................................................... 29
3.1
Description of the Study......................................................... 29
3.2
End of Study and Length of Study......................................... 31
3.3
Rationale for Study Design.................................................... 31
3.3.1
Rationale for Remdesivir and Tocilizumab Dose 
and Schedule......................................................................... 31
3.3.2
Rationale for Patient Population ............................................ 32
3.3.3
Rationale for Control Group................................................... 33
3.3.4
Rationale for Biomarker Assessments................................... 33
4.
MATERIALS AND METHODS .................................................................... 33


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4.1
Patients.................................................................................. 33
4.1.1
Inclusion Criteria.................................................................... 33
4.1.2
Exclusion Criteria................................................................... 35
4.2
Method of Treatment Assignment and Blinding..................... 35
4.2.1
Treatment Assignment........................................................... 35
4.2.2
Blinding.................................................................................. 36
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 37
4.3.1
Study Treatment Formulation and Packaging........................ 37
4.3.1.1
Remdesivir............................................................................. 37
4.3.1.2
Tocilizumab and Placebo....................................................... 37
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 37
4.3.2.1
Remdesivir............................................................................. 37
4.3.2.2
Tocilizumab and Placebo....................................................... 38
4.3.3
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 39
4.3.4
Continued Access to Remdesivir........................................... 40
4.3.5
Continued Access to Tocilizumab.......................................... 40
4.4
Concomitant Therapy ............................................................ 40
4.4.1
Permitted Therapy................................................................. 40
4.4.2
Cautionary Therapy ............................................................... 41
4.4.2.1
Medications Given with Precaution Due to Effects 
Related to CYP Enzymes ...................................................... 41
4.4.2.2
Herbal Therapies................................................................... 41
4.4.3
Prohibited Therapy ................................................................ 41
4.5
Study Assessments............................................................... 42
4.5.1
Informed Consent Forms and Screening Log........................ 42
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 43
4.5.3
Physical Examinations........................................................... 43
4.5.4
Vital Signs and Oxygen Saturation........................................ 44
4.5.5
Assessments Specific to National Early Warning 
Score 2 .................................................................................. 44




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5.2
Safety Parameters and Definitions ........................................ 54
5.2.1
Adverse Events ..................................................................... 54
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 54
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 55
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 56
5.3.1
Adverse Event Reporting Period ........................................... 56
5.3.2
Eliciting Adverse Event Information....................................... 56
5.3.3
Assessment of Severity of Adverse Events ........................... 56
5.3.4
Assessment of Causality of Adverse Events ......................... 57
5.3.5
Procedures for Recording Adverse Events............................ 58
5.3.5.1
Infusion-Related Reactions.................................................... 58
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 58
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 59
5.3.5.4
Persistent or Recurrent Adverse Events................................ 59
5.3.5.5
Abnormal Laboratory Values ................................................. 59
5.3.5.6
Abnormal Vital Sign Values ................................................... 60
5.3.5.7
Abnormal Liver Function Tests.............................................. 61
5.3.5.8
Deaths ................................................................................... 61
5.3.5.9
Preexisting Medical Conditions.............................................. 61
5.3.5.10
Lack of Efficacy or Worsening of Severe 
COVID-19 Pneumonia........................................................... 62
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 62
5.3.5.12
Cases of Accidental Overdose or Medication 
Error....................................................................................... 62
5.3.5.13
Safety Biomarker Data........................................................... 63
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 64
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 65
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 65
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 65


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5.4.2.2
Events That Occur after Study Drug Initiation........................ 65
5.4.3
Reporting Requirements for Pregnancies.............................. 66
5.4.3.1
Pregnancies in Female Patients............................................ 66
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 66
5.4.3.3
Abortions ............................................................................... 66
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 67
5.5
Follow-Up of Patients after Adverse Events .......................... 67
5.5.1
Investigator Follow-Up........................................................... 67
5.5.2
Sponsor Follow-Up ................................................................ 67
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 67
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 68
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 68
6.1
Determination of Sample Size ............................................... 69
6.2
Summaries of Conduct of Study............................................ 69
6.3
Treatment Group Comparability ............................................ 69
6.4
Efficacy Analyses .................................................................. 70
6.4.1
Primary Efficacy Endpoint...................................................... 70
6.4.2
Secondary Efficacy Endpoints............................................... 71
6.4.3
Exploratory Efficacy Endpoints.............................................. 72
6.5
Safety Analyses..................................................................... 73
6.6
Pharmacokinetic Analyses..................................................... 74
6.7
Biomarker Analyses............................................................... 74
6.8
Interim Analyses .................................................................... 74
6.9
External Data......................................................................... 75
7.
DATA COLLECTION AND MANAGEMENT ............................................... 75
7.1
Data Quality Assurance......................................................... 75
7.2
Electronic Case Report Forms............................................... 76
7.3
Source Data Documentation.................................................. 76
7.4
Use of Computerized Systems .............................................. 77
7.5
Retention of Records............................................................. 77


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8.
ETHICAL CONSIDERATIONS.................................................................... 77
8.1
Compliance with Laws and Regulations ................................ 77
8.2
Informed Consent.................................................................. 77
8.3
Institutional Review Board or Ethics Committee.................... 79
8.4
Confidentiality........................................................................ 79
8.5
Financial Disclosure .............................................................. 80
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 80
9.1
Study Documentation ............................................................ 80
9.2
Protocol Deviations................................................................ 80
9.3
Management of Study Quality ............................................... 80
9.4
Site Inspections ..................................................................... 81
9.5
Administrative Structure......................................................... 81
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 81
9.7
Protocol Amendments ........................................................... 82
10. REFERENCES ........................................................................................... 83
LIST OF TABLES
Table 1
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 57
Table 2
Causal Attribution Guidance ....................................................... 58
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 31
LIST OF APPENDICES
Appendix 1
Schedule of Activities:  Screening, Days 1 and 2....................... 85
Appendix 2
Schedule of Activities:  Days 328............................................. 89
Appendix 3
Schedule of Activities:  After Day 28.......................................... 92
Appendix 4
National Early Warning Score 2 (NEWS2)................................. 95


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
MULTICENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF REMDESIVIR PLUS 
TOCILIZUMAB COMPARED WITH REMDESIVIR
PLUS PLACEBO IN HOSPITALIZED PATIENTS 
WITH SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
WA42511
VERSION NUMBER:
6
EUDRACT NUMBER:
2020-002275-34
IND NUMBER:
148225
NCT NUMBER:
NCT04409262
TEST PRODUCTS:
Tocilizumab (RO4877533)
Remdesivir
MEDICAL MONITOR:
, M.D., M.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by the CRO.


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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
REMDESIVIR PLUS TOCILIZUMAB COMPARED WITH 
REMDESIVIR PLUS PLACEBO IN HOSPITALIZED PATIENTS 
WITH SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
WA42511
VERSION NUMBER:
6
EUDRACT NUMBER:
2020-002275-34
IND NUMBER:
148225
NCT NUMBER:
NCT04409262
TEST PRODUCTS:
Tocilizumab (RO4877533)
Remdesivir
PHASE:
Phase III
INDICATION:
Severe COVID-19 pneumonia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of combination therapy with remdesivir plus 
tocilizumab compared with remdesivir plus placebo in hospitalized patients with severe
coronavirus disease 2019 (COVID-19) pneumonia.  Specific objectives and corresponding 
endpoints for the study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of the remdesivir plus 
tocilizumab arm compared with the remdesivir plus placebo arm for the treatment of severe 
COVID-19 pneumonia on the basis of the following endpoint:

Time from randomization to hospital discharge or “ready for discharge” up to Day 28
Hospital discharge or “ready for discharge” is defined as a score of 1 on the 7-
category ordinal scale.  
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of the remdesivir plus 
tocilizumab arm compared with the remdesivir plus placebo arm for the treatment of severe 
COVID-19 pneumonia on the basis of the following endpoints:

Time to mechanical ventilation or death up to Day 28, defined as the time from
randomization to the first occurrence of mechanical ventilation or death (whichever occurs 
first)

Time to improvement of at least 2 categories relative to baseline on a 7-category ordinal 
scale of clinical status up to Day 28

Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical 
status on Days 7, 14, 21, 28, and 60


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
Proportion of patients requiring initiation of mechanical ventilation postbaseline up to 
Day 28 and Day 60 (patients who do not require mechanical ventilation at baseline)

Proportion of patients who are alive and free of respiratory failure at Day 28 and Day 60 
(patients requiring mechanical ventilation at baseline)

Duration of mechanical ventilation (patients who require mechanical ventilation at baseline)
up to Day 28

Time to death up to Day 28 and Day 60

Mortality on Days 14, 28, and 60 (proportions at specified time points)

Time to recovery up to Day 28, defined as time from randomization to the time when a 
category of 2 on the 7-category ordinal scale (non-ICU hospital ward or “ready for 
hospital ward” not requiring supplemental oxygen), or better is observed 

Proportion of patients who are discharged or "ready for discharge" up to Day 28

Proportion of patients who require initiation of mechanical ventilation 
postbaseline or die up to Day 28
A pre-defined meta-analysis may be performed on mortality as well as the primary 
and selected secondary endpoints with results of Studies WA42380 and ML42528.
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of the remdesivir plus 
tocilizumab arm compared with the remdesivir plus placebo arm for the treatment of severe 
COVID-19 pneumonia on the basis of the following endpoints:

Time to clinical improvement (TTCI) up to Day 28, defined as time from randomization
to National Early Warning Score 2 (NEWS2) score of 2 maintained for 24 hours:

Time to clinical failure up to Day 28, defined as the time from randomization to the first 
occurrence of mechanical ventilation, ICU admission, death, or withdrawal from study 
prior to discharge (whichever occurs first)
For patients entering the study already on mechanical ventilation, clinical failure is 
defined as a one-category worsening on the ordinal scale, withdrawal from study
prior to discharge, or death.

Proportion of patients requiring initiation of ICU care postbaseline up to Day 28 and Day 60

Duration of ICU stay up to Day 28

Duration of supplemental oxygen use up to Day 60

Proportion of patients requiring initiation of vasopressor use postbaseline up to Day 28

Duration of vasopressor use up to Day 28

Proportion of patients requiring initiation of extracorporeal membrane oxygenation (ECMO)
postbaseline up to Day 28 and up to Day 60

Duration of ECMO up to Day 28

Organ failure-free days from randomization to Day 28

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load up to Day 28 
and Day 60

Time to reverse-transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 virus 
negativity up to Day 60 (respiratory samples) or Day 14 (serum samples)
Safety Objective
The safety objective for this study is to evaluate the safety of the remdesivir plus tocilizumab 
arm compared with the remdesivir plus placebo arm for the treatment of severe COVID-19 
pneumonia on the basis of the following endpoints:


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
Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)

Proportion of patients with any post-treatment infection at specified timepoints

Change from baseline in targeted clinical laboratory test results 
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of remdesivir 
and metabolite(s) in patients with severe COVID-19 pneumonia on the basis of the following 
endpoint:

Plasma concentration of remdesivir and metabolite(s) at specified timepoints
Biomarker Objective 
The exploratory biomarker objectives for this study are to identify and/or evaluate biomarkers 
that could be predictive of response to remdesivir plus tocilizumab combination treatment 
(i.e., predictive biomarkers), may serve as early surrogates of efficacy or be associated with 
efficacy, may be associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), may be associated with susceptibility to developing adverse events or could lead 
to improved adverse event monitoring or investigation (i.e., safety biomarkers), could provide 
further evidence of tocilizumab pharmacological activity (i.e., pharmacodynamic biomarkers), or 
could overall increase our knowledge and understanding of disease pathogenesis and drug 
safety, on the basis of the following endpoint:

Relationship between biomarkers in serum, peripheral blood mononuclear cells (PBMCs), 
blood, and tissue and efficacy or safety endpoints
STUDY DESIGN
Description of the Study
This is a Phase III, randomized, double-blind, multicenter study to assess the efficacy and 
safety of remdesivir plus tocilizumab compared with remdesivir plus placebo in hospitalized 
patients with severe COVID-19 pneumonia.  The Sponsor intends to enroll patients who have 
been diagnosed with severe COVID-19 pneumonia and meet the entry criteria in centers 
globally.  Enrollment may be up to 800 patients but will target approximately 650 patients.
In addition to the randomized patients from this study, patients from the Phase III studies 
WA42380 and ML42528 will be included in a meta-analysis of the primary and secondary 
endpoints.  This analysis will assist in the interpretation of the effect of tocilizumab in 
combination with remdesivir compared with tocilizumab alone.
Patients must be at least 12 years of age and hospitalized with confirmed COVID-19 infection 
per WHO criteria, including a positive polymerase chain reaction (PCR) of any specimen 
(e.g., respiratory, blood, urine, stool, other bodily fluid).  At the time of enrollment, patients must 
require supplemental oxygen 6 L/min to maintain SpO2 93%.
Patients in whom, in the opinion of the treating physician, progression to death is imminent and 
inevitable within the next 24 hours, irrespective of the provision of treatments, will be excluded 
from the study.  Patients with active tuberculosis (TB) or suspected active bacterial, fungal, viral, 
or other infection (besides COVID-19) will be excluded from the study.  
Patients will be randomized as soon as possible after screening at an initial 2:1 ratio to receive 
blinded treatment of either remdesivir plus tocilizumab or remdesivir plus placebo.  Study 
treatment will be given in combination with standard supportive care.  The randomization will be 
stratified by geographic region (North America, Europe, Other) and a 2-level factor based on the 
assessment of the 7-category ordinal scale of clinical status at screening, with levels 45 and 6.  
The proportion of randomized patients in the scale6 stratum will also be no more than 25%.
Patients assigned to the remdesivir plus tocilizumab (RDVTCZ) arm will receive remdesivir as 
a 200 mg IV loading dose followed by one infusion of tocilizumab 8 mg/kg (maximum dose of 
800 mg) on Day 1.  Patients will subsequently be administered a 100 mg once-daily IV 


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maintenance dose of remdesivir from Days 210.  Remdesivir will be discontinued at the time of
hospital discharge even if 10 days of remdesivir dosing have not been completed.
Remdesivir dosing must be adjusted for patients that enter the study having received prior 
remdesivir.  Patients who received remdesivir prior to randomization must not exceed 10 days 
of dosing in total (including remdesivir received prior to the study and during the study).  If a 
patient received 1 dose of remdesivir (200-mg loading dose) prior to Day 1, the patient should 
receive remdesivir 100 mg on Days 19.  If a patient received 2 doses of remdesivir (200-mg 
loading dose followed by 100-mg maintenance dose) prior to Day 1, the patient should receive 
remdesivir 100 mg on Days 18.  Patients who received remdesivir prior to trial entry must not 
receive a second 200-mg loading dose on Day 1.  The same sequence and timing of remdesivir 
and tocilizumab will be followed on Days 1 and 2 regardless of whether the patient has received 
remdesivir prior to randomization.
For both arms, if the patient has a sustained fever or clinically significant worsening of signs or 
symptoms (e.g., an increased supplemental oxygen requirement), one additional infusion of 
blinded tocilizumab/placebo can be given 824 hours after the first tocilizumab/placebo infusion.  
The second dose of blinded tocilizumab must not be given if the patient develops an adverse 
event or laboratory abnormalities that warrant discontinuation of tocilizumab. 
Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity (for a total of 2 screenings per participant) at the investigator’s 
discretion.  Patients are not required to re-sign the consent form if they are re-screened within 
7 days after previously signing the consent form.  The investigator will record the reasons for 
screen failure in the screening log.
The study assessments to be conducted include the following: physical examination, vital signs, 
oxygen saturation, assessment of consciousness, presence and absence of respiratory support, 
chest X-ray, ECG, adverse events, concomitant therapies, clinical laboratory tests, and 
nasopharyngeal swabs.
Patients will be followed up for a total of 60 days after first dose of study drug.
If patients are discharged from hospital prior to Day 28, follow-up visits should be conducted on 
Day 14, Day 21, and Day 28 (2 days).  Follow-up visits on Day 14 and Day 21 may be 
conducted as telephone visits.  Patients should return to the site for the Day 28- visit, if at all 
possible.  After Day 28, all patients should have follow-up visits on Day 35, Day 45, and Day 60.  
The Day 35- and Day 45-visits may be conducted by telephone for discharged patients.  
Patients should return to the site for the Day 60 visit, if at all possible.
Number of Patients
The target enrollment for the study is approximately 650 hospitalized patients with severe 
COVID-19 pneumonia, but up to 800 patients may be enrolled to achieve approximately 
520 patients discharged by Day 28.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Documented informed consent to participate in the study

Signed Assent Form when appropriate, as determined by the patient's age and individual 
site and country standards

Age 12 years at time of informed consent

Ability to comply with the study protocol, in the investigator's judgment

Hospitalized with COVID19 pneumonia confirmed per a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or 
CT scan 
The PCR test must be collected 7 days before randomization.  

Requiring 6 L/min supplemental oxygen to maintain SpO2 93%

Agrees to not participate in another clinical trial for the treatment of COVID-19 while 
participating in this study


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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 90 days after the final dose of study drug.  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of
childbearing potential may be adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 60 days after 
the final dose of study drug to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of preventing drug exposure.  If required per local 
guidelines or regulations, information about the reliability of abstinence will be 
described in the local Informed Consent Form.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known severe allergic reactions to tocilizumab or other monoclonal antibodies

Known hypersensitivity to remdesivir, the metabolites, or formulation excipients

Active TB infection 

Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) 

In the opinion of the investigator, progression to death is imminent and inevitable within the 
next 24 hours, irrespective of the provision of treatments

Treatment with immunosuppressive or immunomodulatory therapy (including tocilizumab) 
within the past 3 months

Concurrent treatment with other agents with actual or possible direct-acting antiviral activity 
against SARS-CoV-2 within 24 hours prior to study drug dosing
In addition, patients with prior or current treatment with 2 doses remdesivir for 
COVID-19 are excluded.

Participating in another drug clinical trial 

Estimated glomerular filtration rate (eGFR) 30 mL/min (including patients receiving 
hemodialysis or hemofiltration), using the equation described in the FDA EUA Fact Sheet 
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
ALT or AST 5upper limit of normal (ULN) detected within 24 hours of screening 
(according to local laboratory reference ranges)

ANC 1000/L at screening 

Platelet count 50,000/L at screening 

Body weight 40 kg

Pregnant or breastfeeding, or positive pregnancy test in a predose examination

Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of 
randomization 

Any serious medical condition or abnormality of clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for the last follow-up is received from the last patient, 
whichever occurs later.  The end of the study is expected to occur approximately 2 months after 
the last patient is enrolled.  
In addition, the Sponsor may decide to terminate the study at any time.
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.
Investigational Medicinal Products
Test Products (Investigational Drugs)
The investigational medicinal products (IMPs) for this study are remdesivir IV, tocilizumab IV, 
and placebo for tocilizumab IV 
Patients assigned to the remdesivir plus tocilizumab (RDV TCZ) arm will receive remdesivir 
loading dose followed by one infusion of tocilizumab on Day 1, and once-daily maintenance 
dose of remdesivir from Days 210. 
Patients assigned to the remdesivir plus placebo (RDV placebo) arm will receive remdesivir as 
loading dose followed by one infusion of tocilizumab-placebo on Day 1, and once-daily 
maintenance dose of remdesivir from Days 210.
For both arms, if the patient has a sustained fever or clinically significant worsening of signs or 
symptoms (e.g., an increased supplemental oxygen requirement), one additional infusion of 
blinded tocilizumab/placebo can be given 824 hours after the first tocilizumab/placebo infusion.  
The second dose of blinded tocilizumab must not be given if the patient develops an adverse 
event or laboratory abnormalities that warrant discontinuation of tocilizumab.
Administration of study treatments will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of the remdesivir plus 
tocilizumab arm compared with remdesivir plus placebo arm using the following endpoint:

Time from randomization to hospital discharge or “ready for discharge” up to Day 28
Hospital discharge or “ready for discharge” is defined as a score of 1 on the 7-
category ordinal scale. Patients will meet the endpoint at the time of 
discharge or the time that they achieve category 1 of the 7-category ordinal 
scale, provided that they do not have any further ordinal scale 
assessments category 1 on or prior to Day 28, they are not re-hospitalized 
on or prior to Day 28 and they do not die on or prior to Day 28.


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The distribution of time from randomization to hospital discharge (or ready for discharge) will 
be compared with the remdesivir plus tocilizumab arm and the remdesivir plus placebo arm up 
to Day 28.  Patients discharged after Day 28 will be administratively censored.  The distributions 
will be compared using an appropriate method for comparing censored event distributions such 
as the Cox model.  Kaplan-Meier and cumulative incidence plots will be presented as well as 
median time to discharge (or ready for discharge), with 95% confidence intervals for the 
remdesivir plus tocilizumab arm and the remdesivir plus placebo arm.
Determination of Sample Size
The primary endpoint, time to discharge or “ready for discharge,” is event driven.  Based on the 
severe cohort receiving 10 days of remdesivir in Gilead’s SIMPLE trial (Study GS-US-540-5773), 
the median time to discharge or “ready for discharge” was 11 days.  Assuming a median time to 
discharge or “ready for discharge” of 11 days in the remdesivir plus placebo arm, a hazard ratio 
of 1.3 or an approximately 2.5-day reduction in median time for remdesivir plus tocilizumab 
versus remdesivir plus placebo, and a 2:1 randomization to remdesivir plus tocilizumab or 
remdesivir plus placebo, approximately 650 patients are needed to accrue approximately 
520 events to achieve approximately 80% power.  A reduction of at least 2 days in median time 
to discharge was considered clinically meaningful and the sample size was increased to ensure 
that a minimum effect size could be detected.  Further sample size adjustments may be 
considered during the study based on external information.  The sample size may be increased 
up to a maximum of approximately 800 randomized patients if fewer events than expected are 
observed or further shifts in standard of care warrant reassessing sample size assumptions.
Interim Analyses 
There will be up to three optional interim analyses.  The first interim analysis can occur after 
approximately one-third to one-half of the patients have been assessed for the primary endpoint 
on Day 28, depending on enrollment rate.  There may be up to two additional unplanned interim 
analyses, and these will be considered if there are major changes to the study design following 
the first interim analysis.
Full statistical details of any optional interim analyses, along with the rationale and timing will be 
documented in an interim SAP, which will be made available to the relevant health authorities 
before the data snapshot for the first interim analysis. Only the Data Monitoring Committee
(DMC) will be unblinded and decision criteria will be specified in the interim SAP.  Should an 
unblinded interim analysis occur, any necessary adjustment to the type 1 error rate will be 
specified in the SAP prior to unblinding the study.
The optional interim analysis will be based on the time to discharge (or ready for discharge) and 
mortality.  Questions to be addressed at the interim analysis might include futility as well as 
potential efficacy.
The DMC will also evaluate safety according to policies and procedures detailed in the DMC 
Charter.  Regular safety reviews will begin after approximately 45 patients (15 remdesivir plus 
placebo and 30 remdesivir plus tocilizumab) have been enrolled and have reached 14 days of 
follow-up.  Early stopping criteria based on compelling efficacy or an imbalance in adverse 
events will be detailed in the DMC Charter.  The safety interim analyses will also be conducted 
by a statistical programmer and statistician independent from the study management team and 
will be reviewed by the DMC.  Interactions between the DMC and Sponsor will be carried out as 
specified in the DMC Charter.
The DMC initially consisted of Sponsor representatives not involved in any operational aspects 
of the study and a Scientific Oversight Committee of external experts (responsibilities and 
operating principles of the DMC are described in a charter, the Internal Monitoring Committee 
and Scientific Oversight Committee Agreement).  The DMC responsibilities transitioned to a 
fully independent Data Monitoring Committee (iDMC) prior to the third scheduled safety review 
after approximately 300 patients reached Day 28 of follow-up.  The iDMC will also conduct a 
fourth scheduled safety data review when at least 450 patients have reached Day 28.  Data 
processing will be handled by a Sponsor statistician and statistical programmer independent of 
the study management team.  Details are reported in the iDMC Charter.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ARDS
acute respiratory distress syndrome
CAR
chimeric antigen receptor
CoV
coronavirus
COVID-19
coronavirus disease 2019
CRP
C-reactive protein
CRS
cytokine-release syndrome
CT
computed tomography (scan)
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
EC
Ethics Committee
eCRF
electronic Case Report Form
eGFR
estimated glomerular filtration rate
ECMO
extracorporeal membrane oxygenation
EDC
electronic data capture
FDA
(U.S.) Food and Drug Administration
FiO2
fraction of inspired oxygen
GCA
giant cell arteritis
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
ICU
intensive care unit
iDMC
independent Data Monitoring Committee
IL-6
interleukin 6
IL-6R
interleukin-6 receptor
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IQR
interquartile range
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
MERS-CoV
Middle East respiratory syndrome corona virus
mITT
modified intent-to-treat (population)
MOD
multiple-organ dysfunction
MOF
multi-organ failure
NCI
National Cancer Institute
NEWS2
National Early Warning Score 2
PaO2
partial pressure of oxygen


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Abbreviation
Definition
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PCT
procalcitonin
pJIA
polyarticular juvenile idiopathic arthritis
PK
pharmacokinetic
PO
proportional odds
PY
patient years
QD
once a day
RA
rheumatoid arthritis
RDV
remdesivir
RT-PCR
reverse-transcriptase polymerase chain reaction
SAP
Statistical Analysis Plan
SARS-CoV
severe acute respiratory syndrome coronavirus
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBECD
sulfobutylether-beta-cyclodextrin
sIL6-R
soluble interleukin-6 receptor
sJIA
systemic juvenile idiopathic arthritis
SOC
standard of care
SpO2
peripheral capillary oxygen saturation
TAK
Takayasu arteritis
TB
tuberculosis
TCZ
tocilizumab
TTCI
time to clinical improvement
ULN
upper limit of normal


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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 corona virus (MERS-CoV) and severe acute 
respiratory syndrome coronavirus (SARS-CoV).
Coronavirus disease 2019 (COVID-19), is caused by a novel coronavirus strain 
(SARS-CoV-2) and was newly named on 11 February 2020 by the 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.  The WHO subsequently declared a 
pandemic on 11 March 2020.
According to the WHO, as of 19 May 2020 more than 4,500,000 cases of COVID-19 
infection were reported in more than 200 countries and territories worldwide, with more 
than 300,000 deaths (WHO 2020a).  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).  Approximately 20% of patients 
who seek medical care go on to experience complications related to COVID-19
pneumonia, which may progress to acute respiratory distress syndrome (ARDS) and/or 
multi-organ failure (MOF) and death (WHO 2020a).  To date, there is no vaccine 
effective in preventing COVID-19 disease.
1.2
BACKGROUND ON REMDESIVIR
Remdesivir is a broad-spectrum nucleotide prodrug that inhibits RNA-dependent RNA 
polymerase activity among a diverse group of RNA viruses including filoviruses 
(e.g., Ebola, Sudan, Marburg), paramyxoviruses (e.g., Nipah, Hendra), and pathogenic 
coronaviruses (Warren et al. 2016; Lo et al. 2017, 2019). Multiple nonhuman primate 
studies demonstrated the therapeutic efficacy of remdesivir against Ebola virus (Warren 
et al. 2016; Lo et al. 2019). Remdesivir was used in a randomized clinical trial for Ebola 
(the PALM study; NCT03719586) (Mulangu et al. 2019). While remdesivir was 
demonstrated to be inferior to investigational treatment with monoclonal antibodies 
MAb114 and REGN-EB3 in the PALM study, the lack of a control arm limits 
interpretation of the clinical efficacy of remdesivir. Studies in human airway epithelial 
cell assays demonstrated that remdesivir inhibits replication of coronaviruses, including 
MERS-CoV (Sheahan et al. 2017). In mouse infection models, remdesivir had 
therapeutic efficacy against SARS-CoV and MERS-CoV (Sheahan et al. 2017, 2020).  
An in vitro study with mouse hepatitis virus (a murine coronavirus) found that remdesivir
inhibits coronavirus replication through interference with the viral polymerase, despite 
the presence of a viral proofreading exoribonuclease (Agostini et al. 2018). In that study, 
coronaviruses that were partially resistant to inhibition by remdesivir were still sensitive 


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to higher concentrations of remdesivir, and fitness was impaired in the resistant viruses 
as compared with wild-type MERS-CoV. In a recent non-human primate study, 
therapeutic remdesivir treatment initiated 12 hours post inoculation with MERS-CoV 
provided clinical benefit with a reduction in clinical signs, reduced virus replication in the 
lungs, and decreased presence and severity of lung lesions (de Wit et al. 2013, 2020). 
Activity of remdesivir against SARS-CoV-2 at low-micromolar concentration was recently 
confirmed in cell culture assays (Wang et al. 2020). Finally, interim analysis data of a 
randomized, placebo-controlled trial showed that remdesivir was associated with a 
shorter time to recovery compared with placebo in patients with severe COVID-19 
disease (FDA 2020a).
Refer to the Remdesivir Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
EXPERIENCE WITH REMDESIVIR IN COVID-19 PNEUMONIA
A compassionate use case series evaluating remdesivir as a possible treatment of 
COVID-19 was conducted at hospitals in North America, Europe, and Asia between
January and March 2020 (Grein et al. 2020).  This case series evaluated off-label 
treatment with remdesivir in a cohort of patients hospitalized due to COVID-19. All 
patients had a peripheral capillary oxygen saturation (SpO2) 94% while breathing 
ambient air or were receiving oxygen support. Patients were administered remdesivir
200 mg IV on the first day of treatment, followed by remdesivir 100 mg IV on the next 
9 consecutive days.
A total of 61 patients received at least one dose of remdesivir in this case series and 
40 patients completed the full 10-day course of remdesivir. Over a median follow-up of 
18 days (interquartile range [IQR]: 1323 days) after receiving the first dose of 
remdesivir, 36 of 53 patients (68%) showed an improvement in oxygen support, and 8 of 
53 patients (15%) showed worsening. Improvement was observed in all 12 patients who 
were breathing ambient air or receiving low-flow supplemental oxygen at start of 
treatment and in 5 of 7 patients (71%) who were receiving non-invasive oxygen support. 
In addition, 17 of 30 patients (57%) who were receiving invasive mechanical ventilation 
were extubated, and 3 of 4 patients (75%) who were receiving extracorporeal membrane 
oxygenation (ECMO) stopped receiving it. After 28 days of follow-up, the cumulative 
incidence of clinical improvement, as defined by either a decrease of two or more points 
on the six-point ordinal scale or live discharge, was 84%.
Seven of the 53 patients (13%) who completed 10 days of remdesivir treatment died. 
The median time to death was 15 days after initiation of remdesivir (IQR: 917 days).  
Six of 34 patients (18%) who received invasive ventilation died compared with 1 of 
19 patients (5%) who did not receive invasive ventilation. Adverse events were reported
in 32 patients (60%), the most common of which were increased hepatic enzymes (23%), 
diarrhea (9%), rash (8%), renal impairment (8%), and hypotension (8%). Twelve 
patients (23%) had serious adverse events and the most common 


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eventsmultiple-organ-dysfunction (MOD) syndrome, septic shock, acute kidney injury, 
and hypotensionwere reported in patients who were receiving intensive ventilation at 
baseline (Grein et al. 2020).
A Phase III study evaluating remdesivir in patients with mild-to-moderate COVID-19 was 
initiated in China in February 2020 but was suspended in April 2020 due to lack of 
eligible patients (NCT04252664).  A study in patients with severe COVID-19 in China 
was also terminated in April due to lack of eligible patients (NCT04257656).  However, a 
number of trials are still ongoing outside of China. A randomized, Phase III study is 
evaluating response to treatment with a 5- or 10-day course of remdesivir plus standard 
of care (SOC) in patients with severe COVID-19 (NCT04292899). A further randomized 
Phase III study is assessing 5- and 10-day dosing of remdesivir plus SOC compared 
with SOC in patients with moderate COVID-19 (NCT04292730). The safety and efficacy 
of remdesivir is also being assessed in several adaptive trials alongside other novel 
therapeutic agents in hospitalized adults diagnosed with COVID-19 (NCT04280705, 
NCT04321616, NCT04315948, and NCT04280705). Favorable interim results of one of 
these trials formed the basis for the Emergency Use Authorization for the use of 
remdesivir in hospitalized patients with severe COVID-19 disease in the US (FDA 
2020a).
1.4
BACKGROUND ON TOCILIZUMAB
Tocilizumab is a recombinant humanized, anti-human monoclonal antibody of the IgG1 
subclass directed against soluble interleukin-6 receptor (sIL-6R) and membrane-bound 
IL-6R.  Tocilizumab binds specifically to both sIL-6R and membrane-bound IL-6R and 
has been shown to inhibit both soluble and membrane-bound IL-6Rmediated signaling.  
Interleukin-6 (IL-6) is a pleiotropic pro-inflammatory multifunctional cytokine produced by 
a variety of cell types and has been shown to be involved in diverse physiological 
processes such as T-cell activation; induction of acute phase proteins; stimulation of 
hematopoietic precursor cell growth and differentiation; proliferation of hepatic, dermal, 
and neural cells; bone metabolism; lipid metabolism; hepatoprotection; and fibrosis.  
Elevated tissue and serum levels of IL-6 have been implicated in the disease pathology 
of several inflammatory and autoimmune disorders including rheumatoid arthritis (RA), 
Castleman disease, systemic juvenile idiopathic arthritis (sJIA), polyarticular juvenile 
idiopathic arthritis (pJIA), giant cell arteritis (GCA), Takayasu arteritis (TAK), systemic 
sclerosis, 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 tocilizumab has 
been approved in the European Union and certain other countries. 
Tocilizumab has IV and SC formulations.  Some of the above-listed indications (RA, sJIA, 
and pJIA) have received approval for both the IV and SC formulations, whereas others 
have received approval exclusively for the IV (Castleman disease and CRS) or the SC 
(GCA and TAK) formulation. 


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The estimated cumulative clinical trial exposure to tocilizumab from the Development 
International Birth Date (28 April 1997) until 10 April 2019 (the data lock point for the
Periodic BenefitRisk Evaluation Report) was 24,826 patients (40154.98 patient years 
[PY]). Since the International Birth Date (11 April 2005), the estimated cumulative 
market exposure to tocilizumab until 10 April 2019 was 1,301,050 patients (1,053,779 
PY). The combined cumulative postmarketing exposure of patients to IV tocilizumab is 
estimated to be 896,672 patients (726,347 PY). The combined cumulative 
postmarketing exposure of patients to SC tocilizumab is 404,378 (327,432 PY).
Refer to the Tocilizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.5
TOCILIZUMAB TREATMENT IN CYTOKINE-RELEASE 
SYNDROME OF CAR T-CELL THERAPY
CRS has been identified as a clinically significant, on-target, off-tumor side effect of the 
chimeric antigen receptor (CAR) T-cell therapies used for treatment of malignancies. 
Characteristics of CRS include fever, fatigue, headache, encephalopathy, hypotension, 
tachycardia, coagulopathy, nausea, capillary leak, and MOD. The reported incidence of 
CRS after CAR T-cell therapy ranges from 50% to 100%, with 13%48% of patients 
experiencing the severe or life-threatening form. Serum levels of inflammatory cytokines 
are elevated, particularly IL-6. The severity of symptoms may correlate with the serum 
cytokine concentrations and the duration of exposure to the inflammatory cytokines.
On 30 August 2017, the FDA approved tocilizumab (Actemra) for the treatment of 
severe or life-threatening CAR T cellinduced CRS in adults and in pediatric patients 
2 years of age and older. The approved dose is 8 mg/kg for body weight 30kg and 
12 mg/kg for body weight 30 kg.  Up to three additional doses may be given if no 
improvement of sign/symptoms, and the interval between the subsequent doses should 
be at least 8 hours.
The approval of tocilizumab was based on a retrospective analysis of data for patients 
treated with tocilizumab who developed CRS after treatment with tisagenlecleucel 
(Kymriah) or axicabtagene ciloleucel (Yescarta) in prospective clinical trials, (Le et al. 
2018). Of the 45 patients, 31 patients (69%) from the tisagenlecleucel series achieved a 
response (defined as being afebrile and off vasopressors for at least 24 hours within 
14 days of the first dose of tocilizumab, if no more than two tocilizumab doses were 
given without use of additional treatment other than corticosteroids), 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, sex, race, ethnicity, grade of CRS at first dose of tocilizumab, and duration of CRS 
prior to treatment with tocilizumab.  There were no reports of adverse reactions 
attributable to tocilizumab.


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Pharmacokinetic (PK) data were available for 27 patients after the first dose of 
tocilizumab and for 8 patients after a second dose of tocilizumab.  Based on 131 PK 
observations, the geometric mean (% coefficient variation) maximum concentration of 
tocilizumab 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 tocilizumab than healthy volunteers and other patient populations, and 
simulations showed that exposure was considered acceptable with up to four doses of 
tocilizumab at least 8 hours apart in patients with CRS.
Tocilizumab is also approved for CAR T cellinduced severe or life-threatening CRS in 
the European Union and certain other countries.
1.6
EXPERIENCE WITH TOCILIZUMAB IN COVID-19 PNEUMONIA
Physicians in China initiated the off-label use of tocilizumab in the treatment of patients 
with 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 
tocilizumab (Xu et al. 2020), an ongoing investigator-sponsored randomized, controlled 
trial (n188) has been initiated in the same population in China, testing the same 
tocilizumab dose regimen, with approximately 70 patients enrolled.  At present, the 
21-patient publication (Xu et al. 2020) is the only robust published clinical data the 
Sponsor is aware of regarding the use of tocilizumab in the treatment of patients with 
severe COVID-19 pneumonia.
On 3 March 2020, tocilizumab 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 patients with 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, SpO2 93%, partial 
pressure of oxygen (PaO2) to fraction of inspired oxygen (FiO2) ratio (the ratio 
between the blood pressure of the oxygen [PaO2] and the 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 MOD or MOF
This occurred in 5% of cases (Wu et al. 2020).
Because body weight measurement is not always feasible in urgent circumstances, the
dosing regimen used in China is a single, fixed dose of tocilizumab 400 mg 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. 
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treatment is not permitted for people with active infections including tuberculosis (TB), 
bacterial, or fungal.  
Results from 21 Patients Treated with Tocilizumab in China
In February 2020, 21 patients with severe or critical COVID-19 pneumonia were treated 
with tocilizumab 400 mg IV plus SOC. 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 4 patients (19.0%) were assessed as critical.  Most patients (85%) presented 
with lymphopenia.  C-reactive protein (CRP) levels were increased in all 20 patients 
evaluated (mean: 75.06 [66.80] mg/L).  The median procalcitonin (PCT) value was 
0.33 (0.78) ng/mL, and only 2 of 20 patients (10.0%) presented with an abnormal value.  
Mean IL-6 level before tocilizumab was 132.38 (278.54) pg/mL (normal 7 pg/mL).
SOC consisted of lopinavir, methylprednisolone, other symptom relievers, and oxygen 
therapy as recommended by the Diagnosis and Treatment Protocol for Novel 
Coronavirus Pneumonia (Trial Version 6) (China National Health Commission 2020). 
All 21 patients had received routine SOC treatment for a week before deteriorating with 
sustained fever, hypoxemia, and chest computed tomography (CT) image worsening.
Eighteen patients (85.7%) received tocilizumab once, and 3 patients (14.3%) had a 
second dose due to fever within 12 hours.  According to the authors, after tocilizumab
treatment, fever returned to normal and all other symptoms improved remarkably. 
Fifteen of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed 
no oxygen therapy.  CT scans showed significant remission of opacities in both lungs in 
19 of 20 patients (90.5%) after treatment with tocilizumab.  The percentage of 
lymphocytes in peripheral blood, which was decreased in 17 of 20 patients (85%) before 
treatment (mean: 15.52[8.89]%), returned to normal in 10 of 19 patients (52.6%) on the 
fifth day after treatment.  Abnormally elevated CRP decreased significantly in 16 of 
19 patients (84.2%).  No adverse drug reactions and no subsequent pulmonary 
infections were reported.
Nineteen patients (90.5%) were discharged at the time of the report, including 2 critical 
patients.  There were no deaths among the 21 treated patients.
The study authors concluded that tocilizumab is an effective treatment for patients with 
severe COVID-19 pneumonia (Xu et al. 2020).
A randomized, double-blind, Phase III study evaluating the safety and efficacy of 
tocilizumab administered intravenously compared with placebo plus SOC therapy in 
hospitalized patients with severe COVID-19 pneumonia is currently ongoing
(NCT04320615). 


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1.7
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
There are currently no drugs licensed for the treatment of patients with COVID-19
pneumonia, but the FDA has recently issued an Emergency Use Authorization for the 
use of remdesivir in hospitalized patients with severe COVID-19 disease (FDA 2020a). 
Given the results of studies outlined above, remdesivir in combination with tocilizumab
could provide better efficacy, offering the potential to treat COVID-19 pneumonia in 
hospitalized populations more effectively than remdesivir alone. Extensive safety data 
have previously been generated on the use of tocilizumab in other indications. In 
addition, data for remdesivir and tocilizumab in patients with severe COVID-19 
pneumonia have shown both agents to be well tolerated in this patient population.
Therefore, a study investigating the safety and efficacy of combination therapy with 
remdesivir plus tocilizumab compared with remdesivir alone in hospitalized patients with 
severe COVID-19 pneumonia is justified to address the high unmet need and burden of 
disease in this severely ill population. 
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of combination therapy with remdesivir 
plus tocilizumab compared with remdesivir plus placebo in hospitalized patients with 
severe COVID-19 pneumonia.  Specific objectives and corresponding endpoints for the 
study are outlined below.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of the remdesivir 
plus tocilizumab arm compared with the remdesivir plus placebo arm for the treatment of 
severe COVID-19 pneumonia on the basis of the following endpoint:

Time from randomization to hospital discharge or “ready for discharge” up to 
Day 28
–
Hospital discharge or “ready for discharge” is defined as a score of 1 on the 
7-category ordinal scale.
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of the 
remdesivir plus tocilizumab arm compared with the remdesivir plus placebo arm for the 
treatment of severe COVID-19 pneumonia on the basis of the following endpoints:

Time to mechanical ventilation or death up to Day 28, defined as the time from 
randomization to the first occurrence of mechanical ventilation or death (whichever 
occurs first)

Time to improvement of at least 2 categories relative to baseline on a 7-category 
ordinal scale of clinical status up to Day 28


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
Clinical status as assessed by the investigator using a 7-category ordinal scale of 
clinical status on Days 7, 14, 21, 28, and 60

Proportion of patients requiring initiation of mechanical ventilation postbaseline up to 
Day 28 and Day 60 (patients who do not require mechanical ventilation at baseline)

Proportion of patients who are alive and free of respiratory failure at Day 28 and 
Day 60 (patients requiring mechanical ventilation at baseline)

Duration of mechanical ventilation (patients who require mechanical ventilation at 
baseline) up to Day 28

Time to death up to Day 28 and Day 60

Mortality on Days 14, 28, and 60 (proportions at specified time points)

Time to recovery up to Day 28, defined as time from randomization to the time 
when a category of 2 on the 7-category ordinal scale (non-ICU hospital ward or 
“ready for hospital ward” not requiring supplemental oxygen), or better is observed 

Proportion of patients discharged or "ready for discharge" up to Day 28

Proportion of patients who require initiation of mechanical ventilation 
postbaseline or die up to Day 28
A pre-defined meta-analysis may be performed on mortality as well as the 
primary and selected secondary endpoints with results of Studies WA42380 and 
ML42528.
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of the
remdesivir plus tocilizumab arm compared with the remdesivir plus placebo arm for the 
treatment of severe COVID-19 pneumonia on the basis of the following endpoints:

Time to clinical improvement (TTCI) up to Day 28, defined as time from 
randomization to National Early Warning Score 2 (NEWS2) score of2 maintained 
for 24 hours

Time to clinical failure up to Day 28, defined as the time from randomization to 
the first occurrence of death, mechanical ventilation, ICU admission or withdrawal 
from study prior to discharge (whichever occurs first)
For patients entering the study already on mechanical ventilation, clinical failure 
is defined as a one-category worsening on the ordinal scale, withdrawal from 
study prior to discharge, or death.

Proportion of patients requiring initiation of ICU care postbaseline up to Day 28 and 
Day 60

Duration of ICU stay up to Day 28

Duration of supplemental oxygen use up to Day 60

Proportion of patients requiring initiation of vasopressor use postbaseline up to 
Day 28


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
Duration of vasopressor use up to Day 28

Proportion of patients requiring initiation of ECMO postbaseline up to Day 28 and 
Day 60

Duration of ECMO up to Day 28

Organ failure-free days from randomization to Day 28

SARS-CoV-2 viral load up to Day 28 and Day 60

Time to reverse-transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2
virus negativity up to Day 14 (serum samples) or Day 60 (respiratory samples)
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of the remdesivir plus 
tocilizumab arm compared with the remdesivir plus placebo arm for the treatment of 
severe COVID-19 pneumonia on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 
5.0 (NCI CTCAE v5.0)

Proportion of patients with any post-treatment infection at specified timepoints

Change from baseline in targeted clinical laboratory test results
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the PK profile of remdesivir and 
metabolite(s) in patients with severe COVID-19 pneumonia on the basis of the following 
endpoint:

Plasma concentration of remdesivir and metabolite(s) at specified timepoints 
2.4
BIOMARKER OBJECTIVE
The exploratory biomarker objectives for this study are to identify and/or evaluate 
biomarkers that could be predictive of response to remdesivir plus tocilizumab 
combination treatment (i.e., predictive biomarkers), may serve as early surrogates of 
efficacy or be associated with efficacy, may be associated with progression to a more 
severe disease state (i.e., prognostic biomarkers), may be associated with susceptibility 
to developing adverse events or could lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), could provide further evidence of tocilizumab
pharmacological activity (i.e., pharmacodynamic biomarkers), or could overall increase 
our knowledge and understanding of disease pathogenesis and drug safety, on the basis 
of the following endpoint:

Relationship between biomarkers in serum, peripheral blood mononuclear cells 
(PBMCs), blood, and tissue (listed in Section 4.5.6) and efficacy or safety endpoints


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, randomized, double-blind, multicenter study to assess the efficacy 
and safety of remdesivir plus tocilizumab compared with remdesivir plus placebo in 
hospitalized patients with severe COVID-19 pneumonia.  The Sponsor intends to enroll
patients who have been diagnosed with severe COVID-19 pneumonia and meet the 
entry criteria in centers globally.  Enrollment may be up to 800 patients but will target 
approximately 650 patients.
In addition to the randomized patients from this study, results from the Phase III studies 
WA42380 and ML42528 will be included in a meta-analysis of the primary and 
secondary endpoints. This analysis will assist in the interpretation of the effect of 
tocilizumab in combination with remdesivir compared with tocilizumab alone.
Patients must be at least 12 years of age and hospitalized with confirmed COVID-19 
infection per WHO criteria, including a positive polymerase chain reaction (PCR) of any 
specimen (e.g., respiratory, blood, urine, stool, other bodily fluid).  At the time of 
enrollment, patients must require 6 L/min supplemental oxygen to maintain 
SpO2 93%.
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 TB or suspected active 
bacterial, fungal, viral, or other infection (besides COVID-19) will be excluded from the 
study.  
Patients will be randomized as soon as possible after screening at a 2:1 ratio to receive 
blinded treatment of either remdesivir plus tocilizumab or remdesivir plus placebo. Study 
treatment will be given in combination with standard supportive care. The randomization 
will be stratified by geographic region (North America, Europe, Other) and a 2-level 
factor based on the assessment of the 7-category ordinal scale of clinical status at 
screening, with levels 45 and 6. The proportion of randomized patients in the scale 6 
stratum will also be no more than 25%.
Patients assigned to the remdesivir plus tocilizumab (RDVTCZ) arm will receive 
remdesivir as a 200 mg IV loading dose followed by one infusion of tocilizumab 8 mg/kg 
(maximum dose of 800 mg) on Day 1. Patients will subsequently be administered a 
100 mg once-daily IV maintenance dose of remdesivir from Days 210. Remdesivir will 
be discontinued at the time of hospital discharge even if 10 days of remdesivir dosing 
have not been completed.
Patients assigned to the remdesivir plus placebo (RDV placebo) arm will receive 
remdesivir as a 200 mg IV loading dose followed by one infusion of tocilizumab-placebo 


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on Day 1. Patients will subsequently be administered a 100 mg once-daily IV 
maintenance dose of remdesivir from Days 210.  Remdesivir will be discontinued at the 
time of hospital discharge even if 10 days of remdesivir dosing have not been 
completed.
Remdesivir dosing must be adjusted for patients that enter the study having received 
prior remdesivir. Patients who received remdesivir prior to randomization must not 
exceed 10 days of dosing in total (including remdesivir received prior to the study and 
during the study).  If a patient received 1 dose of remdesivir (200-mg loading dose) prior 
to Day 1, the patient should receive remdesivir 100 mg on Days 19.  If a patient 
received 2 doses of remdesivir (200-mg loading dose followed by 100-mg maintenance
dose) prior to Day 1, the patient should receive remdesivir 100 mg on Days 18.
Patients who received remdesivir prior to trial entry must not receive a second 200-mg 
loading dose on Day 1. The same sequence and timing of remdesivir and tocilizumab 
will be followed on Days 1 and 2 regardless of whether the patient has received 
remdesivir prior to randomization (see Appendix 1).
For both arms, if the patient has a sustained fever or clinically significant worsening of 
signs or symptoms (e.g., an increased supplemental oxygen requirement), one 
additional infusion of blinded tocilizumab/placebo can be given 824 hours after the first 
tocilizumab/placebo infusion. The second dose of blinded tocilizumab must not be given 
if the patient develops an adverse event or laboratory abnormalities that warrant 
discontinuation of tocilizumab as described in Section 5.1.2.
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of 2 screenings per participant) at the 
investigator’s discretion.  Patients are not required to re-sign the consent form if they are 
re-screened within 7 days after previously signing the consent form.  The investigator will 
record the reasons for screen failure in the screening log as described 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, chest X-ray, ECG, adverse events, concomitant therapies, clinical 
laboratory tests, and nasopharyngeal swabs. Please see Appendix 1, Appendix 2, and 
Appendix 3 for details concerning the timing of these assessments.
Patients will be followed up for a total of 60 days after first dose of study drug.
If patients are discharged from hospital prior to Day 28, follow-up visits should be 
conducted on Day 14, Day 21, and Day 28 (2 days).  Follow-up visits on Day 14 and 
Day 21 may be conducted as telephone visits.  Patients should return to the site for the
Day 28-visit, if at all possible.  After Day 28, all patients should have follow-up visits on 
Day 35, Day 45, and Day 60.  The Day 35- and Day 45-visits may be conducted by 


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telephone for discharged patients. Patients should return to the site for the Day 60 visit,
if at all possible.
Figure 1 presents an overview of the study design.  Schedules of activities are provided 
in Appendix 1, Appendix 2, and Appendix 3.
Figure 1
Study Schema
COVID-19coronavirus disease 2019; DDay; PBO placebo; RDVremdesivir; TCZtocilizumab.
Notes: Baseline refers to study baseline (not the COVID-19 diagnosis date). Patients who 
received remdesivir prior to randomization will not exceed 10 days of dosing in total.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for the last follow-up is received from the last 
patient, whichever occurs later.  The end of the study is expected to occur approximately 
2 months after the last patient is enrolled.
In addition, the Sponsor may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 8 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Remdesivir and Tocilizumab Dose and Schedule
The 10-day remdesivir dosing regimen selected for this study is consistent with the 
Emergency Use Authorization for remdesivir for treatment of COVID-19 in adults and 
children hospitalized with severe disease weighing more than 40 kg (FDA 2020b).
Patients weighing less than 40 kg will not be permitted into the study, as the remdesivir
dosing regimen may not be appropriate for such patients.  


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The tocilizumab dosing regimen chosen in this study is consistent with the approved 
tocilizumab dosage for patients with CAR T cellinduced CRS (weight 30 kg), recent 
off-label experience in China (one additional infusion if fever not improved within 
12 hours), and the permitted use of three additional infusions of tocilizumab (8 hours 
between infusions) for CAR T cellinduced CRS. The proposed one additional infusion
of tocilizumab if the patient has a sustained fever or clinically significant worsening of 
signs or symptoms (e.g., an increased supplemental oxygen requirement) is justified
based on these data.
Patients will be followed up for a period of 60 days after randomization. In the case 
series of patients who received compassionate-use remdesivir, a 28-day follow-up 
period was sufficient time to permit assessment of treatment outcome (Grein et al. 
2020).  This follow-up duration for tocilizumab-treated patients is supported by historical 
data from studies performed in healthy subjects and patients with RA (Studies LRO300 
and LRO301), where the mean apparent tocilizumab 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 every 4 weeks. Moreover, modeling of free 
sIL-6R 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 with 
clinical symptoms due to COVID-19 experience mild disease, require only symptomatic 
relief, and can recover at home.  However, approximately 20% of symptomatic patients 
require hospitalization due to more severe disease.  A study of 138 hospitalized patients 
with COVID-19 in China found that 26% of patients admitted to hospital required transfer
to the 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 showed that 13 of 41 patients (32%) admitted to a hospital 
were also admitted to an ICU and 6 patients (15%) died (Huang et al. 2020). A recent 
case series of 393 patients admitted to two hospitals in New York City reported 
respiratory failure leading to invasive mechanical ventilation in 130 patients (33.1%).  
Only 43 of these patients (33.1%) had been extubated at the time of publication, while
40 of the patients (10.2%) had died, and the remaining 260 patients (66.2%) had been 
discharged from the hospital (Goyal et al. 2020).
Given the significant unmet need in patients hospitalized with severe COVID-19, and 
based on the emerging evidence for remdesivir and tocilizumab use in patients with 
COVID-19 pneumonia, this study is designed to evaluate the efficacy and safety of 
remdesivir in combination with tocilizumab compared with remdesivir alone in this 
population.  Morbidity and mortality are particularly high for elderly patients and those 


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with comorbidities. This study will include both of these groups, with no upper age limit.
Furthermore, to align with the patient population studied in the remdesivir Phase III
program, adolescent patients aged 12 or older will also be permitted to enroll into the 
study.
3.3.3
Rationale for Control Group
The study will compare the efficacy and safety of remdesivir plus tocilizumab with 
remdesivir plus placebo in patients with severe COVID-19 pneumonia. 
Placebo-controlled clinical trials to evaluate remdesivir or tocilizumab in patients with 
severe COVID-19 pneumonia are ongoing and will report the efficacy and safety of each 
treatment compared with placebo. Based on emerging data, remdesivir can now be 
considered a standard treatment for severe COVID-19 pneumonia and the control arm of 
this study will therefore be treatment with remdesivir plus placebo.
3.3.4
Rationale for Biomarker Assessments
COVID-19 is a heterogeneous disease, and patients with severe COVID-19 have shown 
various levels of IL-6 pathway activation and present at varying stages of viral 
progression (Xu et al. 2020). Therefore, all patients may not benefit equally from 
remdesivir plus tocilizumab combination therapy. The exploratory biomarkers will be 
assessed to understand which patients are most likely to respond to the combination 
treatment relative to remdesivir monotherapy. Biomarker data assessed in conjunction 
with both virological and clinical outcome measures should provide a deeper 
understanding of efficacy as well as progression of COVID-19.
4.
MATERIALS AND METHODS
4.1
PATIENTS
The target enrollment for the study is approximately 650 hospitalized patients with 
severe COVID-19 pneumonia, but up to 800 patients may be enrolled to achieve 
approximately 520 patients discharged by Day 28.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Documented informed consent to participate in the study

Signed Assent Form when appropriate, as determined by the patient's age and 
individual site and country standards

Age 12 years at time of informed consent

Ability to comply with the study protocol, in the investigator's judgment

Hospitalized with COVID-19 pneumonia confirmed per a positive PCR of any 
specimen (e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by 
chest X-ray or CT scan
The PCR test must be collected 7 days before randomization.


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
Requiring 6 L/min supplemental oxygen to maintain SpO2 93%

Agrees to not participate in another clinical trial for the treatment of COVID-19 while 
participating in this study

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 90 days after the final dose 
of study drug.  Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
60 days after the final dose of study drug to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.


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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 tocilizumab or other monoclonal antibodies

Known hypersensitivity to remdesivir, the metabolites, or formulation excipients

Active TB infection 

Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) 

In the opinion of the investigator, progression to death is imminent and inevitable 
within the next 24 hours, irrespective of the provision of treatments

Treatment with immunosuppressive or immunomodulatory therapy (including 
tocilizumab) within the past 3 months

Concurrent treatment with other agents with actual or possible direct-acting antiviral 
activity against SARS-CoV-2 within 24 hours prior to study drug dosing
In addition, patients with prior or current treatment with 2 doses of remdesivir 
for COVID-19 are excluded.

Participating in another drug clinical trial 

Estimated glomerular filtration rate (eGFR) 30 mL/min (including patients receiving 
hemodialysis or hemofiltration), using the equation described in the FDA EUA Fact 
Sheet for remdesivir (FDA 2020b)

ALT or AST 5upper limit of normal (ULN) detected within 24 hours of screening
(according to local laboratory reference ranges)

ANC 1000/L at screening

Platelet count 50,000/L at screening

Body weight 40 kg

Pregnant or breastfeeding, or positive pregnancy test in a predose examination

Treatment with an investigational drug within 5 half-lives or 30 days (whichever is 
longer) of randomization

Any serious medical condition or abnormality of clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion 
of the study
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1
Treatment Assignment
This is a randomized, double-blind study.  After initial 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 


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identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS).
Patients will be randomly assigned to one of the below listed treatment arms.

Remdesivir plus tocilizumab (RDVTCZ) 

Remdesivir plus placebo (RDVplacebo) 
Randomization will occur at an initial 2:1 ratio through use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm at the 
specified ratio. The randomization will be stratified by geographic region (North America, 
Europe, Other) and a 2-level factor based on the assessment of the 7-category ordinal 
scale of clinical status at screening, 45 or 6. The proportion of randomized patients in 
the scale6 stratum will also be no more than 25%.
4.2.2
Blinding
Study site personnel and patients will be blinded to TCZ treatment assignment during 
the study.  The Sponsor and its agents will also be blinded to TCZ treatment assignment, 
with the exception of individuals who require access to patient treatment assignments to 
fulfill their job roles during a clinical trial. These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, unblinded pharmacist (if required), IxRS service provider, and Data 
Monitoring Committee (DMC) members and support staff as specified in the DMC 
Charter who may be Roche employees but independent of the study team.
Investigators, site staff, Roche monitors, project statisticians, and the project team will be 
blinded from PK and pharmacodynamic results (including CRP) until the primary 
analysis.  Study centers may be unblinded after the final study results are reported.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
accessing IxRS.  The investigator is not required to contact the Medical Monitor prior to 
breaking the treatment code; however, the treatment code should not be broken except 
in emergency situations.
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are remdesivir IV, 
tocilizumab IV, and placebo for tocilizumab IV.
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
Remdesivir 
Remdesivir will be supplied by the Sponsor as a sterile lyophilized solid containing 
100 mg of remdesivir to be reconstituted with 19 mL of sterile water for injection and 
diluted into IV infusion fluids prior to IV infusion. Following reconstitution, each vial 
contains a 5 mg/mL remdesivir concentrated solution with sufficient volume to allow 
withdrawal of 20 mL (100 mg of remdesivir).
For information on the formulation and handling of remdesivir, see the remdesivir
pharmacy manual and remdesivir Investigator's Brochure, as well as the fact sheet for 
use of remdesivir for patients with severe COVID-19 disease (FDA 2020b).
4.3.1.2
Tocilizumab and Placebo
Tocilizumab/placebo will be supplied by the Sponsor as a sterile IV solution for infusion
for reconstitution in 20-mL glass vials with a 10-mL fill in each (200 mg/10 mL of 
tocilizumab/placebo).  An appropriate number of vials (depending on the patient’s 
bodyweight) of tocilizumab/placebo will be assigned to each patient for the infusion.  The 
amount of solution that is withdrawn from each vial will depend on the patient’s allocated 
dose.
Alternatively, due to limitations on placebo supplies, normal saline may be given at an 
equal volume as a placebo in place of the solution for infusion (requires unblinded 
pharmacist).
For information on the formulation and handling of tocilizumab, see the tocilizumab
pharmacy manual and tocilizumab Investigator's Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
4.3.2.1
Remdesivir 
Remdesivir will be administered by IV infusion at doses of 200 mg and 100 mg. 
Remdesivir must be administered under close supervision of the investigator in a setting 
where medications and resuscitation facilities are available. 
Ambient vials of the lyophilized formulation of remdesivir should be stored below 30C
(86F). The lyophilized formulation needs to be reconstituted and then diluted into IV 
infusion fluids before use.  After reconstitution, the total storage time before completion 


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of administration (including any time before or after dilution) should not exceed 4 hours 
at room temperature (20°C25°C [68F77F]) or 24 hours at refrigerated temperature 
(2°C8°C [36F46F]).
The remdesivir will be administered at room temperature by controlled infusion into a 
vein over 30120 minutes.  The infusion rate must be kept steady over the course of the 
infusion.  The entire 100 mL250 mL content of the infusion bag must be administered.  
A total of at least 30 mL of normal saline will be administered following the infusion of 
study treatment to flush the remaining study drug through the IV set.
Remdesivir does not meet the criteria for a hazardous compound as defined by National 
Institute for Occupational Safety and Health and American Society of Health-System 
Pharmacists hazard classification systems.  The study products may be prepared in a 
standard hospital pharmacy.
Refer to the Remdesivir Investigator’s Brochure for further instructions regarding 
recommended storage conditions and packaging configuration, as well as the fact sheet 
for use of remdesivir for patients with severe COVID-19 disease (FDA 2020b).
4.3.2.2
Tocilizumab and Placebo
Tocilizumab/placebo will be administered by IV infusion at doses of 8 mg/kg.  The 
maximum dose of tocilizumab that will be administered is 800 mg.  The dose of 
tocilizumab infusion will be calculated on the basis of body weight (see Appendix 1).  
One additional infusion of blinded treatment of tocilizumab or placebo can be given
824 hours after the first tocilizumab/placebo infusion. The second dose of blinded 
tocilizumab must not be given if the patient develops an adverse event or laboratory 
abnormalities that warrant discontinuation of tocilizumab as described in Section 5.1.2.
Tocilizumab/placebo must be administered under close supervision of the investigator in 
a setting where medications and resuscitation facilities are available.  The 
tocilizumab/placebo infusion must not be started until at least 1 hour after the end of the 
remdesivir/placebo infusion.  Patients should be monitored for at least 2 hours after the 
tocilizumab infusion is completed. 
The tocilizumab/placebo vials must be stored at a temperature of 2C8C (36F46F).  
The infusion bag of tocilizumab/placebo should be diluted to 100-mL using aseptic 
technique.  The fully diluted tocilizumab/placebo solutions for infusion using 0.9% 
Sodium Chloride Injection, USP may be stored at 2C-8C (36F46F) or at room 
temperature for up to 24 hours and should be protected from light. 
If stored at 2C8C (36F46F), the infusion bag should be allowed to return to room 
temperature before administration. The tocilizumab will be administered at room 
temperature by controlled infusion into a vein over a 1-hour period. In exceptional cases 
this time may be extended up to 6 hours.  The infusion rate must be 10 mL/hr for 


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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 at least 
20 mL of normal saline will be administered following the infusion of study treatment to 
flush the remaining study drug through the IV set.  If a second tocilizumab/placebo 
infusion is given 824 hours after the first tocilizumab/placebo infusion, there must be at 
least 2 hours after completion of the second tocilizumab/placebo infusion before the Day 
2 remdesivir infusion is administered.
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 IMPs (remdesivir and tocilizumab/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 remdesivir and tocilizumab/placebo, and 
only authorized staff may supply or administer remdesivir and tocilizumab/placebo.
Remdesivir and tocilizumab/placebo will either be disposed of at the study site according 
to the study site's institutional standard operating procedure or be returned to the 
Sponsor with the appropriate documentation.  The site's method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log.


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Refer to the pharmacy manuals and/or the remdesivir and tocilizumab Investigator's 
Brochures for information on IMP handling, including preparation and storage, and 
accountability. 
4.3.4
Continued Access to Remdesivir 
Since remdesivir treatment is not intended for continued therapy, the Sponsor does not 
have any plans to provide remdesivir or any other study treatments to patients who have 
completed the study.
4.3.5
Continued Access to Tocilizumab
Currently, the Sponsor does not have any plans to provide Roche IMPs (tocilizumab) or 
any other study treatments to patients who have completed the study.
The Sponsor may evaluate whether to continue providing tocilizumab in accordance with 
the Roche Global Policy on Continued Access to Investigational Medicinal Product, 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs) used by a patient in addition to protocol-mandated treatment 
from 7 days prior to initiation of study drug to the study completion/discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).
4.4.1
Permitted Therapy 
All patients will receive standard supportive care for the treatment of severe COVID-19 
pneumonia.  Use of the following therapies during the study is permitted as described 
below:

Non-steroidal anti-inflammatory drugs or antipyretic drugs.

Acetaminophen and paracetamol 

Azithromycin is permitted if part of the local SOC.  Broad-spectrum antibiotics are 
also permitted when clinically indicated.

Low-dose corticosteroids are permitted if part of the local SOC.  If corticosteroids 
are given, the Sponsor recommends giving the lowest possible dose and duration of 
treatment and that the dose should not exceed methylprednisolone 1 mg/kg, or 
equivalent, for 10 days.  
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with ibuprofen, 
diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, ranitidine), or 
equivalent medications per local standard practice.  Serious infusion-associated events 


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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
Remdesivir is a substrate for CYP2C8, CYP2D6, and CYP3A4. However, 
co-administration with inhibitors of these CYP isoforms is unlikely to markedly increase 
remdesivir levels, as its metabolism is likely to be predominantly mediated by hydrolase 
activity. 
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 tocilizumab, it is expected that the formation of CYP450 
enzymes could be normalized.  When starting tocilizumab therapy, patients taking 
medications that are individually dose adjusted and metabolized by means of CYP450, 
CYP3A4, CYP1A2, or CYP2C9 (e.g., atorvastatin, calcium channel blockers, 
theophylline, warfarin, phenytoin, cyclosporine, or benzodiazepines) are recommended 
to be monitored, as doses may need to be adjusted to maintain their therapeutic effect.
The above list of medications is not necessarily comprehensive.  The investigator should 
consult the prescribing information when determining whether a concomitant medication 
can be safely administered with study treatment.  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above.
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is prohibited 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:

Convalescent plasma or immunoglobulins for treatment of COVID-19

Chloroquine or hydroxychloroquine

Lopinavir / ritonavir

Rifampin

Treatment with any investigational agent, cell-depleting therapies, anti-viral agents,
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, 
anti-thymocyte globulin, and azathioprine

Immunization with a live attenuated vaccine through Day 28


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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 activities):
1.
Clinical assessments:  clinical status, clinical signs and symptoms, oxygen 
saturation, vital signs
2.
Safety assessments: review of adverse events, concomitant medications
3.
Laboratory samples:  On days when study drug is administered, all samples 
(including predose PK, safety, and biomarkers) must be taken prior to the remdesivir
infusion, except for postdose samples for PK analyses, which will be obtained after 
study drug treatment.
4.
Review of creatinine and liver function test results before IV infusion of remdesivir:
baseline (Day 1) and up to and including Day 10
5.
IV infusion of remdesivir:  baseline (Day 1) and up to and including Day 10
6.
Safety assessments: vital signs post remdesivir administration/pre-tocilizumab or
placebo administration (if indicated)
7.
IV infusion of tocilizumab/placebo:  only at baseline (Day 1) and an additional dose 
824 hours after the initial infusion (if required)
8.
Safety assessments: vital signs post-tocilizumab administration (if indicated)
Schedules of activities are found in Appendix 1, Appendix 2, and Appendix 3.
If patients are discharged from hospital prior to Day 28, follow-up visits should be 
conducted on Days 14, 21, 28, 35, 45, and 60.

Follow-up visits on Days 14 and 21 may be conducted as telephone visits.

Follow-up visit on Day 28 should be in person at the site, if at all possible.

Follow-up visits on Days 35 and 45 may be conducted as telephone visits.

Follow-up visit on Day 60 should be in person at the site, if at all possible.
Remdesivir will be discontinued at the time of hospital discharge if hospital discharge 
occurs before completion of 10 days of remdesivir dosing.  Patients should remain in the 
study and complete all follow-up visits as described above (starting from the Day 14 
visit).
If patients are discharged from hospital after Day 28, follow-up visits should be 
conducted on Days 35, 45, and 60 as described above. 
4.5.1
Informed Consent Forms and Screening Log
Documented informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations). Assent 
should be documented when appropriate, as determined by the patient’s age and 
individual site and country standards.  Written informed consent should be obtained, 


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when possible.  In the pandemic situation where access to hospitals is limited, if allowed
in accordance with local regulation, verbal consent can be obtained from the patient or 
the patient’s legally authorized representative and must be documented by the 
investigator or the authorized designee.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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 prescription medications 
used by the patient within 7 days prior to first dose of study drug will be recorded.  
Vitamins, herbal supplements, over-the-counter cold medicines and antipyretics taken at 
home prior to hospitalization do not need to be recorded. Record all medications
administered during the study.  Antipyretics and other medications given for symptomatic 
care can be recorded only once, even if given multiple times during the hospital course, 
except when given as a treatment for an adverse event where recording is required.  At 
the time of each follow-up visit, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal (GI), and neurologic systems.  Any 
abnormality identified at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations may be performed as clinically 
indicated.  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.
In addition, patient body weight will be measured at the timepoints specified in the 
schedules of activities (see Appendix 1, Appendix 2, and Appendix 3). If it is not feasible 
to weigh bed-bound patients, historical body weight may be used.


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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 vital signs.  For patients requiring supplemental 
oxygen, the oxygen flow rate (L/min) and/or FiO2 should be recorded. 
To allow assessment of the NEWS2 score (see Section 4.5.5), all of the vital sign 
parameters and oxygen saturation should be recorded together twice per day, 
approximately every 12 hours, for the duration of the hospitalization during the study. 
This is to ensure that the measurements reflect the patient’s condition over the entire 
day, where possible. If vital signs or oxygen saturation are measured more than once 
during a 12-hour period, the worst values (highest temperature, respiratory rate, and 
pulse rate; lowest blood pressure, oxygen saturation, and consciousness level) during 
that period should be recorded on the eCRF. Following hospital discharge these 
parameters should be recorded once at each return visit to the clinic. Vital signs will not 
be recorded if follow-up visits are conducted by telephone. 
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
4.5.5
Assessments Specific to National Early Warning Score 2
In addition to the vital measurements, the patient’s consciousness level and the 
presence or absence of respiratory support must be recorded. The NEWS2 parameter 
for respiratory support is the selection of either air or “oxygen” and can include other 
forms of ventilation to maintain oxygen saturation (see Appendix 4).  The form of 
ventilation used should be recorded on the eCRF.
These should be recorded at the same time points as the vital sign measurements (see 
Section 4.5.4 and Appendix 1, Appendix 2, and Appendix 3).
NEWS2 values do not need to be calculated by the site, but will be calculated 
electronically by the Sponsor based on vital sign parameters and NEWS2-related 
assessments recorded by the investigator in the appropriate eCRF. 
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be measured by study site's local 
laboratory:

PaO2/FiO2 (if arterial blood gases are measured during screening or follow-up)

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes), and 
lymphocyte subsets (T cells, B cells, and natural killer cells; if the test is available at 


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the site, or if the site can ship the blood sample on the day of collection to the 
central laboratory for testing)

Coagulation: INR, PTT, D-dimer, fibrinogen 

Chemistry panel (serum or plasma): bicarbonate , sodium, potassium, chloride, 
glucose, BUN, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, 
ALP, ALT, AST, LDH, PCT, and ferritin

Pregnancy test
All women of childbearing potential, including those who have had a tubal 
ligation, 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 PCR (screening): nasopharyngeal swab or other respiratory
specimen, blood, urine, stool, or other bodily fluid
Samples for the following laboratory tests will be sent to designated central laboratories
or to the Sponsor or a designee for analysis:

Plasma samples for PK analysis (for sites capable of sample collection)

Serum samples for exploratory biomarker research

Serum samples for SARS-CoV-2 antibody titer

Nasopharyngeal swabs and other respiratory samples (e.g., endotracheal tube 
aspirates) for SARS-CoV-2 virology tests (viral load and other exploratory analysis
including potential viral resistance assessment)

Blood PAXgeneRNA for RNA sequencing or quantitative PCR

Blood for PBMC isolation and cryopreservation (for sites capable of sample 
collection). If PBMC isolation or cryopreservation is not feasible for the site, then 
blood samples may alternatively be shipped on the day of collection to the central 
laboratory)

Blood for lymphocyte subsets (T cells, B cells, and natural killer cells) (for sites 
capable of sample collection). If not tested in the local laboratory, then the site can 
ship the blood sample on the day of collection to the central laboratory for testing
Exploratory biomarker research may include, but will not be limited to, analysis of 
inflammatory mediators and/or cytokines such as IL-6, CRP, ARDS-related variables, 
anti-SARS-CoV-2 antibody, viral load, and viral resistance analysis.
In countries where acceptable, research may involve extraction of DNA, cell-free DNA, 
or RNA; analysis of mutations, single nucleotide polymorphisms, and other genomic 
variants; and genomic profiling through use of next-generation sequencing of a
comprehensive panel of genes.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.


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Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions:

Plasma samples collected for PK analysis may be needed for additional PK assay 
development and validation, and biomarker research; therefore, these samples will 
be destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Serum, PBMCs, blood PAXgene RNA, and tissue-derived samples (nasopharyngeal 
swabs and other respiratory samples) collected for biomarker research will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.7
Kidney and Liver Function Monitoring
Patients must be assessed for creatinine and liver function prior to each dose of 
remdesivir, tocilizumab, or tocilizumab placebo.  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.  On subsequent days
of remdesivir dosing, creatinine and liver function tests will be assessed daily prior to 
dosing as per the schedules of activities (Appendix 1 and Appendix 2).  Results must be 
reviewed by the investigator before dose administration.  Dosing will occur only if the 
clinical assessment and local laboratory chemistry panel values are acceptable.
4.5.8
Chest X-Rays and CT Scan
Chest X-ray/CT scan findings at baseline should be recorded on the appropriate 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.


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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 of clinical status will be 
recorded at baseline on Day 1 and then again once daily every morning (between 
8:00 a.m. and 12:00 p.m.) 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 2 L supplemental 
oxygen)
2.
Non-ICU hospital ward (or “ready for hospital ward”) not requiring supplemental 
oxygen
3.
Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen
4.
ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
5.
ICU, requiring intubation and mechanical ventilation 
6.
ICU, requiring ECMO or mechanical ventilation and additional organ support 
(e.g., vasopressors, renal replacement therapy)
7.
Death
Patients who are ready to be discharged but are still hospitalized (e.g., due to 
non-medical or administrative reasons) will be assigned an ordinal scale category of 1. 
Patients in a non-ICU hospital ward who are eligible for ICU care based on clinical 
presentation but are awaiting ICU care will be assigned an ordinal scale category of 4. 
Patients in an ICU for administrative or non-medical reasons, who are ready for a 
non-ICU hospital ward, will be assigned an ordinal scale category of 2 (if not requiring 
supplemental oxygen), 3 (if requiring supplemental oxygen), or 4 (if requiring 
non-invasive ventilation or high-flow oxygen).
In general, patients with oxygen saturation consistently 90% should be considered for 
escalation to a higher clinical status category, while patients with oxygen saturation 
consistently 96% should be considered for de-escalation to a lower category.  Patients 
on supplemental oxygen should be evaluated at least daily and considered for reduction 
or discontinuation of oxygen support. Actual changes in level of support will be at the 
discretion of the clinician(s) treating the patient based on the patient’s overall condition 
and may be dictated by other clinical and non-clinical considerations. 


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Normal body temperature is defined as oral, rectal, axillary, temporal, or tympanic 
temperature 36.1C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

Severe allergic reaction to remdesivir or tocilizumab/placebo

Discharge from hospital
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.
Patients who discontinue from the study treatment should continue in the study and 
complete all assessments through Day 60.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up
Every effort should be made to obtain information on patients lost to follow up but have 
not withdrawn consent.  The primary reason for withdrawal from the study should be 
documented on the appropriate eCRF.  If a patient requests to be withdrawn from the 
study, this request must be documented in the source documents and signed by the 
investigator.  Patients who withdraw from the study will not be replaced.


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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 tocilizumab
in clinical studies, post-marketing experience with tocilizumab, and experience with 
remdesivir in clinical trials.  The important safety risks for tocilizumab and potential risks 
for remdesivir are outlined below.  Please refer to the Tocilizumab Investigator's 
Brochure and the Remdesivir Investigator’s Brochure for a summary of safety 
information for the respective molecules.  There are no robust data concerning the use 
of tocilizumab and remdesivir in combination.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events and laboratory abnormalities, including criteria for dosage modification 
and treatment interruption or discontinuation, are provided below.


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5.1.1
Potential Risks Associated with Remdesivir
Remdesivir is an investigational therapeutic agent. As of 14 February 2020, 138 healthy 
adults have been dosed with remdesivir in four Phase I clinical trials. A few subjects to 
date experienced constipation, heartburn, itching, unusual feelings in the ear, dizziness, 
loss of appetite, nausea, vomiting, shaking of the leg and arm, headache, loose stool, or 
upset stomach. These adverse events were temporary, lasting only a few days, and 
none were serious.  
5.1.1.1
Infusion Related Reactions
Infusion-related reactions have been observed during, and/or have been temporally 
associated with, administration of remdesivir.  Signs and symptoms may include 
hypotension, nausea, vomiting, diaphoresis, and shivering.
5.1.1.2
Elevated Liver Enzymes
In clinical studies, transient elevations in ALT and AST have been observed with single 
doses of remdesivir up to 225 mg and multiple doses of remdesivir 150 mg once a day 
(QD) for up to 14 days. Mild (Grade 1) reversible PT prolongation was also noted in 
some subjects but without any clinically significant change in INR or other evidence of 
hepatic effects. The mechanism of these elevations is currently unknown.  Based on 
these clinical observations, patients with ALT or AST 5 ULN will not be eligible for 
study enrollment. Regular laboratory assessments will be performed to monitor hepatic 
function.  Any observed liver function-related laboratory abnormalities or possibly related 
adverse events will be treated appropriately and followed to resolution. 
5.1.1.3
Kidney Toxicity
In nonclinical animal studies, toxicity studies found dose-dependent and reversible 
kidney injury and dysfunction. In clinical studies, no evidence of nephrotoxicity has been 
observed with single doses of remdesivir up to 225 mg or multiple doses of remdesivir
150 mg QD for up to 14 days. A 200-mg dose of lyophilized formulations of remdesivir
contains 4 g, respectively, of sulfobutylether-beta-cyclodextrin (SBECD), for which the 
maximum daily recommended daily dose (based on a European Medicines Agency 
safety review) is approximately 250 mg/kg. Because SBECD is renally cleared, patients 
with moderate or severe renal impairment may have SBECD exposures greater than 
patients with less severe renal impairment or normal renal function.  Based on this 
information, patients with an eGFR of less than 30 mL/min (including patients requiring 
hemodialysis or hemofiltration) will not be eligible for study enrollment.
5.1.1.4
CYP450 Enzyme Normalization
Remdesivir is a substrate for CYP2C8, CYP2D6, and CYP3A4. However, 
co-administration with inhibitors of these CYP isoforms is unlikely to markedly increase 
remdesivir levels, as its metabolism is likely to be predominantly mediated by hydrolase 
activity.


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5.1.1.5
Viral Resistance
There is the potential of the SARS-CoV-2 developing resistance to remdesivir, which 
could result in decreased efficacy. The clinical impact of the development of resistance 
is not clear at this time.
5.1.2
Risks Associated with Tocilizumab
This section highlights the main risks for this study population and following one to two
doses of tocilizumab.  For a complete list of all identified or potential risks of tocilizumab
therapy, please refer to the current version of the Tocilizumab Investigator’s Brochure. 
5.1.2.1
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 tocilizumab 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
Tocilizumab infusions will be administered to patients at the site under close supervision.  
Healthcare professionals administering tocilizumab infusions should be trained in the 
appropriate procedures for tocilizumab 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 
tocilizumab.  The patient should be treated according to the SOC for management of the 
hypersensitivity reaction. 
If a patient has symptoms of serious hypersensitivity reactions, such as anaphylaxis, or 
requires an interruption of the study drug because of symptoms of hypersensitivity 
including anaphylaxis, administration of tocilizumab must be discontinued permanently.
5.1.2.2
Serious Infections and Opportunistic Infections
Physicians should exercise caution when considering the use of tocilizumab 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 tocilizumab on CRP 
and neutrophils, and the signs and symptoms of infection, should be considered when 


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evaluating a patient for a potential infection.  It is recommended that neutropenic 
patients (ANC 1000/L) undergo weekly surveillance blood cultures during the study.
If a patient develops a serious infection, the second administration of 
tocilizumab/placebo must not be given
5.1.2.3
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.
The second administration of tocilizumab/placebo must not be given for patients who 
develop GI perforations.
5.1.2.4
Hematologic Abnormalities
Decreases in neutrophil counts, platelet counts, and fibrinogen levels have been 
observed following treatment with tocilizumab 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.
5.1.2.5
Demyelinating Disorders
The effect of treatment with tocilizumab on demyelinating disorders is not known; events 
have been reported rarely.  Physicians should exercise caution when considering the 
use of tocilizumab in patients with preexisting or recent-onset demyelinating disorders.
Patients should be closely monitored for signs and symptoms potentially indicative of 
central demyelinating disorders.
5.1.2.6
Elevated Liver Enzymes
In clinical trials, mild and moderate elevations of hepatic transaminases have been 
observed with tocilizumab treatment. 
The second infusion of tocilizumab/placebo must not be given in patients with ALT or 
AST 5 ULN.
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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5.1.2.7
CYP450 Enzyme Normalization
The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, 
that stimulate chronic inflammation.  Tocilizumab normalizes expression of these 
enzymes.  The effect of tocilizumab 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 tocilizumab, patients taking medicinal products 
that 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.
5.1.3
Management of Patients Who Experience Adverse Events
5.1.3.1
Tocilizumab Dose Modification and Treatment Interruption
If the patient has a sustained fever or clinically significant worsening of signs or 
symptoms (e.g., an increased supplemental oxygen requirement), one additional 
infusion of blinded tocilizumab/placebo can be given 824 hours after the initial first 
tocilizumab/placebo infusion.  The second dose of blinded tocilizumab must not be given 
if the patient develops an adverse event or laboratory abnormalities that warrant 
discontinuation of tocilizumab as described in Section 5.1.2.
5.1.3.2
Remdesivir Treatment Interruption
There are no clinical safety or PK data available for remdesivir in patients with renal 
and/or hepatic impairment.
If the eGFR decreases to an eGFR 30 mL/min (using the equation described in the 
FDA EUA Fact Sheet for remdesivir), remdesivir should not be given.  Dosing may be 
resumed if the eGFR returns to 30 mL/min. Creatinine should be measured daily to 
assess renal function on remdesivir dosing days. If the patient’s renal function worsens 
to the point that he or she requires hemodialysis or hemofiltration, remdesivir will be 
discontinued.
If the ALT and/or AST increases to 5 ULN, the dose of remdesivir should be held and 
not be restarted until the ALT and AST 5 ULN. Remdesivir dosing should be placed 
on hold and may be discontinued, following a review of all available clinical data by the 
medical monitor and discussion with the investigator, if any of the following occurs:

ALT 3x ULN and total bilirubin 2x ULN, confirmed by immediate repeat testing

ALT elevation accompanied by signs or symptoms of liver inflammation or 
increasing conjugated bilirubin, alkaline phosphatase, or INR

Suspected drug-related event of hypersensitivity during the infusion (as described in 
Section 5.5.1). Subjects who have an IV infusion stopped for a safety related issues 
will not continue with dosing.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 and
Section 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE
v5.0; see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Serious and/or medically significant infections

Myocardial infarction or acute coronary syndrome

GI perforations

Anaphylaxis or hypersensitivity reactions 

Stroke


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
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 until 60 days after the 
first dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for 
assessing adverse event severity.  Table 1 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 1
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE v5.0, which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to a study drug, indicating "yes" or "no"
accordingly.  For patients in this study who are potentially receiving combination therapy, 
causality will be assessed individually for each protocol-mandated study drug. The 
following guidance should be taken into consideration (see also Table 2):

Temporal relationship of event onset to the initiation of study drugs

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 2
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
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
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.3
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 
patient, 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 GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
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.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
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., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).


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5.3.5.7
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 and2baseline in combination with 
total bilirubin 2ULN and 2baseline

Treatment-emergent ALT or AST 3ULN and2baseline 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).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of COVID-19 pneumonia.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed solely to progression of COVID-19 pneumonia, "COVID-19 
pneumonia progression" should be recorded on the Adverse Event eCRF.
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
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.


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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").
5.3.5.10
Lack of Efficacy or Worsening of Severe 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.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.

An event that leads to hospitalization under the following circumstances should not 
be reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
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


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
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 
tocilizumab or remdesivir (or tocilizumab 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 tocilizumab or remdesivir (or 
tocilizumab placebo), regardless of whether they result in an adverse event, should be 
recorded on the Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.13
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.


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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/Ethics 
Committee (EC).


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5.4.1
Medical Monitors and Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
(North and South American time zones)
Medical Monitor:
, M.D., M.S. 
Mobile Telephone No.:
Alternate Medical Monitor Contact Information for All Sites
(European time zones)
Medical Monitor:
, M.D.
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported during the 60-day follow-up period.  Investigators should record 
all case details that can be gathered immediately (i.e., within 24 hours after learning of 
the event) on the Adverse Event eCRF and submit the report via the electronic data 
capture (EDC) system.  A report will be generated and sent to Roche Safety Risk 
Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.


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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 90 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.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should counsel 
the patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
60 days after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
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 


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more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
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) 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 


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paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
Tocilizumab
Tocilizumab Investigator's Brochure
Remdesivir
Remdesivir Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
A DMC will monitor the incidence of the above-listed anticipated events during the study.  
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
All primary and secondary efficacy outcomes will be analyzed in the 
modified-intent-to-treat (mITT) population.  The mITT population is defined as all patients 
randomized in the study who received any amount of tocilizumab/placebo and are
grouped according to their treatment assignment at randomization:  remdesivir plus 
tocilizumab, or remdesivir plus placebo. 


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Safety analyses will be performed on the safety-evaluable population, which consists of 
all patients who receive any amount of study treatment (remdesivir and/or 
tocilizumab/placebo).  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 primary endpoint, time to discharge or “ready for discharge,” is event driven. Based 
on the severe cohort receiving 10 days of remdesivir in Gilead’s SIMPLE trial 
(Study GS-US-540-5773), the median time to discharge or “ready for discharge” was 
11 days.  Assuming a median time to discharge or “ready for discharge” of 11 days in 
the remdesivir plus placebo arm, a hazard ratio of 1.3 or an approximately 2.5-day 
reduction in median time for remdesivir plus tocilizumab versus remdesivir plus placebo, 
and a 2:1 randomization to remdesivir plus tocilizumab or remdesivir plus placebo, 
approximately 650 patients are needed to accrue approximately 520 events to achieve 
approximately 80% power. A reduction of at least 2 days in median time to discharge 
was considered clinically meaningful and the sample size was increased to ensure that a 
minimum effect size could be detected. Further sample size adjustments may be 
considered during the study based on external information. The sample size may be 
increased up to a maximum of approximately 800 randomized patients if fewer events 
than expected are observed or further shifts in standard of care warrant reassessing 
sample size assumptions.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, are randomized, 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 (including, but not limited to, age, sex, race, 
geographic region, NEWS2 score, ordinal scale category for clinical status, IL-6, 
mechanical ventilation) will be summarized using means, standard deviations, medians, 
and ranges for continuous variables and proportions for categorical variables, as 
appropriate.  Summaries will be presented by treatment group, and will be presented for 
the mITT population. The safety population may be presented in a similar fashion if 
there are differences.


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Medical history data, including 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
Efficacy analyses will use the mITT population defined as all randomized patients who 
have received any amount of tocilizumab/placebo. To enable a more comprehensive 
evaluation of the treatment effect of tocilizumab combined with remdesivir compared 
with tocilizumab alone, external data may be leveraged appropriately in a meta-analysis 
of this trial combined with WA42380 and ML42528.
Sensitivity analyses to evaluate the robustness of results to the primary analysis
methods (e.g., handling of dropouts, etc.) may be conducted and will be described in the 
SAP.  Full details of adjustments to significance levels for hypothesis tests resulting from 
any interim analyses, and for other instances of multiplicity and/or sequential order of 
analyses will be predefined in the SAP. Censoring rules for each endpoint will be 
predefined in the SAP. 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 the remdesivir
plus tocilizumab arm compared with remdesivir plus placebo arm using the following 
endpoint:

Time from randomization to hospital discharge or “ready for discharge” up to Day 
28
Hospital discharge or “ready for discharge” is defined as a score of 1 on the 
7- category ordinal scale. Patients will meet the endpoint at the time of 
discharge or the time that they achieve category 1 of the 7-category 
ordinal scale, provided that they do not have any further ordinal scale 
assessments category 1 on or prior to Day 28, they are not 
re-hospitalized on or prior to Day 28 and they do not die on or prior to 
Day 28.
The distribution of time from randomization to hospital discharge (or "ready for 
discharge”) will be compared with the remdesivir plus tocilizumab arm and the 
remdesivir plus placebo arm up to Day 28.  Patients discharged after Day 28 will be 
administratively censored.  The distributions will be compared using an appropriate 
method for comparing censored event distributions such as the Cox model.  Kaplan-
Meier and cumulative incidence plots will be presented as well as median time to 


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discharge (or “ready for discharge”), with 95% confidence intervals for the remdesivir 
plus tocilizumab arm and the remdesivir plus placebo arm. 
6.4.2
Secondary Efficacy Endpoints
Time to event secondary endpoints outlined below will be compared between the
remdesivir plus tocilizumab arm and the remdesivir plus placebo arm using an 
appropriate test to compare time to event distributions, such as the Cox model.  If 
death is identified as a competing risk then that will be considered in the method chosen 
or in the definition of the endpoint.  Tests will appropriately include geographic 
region (North America, Europe, Other) and the 2-level factor based on the assessment 
of the 7-category ordinal scale of clinical status at screening (45, 6). Details will be 
addressed in the SAP. The cumulative incidence plot, median time to response, their 
95% CIs, and a p-value will be presented for secondary time to event endpoints.

Time to mechanical ventilation or death up to Day 28, defined as the time from 
randomization to the first occurrence of mechanical ventilation or death 
(whichever occurs first)

Time to improvement of at least 2 categories relative to baseline on a 7-category 
ordinal scale of clinical status up to Day 28

Time to death up to Day 28 and Day 60

Time to recovery up to Day 28, defined as time from randomization to the time 
when a category of 2 on the 7-category ordinal scale (non-ICU hospital ward or 
“ready for hospital ward” not requiring supplemental oxygen), or better is observed
Secondary efficacy incidence endpoints outlined below will be analyzed using the
Cochran-Mantel-Haenszel test statistic adjusted by the stratification factors (geographic 
region [North America, Europe, Other]) and a 2-level factor based on the assessment of 
the 7-point ordinal scale of clinical status at screening, with levels 45, and 6, unless 
stated otherwise. The weighted difference in proportions for the treatment group 
comparison will be presented, together with a 95% CI using the extended 
Mantel-Haenszel method.  Missing data will be imputed as a non-responder, unless 
specified otherwise in the SAP.

Proportion of patients who are discharged or ready for discharge up to Day 28, as 
defined in Section 6.4.1

Proportion of patients requiring initiation of mechanical ventilation postbaseline up to 
Day 28 and Day 60 (patients who do not require mechanical ventilation at baseline)

Proportion of patients who require initiation of mechanical ventilation post 
baseline or die up to Day 28

Proportion of patients who are alive and free of respiratory failure at Day 28 and 
Day 60 (patients requiring mechanical ventilation at baseline)

Mortality at Days 14, 28, and 60. The difference in proportions for the treatment 
group comparison will be presented together with a 95% CI using an appropriate 
method. 


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Secondary efficacy ordinal endpoints are summarized below. Ordinal data will be 
analyzed using an appropriate cumulative link model such as PO or a robust alternative 
such as a variant of Wilcoxon-Mann-Whitney U comparing the remdesivir plus 
tocilizumab arm and the remdesivir plus placebo arm.  The testing approach will account 
for stratification factors at randomization:  geographic region [North America, Europe, 
Other] and a 2-level factor based on the assessment of the 7-category ordinal scale of 
clinical status at screening, with levels 45 or 6.  The appropriate effect size will be 
presented with p-value and 95% CI as well as descriptively by visit.

Clinical status as assessed by the investigator using a 7-category ordinal scale of 
clinical status on Days 7, 14, 21, 28, and 60
Duration endpoints will be summarized descriptively using the means, with 95% CIs for 
the means and difference in means by treatment group and/or cumulative incidence 
plots:

Duration of mechanical ventilation (patients who require mechanical ventilation at 
baseline) up to Day 28
Primary and selected secondary endpoints may be compared across this trial, WA42380, 
and ML42528 in a meta-analysis using similar approaches. Further details of the 
secondary endpoint analysis and meta-analysis will be included in the SAP and the 
meta-analysis plan, respectively. 
6.4.3
Exploratory Efficacy Endpoints
Exploratory time to event endpoints outlined below will be compared between the 
remdesivir plus tocilizumab arm and the remdesivir plus placebo arm using an 
appropriate summary method to compare time to event distributions, if death is identified 
as a competing risk then that will be considered in the method chosen or in the 
definition of the endpoint.  Tests will appropriately include geographic region (North 
America, Europe, Other) and the 2-level factor based on the assessment of the 
7-category ordinal scale of clinical status at screening (45, 6).  Details on statistical 
analysis methods used and censoring rules will be addressed in the SAP.

TTCI up to Day 28, defined as time from randomization to NEWS2 score of2 
maintained for 24 hours

Time to clinical failure up to Day 28, defined as the time from randomization to the 
first occurrence of death, mechanical ventilation, ICU admission or withdrawal from 
study prior to discharge (whichever occurs first)

Proportion of patients requiring initiation of ICU care postbaseline up to Day 28 and 
Day 60

Duration of ICU stay (days) up to Day 28 will be summarized using the means
along with 95% CIs for the means by treatment group.

Duration of supplemental oxygen use (days) up to Day 60 will be summarized 
using the means along with 95% CIs for the means by treatment group.


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
Proportion of patients requiring initiation of vasopressor use postbaseline up to 
Day 28 will be summarized descriptively.

Duration of vasopressor use up to Day 28 will be summarized using the means
along with 95% CIs for the means by treatment group.

Proportion of patients requiring initiation of ECMO postbaseline up to Day 28 and 
Day 60 will be summarized descriptively.

Duration of ECMO up to Day 28 will be summarized using the means along with 
95% CIs for the means by treatment group.

Organ failure-free days from randomization to Day 28 will be summarized 
descriptively using the means, with 95% CI for the means by treatment group. In 
addition, a summary of individual organ failure over time will be provided.

SARS-CoV-2 viral load over time up to Day 28 and Day 60 will be summarized 
descriptively by timepoint and treatment group for respiratory and serum 
samples.

Time to RT-PCR SARS-CoV-2 virus negativity up to Day 14 (serum samples) or
Day 60 (respiratory samples) will be analyzed using similar methods to the other 
time to analyses but account for interval censoring.
6.5
SAFETY ANALYSES
Safety assessments will be performed on the safety-evaluable population, which 
consists of all patients who receive any amount of study treatment.  In all safety 
analyses, patients will be grouped according to the treatment that the patients actually 
received, rather than the treatment assigned at randomization. Details with respect to 
grouping will be specified in the SAP.
Safety will be assessed through descriptive summaries of treatment emergent adverse 
events (nature, frequency, severity, and causality). Adverse events will also be listed 
and 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.
Separate summaries will be generated for serious adverse events, deaths, adverse
events leading to discontinuation of study drug, and adverse events of special interest.  
Adverse events will be summarized by MedDRA term, appropriate thesaurus level, and
toxicity grade.  Descriptive summaries of laboratory values and change from baseline 
throughout the study will be tabulated by treatment arm. For selected parameters, 
changes from the proportion of patients experiencing clinically significant changes 
relative to baseline will be summarized by treatment arm.  Values, along with change 
from baseline, will be summarized using descriptive statistics for each vital sign 
parameter.
The proportion of patients with any post-treatment infection will be summarized at time 
points including Day 60.


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A treatment-emergent adverse event are defined as any new adverse event reported or 
any worsening of an existing condition on or after the first dose of study drug.
6.6
PHARMACOKINETIC ANALYSES
Plasma concentrations and PK parameters for remdesivir and metabolite(s) may be 
listed and summarized using descriptive statistics by group.
For summary statistics, PK concentration values below the limit of quantitation will be 
treated as zero at predose and one-half of the lower limit of quantitation for sample 
collected during the remdesivir infusion.
6.7
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies.
6.8
INTERIM ANALYSES
There will be up to three optional interim analyses. The first interim analysis can occur 
after approximately one-third to one-half of the patients have been assessed for the 
primary endpoint on Day 28, depending on enrollment rate. There may be up to two 
additional unplanned interim analyses, and these will be considered if there are major 
changes to the study design following the first interim analysis.
Full statistical details of any optional interim analyses, along with the rationale and timing 
will be documented in an interim SAP, which will be made available to the relevant 
health authorities before the data snapshot for the first interim analysis.  Only the DMC 
will be unblinded and decision criteria will be specified in the interim SAP.  Should an 
unblinded interim analysis occur, any necessary adjustment to the type 1 error rate will 
be specified in the SAP prior to unblinding the study.
The optional interim analysis will be based on the time to discharge (or ready for 
discharge) and mortality.  Questions to be addressed at the interim analysis might 
include futility as well as potential efficacy.
The DMC will also evaluate safety according to policies and procedures detailed in the
DMC Charter. Regular safety reviews will begin after approximately 45 patients 
(15 remdesivir and 30 combination) have been enrolled and have reached 14 days of
follow-up.  Early stopping criteria based on compelling efficacy or an imbalance in 
adverse events will be detailed in the DMC Charter.  The safety interim analyses will 
also be conducted by a statistical programmer and statistician independent from the 
study management team and will be reviewed by the DMC.  Interactions between the 
DMC and Sponsor will be carried out as specified in the DMC Charter.


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The DMC initially consisted of Sponsor representatives not involved in any operational 
aspects of the study and a Scientific Oversight Committee of external experts 
(responsibilities and operating principles of the DMC are described in a charter, the 
Internal Monitoring Committee and Scientific Oversight Committee Agreement).  The 
DMC responsibilities transitioned to a fully independent Data Monitoring Committee 
(iDMC) prior to the third scheduled safety review after approximately 300 patients 
reached Day 28 of follow-up. The iDMC will also conduct a fourth scheduled safety data 
review when at least 450 patients have reached Day 28. Data processing will be 
handled by a Sponsor statistician and statistical programmer independent of the study 
management team. Details are reported in the iDMC Charter.
6.9
EXTERNAL DATA
Trials WA42380 and ML42528 may be included in a meta-analysis of mortality, the 
primary endpoint, and selected secondary endpoints.  Both trials compare 8 mg/kg IV
TCZ with placebo.  If further relevant studies are identified prior to analysis, they may 
also be included in the pre-defined meta-analysis.  Prior to inclusion, external data will 
be checked for consistency of measured endpoints so that endpoints can be assessed.
Full details of the analysis and trial inclusion criteria will be specified in the meta-
analysis plan.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Due to the pandemic situation, access to hospitals is restricted; therefore, only remote 
data monitoring will be performed for this study.  Study monitors will perform ongoing 
remote data review to confirm that critical protocol data (i.e., source data) entered into 
the eCRFs by authorized site personnel are accurate and complete. Sites will be asked 
to implement a quality-control step of a second person reviewing the data entry in the 
eCRF where possible.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.


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7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 


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the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative or where allowed, health care provider (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 or the patient’s legally authorized representative and this must be 
documented by the investigator or authorized designee.  The case history or clinical 
records for each patient shall document the informed consent process and that informed 
consent was obtained prior to participation in the study.
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 with 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 informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 


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separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC (national or 
regional) by the Principal Investigator and reviewed and approved by the IRB/EC before 
the study is initiated.  In addition, any patient recruitment materials must be approved by 
the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6).


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 


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to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted remotely by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 100 sites globally will participate to enroll up to 800 patients.  Enrollment 
will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
A DMC will be employed to monitor and evaluate patient safety throughout the study.
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 


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has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading 
exoribonuclease. MBio 2018;9:e0022118.
De Neve J and Thas O. A regression framework for rank tests based on the probabilistic 
index model. J Am Stat Assoc 2015;110:127683.
de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) 
treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad 
Sci 2020;117:67716.
de Wit E, Rasmussen AL, Falzarano D, et al. Middle East respiratory syndrome 
coronavirus (MERS-CoV) causes transient lower respiratory tract infection in 
rhesus macaques. Proc Natl Acad Sci 2013;110:16598603.
[FDA] U.S Food and Drug Administration. Emergency Use Authorization for use of 
remdesivir in COVID-19. [Resource on the internet]. 2020a [Dated 1 May 2020, 
last accessed 14 May 2020]. Available from: 
https://www.fda.gov/media/137564/download
[FDA] U.S Food and Drug Administration. Fact Sheet For Health Care Providers -
Emergency Use Authorization Of Remdesivir. [Resource on the internet]. 2020b 
[Last accessed 25 June 2020]. Available from: 
https://www.fda.gov/media/137566/download
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.
Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of Covid-19 in New York City. 
N Engl J Med 2020 Apr 17; DOI: 10.1056/NEJMc2010419.
Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with 
severe Covid-19. N Engl J Med 2020; DOI: 10.1056/NEJMoa2007016.
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.
Lo MK, Feldmann F, Gary JM, et al. Remdesivir (GS-5734) protects African green 
monkeys from Nipah virus challenge. Sci Transl Med 2019;11(494):eaau9242.
Lo MK, Jordan R, Arvey A, et al. GS-5734 and its parent nucleoside analog inhibit filo-, 
pneumo-, and paramyxoviruses. Sci Rep 2017;7:43395.
Mulangu S, Dodd LE, Davey Jr RT, et al. A randomized, controlled trial of Ebola virus 
disease therapeutics. N Engl J Med 2019;381:2293303.


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Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits 
both epidemic and zoonotic coronaviruses. Sci Transl Med 2017;9(396).
Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir 
and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat 
Commun 2020;11:14.
Vincent JL. Organ dysfunction in patients with severe sepsis. Surg Infect 2006;7:s69.
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 
novel coronavirusinfected pneumonia in Wuhan, China. JAMA 2020. 
doi:10.1001/jama.2020.1585.
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the 
recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 
2020;30:26971.
Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 
against Ebola virus in rhesus monkeys. Nature 2016;531(7594):3815.
[WHO] World Health Organization. Coronavirus disease (COVID-19) situation reports 
[Resource on the internet]. 2020a [updated 19 May 2020; cited 19 May 2020]. 
Available from: 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-
reports
[WHO] World Health Organization. Clinical management of severe acute respiratory 
infection when novel coronavirus (nCoV) infection is suspected [Resource on the 
internet]. 2020b [updated 13 March 2020;  cited 12 April 2020]. Available from: 
https://www.who.int/publications-detail/clinical-management-of-severe-acute-
respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected
Wu Z and McGoogan JM. Characteristics of and important lessons from the coronavirus 
disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases 
from the Chinese Center for Disease Control and Prevention. JAMA 2020. 
doi:10.1001/jama.2020.2648.
Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with 
tocilizumab. ChinaXiv preprint. [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
Schedule of Activities:  Screening, Days 1 and 2
Study Day
Screening a, b
Day 1
Day 2
2 to 0
Time After Initial Treatment
(Assessment Window)
Baseline
0
Predose
1 hour
After End of 
RDV Infusion
(2 hrs)
15 min
After End of 
TCZ Infusion
(3 hrs)
24 hrs
(4 hrs)
36 hrs
(4 hrs)
Informed consent
x
Inclusion/exclusion criteria
x
x
Demographic data
x
Randomization
x
Medical history
x
Complete physical examination c
x
Weight d
x
COVID-19 diagnosis e
x
Chest X-ray/CT scan f
x
ECG
x
Pregnancy test g
x
PaO2/FiO2 h
Optional h
  Optional  
SpO2 i
x
x
x
x
x
x
Vital signs i
x
x
x
x
x
x
Ordinal scoring j
x
x
Adverse events k
x k
x k
x
x
x
x


Appendix 1: Schedule of Activities:  Screening, Days 1 and 2
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Study Day
Screening a, b
Day 1
Day 2
2 to 0
Time After Initial Treatment
(Assessment Window)
Baseline
0
Predose
1 hour
After End of 
RDV Infusion
(2 hrs)
15 min
After End of 
TCZ Infusion
(3 hrs)
24 hrs
(4 hrs)
36 hrs
(4 hrs)
Concomitant medications l
x
x
x
Hematology m
x 
x
x
Chemistry (full panel) n
x 
x
Chemistry (only ALT, AST, total bilirubin, ALP, 
and creatinine)
x
Coagulation o
x
x
RDV administration p
x
x
TCZ/placebo administration q
x
Central Labs
Serum sample for exploratory biomarkers p
x
x
Nasopharyngeal swab: SARS-CoV-2 viral load 
and exploratory biomarkers r
x
x r
Serum SARS-CoV-2 antibody titer
x
Cryopreserved PBMCs s
x
x
Blood in PAXgenetubes for RNA analyses t
x


Appendix 1: Schedule of Activities: Screening, Days 1 and 2
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CTcomputed tomography; eCRF electronic case report form; hrs hours; minminute; NEWS2National Early Warning Score 2; NKnatural 
killer (cell); PaO2/FiO2arterial oxygen partial pressure/fraction of inspired oxygen; PBMCs peripheral blood mononuclear cells; 
PCRpolymerase chain reaction; PCT procalcitonin; RDVremdesivir; SARS-Cov-2severe acute respiratory syndrome coronavirus 2; 
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 (including physical exam) performed prior to obtaining informed consent and within 
24 hours before screening 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.  The screening and baseline visit may be 
performed on the same day, provided that the patient meets all of the study entry criteria as outlined in Section 4.1.1 and Section 4.1.2 prior to 
randomization.  If the screening and baseline visits occur on the same day, assessments do not need to be repeated.
c A complete physical examination, performed at screening and per the investigator’s discretion during the study, includes an evaluation of the 
head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 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 after randomization should be reported as adverse events (see Section 5.3). 
d If it is not feasible to weigh bed-bound patients, historical body weight may be used.
e COVID-19 test (SARS-CoV-2 PCR) to confirm diagnosis should be collected within 7 days prior to randomization. 
f
Screening chest X-ray or CT scans should be performed within 48 hours prior to randomization.   
g For women of childbearing potential, including those who have had a tubal ligation will have a pregnancy test at screening.  If a urine pregnancy 
test is positive, it must 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.  
i
On Day 1, all vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressure, and body temperature), oxygen 
saturation (SpO2), and NEWS2-specific assessments (i.e., consciousness and presence or absence of oxygen support) must be recorded 
1) prior to administration of remdesivir, 2) after administration of remdesivir/prior to administration of tocilizumab/placebo and 3) after 
administration of tocilizumab/placebo. On Day 2, measurements should be recorded together twice daily approximately every 12 hours.  If 
measured more than once during a 12 hour period on Day 2, 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.  For patients requiring 
supplemental oxygen, the oxygen flow rate (L/min) and/or FiO2 should be recorded.
j
Assessment of clinical status using the ordinal scale should be recorded at baseline on Day 1 and again daily every morning (between 
8:00 a.m. and 12:00 p.m.) for patients who remain hospitalized.  See Section 4.5.10 for additional details.


Appendix 1: Schedule of Activities: Screening, Days 1 and 2
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88/Protocol WA42511, Version 6
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 first 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) 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), and lymphocyte subsets (T cells, B cells, and NK cells; if the test is available at the site, or if the site can ship the 
blood sample on the day of collection to the central laboratory for testing.  Samples are not required if neither of these options is available).
n Chemistry panel (serum or plasma) includes bicarbonate, sodium, potassium, chloride, glucose, BUN, creatinine, total protein, albumin, 
phosphorus, calcium, total bilirubin, ALP, ALT, AST, LDH, ferritin, and PCT.
o Coagulation panel includes INR, PTT, D-dimer and fibrinogen.
p Remdesivir should be administered after review of hematology and chemistry safety labs and collection of all central lab samples.  The initial 
infusion of remdesivir should be given within 4 hours of randomization.  If the patient received remdesivir prior to randomization, the remdesivir 
dose on Day 1 will be a 100-mg maintenance dose.  If a second tocilizumab/placebo infusion is given, there must be at least 2 hours after 
completion of the second tocilizumab/placebo infusion before the Day 2 remdesivir infusion is administered in this instance, the visit window 
on Day 2 at 24 hours may be extended to 6 hours.
q The infusion of tocilizumab/placebo must not be given until at least 60 minutes after the infusion of remdesivir is complete. If the patient has a 
sustained fever or clinically significant worsening of signs or symptoms (e.g., an increased supplemental oxygen requirement), one additional 
infusion of blinded tocilizumab/placebo can be given 824 hours after the first tocilizumab/placebo infusion (see Section 5.1.3.1).
r
Viral load will be assessed by nasopharyngeal swab or other respiratory sample (e.g., endotracheal tube aspirate).  Sample collection on Day 2 
is optional. Where possible the same nostril should be used.  Patients who are intubated and undergo bronchoscopy will have samples taken 
for virological assessment.  Genotypic and phenotypic viral resistance may be assessed in exploratory analyses. Other analyses may include 
evaluation of levels of inflammatory biomarkers.
s For sites capable of performing PBMC isolation and cryopreservation.  If PBMC isolation or cryopreservation is not feasible for the site, then 
blood samples may alternatively be shipped on the day of collection to the central laboratory.  Samples are not required if neither of these 
options is available.
t
The PAXgeneblood RNA tube should be the last tube draw in the phlebotomy procedure to avoid contact with RNA preservation reagent 
inside the tube.


TocilizumabF. Hoffmann-La Roche Ltd
89/Protocol WA42511, Version 6
Appendix 2
Schedule of Activities:  Days 328
Study Day
Days 328 a
Study 
Discontinuation 
b
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
Vital signs c
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
SpO2 c
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 d
   Optional  
Optional
Ordinal scoring e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology h
x
x
x
x
x
x
x
x
Chemistry (full panel) i
x
x
x
x
x
x
x
Chemistry (only ALT, AST, total 
bilirubin, ALP and creatinine)
x
x
x
x
x
Coagulation j
x
x
x
x
x
RDV administration k
x
x
x
x
x
x
x
x
Central Labs
Plasma PK l
x
x
Serum sample for exploratory 
biomarkers
x
x
x
x
x
x
Nasopharyngeal swab: 
SARS-CoV-2 viral load and 
exploratory biomarkers m
x
x m
x
x m
x
x
x
x
x
x


Appendix 2: Schedule of Activities: Days 328
TocilizumabF. Hoffmann-La Roche Ltd
90/Protocol WA42511, Version 6
Study Day
Days 328 a
Study 
Discontinuation 
b
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
Serum SARS-CoV-2 antibody 
titer
x
x
Cryopreserved PBMCs n
x
x
x
x
x
x
Blood in PAXgene
tubes for RNA analyses o
x
x
x
x
NEWS2National Early Warning Score 2; NKnatural killer (cell); PaO2/FiO2arterial oxygen partial pressure/fraction of inspired oxygen; 
PBMCs peripheral blood mononuclear cells; PCT procalcitonin; PKpharmacokinetic; SARS-CoV-2severe acute respiratory syndrome 
coronavirus 2; SpO2peripheral capillary oxygen saturation.
a If patients are discharged from hospital prior to Day 28, follow-up visits should be conducted on Day 14, Day 21 and Day 28 (2 days).  Follow-up
visits on Day 14 and Day 21 may be conducted as telephone visits.  Vital signs and laboratory testing will not be required for telephone visits.  For 
patients discharged with supplemental oxygen prior to Day 28, SpO2 measured by the patient at home should be recorded during telephone visits, if 
available.  Patients should return to the site for the Day 28 visit, if at all possible.
b Patients who discontinue from study treatment should continue in the study and complete all assessments through Day 60 (as outlined in Appendix 2
and Appendix 3).
c All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressure, and body temperature), oxygen saturation and 
NEWS2-specific assessments (i.e., consciousness and presence or absence of oxygen support) should be recorded together twice daily approximately 
every 12 hours while the patient remains hospitalized.  If measured more than once during a 12 hour period, the worst values (highest temperature, 
respiratory rate, and heart rate; lowest blood pressure, oxygen saturation, and consciousness level) during that period should be recorded on the 
eCRF.  Following hospital discharge, these parameters should be recorded once at each return visit to the clinic.  Vital signs and oxygen saturation will 
not be recorded if follow-up visits are conducted by telephone.
d If arterial blood gases are measured.
e Assessment of clinical status using the ordinal scale should be recorded daily every morning (between 8:00 a.m. and 12:00 p.m.) for patients who 
remain hospitalized.  See Section 4.5.10 for additional details.
f
All adverse events will be reported until 60 days after the first dose of study drug.  After this period, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).


Appendix 2: Schedule of Activities: Days 328
TocilizumabF. Hoffmann-La Roche Ltd
91/Protocol WA42511, Version 6
g Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, 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.
h Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes), and lymphocyte subsets (T cells, B cells, and NK cells; if the test is available at the site, or if the site can ship the blood 
sample on the day of collection to the central laboratory for testing.  Samples are not required if neither of these options is available).  Hematology labs 
will not be performed if follow-up visits are conducted by telephone.
i
Chemistry panel (serum or plasma) includes bicarbonate, sodium, potassium, chloride, glucose, BUN, creatinine, total protein, albumin, phosphorus, 
calcium, total bilirubin, ALP, ALT, AST, LDH, ferritin, and PCT.  Chemistry labs will not be performed if follow-up visits are conducted by telephone.
j
Coagulation panel includes INR, PTT, D-dimer and fibrinogen. Coagulation labs will not be performed if follow-up visits are conducted by telephone.
k Remdesivir should be administered after review of chemistry safety labs and collection of all central lab samples. If a patient is discharged from 
hospital before Day 10, remdesivir will be discontinued at that time. Patients who received remdesivir prior to randomization will not exceed 10 days of 
remdesivir dosing in total.  
l
On Day 4 and Day 7, PK samples should be drawn prior to the start of remdesivir infusion (predose) and also 3060 minutes after the start of the 
remdesivir infusion if possible.  All PK samples must be drawn from the opposite arm as the remdesivir infusion. PK samples are not required if 
collection and processing is not feasible. 
m Patients who remain in hospital will have viral load assessed by nasopharyngeal swab or other respiratory sample (e.g., endotracheal tube aspirate). 
Sample collection on Day 4 and Day 6 is optional.  Where possible the same nostril should be used. Genotypic and phenotypic viral resistance may 
be assessed in exploratory analyses. Other analyses may include evaluation of levels of inflammatory biomarkers.
n For sites capable of performing PBMC isolation and cryopreservation.  If PBMC isolation or cryopreservation is not feasible for the site, then blood 
samples may alternatively be shipped on the day of collection to the central laboratory.  Samples are not required if neither of these options is
available.
o The PAXgeneblood RNA tube should be the last tube draw in the phlebotomy procedure to avoid contact with RNA preservation reagent inside the 
tube.


TocilizumabF. Hoffmann-La Roche Ltd
92/Protocol WA42511, Version 6
Appendix 3
Schedule of Activities:  After Day 28
Study 
Completion/
Discontinuation
Study Day
(Assessment Window)
35 a
(3 days)
45 a
(3 days)
60
(3 days)
Vital signs b
x
x
x
SpO2 b
x
x
x
Ordinal scoring c
x
x
x
Adverse events d
x
x
x
Concomitant medications e
x
x
x
Hematology f
x
x
x
Chemistry g
x
x
x
Coagulation h
x
x
x
Central Labs
Nasopharyngeal swab: SARS-CoV-2 viral load and 
exploratory biomarkers i
x i
x i
x
Serum sample for exploratory biomarkers
x
x
Serum SARS-CoV-2 antibody titer
x
Cryopreserved PBMCs j
x
Blood in PAXgenetubes for RNA analyses k
x
NKnatural killer (cell); PMBCs peripheral blood mononuclear cells; PCT procalcitonin; SARS-CoV-2severe acute respiratory 
syndrome coronavirus 2; SpO2peripheral capillary oxygen saturation.


Appendix 3: Schedule of Activities: After Day 28
TocilizumabF. Hoffmann-La Roche Ltd
93/Protocol WA42511, Version 6
a Patients should have follow up visits on Day 35, Day 45, and Day 60 (3 days).  The Day 35 and Day 45 visits may be conducted by telephone 
for discharged patients. Vital signs and laboratory testing will not be required for telephone visits.  For patients discharged with supplemental 
oxygen, SpO2 measured by the patient at home should be recorded during telephone visits, if available. Patients should return to the site for the 
Day 60 visit, if at all possible.
b For patients who remain in hospital, vital sign measurements and NEWS2-specific assessments should be conducted twice daily.  If measured 
more than once during a 12-hour period, the worst values (highest temperature, respiratory rate, and heart rate; lowest blood pressure, oxygen 
saturation, and consciousness level) during that period should be recorded on the eCRF.  Following hospital discharge, these parameters should 
be recorded once at each return visit to the clinic. Vital signs and oxygen saturation will not be recorded if follow-up visits are conducted by 
telephone.
c Assessment of clinical status using the ordinal scale should be recorded daily every morning (between 8:00 a.m. and 12:00 p.m.) for patients 
who remain hospitalized.
d All adverse events will be reported until 60 days after the first 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).
e Medication (e.g., prescription drugs, over-the-counter drugs) 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.
f
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes), and lymphocyte subsets (T cells, B cells, and NK cells; if the test is available at the site, or if the site can ship the 
blood sample on the day of collection to the central laboratory for testing. Samples are not required if neither of these options is available).
Hematology labs will not be performed if follow-up visits are conducted by telephone.
g Chemistry panel (serum or plasma) includes bicarbonate, sodium, potassium, chloride, glucose, BUN, creatinine, total protein, albumin, 
phosphorus, calcium, total bilirubin, ALP, ALT, AST, LDH, ferritin, and PCT. Chemistry labs will not be performed if follow-up visits are 
conducted by telephone.
h Coagulation panel includes INR, PTT, D-dimer, and fibrinogen. Coagulation labs will not be performed if follow-up visits are conducted by 
telephone.
i
Patients who remain in hospital will have viral load assessed by nasopharyngeal swab or other respiratory sample (e.g., endotracheal tube 
aspirate).  Sample collection on Day 35 and Day 45 is optional.  Where possible the same nostril should be used. Genotypic and phenotypic 
viral resistance may be assessed in exploratory analyses.  Other analyses may include evaluation of levels of inflammatory biomarkers.
j
For sites capable of performing PBMC isolation and cryopreservation. If PBMC isolation or cryopreservation is not feasible for the site, then
blood samples may alternatively be shipped on the day of collection to the central laboratory.  Samples are not required if neither of these 
options is available.


Appendix 3: Schedule of Activities: After Day 28
TocilizumabF. Hoffmann-La Roche Ltd
94/Protocol WA42511, Version 6
k The PAXgeneblood RNA tube should be the last tube draw in the phlebotomy procedure to avoid contact with RNA preservation reagent inside
the tube.


TocilizumabF. Hoffmann-La Roche Ltd
95/Protocol WA42511, Version 6
Appendix 4
National Early Warning Score 2 (NEWS2)
CVPUconfusion, voice, pain, unresponsive; SpO2oxygen saturation. 
The oxygen saturation should be scored according to either the SpO2 Scale 1 or 2 
presented in the table above.  The SpO2 Scale 2 is for patients with a target oxygen 
saturation requirement of 88%92% (e.g., in patients with hypercapnic respiratory failure 
related to advanced lung diseases, such as chronic obstructive pulmonary disease).  
This should only be used in patients confirmed to have hypercapnic respiratory failure by 
blood gas analysis on either a prior or their current hospital admission.
The decision to use the SpO2 Scale 2 should be made by the treating physician and 
should be recorded in the electronic Case Report Form (eCRF).  In all other 
circumstances, the SpO2 Scale 1 should be used.
For physiological parameter “Air or Oxygen?”:  Any patients requiring the use of oxygen 
or other forms of ventilation to maintain oxygen saturations and support respiration 
should be assigned a score of 2.
The consciousness level should be recorded according to the best clinical condition of 
the patient during the assessment.  Patients who are assessed as “Alert” (A) should be 
assigned a score of 0.  Patients assessed as “New Confusion” (C), “Responsive to 
Voice” (V), “Responsive to Pain” (P), or “Unconscious” should be assigned a score of 3.


Appendix 4: National Early Warning Score 2 (NEWS2)
TocilizumabF. Hoffmann-La Roche Ltd
96/Protocol WA42511, Version 6
Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and 
temperature according to the table above. 
NEWS2 values will be calculated electronically throughout the study by the Sponsor 
based upon entry of vital sign parameters by the investigator in the appropriate eCRF.
Example Case Calculation:
An 82-year-old lady was admitted, tested positive to COVID-19 and admitted to high 
dependency unit for non-invasive ventilation.  Her taken observations and corresponding 
NEWS2 score are as follows: 
Physiological Parameter 
Observation
Component Score
Respiratory rate (per min)
26
3
Oxygen saturation (SpO2 %)
95%
1
Supplemental oxygen 
Yes
2
Systolic blood pressure (mmHg)
95
2
Pulse rate (bpm)
109
1
Conscious level
New confusion
3
Temperature (oC)
39
1
Total NEWS2 Score
13
REFERENCE
Royal College of Physicians. National early warning score (NEWS) 2. Standardizing the 
assessment of acute-illness severity in the NHS. London: RCP, 2017.

SAP_001.pdf: 
 
Official Title: A Phase III, Randomized, Double-Blind, Multicenter Study to Evaluate 
the Efficacy and Safety of Remdesivir Plus Tocilizumab Compared 
With Remdesivir Plus Placebo in Hospitalized Patients With Severe 
Covid-19 Pneumonia 
NCT Number: NCT04409262 
Document Date: SAP Version 2: 22-February-2021 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Tocilizumab—F. Hoffmann-La Roche Ltd.
Statistical Analysis Plan WA42511
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND,
MULTICENTER STUDY TO EVALUATE THE
EFFICACY AND SAFETY OF REMDESIVIR PLUS
TOCILIZUMAB COMPARED WITH REMDESIVIR
PLUS PLACEBO IN HOSPITALIZED PATIENTS WITH SEVERE COVID-
19 PNEUMONIA
PROTOCOL NUMBER:
WA42511
STUDY DRUG:
Tocilizumab (RO4877533), Remdesivir
VERSION NUMBER:
2
IND NUMBER:
148225
EUDRACT NUMBER:
2020-002275-34
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, Ph.D (Version 1), 
, M.S. 
(Version 1),
, Ph.D (Version 2)
DATE FINAL:
Version 1: 4 December 2020
DATE AMENDED:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
22-Feb-2021 20:41:04
Company Signatory


Tocilizumab—F. Hoffmann-La Roche Ltd.
2/Statistical Analysis Plan WA42511
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
This Statistical Analysis Plan Version 2 was amended from Version 1 to address health 
authority feedback as follows:

The derivation of the primary endpoint was updated

Two additional secondary endpoints were added:

Proportion of patients discharged or “ready for discharge” up to Day 28

Proportion of patients who require initiation of mechanical ventilation postbaseline or die up 
to Day 28 and up to Day 60

The definition of the analysis populations was clarified

Study Day 1 was changed to the day of randomization rather than the day of first TCZ/PBO 
administration

Time to event endpoints were changed from “time from administration of TCZ/PBO” to “time 
from randomization”

The censoring rules and analysis approach for the time to event endpoints were updated

The analysis method for the duration and ordinal endpoints was updated

Tipping point analyses were added for the primary and key secondary endpoints

The PD analyses section was removed  
Additional minor changes have been made to improve clarity and consistency.


Tocilizumab—F. Hoffmann-La Roche Ltd.
3/Statistical Analysis Plan WA42511
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 8
2.
STUDY DESIGN........................................................................................... 9
2.1
Protocol Synopsis.................................................................. 11
2.2
Endpoints............................................................................... 11
2.2.1
Primary Efficacy Endpoints.................................................... 11
2.2.2
Secondary Efficacy Endpoints............................................... 11
2.2.3
Exploratory Efficacy Endpoints.............................................. 12
2.2.4
Biomarkers ............................................................................ 13
2.2.5
Safety Endpoints ................................................................... 13
2.3
Determination of Sample Size ............................................... 13
2.4
Analysis Timing ..................................................................... 13
3.
STUDY CONDUCT..................................................................................... 14
3.1
Randomization, Stratification and Blinding ............................ 14
3.2
Data Monitoring ..................................................................... 15
4.
STATISTICAL METHODS .......................................................................... 16
4.1
Analysis Populations ............................................................. 16
4.1.1
mITT Population .................................................................... 16
4.1.2
Safety Population .................................................................. 16
4.2
Analysis of Study Conduct..................................................... 16
4.3
Analysis of Treatment Group Comparability .......................... 17
4.3.1
Demographics ....................................................................... 17
4.3.2
Baseline Characteristics ........................................................ 17
4.3.3
Medical History...................................................................... 18
4.3.4
Previous and Concomitant Medications................................. 18
4.4
Visit Labels ............................................................................ 18
4.5
Efficacy Analysis.................................................................... 21
4.5.1
Primary Efficacy Endpoint...................................................... 21
4.5.2
Controlling for Type I Error .................................................... 23
4.5.3
Type I Error Controlled Secondary Endpoints ....................... 24
4.5.3.1
Time to Mechanical Ventilation or Death up to Day 28.......... 24


Tocilizumab—F. Hoffmann-La Roche Ltd.
4/Statistical Analysis Plan WA42511
4.5.3.2
Clinical Status on Day 14....................................................... 25
4.5.3.3
Time to Death up to Day 28................................................... 27
4.5.4
Other Secondary Endpoints................................................... 28
4.5.4.1
Time to Event Analyses......................................................... 28
4.5.4.2
Incidence Endpoints .............................................................. 30
4.5.4.3
Ordinal endpoints .................................................................. 32
4.5.4.4
Duration endpoints ................................................................ 32
4.5.4.5
Meta-Analysis........................................................................ 33
4.5.5
Exploratory Efficacy Endpoints.............................................. 33
4.5.6
Subgroup Analyses ............................................................... 37
4.5.7
Sensitivity and Tipping Point Analyses .................................. 37
4.5.7.1
Prognostic Covariates............................................................ 37
4.5.7.2
Clinical Status at Day 14........................................................ 37
4.5.7.3
Primary Time to Event Endpoint............................................ 38
4.5.7.4
Time to Death and Time to Mechanical Ventilation or 
Death up to Day 28................................................................ 41
4.6
Safety Analyses..................................................................... 41
4.6.1
Exposure to Study Medication............................................... 41
4.6.2
Adverse Events ..................................................................... 42
4.6.3
Laboratory Data..................................................................... 43
4.6.4
Vital Signs.............................................................................. 43
4.7
Interim Analyses .................................................................... 44
5.
REFERENCES ........................................................................................... 44
LIST OF TABLES
Table 1
Time Windows for Assigning Assessment Study Days to Study 
Visits Labels for Deaths and Discharge ...................................... 20
Table 2
Time Windows for Assigning Assessment Study Days to Study 
Visits for Hematology Parameters............................................... 20
Table 3
Time to Hospital Discharge or “Ready for Discharge” Censoring 
Rules........................................................................................... 23
Table 4
Time to Mechanical Ventilation or Death Censoring Rules ......... 25
Table 5
Time to Death Censoring Rules.................................................. 28
Table 6
Time to Improvement in Ordinal Clinical Status Censoring Rules30


Tocilizumab—F. Hoffmann-La Roche Ltd.
5/Statistical Analysis Plan WA42511
LIST OF FIGURES
Figure 1
Study WA42511 Schema............................................................ 11
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 46
Appendix 2
Schedule of Activities:  Screening, Days 1 and 2........................ 53
Appendix 3
Schedule of Activities:  Days 328.............................................. 57
Appendix 4
Schedule of Activities:  After Day 28........................................... 60
Appendix 5
National Early Warning Score 2 (NEWS2).................................. 63


Tocilizumab—F. Hoffmann-La Roche Ltd.
6/Statistical Analysis Plan WA42511
GLOSSARY OF ABBREVIATIONS
AE
adverse event
AEGT
adverse event grouped term
AESI
adverse event of special interest
BAP
biomarker analysis plan
CI
confidence interval
CIF
cumulative incidence function
CMH
Cochran-Mantel-Haenszel
COVID-19
Corona Virus Disease-19
CRP
C-reactive protein
CT
computed tomography
DMC
data monitoring committee
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic Case Report Form
ICU
intensive care unit
iDMC
independent Data Monitoring Committee
IL-6
interleukin 6
iSAP
interim Statistical Analysis Plan
IV
intravenous
IxRS
interactive voice or web-based response system
MAP
meta-analysis Statistical Analysis Plan
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent to treat
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NEWS2
National Early Warning Score 2
PaO2/FiO2
Ratio between the partial pressure of oxygen (PaO2) 
and fraction of inspired oxygen, (FiO2)
PBO
placebo
PD
pharmacodynamics
PI
probabilistic index
PK
pharmacokinetic
PT
preferred term
RDV
remdesivir
SAE
serious adverse event
SAP
Statistical Analysis Plan
SMQ
Standard MedDRA Query


Tocilizumab—F. Hoffmann-La Roche Ltd.
7/Statistical Analysis Plan WA42511
SMT
study management team
SOC
standard of care
TCZ
tocilizumab
TLR
top line report
TTCI
time to clinical improvement
VFDs
ventilator-free days 
WHO
World Health Organisation


Tocilizumab—F. Hoffmann-La Roche Ltd.
8/Statistical Analysis Plan WA42511
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 WA42511. Any 
analyses of biomarkers or virologic data will be covered by a separate analysis plan. 
Analyses of pharmacokinetic data will be covered by a separate analysis plan.
A meta-analysis of this study along with data from Studies WA42380 and ML42528 for 
mortality may be conducted, along with the primary and selected secondary endpoints
and this analysis will be specified in a separate meta-analysis Statistical Analysis Plan
(MAP, see Section 4.5.4.5).
At the start of the pandemic in China, physicians in China initiated the off-label use of 
tocilizumab (TCZ) in the treatment of patients with COVID-19 pneumonia.  The first 
study reported was a 21-patient retrospective study in which patients with severe or 
critical COVID-19 pneumonia were treated with TCZ (Xu et al. 2020).
Patients received TCZ 400 mg intravenous (IV) plus standard of care (SOC).  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 4 patients (19.0%) were 
assessed as critical.  Most patients (85.0%) presented with lymphopenia.  The 
C-reactive protein (CRP) levels were increased in all 20 patients evaluated (mean: 75.06
[66.80] mg/L).  The median procalcitonin value was 0.33 (0.78) ng/mL, and only 2 of 
20 patients (10.0%) presented with an abnormal value.  Mean modified intent to treat
(interleukin-6 [IL-6]) level before TCZ was 132.38 (278.54) pg/mL (normal7 pg/mL).
SOC consisted of lopinavir, methylprednisolone, other symptom relievers, and oxygen 
therapy as recommended by the Diagnosis and Treatment Protocol for Novel 
Coronavirus Pneumonia (Trial Version 6) (China National Health Commission 2020).  
All 21 patients had received routine SOC treatment for a week before deteriorating with 
sustained fever, hypoxemia, and chest computed tomography (CT) image worsening.
According to the authors, after TCZ treatment, fever returned to normal and all other 
symptoms improved remarkably.  Fifteen of the 20 patients (75.0%) had lowered their 
oxygen intake, and 1 patient needed no oxygen therapy.  The CT scans showed 
significant remission of opacities in both lungs in 19 of 20 patients (90.5%) after 
treatment with TCZ.  No adverse drug reactions and no subsequent pulmonary 
infections were reported.
Nineteen patients (90.5%) were discharged at the time of the report, including 2 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 pneumonia (Xu et al. 2020).


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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 patients with severe or critical forms of COVID-19 pneumonia.
Since that initial report, multiple investigator-initiated studies of TCZ for the treatment of 
COVID-19 pneumonia have been published (Gupta et al. 2020; Guaraldi et al. 2020; 
Hermine et al. 2020; Perrone et al. 2020; Salvarani et al. 2020; Stone et al. 2020; 
Guaraldi et al. 2020).  Results have been mixed, with some evidence of benefit in 
patients with severe disease at baseline but no benefit in moderate COVID-19.
In addition, two Sponsor-initiated studies have been conducted.  A randomized, 
double-blind, Phase III study (WA42380) evaluating the safety and efficacy of TCZ
administered intravenously compared with placebo plus SOC therapy in hospitalized 
patients with severe COVID-19 pneumonia read out in August 2020 (NCT04320615). 
Though the primary endpoint did not meet statistical significance, a decrease in time to 
discharge, and a reduction in duration of intensive care unit (ICU) stay were observed.
A second trial in milder patients with COVID-19 (Study ML42528) met the primary 
endpoint of an improvement in time to mechanical ventilation or death.
Given the results of studies outlined above, remdesivir (RDV) in combination with TCZ
could provide better efficacy, offering the potential to treat COVID-19 pneumonia in 
hospitalized populations more effectively than RDV alone. Extensive safety data have 
previously been generated on the use of TCZ in other indications. In addition, data for 
RDV and TCZ in patients with severe COVID-19 pneumonia have shown both agents to 
be well tolerated in this patient population. Therefore, a study investigating the safety 
and efficacy of combination therapy with RDV plus TCZ compared with RDV alone in 
hospitalized patients with severe COVID-19 pneumonia is justified to address the high 
unmet need and burden of disease in this severely ill population.
2.
STUDY DESIGN
Study WA42511 is a Phase III, randomized, double-blind, placebo-controlled, multicenter 
study to assess the efficacy and safety of TCZ in combination with RDV compared with 
matching placebo (PBO) in combination with RDV in hospitalized adult patients with 
severe COVID-19 pneumonia.  The Sponsor intends to enroll approximately 650 patients 
who are diagnosed with COVID-19 pneumonia and meet the entry criteria in centers 
globally.
Patients must be at least 12 years of age with confirmed SARS-CoV-2 (COVID-19)
infection per World Health Organisation (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 require6 L/min supplemental oxygen to 
maintain oxygen saturation (SpO2)93% despite being on SOC, which may include, low 
dose steroids, and supportive care.


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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 or 
suspected active bacterial, fungal, viral, or other infection (besides COVID-19) will be 
excluded from the study.
Patients will be randomized at a 2:1 ratio to receive blinded treatment of either 
TCZRDV or a matching placeboRDV, respectively.  Study treatment will be given in 
combination with standard supportive care.  The randomization will be stratified by 
geographic region (North America, Europe, and other) and a 2-level factor based on the 
assessment of the 7-category ordinal scale of clinical status at screening, with levels 4-5 
and 6. “North America” includes the United States of America, “Europe” includes Spain 
and “Other” includes Russia and Brazil. The proportion of patients at level 6 of the 
ordinal scale will be capped at 25% of the overall study population.
Patients assigned to the TCZRDV arm will receive one infusion of TCZ 8 mg/kg after 
randomization, with a maximum dose of 800 mg, and patients assigned to the
RDVPBO arm will receive one infusion of PBO. Both arms will receive 200 mg RDV
as the loading dose and 100 mg daily for the next 9 days in addition to SOC. Patients 
can have up to 2 doses of RDV prior to randomization.
For both arms, if the clinical signs or symptoms worsen or do not improve (reflected by 
sustained fever or at least a one-category worsening on the 7-category ordinal scale), 
one additional infusion of blinded treatment of TCZ or placebo can be given, 8–24 hours 
after the initial infusion. 
Remdesivir dosing is adjusted for patients that enter the study having received prior 
RDV. Patients who received RDV prior to randomization will not exceed 10 days of 
dosing in total (including RDV received prior to the study and during the study).
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator’s discretion.  The investigator will record the reasons for screen failure in 
the screening log.
The study assessments to be conducted include the following: physical examination, 
vital signs, oxygen saturation, assessment of consciousness, presence and absence of 
respiratory support, adverse events (AEs), concomitant therapies, clinical laboratory 
tests, and nasopharyngeal swabs.  Please see Appendix 2, Appendix 3, and Appendix 4
for details concerning the timing of these assessments.
Figure 1 presents an overview of the study design. The Schedule of Assessments is 
provided in Appendix 2, Appendix 3, and Appendix 4.


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Figure 1
Study WA42511 Schema
nnumber of patients; PBOplacebo; RDVremdesivir; TCZtocilizumab.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2, Appendix 3, and Appendix 4.
2.2
ENDPOINTS
This study will evaluate the efficacy, and safety of TCZRDV compared with a matching
TCZ placeboRDV in hospitalized patients with severe COVID-19 pneumonia.  Specific 
objectives and corresponding endpoints for the study are outlined below.
2.2.1
Primary Efficacy Endpoints
The primary efficacy objective for this study is to evaluate the efficacy of the RDV plus 
TCZ arm compared with RDV plus PBO arm using the following endpoint:

Time from randomization to hospital discharge or “ready for discharge” up to Day 28
Hospital discharge or “ready for discharge” is defined as an ordinal score of 1 
on the 7-category ordinal scale.
2.2.2
Secondary Efficacy Endpoints

Time to mechanical ventilation or death up to Day 28, defined as the time from 
randomization to the first occurrence of mechanical ventilation or death (whichever 
occurs first)

Time to improvement of at least 2 categories relative to baseline on a 7-category 
ordinal scale of clinical status up to Day 28


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
Clinical status as assessed by the investigator using a 7-category ordinal scale of 
clinical status on Days 7, 14, 21, 28 and Day 60 as follow-up.

Proportion of patients requiring initiation of mechanical ventilation postbaseline up to 
Day 28 and up to Day 60 (patients who do not require mechanical ventilation at 
baseline)

Proportion of patients who are alive and free of respiratory failure (patients requiring 
mechanical ventilation at baseline) at Day 28 and Day 60

Duration of mechanical ventilation (patients who require mechanical ventilation at 
baseline) up to Day 28

Time to Death up to Day 28 and up to Day 60

Mortality on Days 14, 28, and 60 (proportions at specified time points)

Time to recovery up to Day 28, defined as time from randomization to the time when 
a category of 2 on the 7-category ordinal scale (non-ICU hospital ward or “ready for 
hospital ward”) not requiring supplemental oxygen, or better is observed 

Proportion of patients discharged or “ready for discharge” up to Day 28

Proportion of patients who require initiation of mechanical ventilation postbaseline or 
die up to Day 28.
A pre-defined meta-analysis may be performed on mortality as well as the primary and
selected secondary endpoints with Studies WA42380 and ML42528 (Section 4.5.4.5).
2.2.3
Exploratory Efficacy Endpoints

Time to clinical improvement (TTCI) up to Day 28, defined as time from 
randomization to National Early Warning Score 2 (NEWS2) score of2 maintained 
for 24 hours:
NEWS2 values will be calculated by the Sponsor based on vital sign 
parameters and NEWS2 related assessments recorded by the investigator in 
the appropriate electronic Case Report Form (eCRF).

Time to clinical failure up to Day 28, defined as the time from randomization to the
first occurrence of death, mechanical ventilation, ICU admission, or withdrawal from 
study prior to discharge (whichever occurs first).
For patients entering the study already on mechanical ventilation, clinical failure 
is defined as a one-category worsening on the ordinal scale, withdrawal from 
study prior to discharge, or death.

Proportion of patients requiring initiation of ICU care post-baseline up to Day 28 and 
Day 60

Duration of ICU stay up to Day 28

Duration of supplemental oxygen use up to Day 60

Proportion of patients requiring initiation of vasopressor use post-baseline up to Day 
28


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
Duration of vasopressor use up to Day 28

Proportion of patients requiring initiation of extracorporeal membrane oxygenation
(ECMO) postbaseline up to Day 28 and up to Day 60

Duration of ECMO up to Day 28

Organ failure-free days from randomization to Day 28

SARS-CoV-2 viral load up to Day 28 and Day 60

Time to reverse-transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2
negativity up to Day 60 (swab samples) and Day 14 (serum samples)
2.2.4
Biomarkers
Exploratory analysis of individual biomarkers in relation to efficacy, safety, exposure 
(listed in Section “Laboratory, Biomarker, and Other Biological Samples” of the protocol) 
and in both blood- and tissue-derived samples will be defined in a separate biomarker 
analysis plan (BAP).
2.2.5
Safety Endpoints

Incidence and severity of AEs, with severity determined according to National 
Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) v5.0

The proportion of patients with any post-treatment infection up to Day 28 and 
Day 60

Change from baseline in targeted clinical laboratory test results
2.3
DETERMINATION OF SAMPLE SIZE
The primary endpoint, time to discharge or “ready for discharge”, is event driven. Based 
on the severe cohort receiving 10 days of RDV in Gilead’s SIMPLE trial 
(Study GS-US-540-5773), the median time to discharge or “ready for discharge” was 
11 days.  Assuming a median time to discharge or “ready for discharge” of 11 days in 
the PBORDV arm, a hazard ratio of 1.3 or an approximately 2.5-day reduction in 
median time for TCZRDV vs PBORDV, and a 2:1 randomization to TCZRDV or 
PBORDV, approximately 650 patients are needed to accrue approximately 520 events 
to achieve approximately 80% power. Further sample size adjustments may be 
considered during the study based on external information. The sample size may be 
increased up to a maximum of approximately 800 randomized patients if fewer events 
than expected are observed or further shifts in SOC warrant reassessing sample size 
assumptions.
2.4
ANALYSIS TIMING
There may be up to three optional interim analyses. Should an interim occur before the 
end of the study, the SAP will be amended to account for the interim. For additional 
information about interim analyses, refer to Section 4.7.


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If efficacy is declared based on an interim analysis, the data will be cleaned, a snapshot 
taken and the data in the snapshot will be reported. There will then be a final snapshot 
when all patients either reach Day 60, or have withdrawn.
If the study does not meet the efficacy criteria at one of the interim looks, or the efficacy 
interim is not performed, no reports for interim data, other than for the data monitoring 
committee (DMC), will be prepared; a snapshot of the data will be taken and the primary 
analysis will occur when the last patient either has withdrawn or completed the Day 28 
visit.
There will be an additional analysis on the final data when all patients have either 
reached Day 60 or withdrawn. A Clinical Study Report based on the final analyses from 
the study will be produced.
3.
STUDY CONDUCT
The plan is to enroll approximately 650 or more patients, up to a total of 800, who have 
been diagnosed with COVID-19 pneumonia and meet the entry criteria in centers 
globally.  Patients will be randomized at a 2:1 ratio to receive blinded treatment of either 
TCZ or a matching PBO, respectively.  Both arms will be administered RDV. For both 
arms, if the clinical signs or symptoms worsen or do not improve, one additional infusion 
of blinded treatment of TCZ or PBO can be given, 8–24 hours after the initial infusion.  
Patients will be followed up for a total of 60 days after randomization.
If patients are discharged from hospital prior to Day 28, follow-up visits should be 
conducted on Day 14, Day 21, and Day 28.  Follow-up visits on Day 14 and Day 21 may 
be conducted as telephone visits.  Patients should return to the site for the Day 28-visit,
if at all possible.  After Day 28, all patients should have follow-up visits on Day 35, 
Day 45, and Day 60.  The Day 35 and Day 45 visits may be conducted by telephone for 
discharged patients.  Patients should return to the site for the Day 60 visit, if at all 
possible.
3.1
RANDOMIZATION, STRATIFICATION AND BLINDING
Patients will be randomized at a 2:1 ratio to receive blinded treatment of either 
TCZRDV or a matching PBORDV, respectively.  The randomization will be stratified 
by geographic region (North America, Europe, and other) and a 2-level factor based on 
the assessment of the 7-category ordinal scale of clinical status at screening, with levels 
45 and 6; and will occur through use of a permuted-block randomization method to 
ensure a balanced assignment to each treatment arm. The proportion of patients in the
ordinal score 6 stratum will be capped at no more than 25% of the overall study 
population.
Study site personnel and patients will be blinded to TCZ treatment assignment during 
the study.  The Sponsor and its agents will also be blinded to TCZ treatment 


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assignment, with the exception of individuals who require access to patient treatment 
assignments to fulfill their job roles during a clinical trial. These roles include the 
unblinding group responsible, clinical supply chain managers, sample handling staff, 
operational assay group personnel, interactive voice or web-based response system 
(IxRS) service provider, and DMC members and support staff as specified in the DMC 
Charter who may be Roche employees but independent of the study team.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious AE
[SAE] for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS.  The investigator is not required to contact the Medical Monitor prior to breaking 
the treatment code; however, the treatment code should not be broken except in 
emergency situations.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
that are considered by the investigator or Sponsor to be related to study drug.  The 
patient may continue to receive treatment, and the investigator, patient, and Sponsor 
personnel, with the exception of the Drug Safety representative and personnel who must 
have access to patient treatment assignments to fulfill their roles (as defined above), will 
remain blinded to treatment assignment.
3.2
DATA MONITORING
A DMC will monitor the incidence of all SAEs, AEs of special interest (AESI), and any 
events requiring the review of aggregate unblinded data during the study, such as 
interim analyses.
The DMC will also evaluate safety according to policies and procedures detailed in a 
DMC Charter. Regular safety reviews will begin after approximately 45 patients 
(30 TCZRDV, 15 PBORDV) have been enrolled and reached 14-day follow-up.  
Early stopping criteria will be detailed in the DMC charter and a separate interim SAP
(iSAP) should an interim occur. Further details of any efficacy interims are provided in 
Section 4.7. Interim analyses will be conducted by a statistical programmer and 
statistician independent from the study management team (SMT) and will be reviewed 
by the DMC.  Interactions between the DMC and Sponsor will be carried out as specified 
in the DMC Charter.
The DMC initially consisted of Sponsor representatives not involved in any operational 
aspects of the study and a scientific oversight committee of external experts
(responsibilities and operating principles of the DMC are described in a charter, the 
Internal Monitoring Committee and Scientific Oversight Committee Agreement). The 
DMC responsibilities transitioned to a fully independent data monitoring committee 
(iDMC) prior to the 3rd scheduled safety review after approximately 300 patients 
reached Day 28 of follow-up. The iDMC will also conduct a 4th scheduled data review 


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when at least 450 patients have reached Day 28. Data processing will be handled by a
Sponsor statistician and statistical programmer independent of the SMT. Details are 
reported in the iDMC charter.
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 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). 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 patients randomized in the study who received any 
amount of TCZ or PBO, with patients grouped according to the treatment assignment at 
randomization (TCZ+RDV or PBO+RDV).
4.1.2
Safety Population
The safety population will consist of all patients who receive any amount of study 
medication (RDV and/or TCZ/PBO). In all safety analyses, patients will be grouped 
according to the treatment that the patients received rather than the treatment assigned 
at randomization (TCZ+RDV or PBO+RDV). If a patient only received RDV and did not 
receive TCZ/PBO, they will be included in the PBO + RDV arm. If a patient only received 
TCZ/PBO and did not receive study RDV, they will be included in the TCZ+RDV or 
PBO+RDV arms based on the TCZ/PBO treatment received.
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients randomized, number of patients who complete the study, and 
number of patients discontinued early will be summarized. Reasons for premature study 
discontinuation will be listed and summarized. A listing of patients who discontinued 
early by treatment group will be produced through Day 28, the listing will include ordinal 
scale category at baseline and at last recorded visit for each patient, as well as 
discharge date and study day if the patient discontinued post discharge.  The number of 
patients lost to follow-up and the number of patients who discontinued will be 
summarized by treatment group and whether discontinuation or loss to follow-up was 
before or after discharge.


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Eligibility criteria and other major protocol deviations will be listed and summarized by 
treatment group.
The patients excluded from the safety and mITT populations will be summarized, 
including the reason for exclusion by treatment group.
A summary of enrollment by country and investigator name will be produced along with a 
listing of the randomized patients by investigator.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (including, but not limited to, age, sex, race, 
geographic region, ordinal scale category for clinical status, interleukin-6 [IL-6], 
mechanical ventilation, RDV prior to randomization, corticosteroids at baseline) will be 
summarized using means, standard deviations, medians and range for continuous 
variables and proportions for categorical variables, as appropriate.  Summaries will be 
presented by treatment group and will be presented for the mITT and may, in addition, 
be presented for the safety population.
4.3.1
Demographics

Sex

Age

Race

Ethnicity

Geographic region
4.3.2
Baseline Characteristics

RDV prior to randomization

Corticosteroid use at baseline

Smoking history (Former/current user)

Diabetes (Yes/ No)

Heart disease (Yes/No)

Hypertension (Yes/No)

Weight

NEWS2 

Ordinal scale category for clinical status 

IL-6

CRP

Ferritin

D-Dimer


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
Mechanical ventilation 

Symptoms at time of COVID-19 diagnosis
–
Fever
–
Cough
–
Shortness of breath
–
Gastrointestinal symptoms (e.g. diarrhea, nausea, loss of appetite)
–
Headache
–
Fatigue
–
Other

Number of days from first COVID-19 symptom at baseline

Number of days from last positive PCR or COVID-19 diagnosis at baseline

Number of days of mechanical ventilation prior to randomization for patient in 
category 5 or 6 at baseline.
4.3.3
Medical History
Medical history data will be summarized descriptively by treatment group using the 
safety population. A glossary showing the mapping of investigator verbatim terms to 
diseases will be produced for the medical history data.
4.3.4
Previous and Concomitant Medications
Previous and concomitant treatments will be summarized descriptively by treatment 
group for the safety population. Previous treatments that have been stopped prior to 
Study Day 1 will be summarized separately, where Study Day 1 is the day of 
randomization. There will be a summary of all concomitant treatments, including those 
that were initiated prior to Study Day 1. Summaries of previous and concomitant steroid 
use will be produced.  In addition, there will be summaries of previous and concomitant
treatments given for COVID-19.
A glossary showing the mapping of investigator verbatim terms to medication 
coded-terms will be produced for previous or concomitant medication.
4.4
VISIT LABELS
For summaries of data not collected by visit, such as AEs, medical history and 
concomitant medications, all data up to the end of study will be included. Exceptions to 
this includes death, discharge from hospital and ICU admission and discharge, which will 
be summarized weekly in descriptive summaries, following the time windowing approach 
described below.
Deaths will also be captured on the 7-category ordinal scale of clinical status. Deaths
confirmed by public record are also captured in the eCRF, which may not have been 


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captured as AEs for patients withdrawn from the study. These events will also be 
incorporated into the windowing for death (Table 1).


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Table 1
Time Windows for Assigning Assessment Study Days to Study 
Visits Labels for Deaths and Discharge
Scheduled Study Day
Efficacy Time Window
1* (Baseline)
1
7 (Week 1)
1 to 7
14 (Week 2)
7 to14
21 (Week 3)
14 to21
28 (Week 4)
21 to28
35 (Week 5)
28 to35
45
35 to45
60
45 to67
*Study Day 1 is the day of randomization.
Patient assessments that are collected at scheduled visits will be assigned to a study 
visit using the actual study day of the assessment; this includes data from 
discontinuation visits and any unscheduled visits. Time windows prior to Day 28, will be 
continuous from the midpoint between two consecutive study visits to the next midpoint, 
as in Table 2, except as indicated, and will be dependent on the schedule of 
assessments for each variable independently.  An example of time windowing for the 
hematology parameters is shown below.
Table 2
Time Windows for Assigning Assessment Study Days to Study 
Visits for Hematology Parameters
Scheduled Study Day
aEfficacy Time Window
1 (Baseline)
2
3
1
2
3
5
3 to5
7 
5 to8
10
8 to11
14 
11 to17
21 
17 to24
28 
24 to28
35 
28 to38
45
38 to52
60
52 to67
a From Week 2 onwards use value nearest to scheduled Study day.


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Where there is more than one efficacy assessment within a time window, then the non-
missing assessment nearest to the scheduled time point will be assigned to that visit. If 
two or more assessments are equidistant from the scheduled time point, then the latest 
assessment will be used for efficacy (other than death or discharge where the 
assessment prior to the visit week will be used as described previously).
For safety parameters such as laboratory parameters and vital signs the ‘worst case’ will 
be used.
For patients who receive study drug on Day 1, baseline is defined at the last pre-dose 
assessment before administration of either study drug on or prior to Day 1. For patients 
who do not receive study drug on Day 1, baseline is the last assessment on or prior to 
Day 1. Where baseline data is not available for the ordinal scale or biomarkers, the first 
available assessment (up to Day 2) will be used as baseline.
4.5
EFFICACY ANALYSIS
All efficacy analyses will use the mITT population unless otherwise stated. 
Sensitivity analyses to evaluate the robustness of results to the primary analysis 
methods (e.g., handling of withdrawals) may be conducted and are described in this 
SAP in each relevant section.
Descriptive subgroup analyses to evaluate the consistency of results across 
pre-specified subgroups may also be conducted as specified in Section 4.5.6.
The primary analysis will occur after the last patient has reached Day 28, analyses and 
censoring rules will be updated for analyses at or up to Day 60 when the database is 
refreshed.
Where the stratification factor of baseline ordinal scale (4-5, 6) is included in an analysis, 
this will take the value at randomization and may differ from the summary of baseline 
ordinal scale categories included in the baseline characteristics, which uses post-
randomization data.
4.5.1
Primary Efficacy Endpoint
The primary efficacy objective for this study is to evaluate the efficacy of the TCZRDV
arm compared with the PBORDV arm for the treatment of severe COVID-19 
pneumonia on the basis of the following endpoint:
The primary efficacy endpoint is the time to hospital discharge or “ready for 
discharge”. Hospital discharge or “ready for discharge” is defined as a score of 1 on 
the 7-category ordinal scale.


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The other primary estimand attributes are:
–
Population: Patients with severe COVID-19 pneumonia as per the 
inclusion/exclusion criteria specified in the protocol (mITT)
–
Treatments: TCZRDV versus PBORDV
–
Intercurrent events:
o
Events that lead to study withdrawal or loss to follow-up: Hypothetical 
strategy, i.e., patients will be censored at time of their last ordinal scale 
assessment, unless they die on or prior to Day 28.
–
Summary measures: 
a)
The hazard ratio (95% confidence interval [CI])
b)
Kaplan-Meier plot
c)
Cumulative incidence function (CIF), i.e., the cumulative probability of being 
discharged or “ready to discharge” over the 28 day follow-up period. The CIF of 
the competing event of death prior to discharge will also be summarized.
d)
Median event time in each treatment arm (95% CI)
Patients will meet the endpoint at the time of discharge or the time that they achieve
category 1 of the 7-category ordinal scale, whichever occurs first, provided that:

they do not have any further ordinal scale assessments > category 1 on or prior 
to Day 28

they are not re-hospitalized on or prior to Day 28

they do not die on or prior to Day 28
Patients who do not meet the event at the point of discharge or category 1 due to re-
hospitalization or ordinal scale assessments > category 1 will still be eligible to meet the 
event at a later time provided the above conditions are met. Patients who die by Day 28, 
regardless of discharge and ordinal scale category prior to death, and patients who 
remain hospitalized at Day 28 with an ordinal scale category >1 will not be considered as 
having met the endpoint.
The time to hospital discharge or “ready for discharge” will be compared between the 
TCZ+RDV and the PBO+RDV arms using the stratified log-rank test with region (North 
America, Europe, Other) and baseline ordinal score (4-5, 6) included as the stratification 
factors at Day 28 using the mITT population. This will be tested at a two-sided 5% 
significance level.
The treatment groups will be compared descriptively using a Cox proportional hazards 
model adjusted for the stratification factors of baseline ordinal score (4-5 or 6) and 


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region (North America, Europe or Other). Kaplan-Meier plots will be produced and CIF
plots will be produced for both the primary outcome and the competing risk of mortality. 
Intercurrent events, such as events leading to loss to follow-up or discontinuation for any 
reason prior to achieving the event or patients who do not have the event, will be 
accounted for through rules, as described in Table 3 below.
Table 3
Time to Hospital Discharge or “Ready for Discharge” Censoring
Rules
Event
Censor
Date and Time
Death
Yes
Day 28
Withdrawal or lost to follow-up for any reason 
prior to discharge or “ready for discharge” 
criterion met (no event or death recorded
including post-withdrawal or lost to follow-up)
Yes
last recorded ordinal scale 
assessment 
Not discharged or “ready for discharge”
Yes
Day 28
In addition, a summary of hospital discharges over time will be produced.
4.5.2
Controlling for Type I Error
In the event of an interim analysis, the primary endpoint will be adjusted based on the 
alpha spending function detailed in an iSAP.
Secondary to time to discharge or “ready for discharge”, 3 key secondary endpoints will 
be tested in a simple gated hierarchy starting with the primary endpoint. The hierarchy 
will be:
1.
Time from randomization to hospital discharge or “ready for discharge” up to Day 28
2.
Time to mechanical ventilation or death up to Day 28
3.
Clinical status as assessed by the investigator using a 7-category ordinal scale of 
clinical status on Day 14
4.
Time to death up to Day 28
Each endpoint will be tested with a fixed two-sided 0.05 error rate if the previous 
endpoint reaches significance starting with the primary. Since each successive 
hypothesis will be gated on the previous test sequentially, there is no penalty on the type 
I error (Dmitrienko and Tamhane 2010).
All other secondary endpoints defined in the protocol have clinical relevance in 
understanding the therapeutic benefit of TCZ. A treatment effect may be observed that 
may not meet statistical significance, but may still be considered clinically meaningful. 
Therefore, all other secondary endpoints will be tested without adjustment.


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4.5.3
Type I Error Controlled Secondary Endpoints
4.5.3.1
Time to Mechanical Ventilation or Death up to Day 28
This secondary efficacy objective evaluates the efficacy of the TCZRDV arm compared 
with the PBORDV arm for the treatment of severe COVID-19 pneumonia on the basis 
of the following endpoint:
The secondary efficacy endpoint time to mechanical ventilation or death up to Day 
28 is the time from randomization to the first occurrence of mechanical ventilation or 
death (whichever occurs first). For patients already on mechanical ventilation at 
baseline, only death will be counted as an event. If no event occurs within the time 
frame, the patient is censored on Day 28.
Time to mechanical ventilation or death will be compared between the TCZRDV and 
the PBORDV groups using the stratified log-rank test, with geographic region (North 
America, Europe, and Other) and baseline ordinal scale (4-5, 6), included as the 
stratification factors using the mITT population. A Kaplan-Meier plot and median time to 
event with 95% CIs will also be presented. In addition, the treatment groups will be
compared descriptively using a Cox proportional hazards model adjusting for the
stratification factors applied at randomization and a hazard ratio with a 95% CI will be
produced.
The other estimand attributes are:
–
Population: Patients with severe COVID-19 pneumonia as per the 
inclusion/exclusion criteria specified in the protocol (mITT)
–
Treatments: TCZRDV versus PBORDV
–
Intercurrent events:
o
Study withdrawal or loss to follow-up: The Sponsor will use public records 
in accordance with local regulations to identify deaths even after loss to 
follow-up. If no such events are found, a hypothetical strategy is used, 
i.e., patients who withdraw or are lost to follow up prior to discharge will 
be censored at time of withdrawal or last recorded visit.
o
Treatment is modified or withdrawn: Treatment policy strategy, i.e. this 
intercurrent event is ignored for this endpoint.
o
Patient discharged from hospital: Treatment policy strategy, i.e. this 
intercurrent event is ignored for this endpoint.
–
Population summary measures:  
a) Median time to event in each treatment arm with 95% confidence intervals
b) The hazard ratio (95% confidence interval [CI])
c) Kaplan-Meier plot


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Table 4
Time to Mechanical Ventilation or Death Censoring Rules
Event
Censor
Date and Time
Withdrawal or lost to follow-up for any reason 
prior to discharge prior to criterion met (not 
followed by death)
Yes
last recorded vital signs 
assessment
Withdrawal or lost to follow-up for any reason on 
or after the day of discharge prior to criterion met 
(not followed by death or readmittance)
Yes
Day 28
Criterion not met
Yes
Day 28
4.5.3.2
Clinical Status on Day 14
This secondary efficacy objective evaluates the efficacy of the TCZRDV arm compared 
with the PBORDV arm for the treatment of severe COVID-19 pneumonia on the basis 
of the following endpoint:
The secondary efficacy endpoint clinical status as assessed by the investigator 
using a 7-category ordinal scale of clinical status. The latest available assessment 
up to Day 14 is used.
Assessment of patient status using an ordinal scale will be recorded at baseline and 
once daily in the morning (between 8:00 a.m. and 12:00 p.m.) 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2 L 
supplemental oxygen)
2. Non-ICU hospital ward (or “ready for hospital ward”) not requiring supplemental 
oxygen
3. Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental 
oxygen
4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow 
oxygen 
5. ICU, requiring intubation and mechanical ventilation 
6. ICU, requiring ECMO or mechanical ventilation and additional organ support 
(e.g., vasopressors, renal replacement therapy)
7. Death
For patients who withdraw before the assessment time, their last postbaseline ordinal 
category prior to withdrawal will be used in the analysis, unless death within the time 
frame was captured from public records or otherwise; in which case death will be used in 
the analysis.  A death or discharge (unless the patient is re-admitted within 12 hrs) will 
always be carried forward to all subsequent assessments regardless of what is recorded 
for the ordinal scale. In addition to imputing the ordinal scale at Day 14 with an earlier 
death or discharge (without re-admittance), captured from ordinal scale or other sources, 


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this imputation rule will also be followed at earlier time points, including the day of death 
or discharge.  If a patient is re-admitted then the ordinal scale data from the point of re-
admittance will be used.
Clinical status will be compared between the TCZ+RDV and PBO+RDV arms using a 
proportional odds model accounting for stratification factors at randomization in the 
model (region [North America, Europe, Other] and baseline ordinal scale [4-5, 6]) using 
the mITT population as the main analysis. The odds ratio, p-value, and 95% confidence 
interval will be presented.
The assumption of proportional odds will be tested and will also be evaluated by visually 
comparing the fitted proportions of patients across the ordinal scale from the model with 
the observed data. 
In addition, the difference in distributions between treatment arms will be evaluated 
using a non-parametric method, the Van Elteren test, including the stratification factors 
at randomization (region [North America, Europe, Other] and baseline ordinal scale [4-5, 
6]). The median ordinal scale result for each treatment group and the corresponding 
95% CI for the median will be presented along with the Van Elteren P-value, as well as 
the difference in medians and a 95% CI for the difference.
Clinical status will also be assessed using a linear regression approach with Huber-
White sandwich estimates for the standard errors. The mean and associated 95% CI in 
each treatment arm will be presented along with the difference in means and a 95% CI 
for the difference. 
The ordinal scale will be summarized by treatment arm showing the number and 
percentage in each category.  Missing data, defined as patients who have not died or 
been discharged and have no subsequent measurements, will be entered into its own 
category.  Deaths and discharge will be carried forward as above.  Stacked bar charts of 
the ordinal scale will be produced by treatment group, the bars will total to 100% and the 
categories, including ‘missing’, will be shown. The summary and stacked bar charts will 
also be produced using the data after the last postbaseline ordinal category has been 
carried forward.
The other estimand attributes are:
–
Population: Patients with severe COVID-19 pneumonia as per the 
inclusion/exclusion criteria specified in the protocol (mITT)
–
Treatments: TCZRDV versus PBORDV
–
Intercurrent events:
o
Discharge from hospital: Composite strategy, this is considered a value of 
1. This assessment of 1 is carried forward to all subsequent 


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assessments, unless a death is observed or the patient is re-hospitalized 
until Day 14.
o
Death: Composite strategy, this is considered a value of 7.
o
Study withdrawal or loss to follow-up: For patients who withdraw before 
the assessment time, a hypothetical approach is used, i.e. their last post-
baseline ordinal category prior to withdrawal will be used in the analysis. 
If a death event up to Day 14 is known (e.g. from public records), a value 
of 7 (“Death”) will be used instead.
o
Treatment is modified or withdrawn: Treatment policy strategy, i.e. this 
intercurrent event is ignored for this endpoint.
–
Population summary measures:  
a) The frequency distribution of clinical status by arm will be tabulated and 
shown graphically.
b) The odds ratio (95% CI)
4.5.3.3
Time to Death up to Day 28
This secondary efficacy objective evaluates the efficacy of the TCZRDV arm compared 
with the PBORDV arm for the treatment of severe COVID-19 pneumonia on the basis 
of the following endpoint:
The secondary efficacy endpoint time to death up to Day 28 is the time from 
randomization to death from any cause. If no event occurred within the time frame, 
the patient is censored on Day 28.
Time to death will be compared between the TCZRDV and the PBORDV groups
using the stratified log-rank test, with geographic region (North America, Europe, and 
Other) and baseline ordinal scale (4-5, 6), included as the stratification factors using the 
mITT population. A Kaplan-Meier plot and median time to event with 95% CIs will also 
be presented for each treatment arm. In addition, the treatment groups will be compared 
descriptively using a Cox proportional hazards model adjusting for the stratification 
factors applied at randomization and a hazard ratio with a 95% CI will be produced.
The other estimand attributes are:
–
Population: Patients with severe COVID-19 pneumonia as per the 
inclusion/exclusion criteria specified in the protocol (mITT)
–
Treatments: TCZRDV versus PBORDV
–
Intercurrent events:
o
Study withdrawal or loss to follow-up: The Sponsor will use public records
in accordance with local regulations to identify deaths even after loss to 
follow-up. If no such events are found, a hypothetical strategy is used, 
i.e., patients who withdraw or are lost to follow up prior to discharge will 
be censored at last known alive date.


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o
Treatment is modified or withdrawn: Treatment policy strategy, i.e. this 
intercurrent event is ignored for this endpoint.
o
Patient discharged from hospital: Treatment policy strategy, i.e. this 
intercurrent event is ignored for this endpoint.
–
Population summary measures:  
a) Median time to event in each treatment arm with 95% confidence intervals
b) The hazard ratio (95% confidence interval [CI])
c) Kaplan-Meier plot
Table 5
Time to Death Censoring Rules
Event
Censor
Date and Time
Withdrawal or lost to follow-up for any reason 
prior to discharge prior to criterion met (not 
followed by death)
Yes
last known alive date
Withdrawal or lost to follow-up for any reason on 
or after the day of discharge prior to criterion met 
(not followed by death or readmittance)
Yes
Day 28
Criterion not met
Yes
Day 28
4.5.4
Other Secondary Endpoints
4.5.4.1
Time to Event Analyses
Other secondary time to event endpoints will be compared between the TCZRDV and 
the PBORDV groups using the stratified log-rank test, with geographic region (North 
America, Europe, and Other) and baseline ordinal scale (4-5, 6), included as the 
stratification factors using the mITT population. A Kaplan-Meier plot and median time to 
event in each treatment arm with 95% CIs will also be presented. In addition, the 
treatment groups will be compared descriptively using a Cox proportional hazards model 
adjusting for the stratification factor applied at randomization and a hazard ratio with a 
95% CI will be produced. For endpoints representing an improvement, a cumulative 
incidence function plot for the event of interest and mortality will be produced.
Other secondary time to event endpoints include:

Time to Death up to Day 60.
–
This endpoint is defined identically to Time to Death up to Day 28 described in 
Section 4.5.3.3, except that patients are censored at Day 60 instead of Day 28 
if no event occurred. Analyses, handling of intercurrent events and population 
summary measures are as described previously.

Time to improvement in ordinal clinical status up to Day 28 (days)
–
Defined as time from randomization to the time when at least a 2-category 
improvement in the 7-category ordinal scale is observed


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
Time from randomization to recovery up to Day 28 (days)
–
Defined as time from randomization to the time when a clinical status of 
discharged or “ready for discharge” (ordinal scale category 1), or non-ICU 
hospital ward or “ready for hospital ward” not requiring supplemental oxygen 
(ordinal scale category 2) is reached
The estimand for all time to event data is the difference in distributions between 
TCZRDV and PBORDV using the stratified log-rank test. In case no events occurred 
up to Day 28, patients are censored on Day 28.
Intercurrent events are those that occur after randomization and either preclude 
observation of the variable or affect its interpretation. Intercurrent events, such as 
events leading to loss to follow-up or discontinuation for any reason prior to achieving 
the event or patients who do not have the event, will be accounted for through censoring 
rules as shown in the tables for each endpoint.

Time to improvement in ordinal clinical status up to Day 28 (days)
Defined as time from randomization to the time when at least a 2-category 
improvement in the 7-category ordinal scale is observed. For patients that are 
discharged and the ordinal scale assessment has not been completed at discharge, 
they will be assumed to be in Category 1 of the ordinal scale at the point of 
discharge, unless they are re-admitted within 12 hours. Intercurrent events, such as 
events leading to loss  to follow-up, or discontinuation from the study for any reason 
prior to achieving the event or patients who do not have the event, will be accounted 
for through censoring rules, as described in the table below. Deaths will be 
censored at Day 28.


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Table 6
Time to Improvement in Ordinal Clinical Status Censoring Rules
Event
Censor
Date and Time
Death (regardless of criterion met)
Yes
Day 28
Withdrawal or lost to follow-up for any reason 
prior to criterion met
Yes
Last recorded ordinal scale 
assessment
Criterion not met
Yes
Day 28

Time from randomization to recovery up to Day 28 (days).
Recovery is defined as clinical status discharged or “ready for discharge” (ordinal 
scale category 1), or non-ICU hospital ward or “ready for hospital ward” not requiring 
supplemental oxygen (ordinal scale category 2). 
Patients will meet the endpoint at the time that they achieve category 2 or better on
the 7-category ordinal scale or at the time that they are discharged, provided that 
they do not have any further ordinal scale assessments > category 2 on or prior to 
Day 28.  Patients who die by Day 28, regardless of discharge and ordinal scale 
category prior to death, and patients who remain hospitalized at Day 28 with an 
ordinal scale category >2 will not be considered as having met the endpoint.
Intercurrent events, such as events leading to loss to follow-up, or discontinuation
for any reason prior to achieving the event or patients who do not have the event, 
will be accounted for through censoring rules, as described in the table below.
Deaths will be censored at Day 28.
Table 7
Time to Recovery Censoring Rules
Event
Censor
Date and Time
Death (regardless of criterion met)
Yes
Day 28
Withdrawal or lost to follow-up for any reason 
prior to criterion met
Yes
Last recorded ordinal scale 
assessment
Criterion not met
Yes
Day 28
4.5.4.2
Incidence Endpoints
Secondary efficacy incidence endpoints will be analyzed using the Cochran-Mantel-
Haenszel test statistic (Mantel 1963), adjusted by the stratification factors at baseline 
geographic region (North America, Europe, and Other) and 7 point ordinal score at 
randomization (4-5, 6) using the mITT population, unless stated otherwise.  The 
weighted difference in proportions for the treatment group comparison will be presented
with a p-value, together with a 95% CI, along with the proportions in each treatment arm 
and associated 95% CIs.


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
Proportion of patients requiring initiation of mechanical ventilation postbaseline up to 
Day 28 and up to Day 60
For patients who are not on mechanical ventilation at baseline (ordinal score 4 or 
less) the incidence of mechanical ventilation by Day 28 and Day 60 will be identified 
from the Vital Signs and Oxygen Saturation eCRF. For patients who have 
withdrawn or died prior to Day 28 or Day 60, the non-responder rule will be applied, 
i.e., it will be assumed that the patient required mechanical ventilation by Day 28 or 
Day 60 in the analysis.  Patients without mechanical ventilation prior to discharge, 
will be assumed to be responders in the analysis except for the following cases:
1.
The patient is readmitted to hospital within 12 hours. The patient will be treated 
as having not been discharged, and any initiation of mechanical ventilation will 
be counted
2.
The patient dies by Day 28 or Day 60, which will be counted as an event.
The number and proportion of patients requiring mechanical ventilation will be 
summarized descriptively by study week.

Proportion of patients who are alive and free of respiratory failure (patients requiring 
mechanical ventilation at baseline) at Day 28 and Day 60
The incidence of patients who come off ventilator support, for patients who enter the 
study on mechanical ventilation will be derived from the Vital Signs and Oxygen
Saturation eCRF. Patients who transition to oxygen support other than mechanical 
ventilation or ECMO will be counted as extubated, unless they die prior to Day 28 or 
Day 60 in the respective analyses in which case they will be counted with patients 
who remain on mechanical ventilation. Patients who are re-intubated will be 
counted as on mechanical ventilation unless they come off ventilation again before 
the end of the 28-day follow-up. Patients who die up to Day 28 or Day 60 in the 
respective analyses will be counted as non-responders and counted with patients 
who continue on mechanical ventilation. Patients who withdraw from the study who 
are not yet extubated, prior to Day 28 or Day 60 in the respective analyses will be 
counted as remaining on mechanical ventilation.  

Difference in mortality at Day 14, 28, and Day 60
The difference in proportion of patients that have died will be compared at the 
specified time points and will be summarized by the proportion who died in each 
group and the difference in proportions as well as 95% CIs for each estimate. All 
deaths post discontinuation and discharge will be included in this analysis as long 
as the death did not occur after patient consent was withdrawn unless information 
can be sourced from public records. Patients who withdraw prior to discharge will 
be imputed as having survived. Deaths occurring between each visit, and 
cumulative deaths by visit will be summarized descriptively to Day 60. 

Proportion of patients discharged or “ready for discharge” up to Day 28


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The proportion of patients who meet the primary endpoint of Time to Hospital 
Discharge or “Ready for Discharge” up to Day 28 defined in Section 4.5.1 will be 
compared across treatment arms.

Proportion of patients who require initiation of mechanical ventilation postbaseline or 
die up to Day 28
The proportion of patients who meet the secondary endpoint of Time to Mechanical 
Ventilation or Death up to Day 28 defined in Section 4.5.3.1 will be compared across 
treatment arms.
4.5.4.3
Ordinal endpoints

Clinical status as assessed by the investigator using a 7-category ordinal scale of 
clinical status on Day 7, 21, 28, and Day 60 as follow-up.
This endpoint is defined in the same way as Clinical Status on Day 14 described in 
Section 4.5.3.2. Analyses and summaries are as described previously.
4.5.4.4
Duration endpoints

Duration of mechanical ventilation up to Day 28
Duration of mechanical ventilation (in patients who require mechanical ventilation at 
baseline) is defined as the number of days postbaseline to Day 28 that a patient is alive 
and requiring mechanical ventilation. Duration of mechanical ventilation will be derived 
from the Vital Signs and Oxygen Saturation eCRF; if mechanical ventilation or ECMO is 
recorded for any part of the day, the day will be counted. Duration of mechanical 
ventilation will be 28 days if the patient is mechanically ventilated from Day 1 to Day 28. 
Duration of mechanical ventilation will be coded as 28 days if a patient dies on or prior to 
Day 28.
For patients withdrawn early from the study but not discharged, if patients were on 
mechanical ventilation at the point of discontinuation it will be assumed that the 
remainder of days to Day 28, are mechanical ventilation days. For patients not requiring
mechanical ventilation at the point of withdrawal, it will be assumed the period from 
withdrawal to Day 28 are not mechanical ventilation days. For patients who are 
discharged, days from discharge to Day 28 will not be counted as mechanical ventilation 
days.
Duration of mechanical ventilation will be analyzed using a linear regression approach 
with Huber-White sandwich estimates for the standard errors, including the stratification 
factors at randomization (region [North America, Europe, Other] and  ordinal scale 
category at baseline [4-5, 6]) as covariates. The mean duration of mechanical 
ventilation for each treatment group and the corresponding 95% CIs for the means will 
be presented along with the P-value, the difference in means and a 95% CI for the 
difference.


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Duration of mechanical ventilation will also be summarized descriptively using the 
means, along with 95% CIs, by treatment group for those patients alive at Day 28, with a 
count of the number of patients who died and are counted as having 28 days duration of 
ventilation.
4.5.4.5
Meta-Analysis
The details of the meta-analysis and data handling from multiple trials will be included in 
a separate meta-analysis plan.
4.5.5
Exploratory Efficacy Endpoints

TTCI up to Day 28
Defined as time from randomization to NEWS2 of2 maintained for 24 hours. The 
NEWS2 is to be assessed twice daily, with approximately 12 hours between each 
assessment. At least two assessments with a score of2 covering a span of at 
least 21.5 hours will be required to meet the criterion with a maximum of 26.5 hours 
between the first and last of these assessments (there must be no assessments 
with a score2 in between). If a patient has a score of2 and is then discharged 
from hospital within 26.5 hours, with no subsequent scores2 before the discharge 
they will have met the endpoint.  No imputation will be done for missing components 
of the NEWS2 score and only complete assessments will be considered in the 
analysis.
Patients who have a score of 2 at baseline will be analyzed in the same way as 
patients with a score that is2 at baseline.
Partial date times may be imputed based on available data, following a conservative 
approach. Patients who die will be censored at Day 28. Patients who withdraw or 
are lost to follow up prior to meeting the criterion will be censored at their last vital 
sign assessment. In case no events occurred up to Day 28, patients are censored 
on Day 28.
This endpoint will be analysed in a similar way to the time to event endpoints in 
Section 4.5.4.1.

Time to clinical failure up to Day 28 including ICU admission
Defined as the time from randomization to the first occurrence of death, mechanical 
ventilation, ICU admission, or withdrawal from the study prior to discharge 
(whichever occurs first). For patients entering the study already on mechanical 
ventilation, clinical failure is defined as a one-category worsening on the ordinal 
scale, withdrawal from study or death. Withdrawals after hospital discharge will not 
be considered as having met clinical failure, unless a later death is recorded in 
which case they will have met the event upon death. Intercurrent events, such as 
events leading to loss to follow-up or discontinuation for any reason prior to the 
event or patients who do not have the event, will be accounted for through 


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censoring rules as described in the table below.Clinical failure status as defined 
above will be summarized descriptively by visit.
Table 8
Time to Clinical Failure Censoring Rules
Event
Censor
Date and Time
Lost to follow-up for any reason prior to 
discharge prior to criterion met (not followed by 
death)
Yes
last recorded vital signs 
assessment
Withdrawal or lost to follow-up for any reason 
on or after the day of discharge prior to criterion 
met (not followed by death or readmittance)
Yes
Day 28
Criterion not met
Yes
Day 28
This endpoint will be analysed in a similar way to the time to event endpoints in 
Section 4.5.4.1.

Proportion of patients requiring initiation of ICU care postbaseline up to Day 28 and 
Day 60
Proportion of patients admitted to the ICU after randomization will be tabulated by 
treatment with the number of patients and 95% CIs in each treatment arm, the 
difference in proportions, 95% CIs and the p-value. Patients who die prior to ICU 
admission in hospital will be treated as an ICU admission. 
This endpoint will be analysed in a similar way to the incidence endpoints in 
Section 4.5.4.2.

Duration of supplemental O2 (days) to Day 60
Duration of supplemental O2 (days) will also be derived from the vital signs and 
oxygen saturation log, where study days with any supplemental oxygen will be 
summed up to and including Day 60. Patients without any supplemental O2 use will 
assigned a duration of zero days. For missing data, the last observation 
postbaseline will be carried forward until either the next observation or the point of 
withdrawal/discharge.  For patients withdrawn early from the study but not 
discharged, if the patients were on supplemental oxygen at the point of withdrawal it 
will be assumed that the remainder of days to Day 60 were on supplemental 
oxygen. For patients not using supplemental oxygen at point of withdrawal it will be 
assumed supplemental oxygen is not required to Day 60.  For patients that are 
discharged, days from discharge to Day 60 will be counted as days without 
supplemental oxygen (unless supplemental oxygen use is recorded on the 
Concomitant Medications eCRF during follow up visits, in which case all days from 
the day after discharge to the end date from the Concomitant Medication eCRF will 
be classed as days with supplemental oxygen and if there is no end date recorded it 


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will be assumed to have continued until Day 60). Duration of supplemental oxygen 
use will be 60 days if a patient dies on or prior to Day 60. 
This endpoint will be analyzed in a similar way to the duration endpoints in 
Section 4.5.4.4.
In addition, the number and the proportion of patients on supplemental oxygen using 
the observed data will be summarized by visit to Day 60. 
The proportion requiring supplemental O2 after discharge will also be summarized 
by treatment.

Duration of ICU stay (days) up to Day 28
Duration of ICU stay (days) will be calculated as the sum of the number days spent 
in ICU up to and including Day 28 based on the admission and discharge dates from 
the ICU stay information log; (ICU discharge date – ICU admission date + 1 day).  
Multiple periods of ICU stay will be summed. Patients without any ICU stays will be 
assigned a duration of zero days.
For patients that are discharged, any ongoing ICU stays without an end date, their 
ICU end date will be imputed as date of discharge and it will be assumed that days 
from discharge to Day 28 do not involve an ICU stay. For patients not in the ICU at 
the point of withdrawal from study it will be assumed that the period to Day 28 has 
no incidences of ICU stay post withdrawal. For patients in ICU on the day of 
withdrawal it will be assumed that they are in the ICU throughout the period to 
Day 28. For patients that die on or prior to Day 28 all days will count as being in the 
ICU.
This endpoint will be analysed in a similar way to the duration endpoints in 
Section 4.5.4.4.

Vasopressor and ECMO use (days) up to Day 28 and up to Day 60
Incidence of vasopressor use (from concomitant medication records) and incidence 
of ECMO use postbaseline by Day 28 (and separately to Day 60) will be 
summarized descriptively.
Duration of vasopressor use (days) and ECMO (days) postbaseline to Day 28 will
be summarized using the mean along with 95% CIs for the mean by treatment 
group. ECMO is collected daily and the total number of days of ECMO use will be 
totaled. Vasopressor duration will use start and stop dates from the concomitant 
medication records.  A concomitant medication record that is ongoing at Day 28 will 
use the upper bound of the Day 28-time window as the end date for the duration.
Duration of vasopressor use and ECMO postbaseline to Day 28 will also be 
summarized in the subgroup of patients with vasopressor use and the subgroup of 
patients with ECMO use, respectively.

Organ failure-free days up to Day 28


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Days without organ failure will be summarized descriptively through Day 28. In 
addition, a summary of individual organ failure over time will be provided.
Organ failure is defined as present on any day when the most abnormal vital 
signs/abnormal lab value meets the definition of clinically significant organ failure 
(Bernard et al. 1995; NHLBI ARDS Clinical Trials Network 2014). Cardiovascular 
organ failure is defined as either systolic BP90 mmHg or the need for 
vasopressor. Renal, hepatic and coagulation parameters will be assessed via blood 
tests in order that the presence of clinically significant organ failure can be 
determined. Renal failure is defined as creatinine2 mg/dL, hepatic failure is 
defined as bilirubin2 mg/dL and coagulation failure is defined as a platelet count 
of 8010³/mm³. Each day a patient is alive and free of a given clinically significant 
organ failure will be scored as a failure-free day for that organ. In the case of no 
data for a particular organ, the last observation post-baseline will be carried forward 
until the next observation or discharge. Any day that a patient is alive and free of all 
4 organ failures (cardiovascular, renal, hepatic, coagulation) will be considered an 
organ failure-free day. If a patient dies on or before Day 28, they will be assigned a 
value of zero organ failure free days in the overall summary of organ failure-free 
days. For patients that are discharged, days from discharge to Day 28 will be 
counted as organ failure-free days, unless they are readmitted in which case the 
available data will be used.

SARS-CoV-2 viral load over time 
SARS-CoV-2 viral load over time will be summarized descriptively by time point and 
treatment group. Both the actual values and change from baseline will be 
summarized. The number and proportion of patients negative and positive will be 
displayed, and the quantitative result will be summarized. Area under curve (AUC)
will be calculated using the trapezoidal method adjusted by the datetime of the last 
available assessment for each patient and summarized by treatment arm with mean
(log[AUC]) and 95% CI’s. The adjustment will be performed by dividing by the 
datetime of the last assessment. The AUC will only be calculated for patients with at 
least two virology assessments.
Any values reported as BLQ will be set to the lower limit of quantitation for the assay 
minus 1. Any values reported as negative will be set to the half of lower limit of 
quantitation for the assay.
This analysis will be conducted for swab samples and serum samples separately.

Time to reverse-transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2
virus negativity 
Defined as days from randomization to when a negative Reverse-Transcriptase 
Polymerase Chain Reaction (RT-PCR) SARS-CoV-2 virus assessment result is 
observed up to Day 60 for swab samples and up to Day 14 for serum samples. Time 


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to reverse-transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 virus 
negativity will be compared descriptively using a Cox proportional hazards model 
adjusted for the stratification factors of baseline ordinal score (4-5 or 6) and region 
(North America, Europe or Other) in the subgroup of patients positive at baseline. A 
Kaplan-Meier plot and a CIF plot of the event of interest and mortality will be 
produced. Patients who die prior to achieving negativity will be censored at Day 60 
in the swab analyses and Day 14 in the serum analyses. Patients who discontinue 
or are lost to follow up prior to meeting the criterion will be censored at their last 
virology assessment. In case no events occurred up to Day 60 in the swab analysis 
and Day 14 in the serum analysis, patients are censored on Day 60 and Day 14, 
respectively.
This analysis will be conducted for swab samples and serum samples separately.
4.5.6
Subgroup Analyses
Exploratory subgroup analysis may be performed either to supplement the topline results 
or as a sensitivity analysis. Analysis of biomarkers will be described in a separate BAP
in which any biomarker analyses will be specified.
The primary endpoint will be analyzed by baseline ordinal score using a forest plot of the 
hazard ratios at each baseline level (except Category 7) including 95% CI’s.
The following exploratory subgroups will be investigated for the primary endpoint and 
Time to Death up to Day 28 using forest plots:

Baseline ordinal score

Steroids (Y/N)

Mechanical Ventilation (Y/N)

Age (12-17, 18-64, 65 and up)

Sex (M/F)

Region (North America, South America, Europe [including Russia])

Race/Ethnicity
4.5.7
Sensitivity and Tipping Point Analyses
4.5.7.1
Prognostic Covariates
Models adjusted for prognostic covariates such as age and individual baseline ordinal 
score category may be fit to the data for the primary and key secondary endpoints.
4.5.7.2
Clinical Status at Day 14
A multiple imputation approach for missing data will be performed using bootstrapping 
by sampling with replacement from non-missing data within treatment group and strata, 
assuming the data were missing at random. The imputed data will be combined with the 
non-missing data to give complete data sets of the same size as the mITT population. 
This will be repeated to obtain 100 complete data sets for each set of imputation 


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parameters. The ordinal logistic regression model (adjusted by stratification factors) will 
be fitted to each of the datasets to obtain the p-value and odds ratio for each of the 
complete datasets. The averages of the p-values and odds ratios from the 100 data sets 
will be presented.
To test the sensitivity of these results to the missing-at-random assumption for each of 
the 100 data sets, the imputed data points will then be adjusted independently by 
treatment group to worse or better outcomes according to a delta (addition of 1 to 6 or 
subtraction 1 to 6). After the delta is applied, adjusted scores below 1 or above 7 will be 
capped at 1 or 7, respectively, so that the data are within the range of possible values for 
the ordinal scale. For each delta adjustment, the ordinal logistic regression model 
(adjusted by stratification factors) will be fitted to each of the datasets to obtain the p-
value and odds ratio for each of the complete datasets. The averages of the p-values 
and odds ratios from the 100 data sets will be presented for each of the delta 
adjustments.
The tipping point will be defined as the delta adjustments at which the p-value changes 
from statistically significant to not statistically significant (or vice versa).
4.5.7.3
Primary Time to Event Endpoint
A sensitivity analysis for the primary endpoint analysed in the mITT population will be 
conducted as described below.
In the following discussion, it is assumed that the mean time to event in the TCZ+RDV 
arm is greater than in the PBO+RDV arm.  If, in reality, the mean time to event is greater 
in the PBO+RDV arm than in the TCZ+RDV arm, then the roles of the two groups in this 
section will be reversed.
The tipping point analysis will impute actual event times for patients whose observed 
time to event is censored due to events other than death.
Times to clinical response will not be imputed for patients whose time to event is:

Observed

Censored due to death 

Censored due to end of follow-up at Day 28
Step 1
For the primary endpoint, event times will be imputed by assigning a censored event 
time of 28 days to patients in the TCZ+RDV arm and an event time equal to the time of 
censoring for patients in the PBO+RDV arm.  This is a “worst case” scenario.  If the 
(non-) significance of the test for the main effect of treatment is unchanged in this 


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sensitivity analysis compared to the main efficacy analysis, no further imputation will 
take place.
For the time to mechanical ventilation or death and the time to death, event times will be 
imputed by assigning a censored event time of 28 days to patients in the PBO+RDV arm 
and an event time equal to the time of censoring for patients in the TCZ+RDV arm.  This 
is a “worst case” scenario.  If the (non-) significance of the test for the main effect of 
treatment is unchanged in this sensitivity analysis compared to the main efficacy 
analysis, no further imputation will take place.
Step 2
Multiple imputation will be used to impute times to event as follows, exploiting the lack of 
memory property of the exponential distribution.
Additional times to event, beyond those actually observed, will be drawn from an 
exponential distribution.  The mean of the distribution will vary between treatment 
groups.  Details of how the means will be calculated are given below.  If the total time to 
event (that is the sum of the actual censored and additional times to event) is greater 
than 28 days, the time to event will be censored at Day 28.  Otherwise, the time to event 
will be set to the largest integer less than or equal to the sum of the observed and 
imputed additional times.
The mean of the distribution of the additional time to event in the PBO+RDV arm will be 
set to the Kaplan-Meier estimate of the mean time to event based on the data observed 
in the study.  The mean of the distribution of the additional time to event in the 
PBO+RDV arm will be defined as follows.
Write ̂ and ̂	
 as the Kaplan-Meier estimates of the mean time to event in the 
PBO+RDV and TCZ+RDV arms respectively.  Similarly, write 
∗
and 	

∗
to represent 
the corresponding means of the imputed additional times to event.
Thus, 
∗
= ̂ as defined above.
Define 	

∗
= 
∗
−(̂ −̂	
)for some real number ρ.  
ρ therefore provides a scale on which the tipping point can be measured.

ρ = 1 implies that the mean of the imputed additional time to event in the 
TCZ+RDV arm is equal to the observed mean.

ρ = 0 implies that the mean imputed time is equal to that observed in the 
PBO+RDV arm (so that treatment with TCZ affords no benefit)


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
As ρ → , the benefit of TCZ increases because the mean of the additional time 
to event decreases and eventually all imputed additional times to event tend to 
zero. 

As ρ → -, the benefit of TCZ decreases because the mean of the additional 
time to event increases and eventually all imputed times to event are censored at 
Day 28.
The number of imputations performed for each value of ρ will be chosen so that the 
estimates derived from the tipping point analysis appear reasonably stable.  The number 
of imputations required may differ for different values of ρ.
The distribution of the p-value associated with a given value of ρ will be summarized by 
its mean, median, 10th and 90th quantiles. 
The tipping point will be defined as the value of ρ at which the mean p-value changes 
from statistically significant to not statistically significant (or vice versa).
The results of the tipping point analysis will be presented in graphical and tabular form.
Practical limits of the values of ρ
The mean of an exponential distribution must be greater than 0.  This implies that
̂ −̂ −̂	
 > 0
So that
 =
̂
̂ −̂	

Where  is the minimum possible value of ρ.
Similarly, as ρ increases, the probability that an imputed additional time to event is 
censored at Day 28 increases.  Thus, a reasonable upper limit for ρ, ρmax(π) say, is given 
by
(  !" #  ! $" > 28 |) > (
Or
)(
−28
̂ −*+(() × ̂ −̂	

) > (
So that


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*+(() =
28
#!-(() + ̂
̂ −̂	

Since the imputed additional survival time is added to the censored survival times 
actually observed, values slightly less than ρmax will also have little or no effect on the 
result of the analysis, so the value of ρmax defined here is somewhat conservative.
4.5.7.4
Time to Death and Time to Mechanical Ventilation or Death up 
to Day 28
The main analyses of these endpoints censor patients who withdrawal or are lost to 
follow up on or after the day of discharge and before the criterion is met (not followed by 
death or re-hospitalization) at Day 28. The main analyses also censor patients who 
withdraw or are lost to follow up prior to discharge and before the criterion is met (not 
followed by death) on the last known alive date for the Time to Death analysis and the 
last recorded vital signs assessment for the Time to Mechanical Ventilation or Death 
analysis. To evaluate the effect of this approach, tipping point analyses, similar to those 
described above, will be conducted for these endpoints.
For each of these endpoints, two tipping point analyses will be conducted.  In the first, 
additional times to event will be imputed for only for patients who withdraw or are lost to 
follow up following discharge.  In the second, additional times to event will be imputed for 
all patients who withdraw or are lost to follow up.
Mean additional times to event will be generated as described in Section 4.5.7.3 and will 
be based on the times to event observed in each group.  ρ will be defined so that a 
positive value indicates a benefit associated with TCZ.
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 received rather than the treatment 
assigned at randomization.
4.6.1
Exposure to Study Medication
Exposure to study drug will be summarized including number of patients with one or two 
doses for TCZ and 1 to 10 doses for RDV.  Patients who are dosed with RDV prior to 
randomization will have those doses counted.  
A listing of patients by treatment group will be prepared detailing dosing of study drugs, 
volume administered and any dose modification due to incomplete dosing or skipped 
doses of TCZ/PBO or RDV not due to death or discharge.


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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 
trial treatment.  Only where the most extreme intensity is greater than the initial intensity 
(or if most extreme intensity is not missing and initial intensity is missing) will events with 
an onset date prior to the start of trial treatment be considered treatment-emergent.  An 
AE with a completely missing start date will be assumed to be treatment-emergent 
unless the AE has a complete non-imputed end date that is prior to Study Day 1.
AEs will be coded and tabulated by system organ class, and/or preferred term (PT) and 
treatment arm. In tabulations, PTs and their associated system organ class will be 
presented in order of descending frequency summed across the treatment arms.
Summaries will be produced up to Day 28 and up to Day 60.
AEs will also be tabulated by severity, as graded according to NCI CTCAE v5.0 scale, 
and relationship to study medication as indicated by the investigator.
The following will also be summarized:

SAEs

AEs leading to withdrawal of study drug

AEs leading to discontinuation from the study

AEs leading to death
Adverse events of special interest will be defined using system organ class, 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 system organ class) 

Opportunistic infections (Roche Standard AEGT Basket) 

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 or remdesivir infusion; and a separate summary using the 
Anaphylactic Reaction SMQ Narrow for events occurring during or within 24 hours 
of the end of tocilizumab or remdesivir infusion) 


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
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 PTs will be produced for all AEs included in the 
analysis. For each AESI table based on SMQs/AEGTs, a corresponding listing of 
the PTs that comprise the SMQ will be produced. 
Listings of AEs and SAEs will be produced. AESIs will also be listed.
The exposure duration on study will be summarized. The exposure duration is the date 
of the last safety assessment or death if present, minus the date of first study treatment 
plus one divided by 365.25.
4.6.3
Laboratory Data
Laboratory data will use ranges from local laboratories and laboratory values will be 
converted to Système International units. 
Summary tables will detail the actual values and changes from baseline of the laboratory 
parameters over visits by treatment arm.  Summaries of the number of patients by CTC 
grade for hematology (WBC, hemoglobin, platelets), liver function tests (alkaline 
phosphatase, ALT, AST, total bilirubin), and renal function (creatinine, BUN) will be 
produced. The number of patients will be summarized by CTCAE grade category for 
baseline and worst postbaseline result.
Patients with values outside the reference will be listed, with an indication of the 
direction of the abnormality (High, Low). 
4.6.4
Vital Signs
Summary statistics on absolute values and their change from baseline for all observed 
vital signs (diastolic blood pressures, systolic blood pressures, respiratory rate, pulse 
rate, body temperature and peripheral oxygen saturation) will be presented over time by 
treatment group. Baseline is as defined in Section 4.4. Additionally, a graphical 
representation of means over time of oxygen saturation and temperature (daily to Day 
28) will be presented. 
For patients requiring supplemental oxygen, summary statistics on absolute values of 
the oxygen flow rate (L/min) and/or fraction of inspired oxygen (FiO2) will be produced 
by visit/ time point and treatment group. 
The level of consciousness will be summarized over time. 
The number and proportion of patients requiring oxygen supplementation or other 
respiratory support will be summarized over time, including type of support given by 
treatment group. Non-invasive positive pressure ventilation and mechanical ventilation 
will be summarized by treatment group.


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4.7
INTERIM ANALYSES
No interim analyses for efficacy have been conducted during the course of this trial.
See Section 3.2 for description of DMC safety monitoring.
5.
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0484-z.
Dmitrienko A and Tamhane A. Chapter 5. Gatekeeping Procedures in Clinical Trials. In 
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Fine P and Robert G. A Proportional Hazards Model for the Subdistribution of a 
Competing Risk, J Am Stat Assoc
1999;94:446, 496-509, DOI: 10.1080/01621459.1999.10474144
Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients with severe 
COVID-19: a retrospective cohort study. The Lancet Rheumatology 
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Gupta S, Wang W, Hayek SS, et al. Association between early treatment with 
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hospitalized with COVID-19 and moderate or severe pneumonia: a randomized 
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Mantel N.  Chi-Square Tests with One Degree of Freedom, Extensions of the Mantel–
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Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report—Second National 
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Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients 
Hospitalized with Covid-19. N Engl J Med 2020.
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http://www.chinaxiv.org/abs/202003.00026


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Appendix 1 Protocol Synopsis
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
REMDESIVIR PLUS TOCILIZUMAB COMPARED WITH 
REMDESIVIR PLUS PLACEBO IN HOSPITALIZED PATIENTS 
WITH SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
WA42511
VERSION NUMBER:
5
EUDRACT NUMBER:
2020-002275-34
IND NUMBER:
148225
NCT NUMBER:
NCT04409262
TEST PRODUCTS:
Tocilizumab (RO4877533)
Remdesivir
PHASE:
Phase III
INDICATION:
Severe COVID-19 pneumonia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of combination therapy with remdesivir plus 
tocilizumab compared with remdesivir plus placebo in hospitalized patients with severe 
coronavirus disease 2019 (COVID-19) pneumonia.  Specific objectives and corresponding 
endpoints for the study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of the remdesivir plus 
tocilizumab arm compared with the remdesivir plus placebo arm for the treatment of severe 
COVID-19 pneumonia on the basis of the following endpoint:

Time from administration of tocilizumab/placebo to hospital discharge or “ready for 
discharge” 
Hospital discharge or “ready for discharge” is defined as a score of 1 on the 7-
point ordinal scale.  Death is defined as a competing risk.
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of the remdesivir plus 
tocilizumab arm compared with the remdesivir plus placebo arm for the treatment of severe 
COVID-19 pneumonia on the basis of the following endpoints:

Time to mechanical ventilation or death, defined as the time from administration of 
tocilizumab/placebo to the first occurrence of mechanical ventilation or death 
(whichever occurs first) 

Time to improvement, defined as the time from administration of tocilizumab/placebo 
to an improvement of at least 2 categories relative to baseline on a 7-category ordinal 
scale of clinical status 


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
Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical 
status on Days 7, 14, 21, 28, and 60

Proportion of patients requiring initiation of mechanical ventilation postbaseline up to 
Day 28 and Day 60 (patients who do not require mechanical ventilation at 
baseline)

Proportion of patients who are alive and free of respiratory failure up to Day 28 
and Day 60 (patients requiring mechanical ventilation at baseline)

Duration of mechanical ventilation (patients who require mechanical ventilation at 
baseline)

Time to death up to Day 28 and Day 60

Mortality rate on Days 14, 28, and 60

Time to recovery, defined as time from administration of tocilizumab/placebo to the time 
when a category of 2, non-ICU hospital ward (or “ready for hospital ward”) not requiring 
supplemental oxygen, or better is observed 
A predefined meta-analysis will be performed on all primary and secondary endpoints.
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of the remdesivir plus 
tocilizumab arm compared with the remdesivir plus placebo arm for the treatment of severe 
COVID-19 pneumonia on the basis of the following endpoints:

Time to clinical improvement (TTCI), defined as time from administration of 
tocilizumab/placebo to National Early Warning Score 2 (NEWS2) score of 2 
maintained for 24 hours:

Time to clinical failure, defined as the time from administration of 
tocilizumab/placebo to the first occurrence of mechanical ventilation, ICU 
admission, death, or withdrawal (whichever occurs first)
For patients entering the study already on mechanical ventilation, clinical 
failure is defined as a one-category worsening on the ordinal scale, 
withdrawal prior to discharge, or death.

Proportion of patients requiring initiation of ICU care postbaseline up to Day 28 
and Day 60

Duration of ICU stay (days)

Duration of supplemental oxygen use (days)

Proportion of patients requiring initiation of vasopressor use postbaseline

Duration of vasopressor use

Proportion of patients requiring initiation of extracorporeal membrane oxygenation (ECMO) 
postbaseline

Duration of ECMO

Organ failure-free days from administration of tocilizumab/placebo to Day 28

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load up to Day 28 
and Day 60

Time to reverse-transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 virus 
negativity
Safety Objective
The safety objective for this study is to evaluate the safety of the remdesivir plus tocilizumab 
arm compared with the remdesivir plus placebo arm for the treatment of severe COVID-19 
pneumonia on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)


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
Proportion of patients with any post-treatment infection at specified timepoints

Change from baseline in targeted clinical laboratory test results 
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of remdesivir 
and metabolite(s) in patients with severe COVID-19 pneumonia on the basis of the following 
endpoint:

Plasma concentration of remdesivir and metabolite(s) at specified timepoints
Biomarker Objective 
The exploratory biomarker objectives for this study are to identify and/or evaluate biomarkers 
that could be predictive of response to remdesivir plus tocilizumab combination treatment 
(i.e., predictive biomarkers), may serve as early surrogates of efficacy or be associated with 
efficacy, may be associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), may be associated with susceptibility to developing adverse events or could lead 
to improved adverse event monitoring or investigation (i.e., safety biomarkers), could provide 
further evidence of tocilizumab pharmacological activity (i.e., pharmacodynamic biomarkers), or 
could overall increase our knowledge and understanding of disease pathogenesis and drug 
safety, on the basis of the following endpoint:

Relationship between biomarkers in serum, peripheral blood mononuclear cells (PBMCs), 
blood, and tissue and efficacy or safety endpoints
STUDY DESIGN
Description of the Study
This is a Phase III, randomized, double-blind, multicenter study to assess the efficacy and 
safety of remdesivir plus tocilizumab compared with remdesivir plus placebo in hospitalized 
patients with severe COVID-19 pneumonia.  The Sponsor intends to enroll patients who have 
been diagnosed with severe COVID-19 pneumonia and meet the entry criteria in centers 
globally.  Enrollment may be up to 800 patients but will target approximately 650 patients. 
In addition to the randomized patients from this study, patients from the Phase III studies 
WA42380 and ML42528 will be included in a meta-analysis of the primary and secondary 
endpoints.  This analysis will assist in the interpretation of the effect of tocilizumab in 
combination with remdesivir compared with tocilizumab alone. 
Patients must be at least 12 years of age and hospitalized with confirmed COVID-19 infection 
per WHO criteria, including a positive polymerase chain reaction (PCR) of any specimen 
(e.g., respiratory, blood, urine, stool, other bodily fluid).  At the time of enrollment, patients must 
require supplemental oxygen 6 L/min to maintain SpO2 93%.
Patients in whom, in the opinion of the treating physician, progression to death is imminent and 
inevitable within the next 24 hours, irrespective of the provision of treatments, will be excluded 
from the study.  Patients with active tuberculosis (TB) or suspected active bacterial, fungal, viral, 
or other infection (besides COVID-19) will be excluded from the study.  
Patients will be randomized as soon as possible after screening at an initial 2:1 ratio to receive 
blinded treatment of either remdesivir plus tocilizumab or remdesivir plus placebo.  Study 
treatment will be given in combination with standard supportive care.  The randomization will be 
stratified by geographic region (North America, Europe, Other) and a 2-level factor based on the 
assessment of the 7-category ordinal scale of clinical status at screening, with levels 45 and 6.  
The proportion of randomized patients in the scale 6 stratum will also be no more than 25%.
Patients assigned to the remdesivir plus tocilizumab (RDV TCZ) arm will receive remdesivir as 
a 200 mg IV loading dose followed by one infusion of tocilizumab 8 mg/kg (maximum dose of 
800 mg) on Day 1.  Patients will subsequently be administered a 100 mg once-daily IV 
maintenance dose of remdesivir from Days 210.  Remdesivir will be discontinued at the time of 
hospital discharge even if 10 days of remdesivir dosing have not been completed.
Remdesivir dosing must be adjusted for patients that enter the study having received prior 
remdesivir.  Patients who received remdesivir prior to randomization must not exceed 10 days 


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49/Statistical Analysis Plan WA42511
of dosing in total (including remdesivir received prior to the study and during the study).  If a 
patient received 1 dose of remdesivir (200-mg loading dose) prior to Day 1, the patient should 
receive remdesivir 100 mg on Days 19.  If a patient received 2 doses of remdesivir (200-mg 
loading dose followed by 100-mg maintenance dose) prior to Day 1, the patient should receive 
remdesivir 100 mg on Days 18.  Patients who received remdesivir prior to trial entry must not 
receive a second 200-mg loading dose on Day 1.  The same sequence and timing of remdesivir 
and tocilizumab will be followed on Days 1 and 2 regardless of whether the patient has received 
remdesivir prior to randomization.
For both arms, if the patient has a sustained fever or clinically significant worsening of signs or 
symptoms (e.g., an increased supplemental oxygen requirement), one additional infusion of 
blinded tocilizumab/placebo can be given 824 hours after the first tocilizumab/placebo infusion.  
The second dose of blinded tocilizumab must not be given if the patient develops an adverse 
event or laboratory abnormalities that warrant discontinuation of tocilizumab. 
Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity (for a total of 2 screenings per participant) at the investigator’s 
discretion.  Patients are not required to re-sign the consent form if they are re-screened within 
7 days after previously signing the consent form.  The investigator will record the reasons for 
screen failure in the screening log.
The study assessments to be conducted include the following: physical examination, vital signs, 
oxygen saturation, assessment of consciousness, presence and absence of respiratory support, 
chest X-ray, ECG, adverse events, concomitant therapies, clinical laboratory tests, and 
nasopharyngeal swabs.
Patients will be followed up for a total of 60 days after first dose of study drug.
If patients are discharged from hospital prior to Day 28, follow-up visits should be conducted on 
Day 14, Day 21, and Day 28 (2 days).  Follow-up visits on Day 14 and Day 21 may be 
conducted as telephone visits.  Patients should return to the site for the Day 28- visit, if at all 
possible.  After Day 28, all patients should have follow-up visits on Day 35, Day 45, and Day 
60.  The Day 35- and Day 45-visits may be conducted by telephone for discharged patients.  
Patients should return to the site for the Day 60 visit, if at all possible.
Number of Patients
The target enrollment for the study is approximately 650 hospitalized patients with severe 
COVID-19 pneumonia, but up to 800 patients may be enrolled to achieve approximately 
520 patients discharged by Day 28.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Documented informed consent to participate in the study

Signed Assent Form when appropriate, as determined by the patient's age and individual 
site and country standards

Age 12 years at time of informed consent

Ability to comply with the study protocol, in the investigator's judgment

Hospitalized with COVID19 pneumonia confirmed per a positive PCR of any specimen 
(e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or 
CT scan 
The PCR test must be collected 7 days before randomization.  

Requiring 6 L/min supplemental oxygen to maintain SpO2 93%

Agrees to not participate in another clinical trial for the treatment of COVID-19 while 
participating in this study

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.


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A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information
about the reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 60 days after 
the final dose of study drug to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of preventing drug exposure.  If required per local 
guidelines or regulations, information about the reliability of abstinence will be 
described in the local Informed Consent Form.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known severe allergic reactions to tocilizumab or other monoclonal antibodies

Known hypersensitivity to remdesivir, the metabolites, or formulation excipients

Active TB infection 

Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) 

In the opinion of the investigator, progression to death is imminent and inevitable within the 
next 24 hours, irrespective of the provision of treatments

Treatment with immunosuppressive or immunomodulatory therapy (including tocilizumab) 
within the past 3 months

Concurrent treatment with other agents with actual or possible direct-acting antiviral activity 
against SARS-CoV-2 within 24 hours prior to study drug dosing
In addition, patients with prior or current treatment with 2 doses remdesivir for 
COVID-19 are excluded.

Participating in another drug clinical trial 

Estimated glomerular filtration rate (eGFR) 30 mL/min (including patients receiving 
hemodialysis or hemofiltration), using the equation described in the FDA EUA Fact Sheet 
for remdesivir

ALT or AST 5 upper limit of normal (ULN) detected within 24 hours of screening 
(according to local laboratory reference ranges)

ANC 1000/L at screening 

Platelet count 50,000/L at screening 


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51/Statistical Analysis Plan WA42511

Body weight 40 kg

Pregnant or breastfeeding, or positive pregnancy test in a predose examination

Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of 
randomization 

Any serious medical condition or abnormality of clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for the last follow-up is received from the last patient, 
whichever occurs later.  The end of the study is expected to occur approximately 2 months after 
the last patient is enrolled.  
In addition, the Sponsor may decide to terminate the study at any time.
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.
Investigational Medicinal Products
Test Products (Investigational Drugs)
The investigational medicinal products (IMPs) for this study are remdesivir IV, tocilizumab IV, 
and placebo for tocilizumab IV 
Patients assigned to the remdesivir plus tocilizumab (RDV TCZ) arm will receive remdesivir 
loading dose followed by one infusion of tocilizumab on Day 1, and once-daily maintenance 
dose of remdesivir from Days 210. 
Patients assigned to the remdesivir plus placebo (RDV placebo) arm will receive remdesivir
as loading dose followed by one infusion of tocilizumab-placebo on Day 1, and once-daily 
maintenance dose of remdesivir from Days 210.
For both arms, if the patient has a sustained fever or clinically significant worsening of signs or 
symptoms (e.g., an increased supplemental oxygen requirement), one additional infusion of 
blinded tocilizumab/placebo can be given 824 hours after the first tocilizumab/placebo infusion.  
The second dose of blinded tocilizumab must not be given if the patient develops an adverse 
event or laboratory abnormalities that warrant discontinuation of tocilizumab.
Administration of study treatments will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of the remdesivir plus 
tocilizumab arm compared with remdesivir plus placebo arm using the following endpoint:

Time from administration of tocilizumab/placebo to hospital discharge or “ready for 
discharge”
Hospital discharge or “ready for discharge” is defined as a score of 1 on the 7-
point ordinal scale.  Death is defined as a competing risk.
The distribution of time from administration of tocilizumab/placebo to hospital discharge (or 
ready for discharge) will be compared with the remdesivir plus tocilizumab arm and the 
remdesivir plus placebo arm up to Day 28.  Patients discharged after Day 28 will be 
administratively censored.  The distributions will be compared using an appropriate method for 
comparing censored event distributions with a competing risk such as the Cox model with 
cause specific hazards.  The competing risk of mortality will be assessed over the 28-day 
period and addressed in the analysis of key secondary endpoints and sensitivity analysis 
(for details, see the SAP).  Cumulative incidence plots will be presented as well as median time 


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52/Statistical Analysis Plan WA42511
to discharge (or ready for discharge), with 95% confidence intervals for the remdesivir plus 
tocilizumab arm and the remdesivir plus placebo arm.
Determination of Sample Size
The primary endpoint, time to discharge or “ready for discharge,” is event driven.  Based on the 
severe cohort receiving 10 days of remdesivir in Gilead’s SIMPLE trial (Study GS-US-540-
5773), the median time to discharge or “ready for discharge” was 11 days. Assuming a 
median time to discharge or “ready for discharge” of 11 days in the remdesivir plus 
placebo arm, a hazard ratio of 1.3 or an approximately 2.5-day reduction in median time for
remdesivir plus tocilizumab versus remdesivir plus placebo, and a 2:1 randomization to
remdesivir plus tocilizumab or remdesivir plus placebo, approximately 650 patients are 
needed to accrue approximately 520 events to achieve approximately 80% power.  A 
reduction of at least 2 days in median time to discharge was considered clinically 
meaningful and the sample size was increased to ensure that a minimum effect size 
could be detected.  Further sample size adjustments may be considered during the 
study based on external information.  The sample size may be increased up to a maximum 
of approximately 800 randomized patients if fewer events than expected are observed or 
further shifts in standard of care warrant reassessing sample size assumptions.
Interim Analyses 
There will be up to three optional interim analyses.  The first interim analysis can occur after 
approximately one-third to one-half of the patients have been assessed for the primary endpoint 
on Day 28, depending on enrollment rate.  There may be up to two additional unplanned interim 
analyses, and these will be considered if there are major changes to the study design following 
the first interim analysis.
Full statistical details of any optional interim analyses, along with the rationale and timing will be 
documented in an interim SAP, which will be made available to the relevant health authorities 
before the data snapshot for the first interim analysis.  Only the Data Monitoring Committee
(DMC) will be unblinded and decision criteria will be specified in the interim SAP.  Should an 
unblinded interim analysis occur, any necessary adjustment to the type 1 error rate will be 
specified in the SAP prior to unblinding the study.
The optional interim analysis will be based on the time to discharge (or ready for discharge) and 
mortality.  Questions to be addressed at the interim analysis might include futility as well as 
potential efficacy.
The DMC will also evaluate safety according to policies and procedures detailed in the DMC 
Charter.  Regular safety reviews will begin after approximately 45 patients (15 remdesivir plus 
placebo and 30 remdesivir plus tocilizumab) have been enrolled and have reached 14 days 
of follow-up.  Early stopping criteria based on compelling efficacy or an imbalance in adverse 
events will be detailed in the DMC Charter.  The safety interim analyses will also be conducted 
by a statistical programmer and statistician independent from the study management team and 
will be reviewed by the DMC.  Interactions between the DMC and Sponsor will be carried out as 
specified in the DMC Charter.
The DMC initially consisted of Sponsor representatives not involved in any operational 
aspects of the study and a Scientific Oversight Committee of external experts 
(responsibilities and operating principles of the DMC are described in a charter, the 
Internal Monitoring Committee and Scientific Oversight Committee Agreement).  The 
DMC responsibilities transitioned to a fully independent Data Monitoring Committee 
(iDMC) prior to the third scheduled safety review after approximately 300 patients 
reached Day 28 of follow-up.  The iDMC will also conduct a fourth scheduled safety 
data review when at least 450 patients have reached Day 28.  Data processing will be 
handled by a Sponsor statistician and statistical programmer independent of the study 
management team.  Details are reported in the iDMC Charter.


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


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Appendix 2 Schedule of Activities:  Screening, Days 1 and 2 (cont.)
Study Day
Screening a, b
Day 1
Day 2
2 to 0
Time After Initial Treatment
(Assessment Window)
Baseline
0
Predose
1 hour
After End of 
RDV Infusion
(2 hrs)
15 min
After End of 
TCZ Infusion
(3 hrs)
24 hrs
(4 hrs)
36 hrs
(4 hrs)
Hematology m
x 
x
x
Chemistry (full panel) n
x 
x
Chemistry (only ALT, AST, total bilirubin, ALP, 
and creatinine)
x
Coagulation o
x
x
RDV administration p
x
x
TCZ/placebo administration q
x
Central Labs
Serum sample for exploratory biomarkers p
x
x
Nasopharyngeal swab: SARS-CoV-2 viral load 
and exploratory biomarkers r
x
x r
Serum SARS-CoV-2 antibody titer
x
Cryopreserved PBMCs s
x
x
Blood in PAXgenetubes for RNA analyses t
x
CTcomputed tomography; eCRF electronic case report form; hrs hours; minminute; NEWS2National Early Warning Score 2; NKnatural 
killer (cell); PaO2/FiO2arterial oxygen partial pressure/fraction of inspired oxygen; PBMCs peripheral blood mononuclear cells; PCR polymerase 
chain reaction; PCT procalcitonin; RDVremdesivir; SARS-Cov-2severe acute respiratory syndrome coronavirus 2; SpO2peripheral capillary 
oxygen saturation; TCZtocilizumab.
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.


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Appendix 2 Schedule of Activities:  Screening, Days 1 and 2 (cont.)
a Results from standard-of-care tests or examinations (including physical exam) performed prior to obtaining informed consent and within 24 hours 
before screening 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.  The screening and baseline visit may be 
performed on the same day, provided that the patient meets all of the study entry criteria as outlined in Section 4.1.1 and Section 4.1.2 prior to 
randomization.  If the screening and baseline visits occur on the same day, assessments do not need to be repeated.
c A complete physical examination, performed at screening and per the investigator’s discretion during the study, includes an evaluation of the 
head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 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 after randomization should be reported as adverse events (see Section 5.3). 
d If it is not feasible to weigh bed-bound patients, historical body weight may be used.
e COVID-19 test (SARS-CoV-2 PCR) to confirm diagnosis should be collected within 7 days prior to randomization. 
f
Screening chest X-ray or CT scans should be performed within 48 hours prior to randomization.   
g For women of childbearing potential, including those who have had a tubal ligation will have a pregnancy test at screening.  If a urine pregnancy 
test is positive, it must 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.  
i
On Day 1, all vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressure, and body temperature), oxygen 
saturation (SpO2), and NEWS2-specific assessments (i.e., consciousness and presence or absence of oxygen support) must be recorded 
1) prior to administration of remdesivir, 2) after administration of remdesivir/prior to administration of tocilizumab/placebo and 3) after 
administration of tocilizumab/placebo.  On Day 2, measurements should be recorded together twice daily approximately every 12 hours.  If 
measured more than once during a 12 hour period on Day 2, 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.  For patients requiring supplemental 
oxygen, the oxygen flow rate (L/min) and/or FiO2 should be recorded.
j
Assessment of clinical status using the ordinal scale should be recorded at baseline on Day 1 and again daily every morning (between 8:00 a.m. 
and 12:00 p.m.) for patients who remain hospitalized.  See Section 4.5.10 for additional details.


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Appendix 2 Schedule of Activities:  Screening, Days 1 and 2 (cont.)
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 first 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) 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), and lymphocyte subsets (T cells, B cells, and NK cells; if the test is available at the site, or if the site can ship the 
blood sample on the day of collection to the central laboratory for testing.  Samples are not required if neither of these options is available).
n Chemistry panel (serum or plasma) includes bicarbonate, sodium, potassium, chloride, glucose, BUN, creatinine, total protein, albumin, 
phosphorus, calcium, total bilirubin, ALP, ALT, AST, LDH, ferritin, and PCT.
o Coagulation panel includes INR, PTT, D-dimer and fibrinogen.
p Remdesivir should be administered after review of hematology and chemistry safety labs and collection of all central lab samples.  The initial 
infusion of remdesivir should be given within 4 hours of randomization.  If the patient received remdesivir prior to randomization, the 
remdesivir dose on Day 1 will be a 100-mg maintenance dose.  If a second tocilizumab/placebo infusion is given, there must be at least 2 hours 
after completion of the second tocilizumab/placebo infusion before the Day 2 remdesivir infusion is administered in this instance, the visit 
window on Day 2 at 24 hours may be extended to 6 hours.
q The infusion of tocilizumab/placebo must not be given until at least 60 minutes after the infusion of remdesivir is complete.  If the patient has a 
sustained fever or clinically significant worsening of signs or symptoms (e.g., an increased supplemental oxygen requirement), one additional 
infusion of blinded tocilizumab/placebo can be given 824 hours after the first tocilizumab/placebo infusion (see Section 5.1.3.1).
r
Viral load will be assessed by nasopharyngeal swab or other respiratory sample (e.g., endotracheal tube aspirate).  Sample collection on Day 2 
is optional.  Where possible the same nostril should be used.  Patients who are intubated and undergo bronchoscopy will have samples taken for 
virological assessment.  Genotypic and phenotypic viral resistance may be assessed in exploratory analyses.  Other analyses may include 
evaluation of levels of inflammatory biomarkers.
s For sites capable of performing PBMC isolation and cryopreservation.  If PBMC isolation or cryopreservation is not feasible for the site, then 
blood samples may alternatively be shipped on the day of collection to the central laboratory.  Samples are not required if neither of these 
options is available.
t
The PAXgeneblood RNA tube should be the last tube draw in the phlebotomy procedure to avoid contact with RNA preservation reagent 
inside the tube.


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Appendix 3 Schedule of Activities:  Days 328
Study Day
Days 328 a
Study 
Discontinuation 
b
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
Vital signs c
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
SpO2 c
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 d
   Optional  
Optional
Ordinal scoring e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology h
x
x
x
x
x
x
x
x
Chemistry (full panel) i
x
x
x
x
x
x
x
Chemistry (only ALT, AST, total 
bilirubin, ALP and creatinine)
x
x
x
x
x
Coagulation j
x
x
x
x
x
RDV administration k
x
x
x
x
x
x
x
x
Central Labs
Plasma PK l
x
x
Serum sample for exploratory 
biomarkers
x
x
x
x
x
x
Nasopharyngeal swab: 
SARS-CoV-2 viral load and 
exploratory biomarkers m
x
x m
x
x m
x
x
x
x
x
x
Serum SARS-CoV-2 antibody 
titer
x
x


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Appendix 3 Schedule of Activities:  Days 328 (cont.)
Cryopreserved PBMCs n
x
x
x
x
x
x
Blood in PAXgene
tubes for RNA analyses o
x
x
x
x
NEWS2National Early Warning Score 2; NKnatural killer (cell); PaO2/FiO2arterial oxygen partial 
pressure/fraction of inspired oxygen; PBMCs peripheral blood mononuclear cells; PCT procalcitonin; 
PKpharmacokinetic; SARS-CoV-2severe acute respiratory syndrome coronavirus 2; SpO2peripheral 
capillary oxygen saturation.
a
If patients are discharged from hospital prior to Day 28, follow-up visits should be conducted on Day 
14, Day 21 and Day 28 (2 days).  Follow-up visits on Day 14 and Day 21 may be conducted as 
telephone visits.  Vital signs and laboratory testing will not be required for telephone visits.  For patients 
discharged with supplemental oxygen prior to Day 28, SpO2 measured by the patient at home should be 
recorded during telephone visits, if available.  Patients should return to the site for the Day 28 visit, if at 
all possible.
b
Patients who discontinue from study treatment should continue in the study and complete all 
assessments through Day 60 (as outlined in Appendix 2 and Appendix 3).
c
All vital sign measurements (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressure, 
and body temperature), oxygen saturation and NEWS2-specific assessments (i.e., consciousness and 
presence or absence of oxygen support) should be recorded together twice daily approximately every 12 
hours while the patient remains hospitalized.  If measured more than once during a 12 hour period, the 
worst values (highest temperature, respiratory rate, and heart rate; lowest blood pressure, oxygen 
saturation, and consciousness level) during that period should be recorded on the eCRF.  Following 
hospital discharge, these parameters should be recorded once at each return visit to the clinic.  Vital 
signs and oxygen saturation will not be recorded if follow-up visits are conducted by telephone.
d
If arterial blood gases are measured.
e
Assessment of clinical status using the ordinal scale should be recorded daily every morning 
(between 8:00 a.m. and 12:00 p.m.) for patients who remain hospitalized.  See Section 4.5.10 for 
additional details.
f
All adverse events will be reported until 60 days after the first 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).
g
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, 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.


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Appendix 3 Schedule of Activities:  Days 328 (cont.)
h
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes), and lymphocyte subsets (T cells, B 
cells, and NK cells; if the test is available at the site, or if the site can ship the blood sample on the day of 
collection to the central laboratory for testing.  Samples are not required if neither of these options is 
available).  Hematology labs will not be performed if follow-up visits are conducted by telephone.
i
Chemistry panel (serum or plasma) includes bicarbonate, sodium, potassium, chloride, glucose, 
BUN, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, AST, LDH, ferritin, 
and PCT.  Chemistry labs will not be performed if follow-up visits are conducted by telephone.
j
Coagulation panel includes INR, PTT, D-dimer and fibrinogen.  Coagulation labs will not be 
performed if follow-up visits are conducted by telephone.
k
Remdesivir should be administered after review of chemistry safety labs and collection of all central 
lab samples.  If a patient is discharged from hospital before Day 10, remdesivir will be discontinued at 
that time. Patients who received remdesivir prior to randomization will not exceed 10 days of 
remdesivir dosing in total.  
l
On Day 4 and Day 7, PK samples should be drawn prior to the start of remdesivir infusion (predose) 
and also 3060 minutes after the start of the remdesivir infusion if possible.  All PK samples must be 
drawn from the opposite arm as the remdesivir infusion.  PK samples are not required if collection and 
processing is not feasible. 
m
Patients who remain in hospital will have viral load assessed by nasopharyngeal swab or other 
respiratory sample (e.g., endotracheal tube aspirate). Sample collection on Day 4 and Day 6 is optional.  
Where possible the same nostril should be used.  Genotypic and phenotypic viral resistance may be 
assessed in exploratory analyses.  Other analyses may include evaluation of levels of inflammatory 
biomarkers.
n
For sites capable of performing PBMC isolation and cryopreservation.  If PBMC isolation or 
cryopreservation is not feasible for the site, then blood samples may alternatively be shipped on the day 
of collection to the central laboratory.  Samples are not required if neither of these options is available.
o
The PAXgeneblood RNA tube should be the last tube draw in the phlebotomy procedure to avoid 
contact with RNA preservation reagent inside the tube


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Appendix 4 Schedule of Activities:  After Day 28
Study 
Completion/
Discontinuation
Study Day
(Assessment Window)
35 a
(3 days)
45 a
(3 days)
60
(3 days)
Vital signs b
x
x
x
SpO2 b
x
x
x
Ordinal scoring c
x
x
x
Adverse events d
x
x
x
Concomitant medications e
x
x
x
Hematology f
x
x
x
Chemistry g
x
x
x
Coagulation h
x
x
x
Central Labs
Nasopharyngeal swab: SARS-CoV-2 viral load and 
exploratory biomarkers i
x i
x i
x
Serum sample for exploratory biomarkers
x
x
Serum SARS-CoV-2 antibody titer
x
Cryopreserved PBMCs j
x
Blood in PAXgenetubes for RNA analyses k
x
NK natural killer (cell); PMBCs peripheral blood mononuclear cells; PCT procalcitonin; 
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2; SpO2 peripheral capillary oxygen 
saturation.
a Patients should have follow up visits on Day 35, Day 45, and Day 60 (3 days).  The Day 35 and Day 
45 visits may be conducted by telephone for discharged patients.  Vital signs and laboratory testing will 
not be required for telephone visits.  For patients discharged with supplemental oxygen, SpO2
measured by the patient at home should be recorded during telephone visits, if available.  Patients 
should return to the site for the Day 60 visit, if at all possible.


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b For patients who remain in hospital, vital sign measurements and NEWS2-specific assessments should 
be conducted twice daily.  If measured more than once during a 12-hour period, the worst values 
(highest temperature, respiratory rate, and heart rate; lowest blood pressure, oxygen saturation, and 
consciousness level) during that period should be recorded on the eCRF.  Following hospital discharge, 
these parameters should be recorded once at each return visit to the clinic.  Vital signs and oxygen 
saturation will not be recorded if follow-up visits are conducted by telephone.


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Appendix 4 Schedule of Activities:  After Day 28 (cont.)
c Assessment of clinical status using the ordinal scale should be recorded daily every morning (between 
8:00 a.m. and 12:00 p.m.) for patients who remain hospitalized.
d All adverse events will be reported until 60 days after the first 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).
e Medication (e.g., prescription drugs, over-the-counter drugs) 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.
f
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes), and lymphocyte subsets (T cells, B 
cells, and NK cells; if the test is available at the site, or if the site can ship the blood sample on the day 
of collection to the central laboratory for testing.  Samples are not required if neither of these options is 
available).  Hematology labs will not be performed if follow-up visits are conducted by telephone.
g Chemistry panel (serum or plasma) includes bicarbonate, sodium, potassium, chloride, glucose, BUN, 
creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, AST, LDH, ferritin, and 
PCT.  Chemistry labs will not be performed if follow-up visits are conducted by telephone.
h Coagulation panel includes INR, PTT, D-dimer, and fibrinogen.  Coagulation labs will not be performed 
if follow-up visits are conducted by telephone.
i
Patients who remain in hospital will have viral load assessed by nasopharyngeal swab or other 
respiratory sample (e.g., endotracheal tube aspirate).  Sample collection on Day 35 and Day 45 is 
optional.  Where possible the same nostril should be used.  Genotypic and phenotypic viral resistance 
may be assessed in exploratory analyses.  Other analyses may include evaluation of levels of 
inflammatory biomarkers.
j
For sites capable of performing PBMC isolation and cryopreservation.  If PBMC isolation or 
cryopreservation is not feasible for the site, then blood samples may alternatively be shipped on the 
day of collection to the central laboratory.  Samples are not required if neither of these options is 
available. 
k The PAXgeneblood RNA tube should be the last tube draw in the phlebotomy procedure to avoid 
contact with RNA preservation reagent inside the tube.


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


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