A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of MSTT1041A or UTTR1147A in Patients With Severe COVID-19 Pneumonia
Phase: PHASE2
Conditions: COVID-19 Pneumonia
Sponsor: Genentech, Inc.

PROTOCOL AMENDMENT APPROVAL 
  
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
MSTT1041A/UTTR1147A—Genentech, Inc. 
Protocol GA42469, Version 4 
 
PROTOCOL 
TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
TO EVALUATE THE SAFETY AND EFFICACY OF 
MSTT1041A OR UTTR1147A IN PATIENTS WITH 
SEVERE COVID-19 PNEUMONIA 
PROTOCOL NUMBER: GA42469 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-002713-17 
IND NUMBER: 
149507 
NCT NUMBER: 
NCT04386616 
TEST PRODUCTS: 
MSTT1041A (RO7187807) 
UTTR1147A (RO7021610)  
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
See electronic date stamp below 
 
 
 
16-Sep-2020 00:19:11
Title
Approver's Name
Company Signatory
Date and Time (UTC)
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
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PROTOCOL HISTORY
Protocol
Version
Date Final
1
10 April 2020
2
27 May 2020
3
3 August 2020
Protocol Number: 
 Report Number: 
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MSTT1041A/UTTR1147A—Genentech, Inc. 
3/Protocol GA42469, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol GA42469 has been amended to change the primary endpoint and increase the 
sample size.  Substantive changes to the protocol, along with a rationale for each 
change, are summarized below: 
• 
The primary endpoint has been changed to “Time to recovery, defined as time to 
score of 1 or 2 on the 7-category ordinal scale (whichever occurs first)” (Sections 
2.1.1, 6.1, and 6.4.1).  The previous primary endpoint, “Clinical status assessed 
using a 7-category ordinal scale at Day 28,” has been moved to the secondary 
efficacy endpoints (Sections 2.1.2 and 6.4.2).  On the basis of published data from 
other clinical trials for COVID-19 pneumonia (Beigel et al. 2020; McCreary and 
Angus 2020), there appears to be growing consensus that time to recovery reflects 
a clinically meaningful outcome measurement for the targeted patient population. 
Additionally, given the variable time course of COVID-19, a fixed time endpoint 
could miss recognition of clinical benefit and therefore may not be optimal (Dodd 
et al. 2020).  
• 
The incidence of mechanical ventilation and extracorporeal membrane oxygenation 
has been combined into a single secondary efficacy endpoint (Sections 2.1.2 and 
6.4.2), as both represent a worsening of the clinical status and choice of 
management may vary between institutions. 
• 
Clarifications have been made to the reporting requirements for possible 
UTTR1147A-mediated dermatologic reactions (Sections 4.6.1, 5.1.3.3, 5.2.3, and 
5.3.5.2). 
• 
The sample size was increased to allow for enrollment of approximately 
390 patients with severe COVID-19 pneumonia, which will provide approximately 
80% power to detect a difference between treatment groups for the new primary 
endpoint, “time to recovery, defined as time to score of 1 or 2 on the 7-category 
ordinal scale (whichever occurs first)”  (Sections 3.1.1, 4.1, and 6.1). 
• 
Language has been updated to clarify that homeopathic remedies, IV fluids, or 
nutritional supplements (e.g., vitamins and minerals) do not need to be reported on 
the Concomitant Medications eCRF (Section 4.4). 
• 
Language has been added to clarify that historic standard-of-care assessments are 
acceptable if performed within 2 days prior to Day 1, unless otherwise specified 
(Appendix 1). 
• 
Language has been updated to clarify the window for central and local lab 
assessments (Appendix 1). 
• 
Language has been added to clarify that visit days in the post-discharge schedule of 
activities should be based on days on study and not on days post-discharge 
(Appendix 2). 
• 
Language regarding the discharge day has been updated to state that certain 
specified assessments do not need to be repeated if performed the day prior to 
discharge (Appendix 2). 
Protocol Number: 
 Report Number: 
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Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics. 
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 22
1.1
Background on COVID-19 Pneumonia.................................. 22
1.2
Background on MSTT1041A (Anti-ST2) ................................ 23
1.2.1
Background on Interleukin-33/ST2 ........................................ 23
1.2.2
Summary of Nonclinical Studies............................................ 24
1.2.3
Summary of Clinical Studies.................................................. 24
1.3
Background on UTTR1147A (IL-22Fc).................................. 25
1.3.1
Background on Interleukin-22................................................ 25
1.3.2
Summary of Nonclinical Studies............................................ 27
1.3.3
Summary of Clinical Studies.................................................. 27
1.4
Study Rationale and Benefit-Risk Assessment...................... 28
1.4.1
MSTT1041A (Anti-ST2) ......................................................... 28
1.4.2
UTTR1147A (IL-22Fc) ........................................................... 30
2.
OBJECTIVES AND ENDPOINTS ............................................................... 31
2.1
Efficacy Objectives ................................................................ 31
2.1.1
Primary Efficacy Objective..................................................... 31
2.1.2
Secondary Efficacy Objective................................................ 32
2.1.3
Exploratory Efficacy Objective............................................... 33
2.2
Safety Objective .................................................................... 33
2.3
Pharmacokinetic Objectives .................................................. 33
2.4
Immunogenicity Objectives.................................................... 34
2.5
Exploratory Biomarker Objective ........................................... 34
3.
STUDY DESIGN......................................................................................... 34
3.1
Description of the Study......................................................... 34
3.1.1
Overview of Study Design ..................................................... 34
3.1.2
Data Monitoring Committee................................................... 36
3.1.3
Safety Monitoring Committee ................................................ 37
3.2
End of Study and Length of Study......................................... 37
3.3
Rationale for Study Design.................................................... 37
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3.3.1
Rationale for MSTT1041A (Anti-ST2) Dose and 
Schedule................................................................................ 37
3.3.2
Rationale for UTTR1147A (IL-22Fc) Dose and 
Schedule................................................................................ 39
3.3.3
Rationale for Patient Population ............................................ 41
3.3.4
Rationale for Control Group................................................... 42
3.3.5
Rationale for Biomarker Assessments................................... 42
4.
MATERIALS AND METHODS .................................................................... 42
4.1
Patients.................................................................................. 42
4.1.1
Inclusion Criteria.................................................................... 42
4.1.2
Exclusion Criteria................................................................... 44
4.2
Method of Treatment Assignment and Blinding..................... 45
4.2.1
Treatment Assignment........................................................... 45
4.2.2
Blinding.................................................................................. 46
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 47
4.3.1
Study Treatment Formulation and Packaging........................ 47
4.3.1.1
MSTT1041A, UTTR1147A, and Placebos............................. 47
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 47
4.3.2.1
MSTT1041A, UTTR1147A, and Placebo............................... 47
4.3.3
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 47
4.3.4
Continued Access to MSTT1041A or 
UTTR1147A........................................................................... 48
4.4
Concomitant Therapy ............................................................ 49
4.4.1
Permitted Therapy................................................................. 49
4.4.2
Cautionary Therapy ............................................................... 49
4.4.2.1
Herbal Therapies................................................................... 49
4.4.3
Prohibited Therapy ................................................................ 49
4.5
Study Assessments ............................................................... 50
4.5.1
Informed Consent Forms and Screening Records................. 50
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 50
4.5.3
Physical Examinations........................................................... 51
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4.5.4
Vital Signs and Oxygen Saturation........................................ 51
4.5.5
Assessments Specific to National Early Warning 
Score 2 .................................................................................. 51
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 52
4.5.7
Electrocardiograms................................................................ 54
4.5.8
Chest X-Rays and CT Scans................................................. 54
4.5.9
Ordinal Scale Determination.................................................. 55
4.5.10
Optional Blood Samples for Whole Genome 
Sequencing (Patients at Participating Sites).......................... 56
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 57
4.6.1
Study Treatment Discontinuation........................................... 57
4.6.2
Patient Discontinuation from the Study.................................. 57
4.6.3
Study Discontinuation............................................................ 58
4.6.4
Site Discontinuation............................................................... 58
5.
ASSESSMENT OF SAFETY....................................................................... 58
5.1
Safety Plan ............................................................................ 58
5.1.1
Risks Associated with MSTT1041A (Anti-ST2)...................... 59
5.1.1.1
Identified Risks ...................................................................... 59
5.1.1.2
Potential Risks....................................................................... 59
5.1.2
Risks Associated with UTTR1147A (IL-22Fc)........................ 60
5.1.2.1
Identified Risks ...................................................................... 60
5.1.2.2
Potential Risks....................................................................... 61
5.1.2.3
Laboratory Abnormalities Associated with 
UTTR1147A (IL-22Fc) ........................................................... 62
5.1.3
Management of Patients Who Experience 
Adverse Events ..................................................................... 63
5.1.3.1
Dose Modifications ................................................................ 63
5.1.3.2
Treatment Interruption ........................................................... 63
5.1.3.3
Management Guidelines........................................................ 63
5.1.3.4
Management of Increases in QT Interval............................... 65
5.1.3.5
Anaphylaxis ........................................................................... 65
5.2
Safety Parameters and Definitions ........................................ 66
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5.2.1
Adverse Events ..................................................................... 66
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 66
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 67
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 68
5.3.1
Adverse Event Reporting Period ........................................... 68
5.3.2
Eliciting Adverse Event Information....................................... 68
5.3.3
Assessment of Severity of Adverse Events ........................... 68
5.3.4
Assessment of Causality of Adverse Events ......................... 69
5.3.5
Procedures for Recording Adverse Events............................ 70
5.3.5.1
Infusion-Related Reactions.................................................... 70
5.3.5.2
Dermatologic Reactions......................................................... 70
5.3.5.3
Diagnosis versus Signs and Symptoms................................. 70
5.3.5.4
Adverse Events That Are Secondary to Other 
Events.................................................................................... 71
5.3.5.5
Persistent or Recurrent Adverse Events................................ 71
5.3.5.6
Abnormal Laboratory Values ................................................. 72
5.3.5.7
Abnormal Vital Sign Values ................................................... 72
5.3.5.8
Abnormal Liver Function Tests.............................................. 73
5.3.5.9
Deaths ................................................................................... 73
5.3.5.10
Preexisting Medical Conditions.............................................. 74
5.3.5.11
Lack of Efficacy or Worsening of COVID-19 
Pneumonia ............................................................................ 74
5.3.5.12
Re-Hospitalization or Prolonged Hospitalization.................... 74
5.3.5.13
Cases of Accidental Overdose or Medication 
Error....................................................................................... 75
5.3.5.14
Safety Biomarker Data........................................................... 76
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 76
5.4.1
Emergency Medical Contacts................................................ 77
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 77
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 77
Protocol Number: 
 Report Number: 
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5.4.2.2
Events That Occur after Study Drug Initiation........................ 77
5.4.3
Reporting Requirements for Pregnancies.............................. 78
5.4.3.1
Pregnancies in Female Patients............................................ 78
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 78
5.4.3.3
Abortions ............................................................................... 79
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 79
5.5
Follow-Up of Patients after Adverse Events .......................... 79
5.5.1
Investigator Follow-Up........................................................... 79
5.5.2
Sponsor Follow-Up ................................................................ 80
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 80
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 80
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 81
6.1
Determination of Sample Size ............................................... 81
6.2
Summaries of Conduct of Study............................................ 81
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 81
6.4
Efficacy Analyses .................................................................. 81
6.4.1
Primary Efficacy Endpoint...................................................... 82
6.4.2
Secondary Efficacy Endpoints............................................... 83
6.4.3
Exploratory Efficacy Endpoints.............................................. 83
6.5
Safety Analyses..................................................................... 83
6.6
Pharmacokinetic Analyses..................................................... 84
6.7
Immunogenicity Analyses...................................................... 84
6.8
Biomarker Analyses............................................................... 85
6.9
Optional Interim Analyses...................................................... 85
7.
DATA COLLECTION AND MANAGEMENT ............................................... 85
7.1
Data Quality Assurance......................................................... 85
7.2
Electronic Case Report Forms............................................... 86
7.3
Source Data Documentation.................................................. 86
7.4
Use of Computerized Systems .............................................. 87
7.5
Retention of Records............................................................. 87
Protocol Number: 
 Report Number: 
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8.
ETHICAL CONSIDERATIONS.................................................................... 87
8.1
Compliance with Laws and Regulations ................................ 87
8.2
Informed Consent.................................................................. 87
8.3
Institutional Review Board or Ethics Committee.................... 89
8.4
Confidentiality........................................................................ 89
8.5
Financial Disclosure .............................................................. 90
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 90
9.1
Study Documentation ............................................................ 90
9.2
Protocol Deviations................................................................ 90
9.3
Site Inspections ..................................................................... 91
9.4
Administrative Structure......................................................... 91
9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 91
9.6
Protocol Amendments ........................................................... 92
10. REFERENCES ........................................................................................... 93
LIST OF TABLES
Table 1
Preclinical Safety Factors for MSTT1041A for the Selected 
Dosing Regimen ......................................................................... 39
Table 2
Preclinical Safety Factors for UTTR1147A for the Selected 
Dosing Regimen ......................................................................... 41
Table 3
Guidelines for Management of Patients Who Experience 
Adverse Events........................................................................... 63
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 69
Table 5
Causal Attribution Guidance ....................................................... 70
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 36
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LIST OF APPENDICES
Appendix 1
Schedule of Activities (Inpatients Only)..................................... 100
Appendix 2
Schedule of Activities (Post-Discharge).................................... 106
Appendix 3
Anaphylaxis Precautions........................................................... 109
Appendix 4
National Early Warning Score 2 (NEWS2)................................ 110
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
TO EVALUATE THE SAFETY AND EFFICACY OF 
MSTT1041A OR UTTR1147A IN PATIENTS WITH 
SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
GA42469
VERSION NUMBER:
4
EUDRACT NUMBER:
2020-002713-17
IND NUMBER:
149507
NCT NUMBER:
NCT04386616
TEST PRODUCTS:
MSTT1041A (RO7187807)
UTTR1147A (RO7021610) 
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the CRO. 
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
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13/Protocol GA42469, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF MSTT1041A OR UTTR1147A IN 
PATIENTS WITH SEVERE COVID-19 PNEUMONIA
PROTOCOL NUMBER:
GA42469
VERSION NUMBER:
4
EUDRACT NUMBER:
2020-002713-17
IND NUMBER:
149507
NCT NUMBER:
NCT04386616
TEST PRODUCTS:
MSTT1041A (RO7187807)
UTTR1147A (RO7021610) 
PHASE:
II
INDICATION:
Severe COVID-19 pneumonia
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the efficacy and safety of MSTT1041A compared with placebo and of 
UTTR1147A compared with placebo, in combination with standard of care (SOC), for the 
treatment of 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 MSTT1041A compared 
with placebo and of UTTR1147A compared with placebo, in combination with SOC, on the basis 
of the following endpoint:

Time to recovery, defined as time to score of 1 or 2 on the 7-category ordinal scale 
(whichever occurs first)
The ordinal scale categories are as follows:
1.
Discharged (or “ready for discharge” as evidenced by normal body temperature and 
respiratory rate, and stable oxygen saturation on ambient air or 2 L supplemental oxygen)
2.
Nonintensive care unit (ICU) hospital ward (or “ready for hospital ward”) not requiring 
supplemental oxygen
3.
Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen
4.
ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen 
5.
ICU, requiring intubation and mechanical ventilation 
6.
ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation 
and additional organ support (e.g., vasopressors, renal replacement therapy)
7.
Death
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of MSTT1041A 
compared with placebo and of UTTR1147A compared with placebo, in combination with SOC,
on the basis of the following endpoints:
Protocol Number: 
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• 
Time to improvement of at least 2 categories relative to baseline on a 7-category ordinal 
scale of clinical status 
• 
Time to hospital discharge or “ready for discharge” (as evidenced by normal body 
temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤ 2 L 
supplemental oxygen) 
• 
Duration of supplemental oxygen 
• 
Proportion of patients alive and free of respiratory failure (requiring non-invasive ventilation, 
high-flow oxygen, mechanical ventilation, or ECMO) at Day 28 
• 
Clinical status assessed using a 7-category ordinal scale at Days 14 and 28 
• 
Incidence of invasive mechanical ventilation or ECMO 
• 
Ventilator-free days to Day 28 
• 
Incidence of ICU stay  
• 
Duration of ICU stay 
• 
Time to clinical failure, defined as the time to death, mechanical ventilation, ICU admission, 
or withdrawal of care (whichever occurs first).  For patients entering the study already in 
ICU or on mechanical ventilation, clinical failure is defined as a one category worsening on 
the ordinal scale, withdrawal, or death. 
• 
Mortality rate at Days 14 and 28 
• 
Time to clinical improvement, defined as a National Early Warning Score 2 of ≤ 2 
maintained for 24 hours 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of MSTT1041A 
compared with placebo and of UTTR1147A compared with placebo, in combination with SOC, 
on the basis of the following endpoints: 
• 
Incidence of vasopressor use 
• 
Duration of vasopressor use 
• 
Incidence of starting hemodialysis 
• 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load on Day 15 and 
Day 28  
• 
Proportion of patients with secondary bacterial infections 
Safety Objective 
The safety objective for this study is to evaluate the safety of MSTT1041A compared with 
placebo and of UTTR1147A compared with placebo, in combination with SOC, 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)  
• 
Change from baseline in targeted vital signs, targeted clinical laboratory test results, and 
targeted ECG parameters 
Pharmacokinetic Objectives  
The pharmacokinetic (PK) objective for this study is to characterize the MSTT1041A and 
UTTR1147A PK profiles on the basis of the following endpoints: 
• 
Serum concentration of MSTT1041A at specified timepoints 
• 
Serum concentration of UTTR1147A at specified timepoints 
The exploratory PK objectives for this study are as follows: 
• 
To evaluate potential relationships between drug exposure and the efficacy and safety of 
MSTT1041A and UTTR1147A on the basis of the following endpoints: 
• 
Relationship between serum concentration or PK parameters for MSTT1041A and 
efficacy and safety endpoints 
Protocol Number: 
 Report Number: 
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
Relationship between serum concentration or PK parameters for UTTR1147A and 
efficacy and safety endpoints

To evaluate potential relationships between selected covariates and exposure to 
MSTT1041A or UTTR1147A on the basis of the following endpoint:

Relationship between selected covariates and serum concentration or PK parameters 
for MSTT1041A

Relationship between selected covariates and serum concentration or PK parameters 
for UTTR1147A
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to UTTR1147A 
and MSTT1041A, individually, on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
Exploratory Biomarker Objective 
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to MSTT1041A or UTTR1147A (i.e., predictive biomarkers), are early 
surrogates of efficacy, are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), can provide evidence of MSTT1041A or UTTR1147A activity 
(i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoint:

Relationship between biomarkers in blood and other fluid and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints
Study Design
Description of the Study
Overview of Study Design
This is a Phase II, randomized, double-blind, placebo-controlled, multicenter study to assess the 
efficacy and safety of MSTT1041A compared with placebo and of UTTR1147A compared with 
placebo, in combination with SOC, in patients hospitalized with severe COVID-19 pneumonia.  
Approximately 390 adult hospitalized patients who have been diagnosed with COVID-19 
pneumonia (defined by a positive polymerase chain reaction [PCR] and evidence of pneumonia
by chest X-ray or computed tomography [CT] scan) are expected to be enrolled.
Patients will be randomized after screening at a 2:2:1:1 ratio to receive blinded treatment of 
either MSTT1041A, UTTR1147A, or their matching placebos.  Study treatment will be given in 
combination with SOC as defined by the site, including, but not limited to, anti-virals, 
host-directed therapies, convalescent plasma, low-dose corticosteroids, and supportive care.  
Randomization will be stratified by need for invasive mechanical ventilation (yes vs. no) and 
region.  Enrollment of patients with a need for invasive mechanical ventilation will be capped at 
approximately 25% of the overall study population. 
Patients assigned to the MSTT1041A or UTTR1147A arm will receive one infusion of 
MSTT1041A 700 mg or UTTR1147A 90 g/kg on Day 1, respectively, and patients assigned to 
the placebo arm will receive one infusion of matching placebo.  A second dose of MSTT1041A 
350 mg, UTTR1147A 90 g/kg, or matching placebo will be given on Day 15 if the patient still 
remains hospitalized with a requirement for supplemental oxygen therapy.  For patients who are 
being discharged or transferred to a different care facility prior to Day 60, a discharge visit 
should be performed.  Subsequently, patients will be followed up remotely (via phone or video 
visit), and should return to the clinic for Day 28 and a study completion visit (Day 60) or early 
discontinuation visit, if possible.  Depending on patient findings during the phone/video visit, 
patients may need to be seen in person within 48 hours at the discretion of the investigator.
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 
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investigator’s discretion.  The investigator will record the reasons for screen failure in the 
screening log.
Patients who are eligible to be re-screened will be required to repeat assessments as follows: 

Within the 2-day screening window:  Repeat only the assessments that triggered screen 
failure.

Outside the 2-day screening window: Repeat all assessments.  The consent process does 
not need to be repeated if re-screening is completed within 7 days after completion of initial 
informed consent.
Note:  Historic standard of care test results are acceptable for CT scan or chest X-ray if 
performed within 7 days prior to randomization, and for influenza and SARS-CoV-2 virology if 
performed within 14 days of randomization.
Number of Patients
Approximately 390 adult patients hospitalized with severe COVID-19 pneumonia will be enrolled 
in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Documented informed consent 

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol

Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive 
PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced 
by chest X-ray or CT scan 

For sites at an altitude 5000 feet:  peripheral capillary oxygen saturation (SpO2) 93% or 
partial pressure of oxygen/fraction of inspired oxygen 300 mmHg or requirement for
supplemental oxygen to maintain SpO2 93%

For sites at an altitude 5000 feet:  requirement for supplemental oxygen to maintain SpO2
at an acceptable level per local standard of care

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 95 days after the final dose of study 
drug.  
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential 
may be adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not adequate methods of contraception.  If required per local guidelines or regulations, 
locally recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.
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
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 95 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:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
95 days after the final dose of study drug
Women of childbearing potential must have a negative pregnancy test at screening.

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

In the opinion of the investigator, progression to death is imminent and inevitable within the 
next 24 hours, irrespective of the provision of treatments

Participating in another clinical drug trial

Treatment with investigational therapy (other than for COVID-19) within 5 half-lives or 
30 days (whichever is longer) prior to initiation of study drug 

Use of Janus kinase inhibitor within 30 days or 5 drug elimination half-lives (whichever is 
longer) prior to screening

Have received high-dose systemic corticosteroids (1 mg/kg/day methylprednisolone or 
equivalent) within 72 hours prior to Day 1

Known HIV infection with CD4 200 cells/L or 14% of all lymphocytes

ALT or AST 10upper limit of normal (ULN) detected at screening 

History of anaplastic large-cell lymphoma or mantle-cell lymphoma

History of cancer within the previous 5 years unless it has been adequately treated and 
considered cured or remission-free in the investigator's judgment

Clinical evidence of active or unstable cardiovascular disease (e.g., acute myocardial 
ischemia or decompensated heart failure) as assessed by the investigator

Elevated cardiac troponin indicative of a recent cardiac event or myocarditis/pericarditis, as 
defined below: 
1.
If high-sensitivity immunoassay is available locally:  high-sensitivity troponin (hs-
troponin) I or T ULN (as per local standard for ULN), unless certain additional criteria 
are met, as outlined below:
–
If the local laboratory reports "indeterminate" or "intermediate" hs-troponin results:  
Patients with hs-troponin in the “intermediate” or “indeterminate” range (per local 
laboratory) may be enrolled if an echocardiogram shows normal left ventricular 
ejection fraction (as per local standard for normal, generally 50%55%) without 
evidence of hypokinesis; if an echocardiogram cannot be obtained, clinical 
evaluation excluding myocarditis/pericarditis is acceptable.
–
If the local laboratory does not report "indeterminate" or "intermediate" hs-troponin 
results:  Patients with hs-troponin ULN to 5ULN may be enrolled if an 
echocardiogram shows normal left ventricular ejection fraction (as per local 
standard for normal, generally 50%55%) without evidence of hypokinesis; if an 
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echocardiogram cannot be obtained, clinical evaluation excluding 
myocarditis/pericarditis is acceptable.
2.
If high-sensitivity immunoassay is not available locally:  conventional cardiac troponin I 
or T ULN, (based on local standard for ULN)
–
Patients with screen failure due to conventional troponin ULN may be 
re-screened and enrolled if a repeat conventional troponin is ULN and an 
echocardiogram shows normal left ventricular ejection fraction (as per local 
standard for normal, generally 50%55%) without evidence of hypokinesis; if an 
echocardiogram cannot be obtained, clinical evaluation excluding 
myocarditis/pericarditis is acceptable.

History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion, including complete left bundle branch block, second- or third-degree 
atrioventricular heart block, or evidence of prior myocardial infarction

Sustained prolongation of QT interval corrected through use of Fridericia's formula (QTcF), 
defined as repeated demonstration of QTcF 480 ms (NCI CTCAE Grade 1)
Patients with prolonged QTcF due to a reversible cause (e.g., electrolyte 
abnormalities) may be re-tested after the underlying cause has been corrected.
For patients with a ventricular pacemaker, there should be appropriate correction for 
heart rate and pacing when determining baseline QTcF (as per Chakravarty et 
al. 2015); absolute QTcF values should not exceed 490 ms.

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction, hypertrophic 
cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy), coronary heart 
disease (symptomatic or with ischemia demonstrated by diagnostic testing), or family 
history of sudden unexplained death or long QT syndrome

History of moderate or severe allergic, anaphylactic, or anaphylactoid reactions or 
hypersensitivity to any component of study treatment  
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 statistical analysis or safety 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 10 months.
Investigational Medicinal Products
Test Product (Investigational Drug)

MSTT1041A 700 mg IV on Day 1, and a second dose of 350 mg IV on Day 15 for patients 
remaining hospitalized with a requirement for supplemental oxygen therapy at that time

UTTR1147A 90 g/kg IV on Day 1, and a second dose of 90 g/kg IV on Day 15 for 
patients remaining hospitalized with a requirement for supplemental oxygen therapy at that 
time
Comparator

Placebo for MSTT1041A via IV on Day 1, and a second dose on Day 15 for patients 
remaining hospitalized with a requirement for supplemental oxygen therapy at that time

Placebo for UTTR1147A via IV on Day 1, and a second dose on Day 15 for patients 
remaining hospitalized with a requirement for supplemental oxygen therapy at that time
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Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of MSTT1041A compared 
with placebo and of UTTR1147A compared with placebo, in combination with SOC, on the basis 
of the following endpoint:

Time to recovery, defined as time to score of 1 or 2 on the 7-category ordinal scale 
(whichever occurs first)
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
Time to recovery will be analyzed using the stratified log-rank test, adjusting for 
stratification factors.  The Kaplan-Meier plot, median time to event, and their 95% CI and p-
value from the stratified log-rank test will be presented.  A Cox proportional hazards 
regression model will be used to estimate the hazard ratio comparing MSTT1041A or 
UTTR1147A with placebo, respectively, adjusting for stratification factors.  Hazard ratios 
and 95% CIs will be presented.  In addition, the p-value from unstratified log-rank test, 
unadjusted hazard ratio, and 95% CI will also be presented.  Further details on the primary 
endpoint analysis will be included in the Data Analysis Plan.
Determination of Sample Size  
A total of approximately 390 patients will be randomly allocated in a 2:2:1:1 ratio to receive 
MSTT1041A, UTTR1147A, or their matching placebos.  The sample size provides 
approximately 80% power using a log-rank Chi-square test to detect a 7-day difference between 
treatment groups in time to recovery, defined as time to score of 1 or 2 on the 7-category 
ordinal scale (whichever occurs first), under the following assumptions: median time to 
improvement in the placebo group is 21 days, with 28 days follow-up, and using a one-sided 5% 
alpha.  The minimal detectable difference is expected to be approximately 5.3 days.   
Optional Interim Analyses
Other than the cumulative data review by the Data Monitoring Committee (DMC) for benefit/risk 
assessment, no formal efficacy interim analyses are planned at this time.  The DMC, after 
reviewing unblinded data, may recommend that a formal efficacy interim analysis be performed.  
Furthermore, to adapt to information that may emerge during the course of this study, the 
Sponsor may choose to add a formal interim analysis at the recommendation of the DMC.  
The interim analysis will be conducted by DMC.  The decision to conduct the optional interim 
analysis, along with the rationale, timing, and statistical details for the analysis, will be 
documented in the Sponsor’s trial master file prior to the conduct of the interim analysis.  The 
DMC Charter will be updated to document potential recommendations the DMC can make as a 
result of the analysis (e.g., stop the study for positive efficacy, stop the study for futility).
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
ARDS
acute respiratory distress syndrome
AUC
area under the concentration–time curve
AUC0-28 d
area under the concentration–time curve from 0 to 
28 days
BNP
brain natriuretic peptide
Cmax
maximum concentration observed
COPD
chronic obstructive pulmonary disease
CoV
coronavirus
COVID-19
coronavirus disease 2019
CRO
contract research organization
CRP
C-reactive protein
CRSwNP
chronic rhinosinusitis with nasal polyps
CT
computed tomography
DAP
Data Analysis Plan
DMC
Data Monitoring Committee
EC
Ethics Committee
eCRF
electronic Case Report Form
ECHO
echocardiogram
ECMO
extracorporeal membrane oxygenation
EDC
electronic data capture
Fc
fragment crystallizable
FDA
Food and Drug Administration
FiO2
fraction of inspired oxygen
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
hs-troponin
high-sensitivity troponin
IBD
inflammatory bowel disease
ICH
International Council for Harmonisation
ICU
intensive care unit
IL
interleukin
IL-1RAcP
interleukin-1 receptor accessory protein
IL-22BP
IL-22 binding protein
IL-22Fc
interleukin-22 immunoglobulin fusion protein
IL-22R
interleukin-22 receptor
IMP
investigational medicinal product
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Abbreviation
Definition
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRR
infusion-related reaction
IxRS
interactive voice or web-based response system
JAK
Janus kinase
LPS
lipopolysaccharide
MAD
multiple ascending dose
mITT
modified intent-to-treat
MOF
multiple organ failure
ms
millisecond
MTD
maximum tolerated dose
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0
NEWS2
National Early Warning Score 2
NOAEL
no-observed-adverse-effect level
NT-proBNP
N-terminal pro-brain natriuretic peptide
PaO2
partial pressure of oxygen
PCR
polymerase chain reaction
PEEP
positive-end expiratory pressure
PD
pharmacodynamic
PK
pharmacokinetic
PRO
patient-reported outcome
Q2W
every 2 weeks
Q4W
every 4 weeks
QTcF
QT interval corrected through use of Fridericia's 
formula
SAD
single ascending dose
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SOC
standard of care
SpO2
peripheral capillary oxygen saturation 
sST2
soluble form of ST2
UC
ulcerative colitis 
ULN
upper limit of normal
WGS
whole genome sequencing
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1.
BACKGROUND
1.1
BACKGROUND ON COVID-19 PNEUMONIA 
Coronaviruses (CoVs) are positive-stranded RNA viruses that are important human and 
animal pathogens and usually cause mild to moderate respiratory illnesses such as the 
common cold.  In the past two decades, Middle East respiratory syndrome coronavirus 
(MERSCoV) and severe acute respiratory syndrome coronavirus (SARS-CoV-) emerged 
from animal reservoirs to cause more serious respiratory illness leading to death.  A third 
novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 
emerged in China at the end of 2019, causing the coronavirus disease 2019 
(COVID-19).  The COVID-19 outbreak was categorized as a pandemic by the WHO on 
March 11, 2020, and globally more than 4 million confirmed cases have been reported 
(WHO 2020a).
The majority of patients with COVID-19 present with symptoms ranging from 
asymptomatic transmission via respiratory droplets to mild disease with fever, cough, 
and shortness of breath that resolve with supportive care.  However, approximately 20% 
of patients develop severe disease requiring hospitalization, and up to 10% of the total 
infected population require intensive care unit (ICU) admission.  The dominant finding in 
patients critically ill with COVID-19 is interstitial pneumonia, which progresses to acute 
respiratory distress syndrome (ARDS) and hypoxemic respiratory failure.  Complications 
of COVID-19 include acute kidney injury, elevated liver enzymes, pericarditis, multiple 
organ failure (MOF), and death (WHO 2020b), with in-hospital mortality rates of 
approximately 25% (Cao et al. 2020; Zhou et al. 2020).  Risk factors for progression to 
severe COVID-19 include advanced age, cardiovascular disease, diabetes mellitus, 
chronic lung disease, and chronic kidney disease (Liang et al. 2020; Wu et al. 2020; 
Zhou et al. 2020).  
ARDS, which is characterized by increased epithelial and endothelial permeability 
leading to alveolar edema, has been observed in 16%42% of patients with severe 
COVID-19 (Guan et al. 2020; Huang et al. 2020; Wu et al. 2020; Zhou et al. 2020).  
Typical imaging findings are consistent with viral pneumonia, showing rapidly worsening 
bilateral pulmonary opacities and ground glass opacification with or without consolidation 
(Bhatraju et al. 2020).  Early phase ARDS with epithelial desquamation, hyaline 
membrane formation, and edema was seen in lung pathology in a patient who died of 
COVID-19 (Xu et al. 2020).  Hyperinflammatory responses, including increased 
pro-inflammatory cytokines (interleukin [IL]-6) and other inflammatory markers (ferritin 
and D-dimer) are associated with increased mortality in patients with COVID-19 (Zhou et 
al. 2020).  Approximately 10% of patients with COVID-19 develop secondary bacterial 
infections, and 50% of those patients have died (Zhou et al. 2020). 
COVID-19 is a serious public health risk.  To date, limited anti-viral and host-directed 
therapies have been shown to be effective for treating COVID-19 and there is no 
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vaccine.  There is a significant unmet medical need for novel therapies to treat the 
complications of COVID-19 pneumonia.
1.2
BACKGROUND ON MSTT1041A (ANTI-ST2)
MSTT1041A (RO7187807, also known as astegolimab) is a fully human, IgG2 
monoclonal antibody that binds with high affinity to ST2 (IL-33 receptor, also referred to 
as IL-1 receptor-like 1 [IL1RL1]), thereby blocking the signaling of IL-33, an inflammatory 
cytokine of the IL-1 family and member of the “alarmin” class of molecules.  MSTT1041A 
has subnanomolar affinity and potency, is active in whole blood, and lacks agonistic 
activity.  
1.2.1
Background on Interleukin-33/ST2
IL-33 is released from epithelial cells in response to allergens, irritants, and infection in 
the various tissues and organs, including the lung and skin (Cevikbas and Steinhoff
2012; Lambrecht and Hammad 2015).  High levels of IL-33 are found in stromal cells, 
particularly at barrier surfaces such as the lung and gastrointestinal (GI) tract.  Within the 
lung, IL-33 is detected in multiple cell types, including epithelial cells, endothelial cells, 
and fibroblasts (Liew et al. 2016).  IL-33 bioavailability is tightly regulated, and under 
homeostatic conditions, this protein is sequestered in the nuclei of these cells.  Cellular 
damage, caused by injury, mechanical stress, or death, leads to the release of bioactive 
IL-33 into circulation, where it initiates and propagates innate and adaptive immune 
responses.  Environmental triggers that promote IL-33 release include allergens, 
irritants, and viral and bacterial infections.  The receptor for IL-33, ST2, is expressed on 
multiple cell types implicated in pulmonary inflammation and disease, including mast 
cells, eosinophils, basophils, innate lymphoid cells, T lymphocytes, macrophages, and 
endothelial cells.  Akin to other IL-1 cytokines, IL-33 activates cells by binding to its 
cognate receptor, which allows for association with interleukin-1 receptor 
accessory protein (IL-1RAcP), the shared receptor for this family.  The formation of the 
IL-33ST2IL-1RAcP receptor complex in turn activates the MyD88 signalosome to 
induce the transcription of genes with pro-inflammatory functions. 
Given the diverse nature of signals that lead to IL-33 release and the wide range of 
target cells, IL-33 is implicated in a number of pathological pathways.  IL-33 release can 
trigger acute exacerbations and/or disease progression in asthma, chronic obstructive 
pulmonary disease (COPD), idiopathic pulmonary fibrosis, ARDS, and atopic dermatitis.  
IL-33 activity is elevated following viral infections, and inhibition of this pathway reduces 
virus-induced exacerbations in rodent models of asthma and COPD (Werder et al. 2018; 
Ravanetti et al. 2019).  ST2- or IL-33deficient mice exposed to cigarette smoke have 
decreased inflammatory responses in response to subsequent respiratory viral infections 
without compromising anti-viral host defense (Kearly et al. 2015).  The absence of the 
IL-33 pathway significantly reduced viral induced leukocyte migration into the lung, 
inflammatory cytokine expression, and subsequent pulmonary pathology.  Furthermore, 
IL-33 is elevated in the serum of patients with ARDS and pulmonary etiology (Lin et al.
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2016).  Blockade of IL-33 activity, either in preventative or therapeutic treatment 
regimens, has demonstrated efficacy in reducing inflammation and ameliorating disease 
preclinical models of ARDS (Yin et al. 2011; Martin-Gonzalez et al. 2013; Lin et al. 2016; 
Liang et al. 2018).  Inhibition of this pathway effectively reduced induction of 
pro-inflammatory cytokines, including IL-6 and tumor necrosis factor-, inflammatory
cell infiltrates, and protected the lung tissues from lipopolysaccharide (LPS) or 
bleomycin-induced injury. For these reasons, anti-ST2 is hypothesized to confer clinical 
benefit to patients with COVID-19 pneumonia by limiting excessive inflammatory 
sequelae while preserving anti-viral responses.
1.2.2
Summary of Nonclinical Studies
The toxicology program was designed to support IV and SC administration of 
MSTT1041A in clinical studies.  MSTT1041A has been shown to have a favorable 
overall nonclinical safety profile.  In 28-day and 6-month repeat–dose toxicity studies, no 
adverse effects were observed in cynomolgus monkeys following biweekly IV or SC 
administration at doses up to 300 mg/kg (the highest dose tested).  There were no 
adverse findings at the injection sites as evidenced by macroscopic and microscopic 
analysis following SC administration at doses up to 300 mg/kg.  In an ex vivo human 
tissue cross reactivity study, biotin-labeled MSTT1041A staining was not observed in 
any human tissues evaluated by immunohistochemistry.
Refer to the RO7187807 Investigator's Brochure for details on nonclinical studies.
1.2.3
Summary of Clinical Studies
MSTT1041A has been investigated in four completed studies, with three Phase I studies 
(single ascending dose [SAD] AMG Study 20110235, multiple ascending dose [MAD] 
AMG Study 20110236, and single-dose pharmacokinetic (PK) AMG Study 2011236 in 
subjects of Japanese heritage, and a Phase IIb study in patients with asthma 
(GB39242 [ZENYATTA]).  Additionally, a Phase II study in patients with atopic dermatitis 
(Study GS40965 [ZARNIE]) and an investigator-initiated study in patients with COPD 
(Study GB40568) are ongoing.
The pharmacokinetics of MSTT1041A were characterized after single and multiple 
(SC and IV) doses in two studies (AMG Studies 20110235 and 20110236).  
 
  Overall 
MSTT1041A was well tolerated in each of these healthy volunteer studies.  There were 
no serious adverse events, deaths, or adverse events that led to treatment or study 
discontinuation.
In the Phase IIb Study GB39242 in patients with severe asthma, the primary endpoint 
(reduction over placebo in incidence of asthma exacerbations at Week 52) was met for 
the MSTT1041A 490-mg dose.  For the secondary efficacy endpoints, a nominally 
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significant benefit over placebo in time to first asthma exacerbation were seen with the 
highest MSTT1041A dose (490 mg).  A total of approximately 451 patients and 
109 healthy subjects have been exposed to at least one dose of MSTT1041A.  
MSTT1041A has been generally well tolerated with adverse events being mostly 
non-serious and of mild to moderate intensity.  Adverse events rates were generally 
similar between the three treatment arms and the placebo arm.  Adverse events leading 
to withdrawal have generally occurred at a rate similar to what would be expected for 
clinical trials in the studies’ respective indications.  
 
 
  None of the incidences of potential MACE were 
considered related to the study drug.  No clinically meaningful changes were observed in 
laboratory parameters, vital signs, or ECG results in the MSTT1041A treatment groups.  
To date, there are no identified risks associated with MSTT1041A. 
Refer to the RO7187807 Investigator's Brochure for details on clinical studies.
1.3
BACKGROUND ON UTTR1147A (IL-22FC)
UTTR1147A (RO7021610) is a human IL-22 fusion protein in which the cytokine IL-22 is 
linked with the fragment crystallizable (Fc) portion of IgG4 to improve the cytokine’s PK 
characteristics.  The Fc portion of the fusion protein incorporates a mutation that 
minimizes the potential for Fc effector function.
1.3.1
Background on Interleukin-22
IL-22 belongs to the IL-10 cytokine family (Ouyang et al. 2019) and binds specifically to 
the IL-22 receptor (IL-22R) heterodimer.  IL-22R is expressed on a variety of epithelial 
and stromal tissues, including lung ciliated epithelial and endothelial cells, GI tract 
epithelium, epidermal keratinocytes, liver hepatocytes, pancreatic acinar epithelium, and 
renal tubular epithelium. IL-22 binding results in activation of receptor-associated 
Jak1/Tyk2 kinases and the transcription factor STAT3 (Dudakov et al, 2015).  IL-22
modulates innate immunity through multiple different regenerative and protective 
mechanisms in epithelial tissues, including the GI tract mucosal epithelium, epidermal 
keratinocytes, and lung epithelial cells (Whittington et al. 2004; Wolk et al. 2004; Aujla et 
al. 2008; Sugimoto et al. 2008; Zheng et al. 2008; Hoegl et al. 2011; Pociask et al. 
2013).  Nonclinical studies have demonstrated that IL-22 promotes endothelial and 
epithelial proliferation, barrier function, and anti-microbial host defense (Ouyang and 
Valdez 2008). Specifically, IL-22 signaling has been shown to increase lung epithelial 
cell proliferation and wound healing (Barthelemy et al. 2017; Nguyen et al. 2020), to 
decrease apoptosis of epithelial and endothelial cells in acute lung injury models (Ren et 
al. 2017; Wu et al. 2017), and to increase expression of tight junction proteins 
(Barthelemy et al. 2017; Abood et al. 2019; Hebert et al. 2020).  IL-22 directly increases 
endothelial barrier function by stabilizing intracellular junction proteins, reducing 
endothelial permeability following LPS, reducing apoptosis, and increasing proliferation 
(He et al. 2016; Hu et al. 2018; Wu et al. 2018).  IL-22 also plays a role in protecting and 
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repairing damage to lung epithelial tissue caused by high-pressure ventilation-induced 
damage (Hoegl et al. 2011) and angiotensin II-induced acute lung injury and edema (Wu 
et al. 2017).  IL-22 decreases levels of cytokines (IL-6, interferon-, IL-17A) and 
chemokines (MCP-1, MIP-1α/β) in bronchoalveolar lavage, which correlates with 
decreased numbers of lung neutrophils and lymphocytes and reduced alveolitis in viral
infection models (Abood et al. 2019; Hebert et al. 2020).  Moreover, treatment with post-
viral murine IL-22 immunoglobulin fusion protein (IL-22Fc), a fusion protein with 
prolonged half-life in vivo, promotes repair of the lung epithelial barrier, reduces 
inflammation, and mitigates the pathological consequences of bacterial superinfections 
(Barthelemy et al. 2018). 
In acute lung injury murine models, IL-22 was shown to be protective against multiple 
viral and bacterial respiratory pathogens and enhanced recovery (Ivanov et al. 2013; 
Pociask et al. 2013; Trevejo-Nunez et al. 2016; Barthelemy et al. 2018; Abood et al. 
2019; Hebert et al. 2020).  IL-22 signaling increases expression of anti-microbial 
proteins, including -defensin and Reg3(the murine homolog of the human Reg3a
gene) (Pichavant et al. 2015; Ito et al. 2017).  In a murine model of bacterial 
superinfection post-influenza, treatment with murine IL-22Fc following viral infection 
increased pulmonary barrier function and decreased inflammation and systemic 
dissemination of bacteria (Barthelemy et al. 2018).  Pretreatment of small intestinal 
epithelial cells with porcine IL-22 prior to infection with swine enteric alpha CoVs showed 
dose-dependent inhibition of viral infection (Xue et al. 2017).  IL-22 treatment of lung 
epithelial cells induces anti-microbial protein production such as Reg3γ (Pichavant et al. 
2015; Ito et al. 2017) and protects against influenza virus-bacterial co-infection (Ivanov 
et al. 2013; Abood et al. 2019) and coronavirus infection (Xue et al. 2017).  
IL-22 induces expression of mucin genes and activation of goblet cells, increasing 
mucus production in the gut, which in turn may contribute to decreased intestinal 
inflammation (Sugimoto et al. 2008, Turner et al. 2013).  This raises the question 
whether goblet cells also promote increased mucus production in the lung, which may 
not be beneficial.  However, internal and external evidence to date suggests that IL-22 
does not promote increased mucin production in the airways.  Different types of mucins 
are expressed in GI and respiratory mucosa.  Lung secretory cells secrete MUC5B and 
MUC5AC, which are important for mucociliary clearance of pathogens.  Studies 
conducted by the Sponsor showed that IL-22Fc treatment of primary human bronchial 
epithelial cells grown at air-liquid interface for 24 hours did not significantly increase 
expression of mucin or secretory cell genes nor alter the ratio of the MUC5AC:MUC5B
gene expression, generally considered a measure of pathogenic mucus.  Similar results 
were seen in the lungs of mice administered murine IL-22Fc intranasally or intravenously
after 24 hours.  In addition, in mice were exposed to cigarette smoke for 8 weeks and 
then treated with IL-22Fc for a week prior to infection with influenza and a week 
post-infection, at which time no lung goblet cell hyperplasia was seen by periodic 
acid-Schiff/Alcian Blue histology staining (unpublished data).  Moreover, neither 
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increased mucus nor lung goblet cell hyperplasia have been reported following IL-22 
treatment in respiratory infection studies (Barthelemy et al. 2018).
Although IL-22 levels in COVID-19 have not yet been studied, IL-22 levels were shown 
to be reduced in the bronchoalveolar lavage of patients with ARDS compared with 
post-operative patients on mechanical ventilation without lung injury (Whittington et al. 
2004). 
1.3.2
Summary of Nonclinical Studies
The toxicology program in rats, cynomolgus monkeys, and minipigs identified the 
potential clinical safety risks of UTTR1147A.  
 
 
 
 
 
 The nonclinical PK profile observed for UTTR1147A in rats, 
cynomolgus monkeys, and minipigs is consistent with that expected for a cytokine fusion 
protein with a humanized IgG4 Fc, demonstrating that fusion of recombinant IL-22 to an 
antibody Fc fragment extends the half-life of IL-22, leading to improved IL-22 exposure 
(Lee et al. 2018).
1.3.3
Summary of Clinical Studies
In a Phase Ia, first-in-human, placebo-controlled SAD study in 68 healthy volunteers 
(Study GA29468), UTTR1147A demonstrated linear and dose-proportional 
pharmacokinetics and was adequately tolerated following IV doses of up to 90 g/kg 
(Rothenberg et al. 2019).  The most common adverse events were on-target 
dermatologic events that were monitorable, manageable with topical emollients, and 
reversible.  Single IV doses of UTTR1147A at 30 g/kg and above produced 
dose-related dermatologic effects such as dry scaly lips, dry skin, erythema, pruritus, 
and skin discomfort, all of which appeared within the first month of dosing and resolved 
within 1 week to 3 months after onset.  No clinically significant changes or findings were 
noted from vital sign measurements, 12-lead ECGs, or body weight measurements.  All 
other abnormal clinical laboratory results reported as treatment-emergent adverse 
events were assessed by the investigator as mild or moderate in intensity and not 
related to UTTR1147A.
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1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Up to approximately 20% of patients with COVID-19 have severe disease, with 25% of 
those patients requiring ICU admission.  Patients with severe COVID-19 develop an 
interstitial pneumonia that progresses to ARDS and hypoxic respiratory failure requiring 
respiratory support, MOF, and death (Guan et al. 2020, Zhou et al. 2020, Wu et al. 2020, 
Ma et al. 2020, WHO 2020b). To date there are no vaccines, anti-viral therapies, or 
host-directed therapies shown in randomized controlled trials to be effective in 
preventing or reducing the risk of progression of COVID-19.  There remains a significant 
unmet need to develop novel therapies to treat patients with severe COVID-19 
pneumonia. 
1.4.1
MSTT1041A (Anti-ST2)
MSTT1041A, an anti-ST2 monoclonal antibody that acts as a pure competitive 
antagonist to block IL-33 signaling, is hypothesized to have the potential to treat severe 
COVID-19 pneumonia by reducing the maladaptive hyper-inflammatory responses to the 
virus, reducing disease progression to ARDS and promoting convalescence, without 
inhibiting the development of protective adaptive immunity and viral clearance (Kearley 
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et al. 2015).  Nonclinical and clinical studies have demonstrated that MSTT1041A has a 
well-tolerated safety profile and potential for efficacy to treat severe COVID-19 
pneumonia, supporting further clinical development. To date, there are no identified 
risks associated with MSTT1041A.  Although not seen in the four completed and two 
ongoing clinical trials to date, as with all protein therapies, there is the possibility that 
administration of MSTT1041A may lead to the development of anti-MSTT1041A 
antibodies, which could lead to adverse events and/or decreased exposure. 
 
 
  Like all monoclonal antibodies, MSTT1041A carries a 
potential risk of hypersensitivity reactions and anaphylaxis/hypersensitivity-like reactions.  
The mechanism of action of MSTT1041A suggests the possibility of decreased Th2 
response to certain infections, particularly helminthic infections. 
 
 
Finally, in mice models of cardiovascular disease, a protective role for IL-33/ST2 has 
been described, and ST2-/- mice had more left ventricular hypertrophy, more fibrosis, and 
impaired survival relative to their wild-type littermates in an experimentally induced acute 
left-ventricular pressure overload model.  However, the translatability of those findings to 
humans remains unknown, 
 
 
 
 
 
Combined, nonclinical and clinical studies have demonstrated that MSTT1041A has a 
well-tolerated safety profile and strong theoretical rationale supporting its potential 
benefit in COVID-19 pneumonia, supporting further clinical development in this 
indication.  The potential risks for MSTT1041A will be mitigated by stringent 
pre-enrollment screening for patients with evidence of clinically apparent or insipient 
cardiovascular disease, including cardiac enzyme elevations that are caused by 
COVID-19, which have been described in 8%12% of the hospitalized patients with 
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severe COVID-19 pneumonia (Lippi and Plebani 2020).  In addition, cardiac enzymes 
will be monitored closely while patients are hospitalized, and cardiovascular 
complications will be subject to expedited reporting requirements.
1.4.2
UTTR1147A (IL-22Fc)
Based on non-clinical studies, UTTR1147A, an IL-22 fusion protein, has the potential to 
treat severe COVID-19 pneumonia by increasing epithelial and endothelial integrity, 
increasing epithelial regeneration, and preventing secondary bacterial infections 
(Ivanov et al. 2013; Pociask et al. 2013; Trevejo-Nunez et al. 2016; Barthelemy et al. 
2018; Abood et al. 2019; Hebert et al. 2020).  
Clinical studies have demonstrated that UTTR1147A has an adequately tolerated safety 
profile. At the dose proposed in this study (90g/kg IV Q2W for two doses), the most 
common adverse events associated with UTTR1147A were dermatologic effects, 
including pruritus, dry lips, erythema, and skin discomfort.  Consequently, dermatologic 
reactions are considered an identified risk of UTTR1147A.  These are expected 
on-target effects and have been non-serious and manageable with topical emollients 
and moisturizers, monitorable, and reversible.
 
 
 
 
  However, the overall incidence of treatment-emergent 
ADAs in the Phase Ia study was low and neutralizing antibodies have not been detected 
to date.  Moreover, in patients with non-infected diabetic foot ulcers who received 
multiple doses of UTTR1147A subcutaneously, there was no increased infection rate 
between treated and placebo patients and no opportunistic or fungal infections were 
reported.  
Finally, based on the ability to stimulate mucins in the GI tract, UTTR1147A treatment 
may induce mucus hypersecretion in the lung.  To date, lung goblet cell hyperplasia has 
not been reported following IL-22 treatment in studies of the respiratory tract 
(Barthelemy et al. 2018)
 
  
 
 
 
 Development of UTTR1147A as a therapeutic for 
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patients with severe COVID-19 pneumonia is further supported by 
 
 
 
The identified and potential risks of 
UTTR1147A will be mitigated by excluding patients with a history of active malignancy, 
by restricting the duration of UTTR1147A exposure (all patients will receive one dose 
and only patients who are higher risk due to remaining hospitalized with a requirement 
for oxygen support will receive a second dose of study drug). 
Furthermore, the study will include safety monitoring, including a Data Monitoring 
Committee comprised of external experts in COVID-19 pneumonia that will frequently
monitor adverse events including dermatologic reactions, use of supplemental oxygen, 
ventilation use, and death between the treatment and placebo arms.  The DMC can 
recommend modifications to the study, including the need for additional safety 
monitoring and measures, dose modification, discontinuation of a treatment arm, and 
halting or stopping the trial if the risk/benefit profile is no longer favorable.
In summary, there are currently no drugs that have demonstrated efficacy in patients 
with COVID-19 pneumonia in adequate and well-controlled studies.  Given the scientific 
rationale provided above, UTTR1147A in combination with standard of care (SOC) 
treatment has the potential to improve morbidity and mortality in hospitalized patients 
with severe COVID-19 pneumonia.  Safety data from randomized controlled trials 
collected for UTTR1147A to date demonstrate that the drug is well tolerated within the 
described exposure limits.  The dermatologic events that have been observed can be 
closely monitored in a hospital setting.  Given that severe COVID-19 pneumonia is 
considered an acute life-threatening event without proven therapy, the potential benefit 
of UTTR1147A counterbalances the risks associated with 1 to 2 doses of UTTR1147A, 
thereby justifying the need for a randomized, placebo-controlled study.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of MSTT1041A compared with placebo 
and of UTTR1147A compared with placebo, in combination with SOC, for the treatment 
of 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 MSTT1041A 
compared with placebo and of UTTR1147A compared with placebo, in combination with 
SOC, on the basis of the following endpoint:

Time to recovery, defined as time to score of 1 or 2 on the 7-category ordinal scale 
(whichever occurs first)
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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 extracorporeal membrane oxygenation (ECMO) or mechanical 
ventilation and additional organ support (e.g., vasopressors, renal replacement 
therapy) 
7. 
Death 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of MSTT1041A 
compared with placebo and of UTTR1147A compared with placebo, in combination with 
SOC, on the basis of the following endpoints: 
• 
Time to improvement of at least 2 categories relative to baseline on a 7-category 
ordinal scale of clinical status 
• 
Time to hospital discharge or “ready for discharge” (as evidenced by normal body 
temperature and respiratory rate, and stable oxygen saturation on ambient air or 
≤ 2 L supplemental oxygen) 
• 
Duration of supplemental oxygen 
• 
Proportion of patients alive and free of respiratory failure (requiring non-invasive 
ventilation, high-flow oxygen, mechanical ventilation, or ECMO) at Day 28 
• 
Clinical status assessed using a 7-category ordinal scale at Days 14 and 28 
• 
Incidence of invasive mechanical ventilation or ECMO 
• 
Ventilator-free days to Day 28 
• 
Incidence of ICU stay  
• 
Duration of ICU stay 
• 
Time to clinical failure, defined as the time to death, mechanical ventilation, ICU 
admission, or withdrawal of care (whichever occurs first).  For patients entering the 
study already in ICU or on mechanical ventilation, clinical failure is defined as a 
one category worsening on the ordinal scale, withdrawal, or death. 
• 
Mortality rate at Days 14 and 28 
• 
Time to clinical improvement, defined as a National Early Warning Score 2 
(NEWS2) of ≤ 2 maintained for 24 hours 
 
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2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of 
MSTT1041A compared with placebo and of UTTR1147A compared with placebo, in 
combination with SOC, on the basis of the following endpoints:

Incidence of vasopressor use

Duration of vasopressor use

Incidence of starting hemodialysis

SARS-CoV-2 viral load on Day 15 and Day 28

Proportion of patients with secondary bacterial infections
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of MSTT1041A compared 
with placebo and of UTTR1147A compared with placebo, in combination with SOC, 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) 

Change from baseline in targeted vital signs, targeted clinical laboratory test results, 
and targeted ECG parameters
2.3
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to characterize the MSTT1041A and UTTR1147A PK 
profiles on the basis of the following endpoints:

Serum concentration of MSTT1041A at specified timepoints

Serum concentration of UTTR1147A at specified timepoints
The exploratory PK objectives for this study are as follows:

To evaluate potential relationships between drug exposure and the efficacy and 
safety of MSTT1041A and UTTR1147A on the basis of the following endpoints:
–
Relationship between serum concentration or PK parameters for MSTT1041A 
and efficacy and safety endpoints
–
Relationship between serum concentration or PK parameters for UTTR1147A 
and efficacy and safety endpoints

To evaluate potential relationships between selected covariates and exposure to 
MSTT1041A or UTTR1147A on the basis of the following endpoint:
–
Relationship between selected covariates and serum concentration or PK 
parameters for MSTT1041A
–
Relationship between selected covariates and serum concentration or PK 
parameters for UTTR1147A
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2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
UTTR1147A and MSTT1041A, individually, on the basis of the following endpoint:

Prevalence of ADAs at baseline and incidence of ADAs during the study
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
2.5
EXPLORATORY BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to MSTT1041A or UTTR1147A 
(i.e., predictive biomarkers), are early surrogates of efficacy, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), can provide 
evidence of MSTT1041A or UTTR1147A activity (i.e., pharmacodynamic [PD]
biomarkers), or can increase the knowledge and understanding of disease biology and 
drug safety, on the basis of the following endpoint:

Relationship between biomarkers in blood and other fluid (listed in Section 4.5.6) 
and efficacy, safety, PK, immunogenicity, or other biomarker endpoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase II, randomized, double-blind, placebo-controlled, multicenter study to 
assess the efficacy and safety of MSTT1041A compared with placebo and of 
UTTR1147A compared with placebo, in combination with SOC, in patients hospitalized 
with severe COVID-19 pneumonia.  Approximately 390 adult hospitalized patients who 
have been diagnosed with COVID-19 pneumonia (defined by a positive polymerase 
chain reaction [PCR] and evidence of pneumonia by chest X-ray or computed 
tomography [CT] scan) are expected to be enrolled.
Patients will be randomized after screening at a 2:2:1:1 ratio to receive blinded treatment 
of either MSTT1041A, UTTR1147A, or their matching placebos.  Study treatment will be 
given in combination with SOC as defined by the site, including, but not limited to,
anti-virals, host-directed therapies, convalescent plasma, low-dose corticosteroids, and 
supportive care.  Randomization will be stratified by need for invasive mechanical 
ventilation (yes vs. no) and region.  Enrollment of patients with a need for invasive
mechanical ventilation will be capped at approximately 25% of the overall study 
population.
Patients assigned to the MSTT1041A or UTTR1147A arm will receive one infusion of 
MSTT1041A 700 mg or UTTR1147A 90 g/kg on Day 1, respectively, and patients 
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assigned to the placebo arm will receive one infusion of matching placebo (see 
Section 4.3).  A second dose of MSTT1041A 350 mg, UTTR1147A 90 g/kg, or 
matching placebo will be given on Day 15 if the patient still remains hospitalized with a 
requirement for supplemental oxygen therapy.  For patients who are being discharged or 
transferred to a different care facility prior to Day 60, a discharge visit should be 
performed. Subsequently, patients will be followed up remotely (via phone or video 
visit), and should return to the clinic for Day 28 and a study completion visit (Day 60) or 
early discontinuation visit, if possible. Depending on patient findings during the 
phone/video visit, patients may need to be seen in person within 48 hours at the 
discretion of the investigator.
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 (see Section 4.5.1).
Patients who are eligible to be re-screened will be required to repeat assessments as 
follows:

Within the 2-day screening window: Repeat only the assessments that triggered 
screen failure.

Outside the 2-day screening window: Repeat all assessments. The consent 
process does not need to be repeated if re-screening is completed within 7 days 
after completion of initial informed consent.
Note: Historic standard of care test results are acceptable for CT scan or chest X-ray if 
performed within 7 days prior to randomization, and for influenza and SARS-CoV-2
virology if performed within 14 days of randomization (see Appendix 1).
Figure 1 presents an overview of the study design.  A schedule of activities for patients
in the hospital is provided in Appendix 1.  A schedule of activities for patients who will be 
discharged from the hospital or transferred to a different care facility prior to Day 60 is 
provided in Appendix 2. 
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Figure 1
Study Schema
PBO placebo; SOCstandard of care.
Screening period will be up to 2 days.
A second dose of study drug will be given on Day 15 if the patient remains hospitalized with a 
requirement for supplemental oxygen therapy, unless the patient meets the study drug 
discontinuation criteria (see Section 4.6.1).
3.1.2
Data Monitoring Committee 
A DMC will review unblinded safety and efficacy data to assess whether treatment with 
MSTT1041A or UTTR1147A is associated with toxicity or worsening disease.  Members 
of the DMC will include representatives from Clinical Science and Drug Safety who are 
not directly involved in the study and representatives from Biostatistics and Statistical 
Programming and Analysis and may invite representatives from other functional areas 
on an ad-hoc basis when additional expertise is required (e.g., Clinical Pharmacology, 
Research).  The DMC will also include at least two external experts in the field, and 
additional experts may be added during the course of the study.  
The DMC will review cumulative safety data through at least Day 14 after the first 
30 patients have been enrolled or after the first 30 days from the first patient enrolled 
(whichever occurs first).  Subsequently, the DMC will review cumulative safety and 
efficacy data after each additional 75 patients have been enrolled or 3 months 
(whichever occurs first); for example, once approximately 75, 150, 225, and 300 patients 
have enrolled.  Ad hoc meetings may be held at the request of the DMC or Sponsor at 
any time to address potential safety concerns.  The DMC will have access to all 
available data at each review to perform an overall benefit/risk assessment.  Data to be 
reviewed will include demographics, concomitant medications, study drug administration, 
ECGs, laboratory data, adverse events, serious adverse events, adverse events of 
special interest, and deaths. 
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At the time of each review, the DMC can make one of the following recommendations:  
the trial continues as planned, additional analyses need to be performed, enrollment is 
held pending further safety evaluations or other study modifications, the MSTT1041A or 
UTTR1147A arm of the trial is stopped, or the trial is stopped.  Final decisions will rest 
with the Sponsor's study team.
Any outcomes of these reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Board (IRB) or Ethics Committee (EC).
A detailed description of the procedures, data flow, and meeting schedule will be 
provided in the DMC Charter.
3.1.3
Safety Monitoring Committee
An SMC consisting of internal team members will review blinded safety and efficacy data 
to assess whether treatment with MSTT1041A or UTTR1147A is associated with toxicity 
or worsening disease.  The SMC will meet to review safety and efficacy data at least as 
frequently as the DMC.  The SMC may also meet to assess the significance of other 
adverse events or safety findings at any time following a request from either an 
investigator or the Sponsor.  
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 statistical analysis or safety 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 10 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for MSTT1041A (Anti-ST2) Dose and Schedule
For the MSTT1041A arm, 700 mg IV will be administered for the first dose.  For patients 
who remain in hospital and on oxygen 2 weeks after the first dose (Day 15), a second 
dose of 350 mg IV will be administered.
The proposed dose is based on clinical experience in healthy subjects (safety, 
pharmacokinetics, and pharmacodynamics) observed in the SAD study (AMG Study 
20110235) and in the MAD study (AMG Study 20110236), as well as in the Phase IIb 
study GB39242 in patients with severe asthma (safety, efficacy, pharmacokinetics, and 
pharmacodynamics).  In Study 20110235, at least 3 subjects (per SC cohort) or at least 
6 subjects (per IV cohort) received SC doses of MSTT1041A up to 420 mg or IV doses 
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of MSTT1041A up to 700 mg.  In Study 20110236, at least 6 subjects per cohort 
received multiple SC or IV doses of MSTT1041A, Q2W or every 4 weeks (Q4W), up to 
700 mg IV.  
A small number of patients with mild asthma (n6) or chronic rhinosinusitis with nasal 
polyps (CRSwNP; n1) were also enrolled in Phase I studies.  MSTT1041A was well 
tolerated in Phase I studies, with no significant safety issues identified, including at the 
highest doses (700 mg IV of MSTT1041A administered as a single dose or Q4W for 
three doses).  
 
In Study GB39242, 502 patients with severe asthma were randomized in a 1:1:1:1 ratio 
to receive 1 of 3 doses of MSTT1041A (70 mg, 210 mg, or 490 mg SC) or placebo Q4W 
for 52 weeks, for a total of 13 doses.  In this study, the 490 mg Q4W dose showed a 
significant reduction over placebo in incidence of asthma exacerbations and met the 
primary endpoint.  MSTT1041A was well tolerated.  Rates of adverse events were 
generally similar between the three treatment arms and the placebo arm, and were 
mostly mild or moderate in intensity. 
 
 
 
The available evidence suggests that circulating levels of the secreted soluble form of 
ST2 (sST2) are significantly increased in patients with ARDS compared with healthy 
subjects or patients with severe asthma.  A median concentration of sST2 of 534 ng/mL 
has been reported in patients with ARDS (Alladina et al. 2016),
 
 
  
As sST2 acts as a decoy to bind and inhibit released IL-33, higher sST2 concentrations 
in patients with ARDS suggest that higher doses of MSTT1041A may be required to 
achieve efficacy in ARDS compared with severe asthma.
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3.3.2
Rationale for UTTR1147A (IL-22Fc) Dose and Schedule
For the UTTR1147A arm, up to two doses of 90 g/kg Q2W IV will be administered on 
Day 1 and Day 15. The proposed dose is supported by the safety, PK, and PD results 
from a completed Phase Ia SAD study in healthy volunteers (Study GA29468), a 
completed Phase Ib MAD study in healthy volunteers and patients with IBD (Study 
GA29469), and an ongoing double-blinded, placebo-controlled 5-arm Phase II study in 
patients with moderate to severe UC (Study GA39925).  In the completed Phase I 
studies, 73 subjects have received at least one IV dose of UTTR1147A.  
 
 
  
In the Phase Ia SAD study, the MTD in 26 healthy volunteers was 90 g/kg IV due to 
serious on-target effects of IL-22 causing non-serious dermatologic events, including dry 
skin, dry lips, pruritus, moderate erythema, and skin hyperesthesia, which are 
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Based on the tolerability profile in patients with UC to date and a potential lower PK 
exposure in the target population, 90 g/kg Q2W was chosen as the dose regimen with 
the highest benefitrisk ratio for patients with severe COVID-19 pneumonia.  In patients 
randomized to UTTR1147A, 90 g/kg IV will be administered on Day 1.  For patients 
who remain hospitalized on supplemental oxygen on Day 15, a second dose at 90 g/kg 
IV will be given.  The first dose of 90 g/kg is targeted to maximize the drug exposure in 
patients with severe COVID-19 pneumonia.  The second dose is targeting the epithelial 
barrier repair and protective mechanisms to help patients with ongoing lung damage and 
pulmonary dysfunction.  
3.3.3
Rationale for Patient Population
Approximately 15%20% of patients with COVID-19 pneumonia have severe disease 
requiring hospitalization and supplemental oxygen and 5% of patients with COVID-19
pneumonia will be admitted to the ICU (WHO 2020b).  Risk factors for progression to 
severe COVID-19 pneumonia are common and include advanced age, cardiovascular 
disease, diabetes mellitus, chronic lung disease, and chronic kidney disease (Liang et al. 
2020; Wu et al. 2020; Zhou et al. 2020).  In a study of 138 hospitalized patients with 
COVID-19 pneumonia in China, 26% of patients required transfer to the ICU and 4.3% of 
patients died (Wang et al. 2020).  In a second study of 1099 Chinese patients with 
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COVID-19 pneumonia, 5% of patients were admitted to the ICU, 2.3% of patients 
underwent invasive mechanical ventilation, and 1.4% of patients died (Guan et al. 2020).  
Patients with severe COVID-19 pneumonia requiring hospitalization and supplemental 
oxygen have significant morbidity and mortality and despite multiple experimental 
therapies in wide use, there are no treatments with proven efficacy to date.  This study 
will enroll patients hospitalized with severe COVID-19 pneumonia requiring 
supplemental oxygen at high risk of developing ARDS, hypoxic respiratory failure and 
death.  
3.3.4
Rationale for Control Group
The study will compare the efficacy and safety of MSTT1041A or UTTR1147A IV 
compared with matching placebos in combination with SOC for the treatment of patients 
with severe COVID-19 pneumonia.  In this study, the SOC regimen will be based on 
institutional guidelines for treatment of severe COVID-19 pneumonia.  Due to the lack of 
proven efficacious treatments for COVID-19, SOC treatment generally includes 
supportive care.  Experimental therapies include anti-viral agents 
(e.g., hydroxychloroquine, ritonavir/lopinavir, remdesivir) and host-directed therapies 
(i.e., antiIL-6, low-dose corticosteroids).  The treatment of all patients with SOC therapy 
ensures that all patients will receive therapy for COVID-19.  This control treatment is 
based on consideration of safety, ethics, and efficacy for treatment of severe COVID-19 
pneumonia.
3.3.5
Rationale for Biomarker Assessments
PD biomarkers will be assessed to demonstrate evidence of biologic activity of 
MSTT1041A and of UTTR1147A in patients with severe COVID-19 pneumonia, to 
characterize PK/PD relationships, and to support selection of a recommended dose and 
dosing regimen selection for future studies.  The exploratory biomarkers will be 
assessed to identify those patients who are most likely to respond to MSTT1041A or 
UTTR1147A, to characterize MSTT1041A and UTTR1147A mechanisms of action, to 
provide further evidence of MSTT1041A and UTTR1147A efficacy, and to understand 
progression of COVID-19.  The relationship between biomarkers and safety, 
immunogenicity, and other biomarker endpoints may also be explored.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 390 hospitalized patients with severe COVID-19 pneumonia will be 
enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Documented informed consent as described in Section 4.5.1

Age 18 years at time of signing Informed Consent Form
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
Ability to comply with the study protocol

Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a 
positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily 
fluid) and evidenced by chest X-ray or CT scan 

For sites at an altitude 5000 feet:  peripheral capillary oxygen saturation (SpO2) 
93% or partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) 
300 mmHg or requirement for supplemental oxygen to maintain SpO2 93%

For sites at an altitude 5000 feet:  requirement for supplemental oxygen to 
maintain SpO2 at an acceptable level per local standard of care

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 95 days after the final dose 
of study drug.
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
95 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 
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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:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 95 days after the final dose of study drug
Women of childbearing potential must have a negative pregnancy test at 
screening.

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

In the opinion of the investigator, progression to death is imminent and inevitable 
within the next 24 hours, irrespective of the provision of treatments

Participating in another clinical drug trial

Treatment with investigational therapy (other than for COVID-19) within 5 half-lives 
or 30 days (whichever is longer) prior to initiation of study drug 

Use of Janus kinase (JAK) inhibitor within 30 days or 5 drug elimination half-lives 
(whichever is longer) prior to screening

Have received high-dose systemic corticosteroids (1 mg/kg/day
methylprednisolone or equivalent) within 72 hours prior to Day 1

Known HIV infection with CD4 200 cells/L or 14% of all lymphocytes

ALT or AST 10 upper limit of normal (ULN) detected at screening 

History of anaplastic large-cell lymphoma or mantle-cell lymphoma

History of cancer within the previous 5 years unless it has been adequately treated 
and considered cured or remission-free in the investigator's judgment

Clinical evidence of active or unstable cardiovascular disease (e.g., acute 
myocardial ischemia or decompensated heart failure) as assessed by the 
investigator

Elevated cardiac troponin indicative of a recent cardiac event or 
myocarditis/pericarditis, as defined below: 
1.
If high-sensitivity immunoassay is available locally:  high-sensitivity troponin (hs-
troponin) I or T ULN (as per local standard for ULN), unless certain additional 
criteria are met, as outlined below:
–
If the local laboratory reports "indeterminate" or "intermediate" hs-troponin 
results:  Patients with hs-troponin in the “intermediate” or “indeterminate” 
range (per local laboratory) may be enrolled if an echocardiogram shows 
normal left ventricular ejection fraction (as per local standard for normal, 
generally 50%55%) without evidence of hypokinesis; if an echocardiogram 
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cannot be obtained, clinical evaluation excluding myocarditis/pericarditis is 
acceptable.
–
If the local laboratory does not report "indeterminate" or "intermediate" hs-
troponin results:  Patients with hs-troponin ULN to 5ULN may be 
enrolled if an echocardiogram shows normal left ventricular ejection fraction
(as per local standard for normal, generally 50%55%) without evidence of 
hypokinesis; if an echocardiogram cannot be obtained, clinical evaluation 
excluding myocarditis/pericarditis is acceptable.
2.
If high-sensitivity immunoassay is not available locally: conventional cardiac 
troponin I or T ULN, (based on local standard for ULN)
–
Patients with screen failure due to conventional troponin ULN may be 
re-screened and enrolled if a repeat conventional troponin is ULN and an 
echocardiogram shows normal left ventricular ejection fraction (as per local 
standard for normal, generally 50%55%) without evidence of hypokinesis; 
if an echocardiogram cannot be obtained, clinical evaluation excluding 
myocarditis/pericarditis is acceptable.

History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion, including complete left bundle branch block, second- or third-
degree atrioventricular heart block, or evidence of prior myocardial infarction

Sustained prolongation of QT interval corrected through use of Fridericia's formula 
(QTcF), defined as repeated demonstration of QTcF 480 ms (NCI CTCAE 
Grade 1)
Patients with prolonged QTcF due to a reversible cause (e.g., electrolyte 
abnormalities) may be re-tested after the underlying cause has been corrected.
For patients with a ventricular pacemaker, there should be appropriate 
correction for heart rate and pacing when determining baseline QTcF (as per 
Chakravarty et al. 2015); absolute QTcF values should not exceed 490 ms.

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction, 
hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy), 
coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic 
testing), or family history of sudden unexplained death or long QT syndrome

History of moderate or severe allergic, anaphylactic, or anaphylactoid reactions or 
hypersensitivity to any component of study treatment  
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1
Treatment Assignment
This is a randomized, double-blind, placebo-controlled study.  After initial written 
informed consent has been obtained, all screening procedures and assessments have 
been completed, and eligibility has been established for a patient, the study site will 
obtain the patient's identification number and treatment assignment from an interactive 
voice or web-based response system (IxRS).
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Patients will be randomly assigned to one of four treatment arms:  MSTT1041A, 
UTTR1147A, or their matching placebos.  Randomization will occur in a 2:2:1:1 ratio 
through use of a permuted-block randomization method to ensure a balanced 
assignment to each treatment arm.  Randomization will be stratified according to need 
for invasive mechanical ventilation (yes vs. no) and region. The proportion of patients 
with a need for invasive mechanical ventilation will be capped at approximately 25% of 
the overall study population.
4.2.2
Blinding
Study site personnel and patients will be blinded to treatment assignment of 
MSTT1041A and UTTR1147A versus their respective placebos during the study.  The 
Sponsor and its agents will also be blinded to treatment assignment of MSTT1041A and 
UTTR1147A versus their respective placebos, with the exception of IxRS service 
provider, and prespecified personnel (e.g., DMC members).
PK samples may be used to assess immunogenicity.  While PK samples must be 
collected from patients assigned to the placebo arm to maintain the blinding of treatment 
assignment, PK and ADA assay results for these patients are generally not needed for 
the safe conduct or proper interpretation of the study data.  Laboratories responsible for 
performing study drug PK and ADA assays will be unblinded to patient treatment 
assignments to identify appropriate samples for analysis.  PK samples from patients 
assigned to the placebo arm will not be analyzed for study drug PK concentration except 
by request (e.g., to evaluate a possible error in dosing). Baseline ADA samples will be 
analyzed for all patients. Postbaseline ADA samples from patients assigned to the 
placebo arm will not be analyzed for ADAs except by request. Baseline and 
postbaseline samples will be collected for all patients.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly. 
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 MSTT1041A and 
matching placebo, and UTTR1147A and matching placebo.
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
MSTT1041A, UTTR1147A, and Placebos
MSTT1041A and UTTR1147A will be supplied by the Sponsor as a sterile, clear, and 
colorless to slightly yellow solution in single-use 5-mL and 2-mL vials, respectively. 
Matching placebos will be supplied by the Sponsor as a sterile solution in respective 
single-use 5-mL and 2-mL vials.  The UTTR1147A diluent will also be supplied by the 
Sponsor.  For information on the MSTT1041A and UTTR1147A formulations, see the 
pharmacy manual and RO7187807 (MSTT1041A) and RO7021610 (UTTR1147A) 
Investigator's Brochures.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, along with any associated adverse events, should be 
reported as described in Section 5.3.5.13.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.2.1
MSTT1041A, UTTR1147A, and Placebo
Doses of MSTT1041A, UTTR1147A, or matching placebo will be prepared per the 
instructions outlined in the pharmacy manual and delivered over 60 (10) minutes.
Weight-based infusions of UTTR1147A, with a maximum dose given to be based on 
100 kg total body weight, will be prepared per the instructions outlined in the pharmacy 
manual.
Patients who experience an infusion-associated adverse event with the initial infusion 
may be premedicated for the next infusion.
4.3.3
Investigational Medicinal Product Handling and Accountability
All IMPs 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 
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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 IMPs, and only authorized staff may 
supply or administer IMPs.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log.
Refer to the pharmacy manual and/or the RO7187807 (MSTT1041A) and RO7021610 
(UTTR1147A) Investigator's Brochures for information on IMP handling, including 
preparation and storage, and accountability.  
4.3.4
Continued Access to MSTT1041A or UTTR1147A
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMPs (MSTT1041A or UTTR1147A) or any other study 
treatments to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing MSTT1041A or UTTR1147A 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
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4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, or herbal remedies) used by a patient in addition to protocol-
mandated treatment from 7 days prior to initiation of study drug until the study 
completion/discontinuation visit.  For concomitant therapy used by a patient 7 days 
prior to initiation, only concomitant therapy for treatment of COVID-19 will be recorded. 
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  Homeopathic remedies, IV fluids, or nutritional 
supplements (e.g., vitamins and minerals) do not need to be reported.
4.4.1
Permitted Therapy 
All patients will receive SOC per local practice for the treatment of severe COVID-19 
pneumonia, with the exception of treatments listed under Section 4.4.3.  The SOC for 
severe COVID-19 pneumonia may include, but is not limited to, anti-viral treatment, 
host-directed therapies, convalescent plasma, low-dose corticosteroids, and supportive 
care.  Participation in another clinical drug trial is prohibited for the duration of this study.
In general, investigators should manage a patient's care with supportive therapies 
as clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by 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
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited during the study as described 
below:

Treatment with any investigational agent (other than for COVID-19), cell-depleting 
therapies, JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib), alkylating agents 
(e.g., chlorambucil, cyclophosphamide), TNF inhibitors, antiIL-1 agents,
thalidomide, anti-thymocyte globulin, and azathioprine

High-dose systemic corticosteroids (1 mg/kg/day methylprednisolone or equivalent
for more than 1 day) 

Plasmapheresis or extracorporeal photopheresis 
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
Immunization with a live or attenuated vaccine 
4.5
STUDY ASSESSMENTS 
The schedules of activities to be performed during the study are provided in Appendix 1
and Appendix 2.  All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Records
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations). Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
Due to the pandemic situation and restricted hospital access, the patient’s legally 
authorized representative may consent remotely with appropriate documentation by the 
investigator or the authorized designee in accordance with applicable regulatory 
guidance. Where informed consent from the patient or the legally authorized 
representative is not feasible, exception from regulatory informed consent requirements 
may be permitted under certain circumstances in accordance with applicable law and 
IRB/EC policies. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a record of all 
patients screened and will 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, 
and home oxygen use will be recorded at screening.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, or herbal remedies) used by 
the patient within 7 days prior to initiation of study treatment will be recorded. For 
concomitant therapy used by a patient 7 days prior to initiation, only concomitant 
therapy for treatment of COVID-19 will be recorded. At the time of each follow-up 
physical examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
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4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, 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 should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs and Oxygen Saturation
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure, and 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) should be recorded.  For patients requiring non-invasive or 
invasive mechanical ventilation, the positive-end expiratory pressure (PEEP) and FiO2 or 
oxygen flow rate (L/min) should be recorded.
To allow assessment of the NEWS2 score (see Appendix 4), site personnel should 
record one representative set of vital sign and oxygen saturation measurements from a 
single timepoint, ideally within 1 hour prior to treatment administration at the baseline 
visit (Day 1) and between 8 a.m. and 12 p.m. at subsequent visits during patient
hospitalization.  When possible, the patient should be assessed at approximately the 
same time each day.  Following hospital discharge, patients may be provided with a 
personal pulse oximeter, which will be used to measure oxygen saturation and pulse 
rate at home.
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 appropriate eCRF.
These should be recorded at the same timepoints as the vital sign measurements. 
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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 sent to the study site's local laboratory 
for analysis:

Arterial blood gases (oxygen, partial pressure of carbon dioxide, PaO2, pH, FiO2,
bicarbonate)
For sites at an altitude 5000 ft, a correction factor should be applied to the 
PaO2 value by using the following equation:
PaO2
FiO2barometric pressure / 760

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered SOC for the region), sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, 
and/or AST, urate, LDH, and ferritin

Coagulation:  INR, PT, aPTT, fibrinogen, and D-dimer

Cardiac hs-troponin I or T via high-sensitivity immunoassay; or conventional cardiac 
troponin I or T, if high-sensitivity immunoassay is not available locally
The same assay should be used for all samples for each patient, if possible.

N-terminal pro-brain natriuretic peptide (NT-proBNP) or brain natriuretic 
peptide (BNP)
The same assay should be used for all samples for each patient, if possible.

CRP

Lactate

SARS-CoV-2 local virology test (PCR): nasopharyngeal swab, oropharyngeal swab, 
bronchoalveolar lavage, or other respiratory specimen; blood; urine; stool; or other 
bodily fluid

Influenza A and influenza B virology test (PCR or rapid antibody test)

Pregnancy test (urine or serum) for women of childbearing potential, including those 
who have had a tubal ligation
Positive urine test results will be confirmed with a serum pregnancy test.  Study 
drug can be administered only if the initial urine or serum pregnancy test result 
is negative or if a positive urine pregnancy test is followed by a negative serum 
pregnancy test.
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The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis:

Serum samples for PK analysis
Serum ADA may be measured using PK samples if ADA samples have not 
been collected at the same timepoint.

Serum samples for ADA analysis

Serum samples for exploratory biomarker research

Blood PAXgeneRNA for RNA sequencing or quantitative PCR

Nasopharyngeal swabs for SARS-CoV-2 central virology tests (viral load and 
exploratory analysis) 
Exploratory biomarker research may include, but will not be limited to, analysis of sST2, 
IL-22, IL-22 binding protein (IL-22BP), CRP, and REG3A, inflammatory mediators, and 
ARDS-related variables.
Research may involve extraction of RNA and genomic profiling through use of next-
generation sequencing (NGS) of a comprehensive panel of genes. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation and biomarker measurements; therefore, these samples 
will be destroyed no later than 15 years after the final Clinical Study Report has 
been completed.

Serum, blood PAXgene, and fluid samples (nasopharyngeal swabs, if applicable) 
collected for biomarker research will be destroyed no later than 15 years after the 
final Clinical Study Report has been completed.  However, the storage period will be 
in accordance with the IRB/EC-approved Informed Consent Form and applicable 
laws (e.g., health authority requirements). 
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.
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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
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated. 
All ECG recordings should 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 
should be performed after the patient has been resting in a supine position for at least 
10 minutes if possible.  All ECGs should be obtained prior to other procedures 
scheduled at that same time (e.g., blood draws) if possible.  Circumstances that may 
induce changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre ECG resting period and during ECG 
recording.
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.  Digital recordings will be stored at site.  The following should be 
recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and QTcF based on the machine readings of the individual 
ECG tracings.  Any morphologic waveform changes or other ECG abnormalities must be 
documented on the eCRF.  If considered appropriate by the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  SOC treatment may be 
instituted per the discretion of the investigator.  If a PK sample is not scheduled for that 
timepoint, an unscheduled PK sample should be obtained.  A decision on study drug 
discontinuation should be made, as described in Section 5.1.3.4.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, medications known to prolong the QT interval including chloroquine, 
hydroxychloroquine, azithromycin, lopinavir/ritonavir).
4.5.8
Chest X-Rays and CT Scans
Chest X-ray or CT scan should be performed during screening per inclusion criteria.  A 
chest CT scan should be performed on Day 60 if a patient is still hospitalized or if an 
in-clinic follow-up visit is performed.  Chest X-ray and/or CT findings should be recorded 
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on the appropriate eCRF.  If additional chest X-rays/CT scans are performed per local 
practice during the patient’s hospitalization or after discharge through Day 60, these 
findings should be provided in the appropriate eCRF.  Upon completion of the study, 
imaging reports and DICOMfiles for chest X-rays and CT scans obtained during the 
study period may be requested by the Sponsor.
4.5.9
Ordinal Scale Determination
Assessment of clinical status using a 7-category ordinal scale will be recorded prior to 
dosing at baseline on Day 1 and then again once daily every morning (ideally, between 
8 a.m. and 12 p.m.) at subsequent visits during patient hospitalization. When possible, 
the patient should be assessed at approximately the same time each day.  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
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.  
However, actual clinical status category should be recorded on the eCRF. Please refer 
to the additional guidance for investigators regarding assessment of clinical status using 
the 7-category ordinal scale. 
Patients on supplemental oxygen should be evaluated at least daily and considered for 
reduction or discontinuation of oxygen support.  Actual changes in level of support will 
be at the discretion of the clinician(s) treating the patient based on the patient’s overall 
condition and may be dictated by other clinical and non-clinical considerations. 
Normal body temperature is defined as oral, rectal, axillary, temporal, or tympanic
temperature 36.1C38.0C.  Normal respiratory rate is defined as 1220 breaths per 
minute. 
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4.5.10
Optional Blood Samples for Whole Genome Sequencing 
(Patients at Participating Sites)
At participating sites, optional blood samples will be collected from consenting patients 
for DNA extraction to enable whole genome sequencing (WGS) to identify variants that 
are predictive of response to study drug, are associated with progression to a more 
severe disease state, are associated with susceptibility to developing adverse events, 
can lead to improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  Research will be 
aimed at exploring inherited characteristics.  The samples may be sent to one or more 
laboratories for analysis.
Collection and submission of blood samples for WGS is contingent upon the review and 
approval of the exploratory research by each site's IRB/EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for WGS, this 
section of the protocol (Section 4.5.10) will not be applicable at that site.
The Informed Consent Form will contain a separate section that addresses optional 
blood samples for WGS.  A separate, specific signature will be required to document a 
patient's agreement to provide optional blood samples.  The investigator should 
document whether or not the patient has given consent to participate and (if applicable) 
the date(s) of consent, by completing the Optional Whole Genome Sequencing Informed 
Consent eCRF.
Genomics is increasingly informing researchers understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
Refer to Section 4.5.6 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses.
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4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Grade 4 dermatologic reactions (as described in Section 5.1.3.3)

Major adverse cardiovascular event

Hs-troponin I or T in the "intermediate" or "indeterminate" range or hs-troponin 
ULN to 5ULN (and above baseline) AND either reduced ejection fraction or 
new hypokinesis by echocardiogram or evidence of myocarditis and/or pericarditis
(as described in Section 5.1.3.3)

Hs-troponin I or T at a level indicative of myocardial ischemia, 5ULN, or category 
above "intermediate" or "indeterminate" (as described in Section 5.1.3.3)

Conventional cardiac troponin I or T ULN, if high-sensitivity immunoassay is not 
available locally (as described in Section 5.1.3.3)

QTcF prolongation or torsades des pointes as described in Section 5.1.3.4, unless 
there is a clear alternative cause for the changes

Grade 3 infusion-related reaction as described in Section 5.1.3.3

Use of prohibited therapy as described in Section 4.4.3
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.
Patients will remain in study and complete all study visits and assessments (with the 
exception of the study drug administration).
4.6.2
Patient Discontinuation from the Study
Hospitalized patients who discontinue the study prematurely should perform a study 
discontinuation visit. Discharged patients who discontinue study prematurely should 
return to the clinic for a study discontinuation visit, if possible, or have a remote (phone 
or video) visit.
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.
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Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
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
MSTT1041A and UTTR1147A are not approved, and clinical development is ongoing.  
The safety plan for patients in this study is based on clinical experience with 
MSTT1041A and UTTR1147A in completed and ongoing studies.  The anticipated 
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important safety risks for MSTT1041A and UTTR1147A are outlined below.  Please refer 
to the RO7187807 (MSTT1041A) and RO7021610 (UTTR1147A) Investigator's 
Brochures for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria treatment discontinuation, are 
provided below.
5.1.1
Risks Associated with MSTT1041A (Anti-ST2)
5.1.1.1
Identified Risks
No risks have been identified yet for MSTT1041A.
5.1.1.2
Potential Risks
5.1.1.2.1
Adverse Effects Related to Immunogenicity 
Administration of MSTT1041A, a protein therapeutic, may lead to the development of 
anti-MSTT1041A antibodies, which could lead to adverse events and/or decreased 
exposure.  For details about immunogenicity rates and associated adverse events, refer 
to the MSTT1041A Investigator’s Brochure.
5.1.1.2.2
Hypersensitivity Reactions and Anaphylaxis/
Hypersensitivity-Like Reactions
Hypersensitivity reactions and anaphylaxis have been described with SC administration 
of monoclonal antibodies (Corominas et al. 2014).  Signs and symptoms may include 
acute onset (minutes to several hours) of one or more of the following:  respiratory 
compromise, reduced blood pressure, skin-mucosal involvement, or GI symptoms 
(Sampson et al. 2006).  The potential for hypersensitivity to MSTT1041A in humans is 
unknown.  However, as with any large-molecule therapeutic, administration of 
MSTT1041A may result in systemic reactions.  Systemic reactions to large-molecule 
therapeutics can be IgE or non-IgE mediated or due to the release of cytokines and are 
generally characterized by signs and symptoms such as skin rash, urticaria, pruritus, 
local or diffuse erythema, angioedema, fever, chills, cough, dyspnea, wheezing, 
bronchospasm, nausea, vomiting, diaphoresis, chest pain, tachycardia or bradycardia, 
and/or hypotension, which can be severe or life threatening.  Effects typically occur 
during or within several hours after drug administration, but they may be delayed. 
Refer to the MSTT1041A Investigator’s Brochure for details about reports of adverse 
events of hypersensitivity reactions and anaphylaxis/hypersensitivity-like reactions.
5.1.1.2.3
Infection
The intended mechanism of action of MSTT1041A suggests inhibitory effects on 
immune responses mediated by Th2 cells, leading to the possibility of a decrease in the 
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protective response to infection, particularly helminthic infections (Molofsky et al. 2015).  
However, as described in Section 5.3 of the MSTT1041A Investigator’s Brochure, a lack 
of significant differences in levels of exploratory biomarkers fractional exhaled nitric 
oxide (reflecting airway IL-4/IL-13 activity) and serum IL-5 between MSTT1041A-treated 
and placebo patients in Study GB39242 (patients with asthma) may reflect a limited 
effect on Type 2 inflammation.  Refer to the MSTT1041A Investigator’s Brochure for 
details about infections related to study treatment. 
5.1.1.2.4
Exacerbation of Cardiovascular Disease
Published studies involving mouse models of cardiovascular disease or in vitro culture 
systems describe potential cardioprotective and atheroprotective roles of the IL-33/ST2 
axis (Sanada et al. 2007; Miller et al. 2008; Seki et al. 2009; McLaren et al. 2010; 
Wasserman et al. 2012).  For example, after experimentally induced acute left 
ventricular pressure overload, which could be relevant to clinical scenarios involving 
increased afterload (e.g., left-sided congestive heart failure or acute hypertension), 
ST2-/- mice had more left ventricular hypertrophy, more fibrosis, and impaired survival 
relative to their wild-type littermates (Sanada et al. 2007).  However, the translatability of 
these findings remains uncertain.  In addition, studies with conflicting data exist 
(Demyanets et al. 2011; Abston et al. 2012; Martin et al. 2015).  
Evidence has shown that the sST2 receptor is a prognostic biomarker of cardiovascular 
disease outcome (Sabatine et al. 2008; Shah et al. 2009; Weir et al. 2010).  Although 
published findings suggest a possible risk of exacerbation of existing cardiovascular 
disease in humans, there are no identified cardiovascular risks associated with inhibiting 
the IL-33/ST2 axis in humans.
Refer to the MSTT1041A Investigator’s Brochure for details about the preclinical and 
clinical experience associated with the potential risk of cardiovascular disease.
5.1.2
Risks Associated with UTTR1147A (IL-22Fc)  
5.1.2.1
Identified Risks
5.1.2.1.1
Dermatologic Reactions
In nonclinical and clinical studies, UTTR1147A caused on-target dose-dependent 
reversible skin changes, including pruritus, dry lips and skin, patchy erythema, skin 
exfoliation (primarily on the face and upper body), and skin discomfort.  In the Phase I 
SAD study GA29468 in healthy volunteers, the MTD of 90 g/kg IV was determined on 
the basis of the intensity of erythema, pruritus, and skin hyperesthesia reported by 3 of 
4 subjects who received UTTR1147A at 120 g/kg IV.  Most dermatologic manifestations 
at doses of up to 90 g/kg were mild (Grade 1) or moderate (Grade 2).  Dermatologic 
findings appeared within a week of dosing, were manageable with topical emollients, 
and resolved within approximately 2 weeks of onset.
In the Phase Ib MAD in healthy volunteers and patients with IBD (Study GA29469), 
similar dermatologic findings have been observed at all dose levels tested (30 g/kg IV
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Q2W, 60 g/kg IV Q2W, 60 g/kg IV Q4W, and 90 g/kg IV Q2W) after the first or 
second dose of UTTR1147A. In healthy volunteers, two doses of UTTR1147A at 
90 µg/kg IV Q2W caused severe (Grade 3) skin discomfort, hyperesthesia, and 
erythema with minimal relief from topical emollients or topical corticosteroids but were 
self-limited and resolved after discontinuation of UTTR1147A treatment, yielding and 
MTD of 60 g/kg IV Q2W.  
In UC patients, two doses of UTTR1147A at 90 g/kg IV q2wk caused moderate 
(Grade 2) erythema that were managed with topical emollients and resolved within 
410 weeks after onset but UTTR1147A was better tolerated and no MTD was reached. 
Overall, dermatologic events (e.g., dry skin, erythema, skin exfoliation, and skin 
discomfort) appeared within the first month of dosing, were manageable with topical 
emollients, and reversible within 4 weeks to 3 months after onset. The drug has been 
well tolerated in an ongoing Phase II study (GA39925) to evaluate the efficacy, safety, 
and pharmacokinetics of UTTR1147A at 30 g/kg Q4W, 60 g/kg Q4W, or 90 g/kg IV 
Q4W compared with vedolizumab or placebo in patients with moderate to severe UC.  
Based on preliminary blinded data, with a data cutoff of 6 March 2020, the overall skin 
adverse event rate is low at 8.2% (8/98 patients). 
Guidelines for management of patients who develop dermatologic reactions are provided 
in Section 5.1.3.3.
5.1.2.2
Potential Risks
5.1.2.2.1
Administration Site Reactions and Infusion Related Reactions 
As with introduction of any foreign biological molecule, the potential risks of UTTR1147A 
include systemic IRRs and local injection/administration site reactions.  IRRs may 
include true acute allergic/hypersensitivity (e.g., anaphylaxis) reactions and acute 
pseudoallergic/hypersensitivity-like (e.g., anaphylactoid) reactions.  Anaphylaxis and 
anaphylactoid reactions are the more severe forms of allergic and pseudoallergic 
reactions, respectively and may have similar or overlapping clinical symptoms.  
Anaphylaxis is associated with prior exposure to the drug, leading to sensitization and 
the development of IgE antibodies, and needs to be distinguished from anaphylactoid 
reactions as the correct diagnosis impacts the decision to re-dose the patient 
(e.g., patients with anaphylaxis should not be re-challenged).  Refer to the UTTR1147A 
Investigator’s Brochure for details about reports of adverse events of infusion related 
reactions.  As UTTR1147A is not administered subcutaneously in this protocol, the 
potential risk for administration site reactions is not relevant.
5.1.2.2.2
Development of Cross Reacting Anti-Drug Antibodies and 
Increased Risk for Opportunistic Bacterial and Fungal 
Infections
Though not seen in human studies to date, there is a possibility that UTTR1147A may 
induce antibodies that neutralize endogenous IL-22 and, thus, be associated with an 
increased risk for opportunistic bacterial and fungal infections.  Since IL-22 plays a role 
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Table 3
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Event
Action to Be Taken
Infusion-related reactions 
General

If infusion is stopped, the approximate volume administered 
should be recorded, as well as all start and stop times.
Grade 1

Continue infusion.

Reduce infusion rate to 50% of original infusion rate.
Grade 2

Interrupt infusion.

Administer supportive treatment if indicated per local or 
institutional standard operating procedures. 

Upon symptom resolution, resume infusion at 50% of original 
infusion rate.

If infusion reaction reoccurs, discontinue study treatment.
Grade 3 or 4

Stop infusion immediately and administer supportive treatment 
per local or institutional standard operating procedures
(see Appendix 3 for guidance on anaphylaxis).

Discontinue study treatment.

Consider obtaining additional supportive data, if available, to 
inform the diagnosis of allergic versus pseudoallergic reaction 
(e.g., serum histamine, serial tryptase measurements).
Cardiac toxicity
High-sensitivity troponin I 
or T in the “intermediate” or 
“indeterminate” range, or
ULN to 5ULN (and 
above baseline)

An echocardiogram to assess for cardiac function is 
recommended.

If echocardiogram shows reduced ejection fraction or new 
hypokinesis or there is clinical evidence of myocarditis and/or 
pericarditis, discontinue study treatment and report as an AESI.

Report as an AESI if it meets criteria for major adverse 
cardiovascular event. a
High-sensitivity troponin I 
or T at a level indicative of 
myocardial ischemia, 
5ULN, or category 
above "intermediate" or 
"indeterminate"

Discontinue study treatment.

An echocardiogram to assess for cardiac function is 
recommended.

Report as an AESI if it meets criteria for major adverse 
cardiovascular event. a
Conventional cardiac 
troponin I or T ULN, if 
high-sensitivity 
immunoassay is not 
available locally

Discontinue study treatment.

An echocardiogram to assess for cardiac function is 
recommended.

Report as an AESI if it meets criteria for major adverse 
cardiovascular event. a
Major adverse 
cardiovascular event b

Discontinue study treatment.

Report as an AESI.
ADAanti-drug antibody; AESIadverse event of special interest; IRRinfusion-related 
reaction; ULNupper limit of normal.
b Refer to Section 5.2.3 for examples of events that qualify as major adverse cardiovascular 
events.
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5.1.3.4
Management of Increases in QT Interval
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes:

Sustained (at least two ECG measurements 30 minutes apart) QTcF that is 
500 ms and 60 ms longer than the baseline value

Sustained absolute QTcF that is 515 ms (or 530 ms for patients with a 
ventricularly paced rhythm)

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 
of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  In 
such a situation, saving all available ECG data is highly suggested.
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval, including other drugs used to treat severe COVID-19 pneumonia, such as 
chloroquine, hydroxychloroquine, azithromycin, lopinavir/ritonavir, etc.).  Consultation 
with a cardiologist or electrophysiologist is recommended, to help in the management of 
such patients.
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied.
5.1.3.5
Anaphylaxis
Refer to Appendix 3 for guidelines on anaphylactic precautions.  These guidelines are 
intended as a reference and should not supersede pertinent local or institutional 
standard operating procedures. 
In accordance with local guidelines, the measurement of tryptase (serum or plasma) and 
histamine (plasma) levels should be considered to support a diagnosis of anaphylaxis, 
although clinicians should treat anaphylaxis regardless of the availability of the results of 
these tests.
During the study, all anaphylaxis events should be accurately reported on the 
appropriate eCRF.
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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the 
safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.10
and 5.3.5.11 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 5.3.5.12)
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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;
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 5.3.5.8)

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.

Suspected infusion related reactions or hypersensitivity reactions, including 
anaphylaxis, within 24 hours of infusion

MACE, including:
–
Death due to primary cardiovascular causes (cardiac arrest secondary to 
progression of disease is excluded)
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–
Non-fatal myocardial infarction or acute coronary syndrome
–
New or worsening heart failure (new globally decreased left ventricular ejection 
fraction on transthoracic ECHO)

Grade 3 dermatologic reactions (as described in Section 5.1.3.3)
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 the study 
completion/discontinuation visit.
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 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
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Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (also see 
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
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Table 5
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).
Causality will be assessed individually for MSTT1041A and UTTR1147A.
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 or anaphylactic reaction).
5.3.5.2
Dermatologic Reactions
For dermatologic adverse events (as described in Section 5.1.2.1.1), details on involved 
body surface area and appearance should be recorded on the Dermatologic Reactions
eCRF.
5.3.5.3
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 
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based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.4
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe 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.
5.3.5.5
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.
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5.3.5.6
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment, including a comparison to baseline values, should be exercised in 
deciding whether an isolated laboratory abnormality should be classified as an adverse 
event. Abnormal laboratory values that were abnormal at baseline should only be 
reported as adverse events if they meet one of the following criteria:

The abnormality represents a deterioration from baseline 

The abnormality had resolved in the intervening period and became newly abnormal

The abnormality persisted when in the investigators judgment it should have 
normalized
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.7
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)
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
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, including a comparison to baseline abnormalities, should be exercised in 
deciding whether an isolated vital sign abnormality should be classified as an adverse 
event.  Abnormal vital signs that were abnormal at baseline should only be reported as 
adverse events if they meet one of the following criteria:

The abnormality represents a deterioration from baseline 

The abnormality had resolved in the intervening period and became newly abnormal

The abnormality persisted when in the investigators judgment it should have 
normalized
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 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.8
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN or 3baseline, if abnormal at 
baseline) 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 (or 3baseline, if abnormal at 
baseline) in combination with total bilirubin 2ULN

Treatment-emergent ALT or AST 3ULN (or 3baseline, if abnormal at 
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 5.3.5.3) 
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).
5.3.5.9
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of COVID-19 pneumonia.
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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.10
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors
(e.g., "more frequent headaches").
5.3.5.11
Lack of Efficacy or Worsening of COVID-19 Pneumonia
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events (with the exception of 
death due to COVID-19 pneumonia progression as described in Section 8).  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.
5.3.5.12
Re-Hospitalization or Prolonged Hospitalization
Any adverse event that results in re-hospitalization (i.e., inpatient admission to a hospital 
following discharge) 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.  
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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 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
5.3.5.13
Cases of Accidental Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
MSTT1041A or UTTR1147A (or matching placebo), adverse events associated with 
special situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
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In addition, all special situations associated MSTT1041A or UTTR1147A (or matching 
placebo), regardless of whether they result in an adverse event, should be recorded on 
the Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.14
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
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than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
PPD Medical Monitor contact information:
Telephone Nos.:
+1 (888) 483 7729 (North America)
+44 1223 374 240 (EMEA/APAC)
+55 11 4504 4801 (Latin America)
Genentech Medical Monitor contact information for all sites:
Medical Monitor:
, M.D., Ph.D.
Telephone Nos.:
 (mobile)
Genentech Alternate Medical Monitor contact information for all sites:
Medical Monitor:
, M.D., Ph.D., MRCP (UK)
Telephone Nos.:
 (mobile)
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 until the completion/discontinuation visit (Study Day 60, unless 
the patient has an early discontinuation).  Investigators should record all case details 
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that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Safety Risk Management by the EDC 
system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur after the 
completion/discontinuation visit are provided in Section 5.6.
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 95 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 
discontinue study drug and 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 
95 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 
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Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  If the authorization has been signed, the investigator should submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.  An investigator who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the treating physician and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
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5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
the study completion/discontinuation visit), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below:
Drug
Document
MSTT1041A
RO7187807 Investigator's Brochure
UTTR1147A
RO7021610 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.
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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
Efficacy analyses will be conducted on the modified intent-to-treat (mITT) population.  
The mITT population is defined as all patients randomized in the study who received at 
least one dose of study drug, with patients grouped according to the treatment assigned 
at randomization.
Safety analyses will be conducted for the safety population, which consists of patients 
who received at least one dose of study drug, with patients grouped according to the 
treatment received.
6.1
DETERMINATION OF SAMPLE SIZE
A total of approximately 390 patients will be randomly allocated in a 2:2:1:1 ratio to 
receive MSTT1041A, UTTR1147A, or their matching placebos.  The sample size 
provides approximately 80% power using a log-rank Chi-square test to detect a 7-day 
difference between treatment groups in time to recovery, defined as time to score of 1 or 
2 on the 7-category ordinal scale (whichever occurs first), under the following 
assumptions: median time to improvement in the placebo group is 21 days, with 28 days 
follow-up, and using a one-sided 5% alpha.  The minimal detectable difference is 
expected to be approximately 5.3 days.  
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized by treatment group.  Reasons for premature study discontinuation will be 
listed and summarized.  Enrollment and major protocol deviations will be listed and 
summarized.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including, but not limited to, age, sex, days 
from illness onset to randomization, geographic region, ordinal scale for clinical status, 
invasive 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 overall and by treatment group for the 
mITT and safety population.
6.4
EFFICACY ANALYSES
Efficacy analyses will be conducted on the mITT population, consisting of all patients 
randomized in the study who received at least one dose of study drug, with patients 
grouped according to the treatment assigned at randomization.
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MSTT1041A placebo and UTTR1147A placebo will be pooled in efficacy analyses.  
Comparison of efficacy will be performed between each of the two treatment groups and 
the pooled placebo.  That is, there are two comparisons:

MSTT1041A with pooled placebo

UTTR1147A with pooled placebo
Sensitivity analyses to evaluate the robustness of results will be conducted with 
comparison of primary efficacy endpoint between MSTT1041A and MSTT1041A 
placebo, and between UTTR1147A and UTTR1147A placebo.
Details on analysis methods, sensitivity analyses, hypothesis testing, and type I error 
control across treatment groups will be specified in the Data Analysis Plan (DAP).
Unless otherwise noted, analyses of efficacy outcome measures will be adjusted by 
stratification factors (the need for invasive mechanical ventilation [yes vs. no] and 
region).
6.4.1
Primary Efficacy Endpoint
The primary efficacy objective for this study is to evaluate the efficacy of MSTT1041A 
compared with placebo and of UTTR1147A compared with placebo, in combination with 
SOC, on the basis of the following endpoint:

Time to recovery, defined as time to score of 1 or 2 on the 7-category ordinal scale 
(whichever occurs first)
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
Time to recovery will be analyzed using the stratified log-rank test, adjusting for
stratification factors.  The Kaplan-Meier plot, median time to event, and their 95% CI
and p-value from the stratified log-rank test will be presented.  A Cox proportional 
hazards regression model will be used to estimate the hazard ratio comparing 
MSTT1041A or UTTR1147A with placebo, respectively, adjusting for stratification 
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factors.  Hazard ratios and 95% CIs will be presented.  In addition, the p-value from 
unstratified log-rank test, unadjusted hazard ratio, and 95% CI will also be presented.  
Further details on the primary endpoint analysis will be included in the DAP. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
•
Time to improvement of at least 2 categories relative to baseline on a 7-category
ordinal scale of clinical status
•
Time to hospital discharge or “ready for discharge” (as evidenced by normal body
temperature and respiratory rate, and stable oxygen saturation on ambient air or
≤ 2 L supplemental oxygen)
•
Duration of supplemental oxygen
•
Proportion of patients alive and free of respiratory failure (requiring non-invasive
ventilation, high-flow oxygen, invasive mechanical ventilation, or ECMO) at Day 28
•
Clinical status assessed using a 7-category ordinal scale at Days 14 and 28
•
Incidence of invasive mechanical ventilation or ECMO
•
Ventilator-free days to Day 28
•
Incidence of ICU stay
•
Duration of ICU stay
•
Time to clinical failure, defined as the time to death, invasive mechanical ventilation,
ICU admission, or withdrawal of care (whichever occurs first).  For patients entering
the study already in ICU or on invasive mechanical ventilation, clinical failure is
defined as a one category worsening on the ordinal scale, withdrawal, or death.
•
Mortality rate at Days 14 and 28
•
Time to clinical improvement, defined as a NEWS2 of ≤ 2 maintained for 24 hours
The secondary endpoints will be analyzed in the mITT population.  Statistical models will 
be adjusted for the covariates as described in Section 6.4.  
Full details of hypothesis testing, analysis methods, type I error control, and missing data 
handling will be documented in the DAP.  
6.4.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints will be analyzed using the same methods as described for 
the secondary endpoints in Section 6.4.2, where appropriate.  
6.5 
SAFETY ANALYSES 
Safety analyses will be conducted on all patients who received at least one dose of 
study drug, with patients grouped according to the treatment received. 
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Safety will be assessed through summaries of exposure to study treatment, adverse 
events, laboratory test results, vital signs, and ECGs.
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to NCI CTCAE v5.0 scale.  All adverse 
events, serious adverse events, adverse events leading to death, adverse events of 
special interest, adverse events leading to discontinuation from study treatment, adverse 
events leading to discontinuation from study, and treatment-emergent adverse events 
will be summarized by treatment groups.  A treatment-emergent adverse event is 
defined as any new adverse event reported or worsening of an existing condition on or 
after the first dose of study drug during.  Deaths and cause of death will be summarized.
Relevant laboratory, vital sign, and ECGs will be summarized by appropriate descriptive 
statistics by treatment groups.  
6.6
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of patients who received at least one dose of 
MSTT1041A or UTTR1147A and have sufficient data to enable estimation of key 
parameters (e.g., Cmax), with patients grouped according to treatment received. 
Estimates for the PK parameters will be tabulated and summarized (mean, standard 
deviation, coefficient of variation, median, minimum, and maximum), as appropriate.  
Individual and mean serum MSTT1041A or UTTR1147A concentration versus time data 
will be tabulated by dose level.  Additional PK analyses will be conducted as appropriate.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received, or, if no 
treatment is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive subjects and ADA-negative subjects at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group. When determining postbaseline incidence, 
subjects are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response). Subjects are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).
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The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
No formal statistical analysis of exploratory biomarkers will be performed.  Data may be 
analyzed in the context of this study and in aggregate with data from other studies. 
6.9
OPTIONAL INTERIM ANALYSES
Other than the cumulative data review by the DMC for benefit/risk assessment, no 
formal efficacy interim analyses are planned at this time. The DMC, after reviewing 
unblinded data, may recommend that a formal efficacy interim analysis be performed.
Furthermore, to adapt to information that may emerge during the course of this study, 
the Sponsor may choose to add a formal interim analysis at the recommendation of the 
DMC.  
The interim analysis will be conducted by DMC.  The decision to conduct the optional 
interim analysis, along with the rationale, timing, and statistical details for the analysis, 
will be documented in the Sponsor’s trial master file prior to the conduct of the interim 
analysis.  The DMC Charter will be updated to document potential recommendations the 
DMC can make as a result of the analysis (e.g., stop the study for positive efficacy, stop 
the study for futility).
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 and resulting restrictions to hospital access, data 
monitoring may be performed remotely or on-site.  Study monitors will perform ongoing 
data review to confirm that critical protocol data (i.e., source data) entered into the 
eCRFs by authorized site personnel are accurate and complete. Sites will be asked to 
implement a QC step of a second person reviewing the data entry in the eCRF where 
possible. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes
(PROs), 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, data (if applicable), 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 before his or her participation in the study.
Due to the pandemic situation and restricted hospital access, the patient’s legally 
authorized representative may consent remotely with appropriate documentation by the 
investigator or the authorized designee in accordance with applicable regulatory 
guidance. Where informed consent from the patient or the legally authorized 
representative is not feasible, exception from regulatory informed consent requirements 
may be permitted under certain circumstances in accordance with applicable law and 
IRB/EC policies.
The case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained prior to participation in the 
study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
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For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
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be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.5).
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.
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9.3
SITE INSPECTIONS
Site visits will be conducted remotely or on site 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.
9.4
ADMINISTRATIVE STRUCTURE
Genentech, a member of the Roche group, is the Sponsor of this study.  A contract 
research organization (CRO) may provide clinical operations oversight, including, but not 
limited to, project management, medical monitoring, site management, data quality 
support, safety reporting, and regulatory activities as specified in the study management 
plans.  Genentech will provide CRO oversight, develop the database and randomization 
scheme, and conduct statistical programming and analysis.  A DMC will provide safety 
monitoring for the study in addition to the ongoing review of safety by the Medical 
Monitor and safety scientist.  EDC will be utilized for this study.  An IxRS will be used to 
assign patient numbers, randomize patients into the study and manage site drug supply.  
A central laboratory will be used for sample management and storage until shipment to 
specialty laboratories or Genentech for analysis.  Local laboratories will be used for 
routine monitoring; local laboratory ranges will be collected.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
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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.
9.6
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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infection when COVID-19 is suspected [resource on the internet]. 2020b [updated: 
13 March 2020; cited: 18 May 2020]. Available from: 
https://www.who.int/publications-detail/clinical-management-of-severe-acute-
respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected.
Wolk K, Kunz S, Witte E, et al. IL-22 increases the innate immunity of tissues. Immunity 
2004;21:24154.
Wu Z, Hu Z, Cai X, et al. Interleukin 22 attenuated angiotensin II induced acute lung 
injury through inhibiting the apoptosis of pulmonary microvascular endothelial cells. 
Sci Rep 2017;7:11.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus 
disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases 
from the Chinese Center for Disease Control and Prevention. JAMA 2020. doi: 
10.1001/jama.2020.2648. [Epub ahead of print]
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 
Xue M, Zhao J, Ying L, et al. IL-22 suppresses the infection of porcine enteric 
coronaviruses and rotavirus by activating STAT3 signal pathway. Antiviral Res. 
2017;142:6875.
Yin H, Li XY, Yuan BH, et al. Adenovirus-mediated overexpression of soluble ST2 
provides a protective effect on lipopolysaccharide-induced acute lung injury in 
mice. Clin Exp Immunol 2011;164:24855.
Zheng Y, Valdez PA, Danilenko DM, et al. Interleukin-22 mediates early host defense 
against attaching and effacing bacterial pathogens. Nat Med 2008;14:2829.
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
98

MSTT1041A/UTTR1147A—Genentech, Inc.
99/Protocol GA42469, Version 4
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients 
with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 
2020;395:105462.
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
99

MSTT1041A/UTTR1147A—Genentech, Inc.
100/Protocol GA42469, Version 4
Appendix 1
Schedule of Activities (Inpatients Only)
SCRcc Baseline
Primary Phase
Follow 
up
SCa
Study day
2 to
RAND
1
2
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 35
45
60 
or 
ED
Visit window
0
b
b
b
b
c
b
b
b
±2
D
±2
D
±3 
D
SCREENING ONLY ASSESSMENTS
Informed consent d
X
Inclusion/exclusion 
criteria
X
COVID-19 
diagnosis e
X
Influenza A and B 
virology e
X
Demographic data
X
Medical history f
X
Complete physical 
examination g
X
Randomization
X
LOCAL LABS & ASSESSMENTS
Height h
X
Weight h
X
X i
Pregnancy test
(urine or serum) j
X
X
X
Chest X-ray/CT 
scan k
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)
(x) (x) (x)
(x)
X
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
100

Appendix 1: Schedule of Activities (Inpatients Only)
MSTT1041A/UTTR1147A—Genentech, Inc.
101/Protocol GA42469, Version 4
SCRcc Baseline
Primary Phase
Follow 
up
SCa
Study day
2 to
RAND
1
2
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 35
45
60 
or 
ED
Visit window
0
b
b
b
b
c
b
b
b
±2
D
±2
D
±3 
D
ECG
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)
(x)
X
(x)
(x)
X
Limited physical 
examination l
(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) (x) (x)
(x)
(x)
Vital signs 
(including SpO2 & 
FiO2) and
NEWS2 m
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
X
X
X
X
X
Arterial blood 
gases n
X
X o
(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) (x)
(x)
(x)
Ordinal scoring p
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
X
X
X
X
Hematology q
X
X o
X
X
X
X
X
X
X
X
X
X
X
Chemistry r
X
X o
X
X
X
X
X
X
X
X
X
X
X
Coagulation (incl. 
d-dimer) s
X o
X
X
X
X
X
X
X
X
NT-proBNP or 
BNP
X
X i
Troponin I or T t
X
X i
CRP
X o
(x)
(x)
(x)
X
(x)
(x)
X
X
Lactate
(x)
(x)
SARS-CoV-2 
virology
(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) (x) (x)
(x)
(x)
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
101

Appendix 1: Schedule of Activities (Inpatients Only)
MSTT1041A/UTTR1147A—Genentech, Inc.
102/Protocol GA42469, Version 4
SCRcc Baseline
Primary Phase
Follow 
up
SCa
Study day
2 to
RAND
1
2
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 35
45
60 
or 
ED
Visit window
0
b
b
b
b
c
b
b
b
±2
D
±2
D
±3 
D
Adverse events u
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
X
X
X
X
Concomitant 
medications v
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
X
X
X
X
Study drug 
administration 
X
X w
CENTRAL LABS
Serum PK 
sample(s) x
X
X
X
X
X
X y
X
X
Serum ADA 
sample z
X
X
X
X
Serum sample for 
biomarkers z
X
X
X
X
X
X y
X
X
Blood in 
PAXgenetubes 
for biomarkers z
X
X
X
X
SARS-CoV-2 viral 
load aa
X
X
X y
X
Blood sample for 
WGS (optional) bb
X
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
102

Appendix 1: Schedule of Activities (Inpatients Only) 
  
MSTT1041A/UTTR1147A—Genentech, Inc. 
103/Protocol GA42469, Version 4 
ADA = anti-drug antibodies; BNP = brain natriuretic peptide; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; CT = computed 
tomography; D = days; eCRF = electronic Case Report Form; ED = early discontinuation visit; FiO2 = fraction of inspired oxygen; h = hours; 
NEWS2 = National Early Warning Score 2; NT-proBNP = N-terminal pro-brain natriuretic peptide; PaO2 = partial pressure of oxygen; 
PK = pharmacokinetic; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; RAND = randomization; SC = study completion; 
SCR = screening; SpO2 = peripheral capillary oxygen saturation; ULN = upper limit of normal; WGS = whole genome sequencing; X = mandatory 
assessment; (x) = Will be recorded on appropriate eCRF if the assessment is clinically indicated per standard of care. 
Notes:  On treatment days, all assessments including collection of laboratory samples should be performed prior to dosing, unless 
otherwise specified.  Once patient is ready for discharge from the hospital (or will be transferred to a different care facility), please refer 
to Appendix 2.  Screening period will be up to 2 days.  All screening assessments will be completed, including review of screening test 
results (except for the influenza virology test) and confirming eligibility, prior to randomizing the patient. 
a Patients who complete a study will perform a study completion visit.  Patients who discontinue the study prematurely should perform a study 
discontinuation visit, if possible. 
b The window for central laboratory sample collection is as follows: On Day 2, collection is 24 ± 2 hours after the end of study drug infusion on 
Day 1, on Day 3, the window is + 2 days, and on Days 7, 21, and 28, the window is ± 2 days.  For local labs (hematology, chemistry, and 
coagulation), the following window applies for Days 7, 10, 17, 21, and 28:  Results from standard-of-care labs can be used if drawn within 
1 day prior to the specified timepoint. 
c It is preferred that the second dose of study drug be administered on Day 15.  In cases where this is not possible, study drug administration can 
occur on Day 14, Day 16, or Day 17, provided a pregnancy test (women of childbearing potential), ECG, vital signs, hematology, chemistry, 
coagulation, NT-proBNP or BNP, troponin I or T, and CRP are performed and evaluated within 2 days prior to study drug administration.  
Samples for central laboratory tests must also be collected prior to study drug administration, with the exception of the post-dose PK sample.  
d Informed consent must be documented before any study-specific screening procedure is performed. 
e For screening, historic results of influenza and SARS-CoV-2 virology, performed within 14 days prior to Day 1 are acceptable.   
f Medical history, including clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, and home oxygen use will be recorded at screening.   
g Physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, gastrointestinal, and neurologic systems. 
h If weight or height cannot be assessed on the indicated study day, the most recent documented value is acceptable (e.g., from hospital 
admission). 
i Assessment is optional (to be performed at the investigator's discretion) for patients who will not receive a second dose.   
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
103

Appendix 1: Schedule of Activities (Inpatients Only)
MSTT1041A/UTTR1147A—Genentech, Inc.
104/Protocol GA42469, Version 4
j
For women of childbearing potential, including those who have had a tubal ligation.  Positive urine test results will be confirmed with a serum 
pregnancy test.  Study drug can be administered only if the initial urine or serum pregnancy test result is negative or if a positive urine pregnancy 
test is followed by a negative serum pregnancy test.
k Chest CT scan will be performed at Screening and Study completion/Discontinuation visit. For Screening, historic test results within 7 days prior 
to Day 1 are acceptable. If chest CT scan is not available for Screening, a chest X-ray is acceptable.
l
Perform a limited, symptom-directed examination as clinically indicated.
m Site personnel should record one representative set of vital signs (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and 
body temperature) and oxygen saturation measurements, as well as NEWS2-specific assessments (i.e., consciousness and presence or 
absence of oxygen support), from a single timepoint, ideally within 1 hour prior to treatment administration at the baseline visit (Day 1) and 
between 8 a.m. and 12 p.m. at subsequent visits during patient hospitalization.  When possible, the patient should be assessed at approximately 
the same time each day.
n Arterial blood gases (oxygen,, partial pressure of carbon dioxide, PaO2, pH, FiO2, bicarbonate) will be collected at screening and Day 1 only for 
patients who are mechanically ventilated and have an existing arterial line. On subsequent visits, arterial blood gases will be recorded only if the 
patient has an existing arterial line and arterial blood gas measurement is clinically indicated per standard of care.
o Local laboratory assessments do not need to be repeated if screening or standard of care labs were drawn the day prior to Day 1.
p Assessment of patient status using the ordinal scale should be recorded prior to dosing at baseline on Day 1 and then again once daily every 
morning (ideally between 8 a.m. and 12 p.m.) at subsequent visits during patient hospitalization. When possible, the patient should be 
assessed at approximately the same time of day.
q Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
r
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, AST, urate, 
LDH, and ferritin.
s Coagulation panel includes INR, PT, aPTT, fibrinogen, and D-dimer.
t
Troponin should be determined via high-sensitivity immunoassay, if possible.  If the high-sensitivity immunoassay is not available locally, 
troponin can be determined via conventional assay.  For troponin values ULN, an echocardiogram may be recommended as described in 
Sections 4.1.2 and 5.1.3.3.
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
104

Appendix 1: Schedule of Activities (Inpatients Only)
MSTT1041A/UTTR1147A—Genentech, Inc.
105/Protocol GA42469, Version 4
u 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 the Study completion/Discontinuation visit.  
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).
v Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal remedies) used by a patient in addition to protocol-mandated 
treatment from 7 days prior to initiation of study drug until the Study completion/Discontinuation visit.  For concomitant therapy used by a patient 
7 days prior to initiation, only concomitant therapy for treatment of COVID-19 will be recorded.
w A second dose of study drug will be given on Day 15 if the patient remains hospitalized with a requirement for supplemental oxygen therapy, 
unless patient meets the study drug discontinuation criteria (see Section 4.6.1). 
x On dosing days (Day 1 and, if applicable, Day 15), predose and postdose (30 [10] minutes after end of infusion) PK samples will be collected.
Single PK samples will be collected at other specified visits, including Day 15 if the second dose is not administered. Leftover PK samples may 
be used for immunogenicity assessment and biomarker measurements.
y Samples should be collected for patients who received a second dose. Sampling is optional for patients who did not receive a second dose.  
z On dosing days, ADA and biomarker samples will be collected predose.
aa If it is possible to only access one nostril for sampling, the same nostril should be used at each sampling time point, if possible (see the 
appropriate laboratory manual for details).
bb Patients must provide consent to participate.  Not applicable for a site that has not been granted approval for WGS sampling. If the sample is 
not collected at the baseline visit for any reason, it may be collected at any later timepoint. 
cc Historic standard-of-care assessments are acceptable if performed within 2 days prior to Day 1, unless otherwise specified. 
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
105

MSTT1041A/UTTR1147A—Genentech, Inc.
106/Protocol GA42469, Version 4
Appendix 2
Schedule of Activities (Post-Discharge)
Discharge 
Day
Remote Visits 
(Telephone or Video Visit)
In-Clinic
Visit a
Remote Visits 
(Telephone or Video Visit)
SC a
Study day
3
7
14
21
28
35
45
60 or ED
Visit window
±1 D
±2 D
±2 D
±2 D
±2 D
±2 D
±2 D
±3 D
LOCAL LABS/ASSESSMENTS
Pregnancy test (urine or 
serum) b
X p
X
Chest X-ray/CT scan c
(x)
(x)
X
ECG
X p
(x)
X
Limited physical examination d
(x)
(x)
X
Vital signs (including SpO2 & 
FiO2) and NEWS2 e
X
X
X
Ordinal scoring f
X
X
X
X
X
X
X
X
X
Hematology g
X p
X
X
Chemistry h
X p
X
X
Coagulation i
X p
X
X
CRP
X p
X
X
Limited vital signs j
X
X
X
X
X
X
Adverse events k
X
X
X
X
X
X
X
X
X
Concomitant medications l
X
X
X
X
X
X
X
X
X
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
106

Appendix 2: Schedule of Activities (Post-Discharge)
MSTT1041A/UTTR1147A—Genentech, Inc.
107/Protocol GA42469, Version 4
Discharge 
Day
Remote Visits 
(Telephone or Video Visit)
In-Clinic
Visit a
Remote Visits 
(Telephone or Video Visit)
SC a
Study day
3
7
14
21
28
35
45
60 or ED
Visit window
±1 D
±2 D
±2 D
±2 D
±2 D
±2 D
±2 D
±3 D
CENTRAL LABS
Serum PK sample m
X p
X
X
Serum ADA sample
X p
X
X
Serum sample for biomarkers
X p
X
X
Blood in PAXgene tubes for 
biomarkers 
X p
SARS-CoV-2 viral load n
X o
X
ADAanti-drug antibodies; CRPC-reactive protein; CTcomputed tomography; ED early discontinuation visit; DDay; FiO2 fraction of 
inspired oxygen; NEWS2National Early Warning Score 2; PKpharmacokinetic; SARS-CoV-2severe acute respiratory syndrome coronavirus 
2; SC study completion; SCR screening; SpO2peripheral capillary oxygen saturation; ULNupper limit of normal; X=mandatory 
assessments; (x)=will be recorded on appropriate eCRF if the assessment is clinically indicated per standard of care.
Notes: Study day refers to days on study (e.g., study Day 3 is 2 days after the randomization day) and not to the number of days 
post-discharge. As discharge dates will vary across patients, this schedule of activities is effective starting on initial discharge day of 
the patient, subsequent visits should align with the patient's day on study, for a maximum total study duration of 60 days, for each 
patient.
a If possible, an in-clinic visit should be performed.  Otherwise, a remote visit (via telephone or video visit) will be performed and the following 
assessments will be recorded: Ordinal scoring, limited vital signs, adverse events, and concomitant medications.
b For women of childbearing potential, including those who have had a tubal ligation, positive urine test results will be confirmed with a serum 
pregnancy test.  
c On Day 60, a chest CT should be performed if possible.
d Perform a limited, symptom-directed examination as clinically indicated.
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
107

Appendix 2: Schedule of Activities (Post-Discharge)
MSTT1041A/UTTR1147A—Genentech, Inc.
108/Protocol GA42469, Version 4
e Vital sign measurement (i.e., respiratory rate, pulse rate, systolic and diastolic blood pressures, and body temperature), oxygen saturation and 
NEWS2-specific assessments (i.e., consciousness and presence or absence of oxygen support) should be recorded together in the morning 
(ideally between 8 a.m. and 12 p.m.), if possible.
f
Assessment of patient status using the ordinal scale should be performed in the morning (ideally between 8 a.m. and 12 p.m.), if possible.
g Hematology includes (WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
h Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, AST, urate.
i
Coagulation panel includes INR, PT, aPTT, fibrinogen, and D-dimer.
j
Following hospital discharge, limited vital signs should be reported, if possible. Limited vital signs include pulse rate, oxygen saturation, and 
details on supplemental oxygen use/mechanical ventilation, if applicable. 
k All adverse events will be reported until the Study completion/Discontinuation visit.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).
l
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, or herbal remedies) used by a patient in addition to protocol-mandated 
treatment from 7 days prior to initiation of study drug until the Study completion/Discontinuation visit.
m Leftover PK samples may be used for immunogenicity assessment.
n If it is possible to only access one nostril for sampling, the same nostril should be used at each sampling time point, if possible (see the 
appropriate laboratory manual for details).
o Collect if patient is discharged on or before Day 15.  
p Assessments do not need to be repeated if protocol or standard-of-care assessments were performed on the day prior to discharge day.
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
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108

MSTT1041A/UTTR1147A—Genentech, Inc.
109/Protocol GA42469, Version 4
Appendix 3
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1. Stop the study treatment infusion.
2. Call for additional medical assistance.
3. Maintain an adequate airway.
4. Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.
5. Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge.
6. Continue to observe the patient and document observations.
7. Consider the measurement of tryptase (serum or plasma) and histamine 
(plasma) levels to support a diagnosis of anaphylaxis
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
109

MSTT1041A/UTTR1147A—Genentech, Inc.
110/Protocol GA42469, Version 4
Appendix 4
National Early Warning Score 2 (NEWS2)
CVPUconfusion, voice, pain, unresponsive; SpO2peripheral capillary 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.
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
110

Appendix 4: National Early Warning Score 2 (NEWS2)
MSTT1041A/UTTR1147A—Genentech, Inc.
111/Protocol GA42469, Version 4
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 
electronic Case Report Form (eCRF).
Example Case Calculation:
An 82-year-old lady was admitted, tested positive to coronavirus disease 2019 
(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 (C)
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.
Protocol Number: 
 Report Number: 
Clinical Study Report: RO7021610 - F. Hoffmann La Roche Ltd
GA42469
1109570
111