Conditions: Covid19
Keywords: SARS-CoV-2 coronavirus coronavirus disease 2019 COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1057
Healthy volunteers: no

Brief summary:
This is a phase 2/3 study in which subjects with coronavirus disease 2019 (COVID-19) will receive VIR-7831 or placebo and will be assessed for safety, tolerability, efficacy, and pharmacokinetics.

Detailed description:

Arms:
arm 1: Participants received 500 mg sotrovimab administered intravenously (IV) arm 2: Participants received placebo administered intravenously (IV)

Interventions: intervention 1: VIR-7831 (sotrovimab) intervention 2: Placebo
Intervention descriptions: intervention 1: VIR-7831 (sotrovimab) given by intravenous infusion (single dose) intervention 2: Sterile normal saline (0.9% NaCl) given by intravenous infusion (single dose)

Protocol document:
Prot_000.pdf: 
Protocol Amendment 2 
Study ID:  214367 
Official Title of Study: A Phase II/III randomized, multi-center, double-blind, placebo-
controlled study to assess the safety and efficacy of monoclonal antibody VIR-7831 for 
the early treatment of coronavirus disease 2019 (COVID-19) in non-hospitalized patients. 
NCT ID: NCT04545060 
Date of Document: 17-JUN-2021


 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase II/III randomized, multi-center, double-blind, placebo-controlled 
study to assess the safety and efficacy of monoclonal antibody VIR-7831 for 
the early treatment of coronavirus disease 2019 (COVID-19) in non-
hospitalized patients 
Sponsor: 
This study is sponsored by Vir Biotechnology, Inc. 
GlaxoSmithKline is supporting Vir Biotechnology, Inc. in the conduct of this 
study. 
Vir Biotechnology, Inc. 
499 Illinois Street, Suite 500 
San Francisco, CA 94158, USA 
Investigational Product: VIR-7831 (GSK4182136) 
Regulatory Identifying 
Numbers: 
IND: IND #149315 
EudraCT: 2020-002871-36 
NCT: NCT04545060 
IND Number: 
149315 
Indication: 
Treatment and prevention of coronavirus disease 2019(COVID-19) 
Study Number: 
VIR-7831-5001 (GSK Study 214367) 
: 
Name:   
 
Telephone: 
 
Email:   
Medical Monitor: 
Name:   
 
Telephone: 
 
Email:   
 
Protocol Version/Date: 
Amendment 2:  17 June 2021 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information that is the property of Vir Biotechnology Inc. This 
confidential information is being provided for the purpose of evaluating or conducting a clinical study. 
This confidential information will be protected by you and your staff against disclosure to or use by third 
parties, except as necessary for the evaluation or conduct of the study. 
 
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INVESTIGATOR SIGNATURE PAGE 
 
VIR BIOTECHNOLOGY, INC 
499 ILLINOIS STREET SUITE 500 
SAN FRANCISCO, CA 94158 
 
STUDY ACKNOWLEDGMENT 
 
A randomized, multi-center, double-blind, placebo-controlled study to assess the 
safety and efficacy of monoclonal antibody VIR-7831 for the early treatment of 
coronavirus disease 2019 (COVID-19) in non-hospitalized patients 
VIR-7831-5001, Protocol Amendment 2, 17 June 2021 
This protocol has been approved by Vir Biotechnology, Inc. The following signature 
documents this approval.  
, Pharm D 
Vir 
, Clinical Research 
 {See Appended Electronic Signature Page} 
Printed Name 
 Signature and Date 
 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all 
necessary details for me and my staff to conduct this study as described. I will conduct 
this study as outlined herein and will make a reasonable effort to complete the study 
within the time designated.  
I will provide all study personnel under my supervision copies of the protocol and access 
to all information provided by Vir Biotechnology, Inc. I will discuss this material with 
them to ensure they are fully informed about the drugs and the study.  
 
 
  
Principal Investigator Printed Name 
 Signature 
 
  
 
 Date 
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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY .................................................................. 8 
1.1. 
Synopsis .............................................................................................. 8 
1.2. 
Study Schema ................................................................................... 14 
1.3. 
Schedule of Activities ....................................................................... 15 
2. 
INTRODUCTION ............................................................................ 19 
2.1. 
Study Rationale ................................................................................. 19 
2.2. 
Background ....................................................................................... 19 
2.3. 
Benefit/Risk Assessment .................................................................. 20 
2.3.1. 
Risk Assessment ............................................................................... 21 
2.3.2. 
Benefit Assessment ........................................................................... 28 
2.3.3. 
Overall Benefit: Risk Conclusion ..................................................... 28 
3. 
OBJECTIVES AND ENDPOINTS .................................................. 29 
4. 
STUDY DESIGN ............................................................................. 32 
4.1. 
Overall Design .................................................................................. 32 
4.2. 
Scientific Rationale for Study Design .............................................. 32 
4.3. 
Justification for Dose ........................................................................ 33 
4.3.1. 
VIR-7831 .......................................................................................... 33 
4.3.2. 
Placebo .............................................................................................. 34 
4.4. 
End of Study Definition .................................................................... 35 
5. 
STUDY POPULATION ................................................................... 36 
5.1. 
Inclusion Criteria .............................................................................. 36 
5.1.1. 
Age and Risk Factors ........................................................................ 36 
5.1.2. 
Type of Participant and Disease Characteristics .............................. 36 
5.1.3. 
Sex and Contraceptive/Barrier Requirements .................................. 36 
5.1.4. 
Informed Consent ............................................................................. 37 
5.2. 
Exclusion Criteria ............................................................................. 37 
5.2.1. 
Medical Conditions ........................................................................... 37 
5.2.2. 
Prior/Concurrent Clinical Study Experience .................................... 38 
5.2.3. 
Other Exclusions ............................................................................... 38 
5.3. 
Lifestyle Considerations ................................................................... 38 
5.4. 
Screen Failures .................................................................................. 38 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
 .......................................................................................................... 39 
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6.1. 
Study Intervention(s) Administered ................................................. 39 
6.2. 
Preparation/Handling/Storage/Accountability .................................. 40 
6.3. 
Measures to Minimize Bias: Randomization and Blinding .............. 40 
6.4. 
Study Intervention Compliance ........................................................ 41 
6.5. 
Dose Modification ............................................................................ 41 
6.6. 
Continued Access to Study Intervention after the End of the Study 41 
6.7. 
Treatment of Overdose ..................................................................... 41 
6.8. 
Concomitant Therapy ....................................................................... 41 
6.8.1. 
Medication Not Permitted During the Study .................................... 42 
6.8.2. 
Permitted Concomitant Medication .................................................. 42 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ............. 43 
7.1. 
Discontinuation of Study Intervention.............................................. 43 
7.1.1. 
Temporary Discontinuation .............................................................. 43 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................. 43 
7.3. 
Lost to Follow Up ............................................................................. 43 
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................ 45 
8.1. 
Screening Period ............................................................................... 46 
8.1.1. 
Medical History ................................................................................ 46 
8.1.2. 
SARS-CoV-2 Diagnostic Testing ..................................................... 46 
8.1.3. 
Secondary Contact Information ........................................................ 46 
8.2. 
Efficacy Assessments ....................................................................... 46 
8.2.1. 
Hospitalization and Death Data Collection ...................................... 46 
8.2.2. 
Active Monitoring of COVID-19 Progression Phone Call ............... 47 
8.2.2.1. 
Lead-In Phase ................................................................................... 47 
8.2.2.2. 
Expansion Phase ............................................................................... 47 
8.2.3. 
Phone Call for Subsequent COVID-19 Illness ................................. 47 
8.2.4. 
Participant Reported Outcome Assessments .................................... 47 
8.2.4.1. 
FLU-PRO Plus Questionnaire .......................................................... 47 
8.2.4.2. 
Health-related Quality of Life (SF-12 Hybrid) ................................. 48 
8.2.4.3. 
Work Productivity and Activity Impairment (WPAI) ...................... 48 
8.3. 
Safety Assessments ........................................................................... 48 
8.3.1. 
Physical Examinations ...................................................................... 48 
8.3.2. 
Vital Signs ........................................................................................ 49 
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8.3.3. 
Electrocardiograms ........................................................................... 49 
8.3.4. 
Cardiac Monitoring ........................................................................... 49 
8.3.5. 
Virologic Measures ........................................................................... 49 
8.3.6. 
Clinical Safety Laboratory Assessments .......................................... 50 
8.3.7. 
Pregnancy Testing ............................................................................ 50 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ............................................................................... 51 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information
 .......................................................................................................... 52 
8.4.2. 
Assessment of Severity ..................................................................... 53 
8.4.3. 
Method of Detecting AEs and SAEs ................................................ 53 
8.4.4. 
Follow-up of AEs and SAEs ............................................................. 53 
8.4.5. 
Regulatory Reporting Requirements for SAEs ................................. 53 
8.4.6. 
Pregnancy ......................................................................................... 53 
8.4.7. 
Cardiovascular and Death Events ..................................................... 54 
8.4.8. 
Adverse Events of Special Interest ................................................... 54 
8.4.8.1. 
Infusion-Related Reactions and Serious Hypersensitivity ............... 54 
8.4.8.2. 
Immunogenicity ................................................................................ 55 
8.4.8.3. 
Antibody Dependent Enhancement .................................................. 55 
8.5. 
Pharmacokinetics .............................................................................. 55 
8.6. 
Genetics ............................................................................................ 56 
8.7. 
Biomarkers ........................................................................................ 56 
8.7.1. 
Resistance Analyses .......................................................................... 57 
8.8. 
Immunogenicity Assessments .......................................................... 57 
9. 
STATISTICAL CONSIDERATIONS ............................................. 58 
9.1. 
Statistical Hypotheses ....................................................................... 58 
9.2. 
Sample Size Determination .............................................................. 58 
9.3. 
Analysis Sets ..................................................................................... 59 
9.4. 
Statistical Analyses ........................................................................... 59 
9.4.1. 
General Considerations ..................................................................... 60 
9.4.2. 
Primary Endpoint(s) .......................................................................... 60 
9.4.3. 
Secondary Endpoint(s) ...................................................................... 60 
9.4.4. 
Exploratory Endpoint(s) ................................................................... 60 
9.4.5. 
Safety Analysis ................................................................................. 61 
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9.4.6. 
Other Analysis .................................................................................. 61 
9.5. 
Interim Analysis ................................................................................ 61 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ........................................................................ 62 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .................................................................................. 62 
10.1.1. 
Regulatory and Ethical Considerations ............................................ 62 
10.1.2. 
Financial Disclosure ......................................................................... 62 
10.1.3. 
Informed Consent Process ................................................................ 63 
10.1.4. 
Data Protection ................................................................................. 63 
10.1.5. 
Committees Structure ....................................................................... 64 
10.1.6. 
Dissemination of Clinical Study Data .............................................. 64 
10.1.7. 
Data Quality Assurance .................................................................... 65 
10.1.8. 
Source Documents ............................................................................ 66 
10.1.9. 
Study and Site Start and Closure ...................................................... 66 
10.1.10. 
Publication Policy ............................................................................. 67 
10.2. 
Appendix 2: Clinical Laboratory Tests ............................................. 67 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ........................... 69 
10.3.1. 
Definition of AE ............................................................................... 69 
10.3.2. 
Definition of SAE ............................................................................. 70 
10.3.3. 
Definition of Cardiovascular Events ................................................ 71 
10.3.4. 
Recording and Follow-Up of AE and SAE ...................................... 71 
10.3.5. 
Reporting of SAE to GSK ................................................................ 73 
10.3.6. 
Expedited Reporting to Health Authorities, Investigators and Ethics 
Committees ....................................................................................... 74 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ............................ 74 
10.4.1. 
Definitions: ....................................................................................... 74 
10.4.2. 
Contraception Guidance: .................................................................. 76 
10.5. 
Appendix 5: Genetics ....................................................................... 77 
10.5.1. 
USE/ANALYSIS OF DNA .............................................................. 77 
11. 
REFERENCES ................................................................................. 81 
 
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LIST OF TABLES 
Table 1: 
Lead-In Phase: Schedule of Activities .............................................. 15 
Table 2: 
Expansion Phase: Schedule of Activities ......................................... 17 
Table 3: 
Overview of Study Intervention ....................................................... 39 
Table 4: 
Protocol-Required Safety Laboratory Tests ..................................... 68 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Title: A randomized, multi-center, double-blind, placebo-controlled study to assess the 
safety and efficacy of monoclonal antibody VIR-7831 for the early treatment of 
coronavirus disease 2019 (COVID-19) in non-hospitalized patients 
Rationale: 
There is an urgent medical need for therapeutics for the treatment of Severe Acute 
Respiratory Syndrome coronavirus-2 (SARS-CoV-2) infection, the cause of coronavirus 
disease 2019 (COVID-19). Early treatment of mild and moderate disease in outpatients 
could prevent the more severe sequelae of COVID-19 requiring hospitalization, such as 
respiratory failure, thromboembolic disease leading to pulmonary embolism and stroke, 
arrhythmias, and shock. Furthermore, a potent treatment given early in disease could 
ameliorate the severity and duration of COVID-19 and potentially reduce transmission. 
Vir Biotechnology, Inc. (Vir) has developed a fully human neutralizing 
anti-SARS-CoV-2 antibody (Pinto et al. 2020), VIR-7831 (GSK4182136), which has an 
Fc-modification (“LS”) that is designed to improve bioavailability in the respiratory 
mucosa (Hope et al. 2019) and increase half-life (Ko et al. 2014). 
The Lead-In phase of this study will serve as the first-in-human (FIH) assessment and 
includes participants with mild/moderate COVID-19 to assess the safety and tolerability 
of VIR-7831. Following initial safety assessment in the Lead-In phase, assessment of 
safety and efficacy will commence in the Expansion phase of this study with the aim of 
preventing disease progression in high-risk participants.  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
Evaluate the efficacy of VIR-7831 versus 
placebo in preventing the progression of 
mild/moderate COVID-19  
Proportion of participants who have 
progression of COVID-19 through Day 29 
as defined by: 
1. Hospitalization > 24 hours for acute 
management of illness 
OR 
2. Death 
Secondary 
 
Safety 
Determine the safety and tolerability of 
VIR-7831 compared to placebo 
 
• 
Occurrence of adverse events (AEs) 
• 
Occurrence of serious adverse 
events (SAEs)  
• 
Occurrence of adverse events of 
special interest (AESI) 
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Objectives 
Endpoints 
Assess the immunogenicity of VIR-7831 
• 
Incidence and titers (if applicable) 
of serum ADA to VIR-7831 
Pharmacokinetics 
Assess the pharmacokinetics (PK) of VIR-
7831 in serum 
 
• 
VIR-7831 pharmacokinetics (PK) 
in serum 
Efficacy 
Evaluate the efficacy of VIR-7831 versus 
placebo in preventing the progression of 
mild/moderate COVID-19 
 
Proportion of participants who have 
progression of COVID-19 through Day 29 
as defined by: 
• 
Visit to a hospital emergency room 
for management of illness  
OR 
• 
Hospitalization for acute 
management of illness 
OR 
• 
Death 
Evaluate the impact of VIR-7831 versus 
placebo on the duration and the severity of 
COVID-19 clinical symptoms 
•  Mean change in FLU-PRO Plus total 
score comparing Vir-7831 vs. 
Placebo (AUC through Day 7) 
• 
Time to symptom alleviation using 
the FLU-PRO Plus 
Evaluate the efficacy of VIR-7831 versus 
placebo in reducing SARS-CoV-2 viral load 
• 
Change from baseline in viral load 
in nasal secretions by qRT-PCR at 
Day 8 
Evaluate the efficacy of VIR-7831 against 
versus placebo in preventing COVID-19 
respiratory disease progression  
• 
Proportion of participants who 
progress to develop severe and/or 
critical respiratory COVID-19 as 
manifest by requirement for and 
method of supplemental oxygen at 
Day 8, Day 15, Day 22, or Day 29 
Evaluate the efficacy of VIR-7831 versus 
placebo in preventing mortality 
• 
29-day, 60-day, and 90-day all-
cause mortality 
Exploratory 
 
Evaluate the impact of VIR-7831 versus 
placebo on incidence and duration of time 
on a ventilator, ICU length of stay (LOS), 
and total hospital LOS 
• 
Total number of ventilator days 
from randomization through 90 
days 
• 
Total intensive care LOS 
• 
Total hospital LOS 
Evaluate the efficacy of VIR-7831 versus 
placebo in preventing hospitalization from 
• 
Proportion of participants 
hospitalized due to non-respiratory 
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Objectives 
Endpoints 
non-respiratory complications of 
COVID-19 
complications of COVID-19 
(cardiac, renal, neurologic, 
hematologic events) by Day 8, Day 
15, Day 22, and Day 29 
Monitor on-treatment emergence of SARS-
CoV-2 resistant mutants against VIR-7831  
• 
Emergence of viral resistance 
mutants to mAb by SARS-CoV-2  
Evaluate the efficacy of VIR-7831 versus 
placebo in reducing duration of SARS-
CoV-2 viral shedding and viremia 
• 
Detection of SARS-CoV-2 in nasal 
secretions by RT-PCR at baseline 
and during follow-up period 
through Day 29 
• 
Detection of SARS-CoV-2 in blood 
by RT-PCR at baseline and during 
follow-up period through Day 29 
Evaluate the efficacy of VIR-7831 versus 
placebo in reducing SARS-CoV-2 viral load 
• 
Change from baseline in viral load 
in nasal secretions by qRT-PCR 
during follow-up period through 
Day 29 
Evaluate the incidence of respiratory co-
infection with SARS-CoV-2 
• 
Respiratory pathogen detection in 
nasal secretions by PCR on Day 1 
Evaluate the effect of VIR-7831 versus 
placebo on potential biomarkers of host 
response to SARS-CoV-2 
• 
Evaluation of host immune 
responses and exploratory 
biomarkers related to SARS-CoV-2 
and/or VIR-7831, including 
genetic, cellular, transcriptomic, 
and proteomic parameters  
Measure the impact of VIR-7831 treatment 
on health-related quality of life and time 
away from work due to COVID19 
• 
 Change from baseline in Work 
Productivity and Activity 
Impairment (WPAI) questionnaire 
• 
Change from baseline for health-
related quality of life according to 
the SF-12 hybrid questionnaire 
Evaluate the impact of VIR-7831 versus 
placebo on the duration and the severity of 
COVID-19 clinical symptoms 
• 
Mean change in FLU-PRO Plus 
total score (AUC through Days 14, 
21) and Domain scores (AUC 
through Days 7, 14, 21) comparing 
Vir-7831 vs. Placebo 
• 
The proportion of participants with 
symptom alleviation using the 
FLU-PRO Plus at Days 7, 14, 21 
 
 
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Overall Design: 
This study is a randomized, double-blind, multi-center, placebo-controlled trial of 
VIR-7831, a monoclonal antibody (mAb) against SARS-CoV-2 for the prevention of 
progression of mild/moderate COVID-19 in high risk adult participants, with interim 
monitoring to allow early stopping for futility, efficacy, or safety. Participants with early, 
mild/moderate COVID-19 who are at high risk for progression of disease will be 
randomized 1:1 to receive a single, intravenous infusion of either VIR-7831 or equal 
volume saline placebo. Comparisons of safety and efficacy will be based on data from 
concurrently randomized participants.  
Screening assessments will be performed within 24 hours before the first dose. Eligible 
participants will be treated in a blinded manner with a single IV dose on Day 1 and 
followed up to 24 weeks. 
The Lead-In phase of this study will serve as the first-in-human assessment and will 
include 20 non-hospitalized participants who have early, mild/moderate COVID-19 and 
are at high risk of disease progression. These participants will be given a single 
intravenous infusion of VIR-7831 and confined for 7 days for safety monitoring. 
Following a safety assessment of unblinded data by an IDMC, the Expansion phase will 
progress, where additional participants with early, mild/moderate COVID-19 and who are 
at high risk of disease progression will be enrolled. 
Brief Summary: 
Lead-In Phase 
The Lead-In phase of the study will evaluate the safety and tolerability of VIR-7831 in 
participants with early, mild/moderate COVID-19 who are at high risk of progression to 
severe disease. This phase will enroll approximately 10 participants in the active arm and 
10 participants in the placebo arm. Participants will be monitored in an in-patient setting 
for a minimum of 7 days including assessments of respiratory status, oxygenation and 
other vital signs and laboratory evaluations. At the end of 7 days they will either be 
discharged to home or be formally hospitalized based on investigator assessment of 
clinical status. Subjects may be hospitalized or moved to a higher level of care, earlier 
than 7 days, at the investigator’s discretion. 
The first two eligible participants enrolled will be randomized 1:1 to VIR-7831 or 
placebo. These sentinel participants will be dosed and monitored for at least 48 hours 
post-dose and if the investigator has no immediate safety concerns, the remainder of the 
participants in the Lead-In phase will be dosed (total of 10 per arm inclusive of the 
sentinel participants). Participants will be stratified by age (≤70 vs. >70 years old) and 
symptom duration (≤3 days vs. 4-5 days).  
During dose administration vital signs will be monitored every 15 minutes over the 
1-hour IV infusion. Vital signs will also be monitored every hour after infusion for 
2 hours and again at 6 hours after infusion. Vital signs, ECG, symptom-directed physical 
examinations(s), and AEs will be reviewed by the investigator. After discharge on Day 8, 
participants will be actively monitored by daily telephone calls (except on in-clinic visit 
days) through Day 15 for AEs and worsening of COVID-19. 
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Starting at Week 8, participants will be monitored monthly via phone call to assess for 
the incidence and of severity of subsequent COVID-19 illness, if any, for a total of 
24 weeks from dosing. 
Timing of visits and frequency of assessments are outlined in the Schedule of Activities, 
Section 1.3. 
Intensive PK and Immunogenicity Sub-study 
All 20 participants enrolled in the Lead-In (N=10 per arm; VIR-7831 or placebo) will be 
assigned to an immunogenicity sub-study and have additional timepoints for PK blood 
sampling. Serum PK and anti-drug antibodies (ADA) samples will be collected as 
detailed in the Schedule of Activities (Section 1.3, Table 1). 
Expansion Phase 
The Expansion phase of the study will progress following assessment of available 
unblinded safety data from the Lead-in phase (N=10 per arm through Day 15 of 
follow-up) by an IDMC. Outpatient participants with early mild/moderate COVID-19 
who are at high risk for progression to severe disease will be randomized in a 1:1 ratio to 
receive a single IV infusion of VIR-7831 or placebo.  
Participants will be monitored through at least 2 hours post-dose prior to discharge from 
the study unit. During dose administration vital signs will be monitored every 15 minutes 
over the 1-hour IV infusion. Vital signs will also be monitored every hour after infusion 
for 2 hours. Participants will subsequently be actively monitored on an outpatient basis 
with in-person study visits at Weeks 1, 2, 3, and 4 and daily telephone calls (except on 
in-clinic visit days) through Day 15 for AEs and worsening of COVID-19. Serum PK and 
anti-drug antibodies (ADA) samples will be collected as detailed in the Schedule of 
Activities (Section 1.3, Table 2). 
Starting at Week 8, participants will be monitored monthly via phone call to assess for 
the incidence and of severity of subsequent COVID-19 illness, if any, for a total of 
24 weeks from dosing. 
Immunology Assessment Sub-study 
Participants in the Lead-In phase will have blood collections for the isolation of 
peripheral blood mononuclear cells (PBMCs) as part of the required sub-study to explore 
the host immune response and potential biomarkers of infection.  
At select participating sites in the Expansion Phase, participants may consent to an 
optional sub-study. Subjects who consent to the optional sub-study will have blood 
collection for the isolation of PBMCs.  
The timepoints for blood collection for the sub-study are outlined in the Schedule of 
Activities (Section 1.3, Table 2). The sub-study will be done at selected sites in the 
United States only. All 20 subjects in the Lead-In Phase will participate in the sub-study. 
Approximately, 40-100 participants will be enrolled in the optional sub-study in the 
Expansion Phase.  
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Number of Participants: 
Lead-In Phase 
Approximately 10 participants in the placebo arm and approximately 10 participants in 
the treatment arm.  
Expansion Phase 
Approximately 670 participants in the placebo arm and approximately 670 participants in 
the treatment arm. 
Intervention Groups and Duration: 
Screening assessments will be performed within 24 hours prior to randomization. Eligible 
participants will be treated in a blinded manner with a single IV dose on Day 1 and 
followed up to 24 weeks. 
In the Lead-In phase, 20 outpatient participants with mild/moderate COVID-19 will be 
randomized 1:1 to receive a single IV dose of VIR-7831 or placebo. Participants will be 
stratified by age (≤70 vs. >70 years old) and symptom duration (≤3 days vs. 4-5 days). 
Participants enrolled in the Lead-In phase of the study will be closely monitored in an 
in-patient setting for a minimum of 7 days. At the end of 7 days they will either be 
discharged to home or be formally hospitalized based on investigator assessment of 
clinical status. Subjects may be hospitalized or moved to a higher level of care, earlier 
than 7 days, at the investigator’s discretion. 
In the Expansion phase, participants with mild/moderate COVID-19 will be randomized 
1:1 to receive a single IV dose of VIR-7831 or placebo.  
Participants in the Expansion phase will be stratified by the following criteria: 
1. Age: ≤70 vs. >70 years old 
2. Duration of COVID-19 symptoms: ≤3 days vs. 4-5 days 
In addition, randomization will be stratified by region of the world to protect against 
imbalances within specific regions which may have different standards of care. 
Independent Data Monitoring Committee (IDMC) 
An IDMC will actively monitor interim unblinded safety (Lead-In phase) and interim 
unblinded safety and efficacy data (Expansion phase) to make recommendations to Vir 
regarding ongoing study conduct as detailed in the IDMC Charter. The IDMC members 
will include physicians with relevant medical training and one statistician. As noted 
above, the IDMC will review unblinded safety data from the Lead-In phase of the study 
prior to initiation of the Expansion phase. In addition, the IDMC will perform regular 
safety reviews during the Expansion phase.  
The first safety review in the Expansion phase will include available safety and 
tolerability data though Day 15 from a total of 60 participants (30 per arm). If deemed 
necessary, an additional safety review will be conducted after approximately 100 
additional participants are enrolled (50 per arm) to review safety and tolerability data 
through Day 15. IDMC members will also review all SAEs via draft CIOMS when they 
become available. Finally, two interim analyses (IA) will be conducted at approximately 
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41% of participants enrolled and approximately 64% of participants enrolled to evaluate 
safety, futility, and efficacy based on data through Day 29 for these participants. 
Additional details regarding the IDMC process will be available in relevant IDMC 
documents. 
Joint Safety Review Team (JSRT) 
A Joint Safety Review Team (JSRT) comprised of team members from clinical research, 
pharmacovigilance and statistics will determine if a safety concern identified during 
instream blinded data review needs to be escalated to the IDMC. The IDMC will act in 
accordance with the process defined in the IDMC Charter. 
1.2. 
Study Schema 
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1.3. 
Schedule of Activities  
Table 1: 
Lead-In Phase: Schedule of Activities 
Study Stage 
Screening 
In-patient 
Follow-up Period 
Study Visit Week 
 
 
W2 
W3 
W4 
W6 
W8 
W12 
W16h 
W20 
W24 
(EOS/EW) 
Study Visit Day ± Visit Window 
D-1 
D1 
D2 
D5 
D8 
D11 
D15±1 D22±1 
D29±2 
D43±3 
D57±4 
D85±7 
D113±7 
D141±7 
D169±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
Xa 
Xa (daily) 
 
Xa 
Xa 
Xa 
 
 
 
 
 
 
Body weight & height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs b  
(including O2 saturation) 
X 
Xb 
X (every 8 hrs) 
 
X 
X 
X 
 
 
 
 
 
X 
Local safety lab assessments 
X 
Xj 
Xj 
X 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory assessments (central) 
 
Xd 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
SARS-CoV-2 diagnostic test i 
(point-of-care or local laboratory test) 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Electrocardiogram 
X 
X (daily) 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for PK analysis 
 
Xc 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
Blood sample for anti-drug antibody 
 
Xd 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
Blood sample for  
anti-SARS-CoV-2 antibody 
 
Xd 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
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Table 1: 
Lead-In Phase: Schedule of Activities (Continued) 
Study Stage 
Screening 
In-patient 
 
Follow-up Period 
Study Visit Week 
 
 
W2 
W3 
W4 
W6 
W8 
W12 
W16h 
W20 
W24 
(EOS/EW) 
Study Visit Day ± Visit Window 
D-1 
D1 
D2 
D5 
D8 
D11 
D15±1 D22±1 
D29±2 
D43±3 
D57±4 
D85±7 
D113±7 
D141±7 
D169±7 
Blood sample for virology 
 
Xd 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Blood sample for FcR and IgG analysis 
(optional test) 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for RNA Paxgene 
(optional test) 
 
Xd 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for virology 
 
Xd 
 
X 
X 
X 
X 
X 
Xg 
 
 
 
 
 
 
Symptom self-assessment (Flu-PRO 
Plus) 
 
X (daily through Day 21) 
 
X 
 
X 
X 
 
 
 
Phone call for active COVID-19 
monitoringe 
 
 
X (daily)e 
 
 
 
 
 
 
 
 
Phone call for subsequent COVID-19 
illness 
 
X 
X 
X 
X 
 
Review/record AEs f 
Xf 
Concomitant medications 
X 
Blood sample for exploratory 
immunology 
 
Xd 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PBMC sample for immunology  
 
Xd 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
a Complete physical examination should be performed on Day 1; all other visits should be symptom-directed physical examinations 
b Vital signs on Day 1 should be recorded prior to dose administration, every 15 min during IV infusion, and at 1, 2 and 6 hours after end of infusion.  
c On Day 1, sample collection will occur pre-dose and at the end of infusion, 1, 2, 6, and 12 hours following end of infusion 
d On Day 1, sample collection will occur pre-dose  
e Daily starting on Day 9, no phone call conducted on in-clinic visit days 
f Adverse events will be assessed up to Week 12. Serious adverse events (SAEs) will be assessed up to Week 24 
g If nasopharyngeal swab sample is positive for SARS-CoV-2 by RT-PCR at Week 4 additional nasopharyngeal swab samples may be collected up to Week 24 
h Week 16 is planned as site phone call to participants only 
i Participants may be tested at screening if symptom onset ≤ 5 days 
j Urine for albumin to creatinine ratio should be collected pre-dose on Day 1 and on Day 2 and performed locally 
 
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Table 2: 
Expansion Phase: Schedule of Activities 
Study Stage 
Screening Dosing 
Follow-up Period 
Study Visit Week 
 
W1 
W2 
W3 
W4 
W8i 
W12 
W16i 
W20 
W24 
(EOS/EW)  
Study Visit Day ± Visit Window 
D -1 
D1 
D5 
D8±1 
D11±1 
D15±1 
D22±1 
D29±2 
D57±4 
D85±7 
D113±7 
D141±7 
D169±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
Xa 
Xa 
 
Xa 
 
Xa 
Xa 
Xa 
 
 
 
 
 
Body weight & height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (including O2 saturation) 
X 
Xb 
 
X 
 
X 
X 
X 
 
 
 
 
X 
Local safety lab assessments 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessments (central) 
 
Xd 
 
X 
 
X 
X 
X 
 
 
 
 
 
SARS-CoV-2 diagnostic test j 
(point-of-care or local laboratory 
test) 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Electrocardiogram (Pre-dose) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Phone call for active COVID-19 
monitoringe 
 
X (daily)e 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for PK analysis 
 
Xc 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood sample for anti-drug antibody 
 
Xd 
 
 
 
 
 
X 
 
X 
 
X 
X 
Blood sample for anti-SARS-CoV-2 
antibody 
 
Xd 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Blood sample for virology  
 
Xd 
 
X 
 
X 
 
X 
 
 
 
 
 
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Table 2: 
Expansion Phase: Schedule of Activities (Continued) 
Study Stage 
Screening Dosing 
Follow-up Period 
Study Visit Week 
 
W1 
W2 
W3 
W4 
W8i 
W12 
W16i 
W20 
W24 
(EOS/EW) 
Study Visit Day ± Visit Window 
D -1 
D1 
D5 
D8±1 
D11±1 
D15±1 
D22±1 
D29±2 
D57±4 
D85±7 
D113±7 
D141±7 
D169±7 
Blood sample for FcR and IgG 
analysis (optional test) 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for RNA Paxgene 
(optional test) 
 
Xd 
 
X 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for virology 
 
Xd 
X 
X 
X 
X 
X 
Xh 
 
 
 
 
 
Symptom self-assessment  
(Flu-PRO Plus) 
 
X (daily through Day 21) 
 
X 
X 
X 
 
 
 
WPAI Questionnaire 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
SF-12 Hybrid Questionnaire 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Long COVID assessment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Phone call for subsequent COVID19 
illness 
 
X 
X 
X 
X 
 
Review/record AEs f 
Xf 
Concomitant medications 
X 
Blood sample for exploratory 
immunology 
 
Xd 
 
X 
 
 
 
 
 
 
 
 
 
PBMC sample for immunology g  
 
Xd 
 
 
 
 
 
X 
 
 
 
 
X 
 
a Complete physical examination should be performed on Day 1; all other visits should be symptom-directed physical examinations 
b Vital signs on Day 1 should be recorded prior to dose administration, every 15 min during IV infusion of study drug, and at 1 and 2 hours after infusion 
c On Day 1, sample will be collected pre-dose and at the end of infusion  
d On Day 1, sample collection will occur pre-dose 
e No phone call conducted on in-clinic visit days 
f Adverse events will be assessed up to Week 12 post dose. Serious adverse events (SAEs) will be assessed up to Week 24. 
g Optional immunology sub-study 
h If nasopharyngeal swab sample is positive for SARS-CoV-2 by RT-PCR at Week 4 additional nasopharyngeal swab samples may be collected up to Week 24 
i Week 8 and Week 16 are planned as site phone call to participants only 
j Participants may be tested at screening if symptom onset ≤ 5 days 
k Except for ABO typing, all other local lab assessments may be performed or not as determined necessary by the investigator or required by local regulations 
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2. 
INTRODUCTION 
2.1. 
Study Rationale  
There is an urgent medical need for therapeutics for the treatment of Severe Acute 
Respiratory Syndrome coronavirus-2 (SARS-CoV-2), the cause of coronavirus disease 
2019 (COVID-19). Early treatment of mild and moderate disease in outpatients could 
prevent the more severe sequelae of COVID-19 requiring hospitalization such as 
respiratory failure, and non-respiratory complications of COVID-19 including 
thromboembolic disease leading to pulmonary embolism and stroke, arrhythmias, and 
shock, among others (Klok 2020; Chen 2020). Furthermore, a potent treatment given 
early in disease could ameliorate the severity and duration of COVID-19 and potentially 
reduce transmission.  
After the first four months of the COVID-19 pandemic, a number of risk factors 
associated with worse clinical disease were identified. Older age and patients with co-
morbidities were more likely to have severe disease requiring hospitalization or die. 
Therefore, this study will enroll adults at high risk of medical complications from 
COVID-19, including but not limited to older adults (age ≥ 55 years) and individuals 
aged ≥ 18 years with comorbidities associated with worse outcomes, including diabetes, 
obesity (BMI > 30), chronic kidney disease, congestive heart failure, chronic obstructive 
pulmonary disease, and moderate to severe asthma (Garg 2020; Petrilli 2020).  
A placebo control is required to distinguish the safety and tolerability of VIR-7831 from 
the background signs and symptoms of COVID-19 and to evaluate its potential benefit on 
clinical outcomes. The use of a placebo arm allows for a valid evaluation of any changes 
in efficacy and safety attributable to VIR-7831 versus those attributable to background 
supportive care given during the study. 
2.2. 
Background 
A novel betacoronavirus was first reported in December 2019 causing severe pneumonia 
in Wuhan, China. Since that time, SARS-CoV-2 has spread throughout the world leading 
to over 16 million confirmed cases and over 650,000 deaths as of July 27, 2020 
(COVID-19 dashboard, Johns Hopkins). There is an urgent need for effective treatment 
throughout the course of illness. Emerging data suggest that morbidity and mortality 
associated with COVID-19 exceeds that of influenza and is impacted by age as well as 
underlying comorbidities that place certain groups at higher risk of poor outcomes. 
Current estimates of overall case fatality rates range from 1.8 to 3.4% with mortality rates 
exceeding 25% for some populations (Ferguson 2020; Bialek 2020). Based on current 
experience in China, the UK, and Italy, experts have estimated that approximately 30% of 
those who are hospitalized will require critical care and that 50% of those in critical care 
will die. In addition, an age-dependent proportion of those that do not require critical care 
will also die (Ferguson 2020). Mortality rates are likely to be impacted by access to 
appropriate care as intensive care unit (ICU) beds and critical care capacity becomes 
overwhelmed. Not only is there a high unmet need for treatment of those with severe 
disease but also for therapies designed to prevent the progression of disease in those with 
early infection. Currently available data suggest that SARS-CoV-2 is associated with a 
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relatively long incubation period, with mean incubation period from exposure to 
symptomatic disease of approximately 5 days with the 95% percentile of the distribution 
at 12.5 days (Li 2020). The median time to progression to severe disease (ICU 
admission/development of ARDS) from onset-of-symptoms has been estimated to be 
12 days (range 8 to 15 days) with a median duration from onset to death or discharge of 
21 days (range 17 to 25 days) (Zhou 2020). In addition, viral loads are highest early in 
the course of disease and tend to fall once severe sequelae have ensued, although remain 
detectable by RT-PCR well into the course of disease (Zou 2020; Wölfel 2020). Notably, 
although viral nucleic acid was detected well after symptom resolution in participants 
with mild infection, shedding of infectious virus in sputum was limited to the first week 
of symptoms (Wölfel 2020). These data suggest that early intervention with a potently 
neutralizing antibody prior to the onset of severe sequelae of disease may effectively 
prevent disease progression and hasten the resolution of disease. Experience with the use 
of neutralizing mAbs in the treatment of uncomplicated acute influenza support the idea 
that the time to intervention may be a key determinant of clinical success. Studies that 
enrolled participants within ≤ 5 days (Ali 2018) or < 72 hours (Hershberger 2019) of 
symptom onset were unable to demonstrate statistically significant faster time to 
resolution of symptoms, whereas a study that enrolled patients with symptom onset no 
greater than 48 hours prior to treatment demonstrated statistically significant reductions 
in time to resolution of symptoms (~2 day reduction compared to the placebo group) 
(Yang 2019).  
Given these factors, a highly potent neutralizing mAb against SARS-CoV2 administered 
prior to progression to severe disease could prevent progression and lead to faster 
resolution of symptoms. 
Vir Biotechnology, Inc. (Vir) has developed a fully human neutralizing 
anti-SARS-CoV-2 antibody, VIR-7831 (GSK4182136), which contains a 2 amino acid 
Fc-modification (“LS”) that is designed to improve bioavailability in the respiratory 
mucosa and increase half-life. VIR-7831 binds to a conserved epitope on the 
SARS-CoV and SARS-CoV-2 spike protein and has been shown to neutralize 
pseudovirus and live virus in several independent laboratories (Pinto D et al. 2020).  
2.3. 
Benefit/Risk Assessment 
Information about the reasonably expected adverse events of VIR-7831 may be found in 
the Investigator’s Brochure. 
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2.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention: VIR-7831 
Infusion reactions including hypersensitivity 
reactions (HSR) 
While VIR-7831 is a fully human IgG, 
infusion-related reactions (IRR) are a 
potential general risk associated with the mAb 
class of therapeutics. 
Participant selection: 
Participants will be excluded if they have a 
history of hypersensitivity to other monoclonal 
antibodies or any of the excipients present in 
the investigational product. 
 
Monitoring: 
• 
Guidelines for monitoring relevant adverse 
events encompassing hypersensitivity, 
angioedema and anaphylaxis as well as for 
the management of acute anaphylactic 
shock and minor allergic episodes will be 
in place at investigational sites. 
 
Mitigation:  
• 
In the sentinel participants and Lead-In 
phase of the FIH study, vital sign 
measurement will be conducted every 15 
minutes during the planned 1-hour IV 
infusion and at 1, 2, and 6 hours post-
infusion. In the Expansion phase, vital 
signs will be monitored every 15 minutes 
over the 1-hour IV infusion and at every 
hour after infusion for 2 hours. 
• 
Infusion related reactions are categorized 
as AESIs 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
• 
Investigators will be provided with general 
guidance on management of 
hypersensitivity reactions and such 
reactions will be managed appropriately 
per local guidelines/medical judgment. Pre-
medications will be permitted at the 
investigator’s discretion and will be 
appropriately documented. 
• 
Investigators will be instructed to 
discontinue IV infusions for participants 
who develop Grade 3 or higher infusion 
reactions.  
• 
If a participant experiences a Grade 2 IRR, 
investigators will be instructed to pause the 
infusion. The infusion may subsequently 
resume at a slower pace of infusion, at the 
investigator’s discretion, and/or after 
symptomatic treatment (e.g., anti-
histamines, IV fluids).  
• 
IV infusion will be administered in the 
clinic with staff trained in emergency care 
& resuscitation procedures & emergency 
care kit on hand during treatment & post 
therapy observation periods. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Immunogenicity 
While VIR-7831 is a fully human IgG, the 
development of anti-drug antibodies (ADA) 
that have the potential to impact safety and/or 
efficacy are a potential general risk associated 
with the mAb class of therapeutics 
This study will include participant follow-up 
for a period of 24 Weeks (estimated 5 half-
lives) to assess for the potential of 
immunogenicity (measurement of ADA) as 
well as if ADA is potentially causally 
associated with specific safety concerns and/or 
impact efficacy 
Antibody Dependent Enhancement (ADE) 
due to sub-neutralizing levels of VIR-7831 
enhancing fusion or leading to FcR mediated 
increased viral uptake and replication with 
virus production 
This is a concern related to the potential for 
participants with sub-neutralizing mAb levels 
to experience a higher incidence of infection 
and/or more severe disease compared to 
participants with no circulating mAb and/or 
established protective immunity to 
SARS-CoV-2.  
ADE associated with Dengue virus 1-4 
serotype infections is one of the most widely 
cited examples in which reinfection with a 
different serotype can, in a minority of 
patients, run a more severe course in the 
setting of limited antibodies generated by 
prior infection.  
The potential for enhanced disease in this 
setting is due to increased uptake of virus by 
FcR-expressing cells, such as macrophages, 
and increased viral replication in these cells. 
Recent data shows that SARS-CoV-2 does not 
replicate efficiently in macrophages 
[Hui 2020], suggesting minimal to no risk of 
ADE via this mechanism.  
Monitoring: 
• 
This study will include participant follow 
up for a period of 24 Weeks to assess for 
the potential of enhanced disease in the 
context of waning VIR-7831 levels. 
Assessments of the overall incidence of 
COVID-19 (initial or re-infection in the 
case of prevention and treatment, 
respectively) as well as the severity of 
disease will be performed by the IDMC to 
assess for imbalances between mAb- and 
placebo-treated participants. 
Mitigation:  
• 
Futility and safety criteria are built into the 
study design to permit early stopping of the 
study for an imbalance in incidence (initial 
or re-infection in the case of prevention and 
treatment, respectively) or severity of 
disease for this study (see Section 10.1.5 
for more details on the IDMC). 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
ADE due to enhanced disease pathology from 
viral antigen-antibody related immune 
complex deposition or complement activation 
and immune cell recruitment in target organs 
There is the possibility that a large amount of 
antibody that binds, but does not neutralize, 
virus in the presence of a high viral load could 
result in immune complex deposition and 
complement activation in tissue sites of high 
viral replication, such as the lungs, vascular 
endothelia, renal or cardiovascular tissue 
[Hamming 2004], leading to tissue 
damage/immune complex disease 
This is hypothesized to have contributed to 
inflammation and airway obstruction 
observed in the small airways of infants who 
received a formalin-inactivated (FI) 
respiratory syncytial virus (RSV) vaccine 
[Polack 2002] and in a few cases of fatal 
H1N1 influenza infection [Wu 2010] 
The potential for enhanced disease in this 
setting may be due to low affinity or cross-
reactive antibodies with poor or no 
neutralizing activity 
Triggering of cytokine release by antibody-
virus-FcR interactions although usually 
highly beneficial due to their direct antiviral 
effects and immune cell recruitment to control 
viral spread in tissues, also has the potential to 
enhance pathologic changes initiated by the 
viral infection 
Observational data from 5000 COVID-19 
patients treated with convalescent plasma, 
although not placebo controlled, is suggestive 
that even polyclonal mixtures of neutralizing 
and non-neutralizing antibodies can be safely 
administered [Joyner 2020] 
Monitoring: 
• 
In this study, periodic review of 
clinical signs and symptoms of 
COVID-19, clinical chemistry, adverse 
events, end-organ disease and 
histopathological diagnoses (as 
available per routine care) will be 
performed by the Joint Safety Review 
Team to identify potential cases of 
immune complex disease 
• 
Additional monitoring in the event a 
participant develops signs or symptoms 
of cardiac complications (See 
Section 8.3)  
• 
In addition, the IDMC will be 
instructed to perform periodic data 
review of clinical signs and symptoms 
of COVID-19, clinical chemistry, any 
cardiac assessments, end-organ disease 
and histopathological diagnoses (as 
available per routine care) with the aim 
of identifying imbalances in the study 
arms with respect to worsening of 
COVID-19-related end-organ 
complications that may reflect 
immune-complex reactions. 
• 
Assessments of the overall duration 
and severity of COVID-19 will be 
performed by the IDMC to assess for 
imbalances between mAb- and 
placebo-treated participants. 
 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
VIR-7831 shows potent binding in vitro as 
well as neutralization of pseudovirus and live 
virus thus this risk is deemed to be low. 
Mitigation: 
Futility and safety criteria are built into the 
study design to permit early stopping of the 
study for an imbalance in or severity of disease 
(see Section 10.1.5 for more details on the 
IDMC) 
Study Procedures  
Infusion site reactions including 
hypersensitivity reactions 
While VIR-7831 is a fully human IgG, 
infusion-related reactions (IRR) are a 
potential general risk associated with the mAb 
class of therapeutics.  
Participant selection:  
• 
Participants will be excluded if they have a 
history of hypersensitivity to other 
monoclonal antibodies or any of the 
excipients present in the investigational 
product. 
 
 
Monitoring:  
• 
Guidelines for monitoring relevant adverse 
events encompassing hypersensitivity, 
angioedema and anaphylaxis as well as for 
the management of acute anaphylactic 
shock and minor allergic episodes will be 
in place at investigational sites. 
• 
For the Lead-In phase of this study, vital 
sign measurements will be conducted every 
15 minutes during the planned 1-hour IV 
infusion and at 1, 2, and 6 hours post-
infusion. For the Expansion phase, vital 
signs will be monitored every 15 minutes 
over the 1-hour IV infusion and at every 
hour after infusion for 2 hours. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
• 
Infusion time can be extended at the 
discretion of the Investigator, Sponsor or 
IDMC based on local infusion-related 
symptoms or other safety findings. 
• 
Joint Safety Review Team reviews will be 
conducted at least every two weeks to 
determine if a significant safety signal of 
severe hypersensitivity reaction is 
identified. The IDMC will be notified per 
Charter for adjudication.  
Mitigation:  
• 
Investigators will be instructed to 
discontinue IV infusions for participants 
who develop Grade 3 or higher infusion 
reactions using DAIDS Table for Grading 
the Severity of Adult and Pediatric Adverse 
Events, version 2.1 (July 2017) Adverse 
Event grading.  
• 
If a participant experiences a Grade 2 IRR, 
investigators will be instructed to pause the 
infusion. The infusion may subsequently 
resume at a slower pace of infusion, at the 
investigator’s discretion, and/or after 
symptomatic treatment (e.g. anti-
histamines, IV fluids).  
• 
Investigators will be provided with general 
guidance on management of 
hypersensitivity reactions and such 
reactions will be managed appropriately 
per local guidelines/medical judgment. Pre-
medications will be permitted at the 
investigator’s discretion and will be 
appropriately documented. 
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2.3.2. 
Benefit Assessment 
Although VIR-7831 has not been studied before in this acutely ill population, there is 
biologic rationale which supports the use of VIR-7831, an antiviral mAb in the early 
treatment of COVID-19 to prevent progression.  
VIR-7831 has been demonstrated in vitro to be a highly potent fully human IgG 
neutralizing SARS-CoV-2 antibody which has the potential to be an effective therapeutic 
in mild to critically ill patients with COVID-19. VIR-7831 does not bind to normal 
human tissues in the tissue cross-reactivity study and there were no adverse findings after 
2 weeks in the 2-week repeat dose monkey toxicity study. The no-observed-adverse-
effect-level (NOAEL) in the monkey study was 500 mg/kg, the highest dose tested. 
The study population to be enrolled in this study has a high unmet medical need. 
VIR-7831 may or may not improve the time to clinical response or overall clinical 
outcome in an individual participant with mild or moderate COVID-19 who participates 
in this study. However, there is potential benefit from their participation in this study 
resulting from their data allowing evaluation of VIR-7831 as a potential treatment for this 
new disease.  
2.3.3. 
Overall Benefit: Risk Conclusion 
The overall benefit-risk assessment takes into account the potential benefit of VIR-7831 
treatment through the potential ability to suppress viral replication and clear infected 
cells. 
Based on the high unmet medical need and considering the measures taken to minimize 
risk to participants participating in this study, the potential risks identified in association 
with VIR-7831 are justified by the anticipated benefits that may be afforded to 
participants with mild to moderate COVID-19. 
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• Evaluate the efficacy of VIR-7831 
versus placebo in preventing the 
progression 
of 
mild/moderate 
COVID-19 
• Proportion of participants who have 
progression of COVID-19 through Day 
29 as defined by: 
1. Hospitalization > 24 hours for acute 
management of illness 
OR 
2. Death  
Secondary 
 
Safety 
• Determine the safety and tolerability of 
VIR-7831 compared to placebo 
 
• 
Occurrence of adverse events (AEs) 
• 
Occurrence of serious adverse events 
(SAEs)  
• 
Occurrence of adverse events of special 
interest (AESI) 
• Assess the immunogenicity of 
VIR-7831 
• 
Incidence and titers (if applicable) of 
serum ADA to VIR-7831 
Pharmacokinetics 
• Assess the pharmacokinetics (PK) of 
VIR-7831 in serum 
 
• VIR-7831 pharmacokinetics (PK) in 
serum 
Efficacy 
• Evaluate the efficacy of VIR-7831 
versus placebo in preventing the 
progression of mild/moderate 
COVID-19 
 
Proportion of participants who have progression 
of COVID-19 through Day 29 as defined by: 
• 
 Visit to a hospital emergency room for 
management of illness  
OR 
• 
Hospitalization for acute management 
of illness 
OR 
• 
Death  
• Evaluate the impact of VIR-7831 
versus placebo on the duration and the 
severity of COVID-19 clinical 
symptoms 
•  Mean change in FLU-PRO Plus total 
score comparing Vir-7831 vs. Placebo 
(AUC through Day 7) 
• 
Time to symptom alleviation using the 
FLU-PRO Plus 
 
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• Evaluate the efficacy of VIR-7831 
versus placebo in reducing SARS-
CoV-2 viral load 
• 
Change from baseline in viral load in 
nasal secretions by qRT-PCR at Day 8 
• Evaluate the efficacy of VIR-7831 
against versus placebo in preventing 
COVID-19 respiratory disease 
progression  
• 
Proportion of participants who progress 
to develop severe and/or critical 
respiratory COVID-19 as manifest by 
requirement for and method of 
supplemental oxygen at Day 8, Day 15, 
Day 22, or Day 29 
• Evaluate the efficacy of VIR-7831 
versus placebo in preventing mortality 
• 
29-day, 60-day, and 90-day all cause 
mortality 
Exploratory 
 
• Evaluate the impact of VIR-7831 
versus placebo on incidence and 
duration of time on a ventilator, ICU 
length of stay (LOS), and total hospital 
LOS 
• Total number of ventilator days from 
randomization through 90 days 
• Total intensive care LOS 
• Total hospital LOS 
• Evaluate the efficacy of VIR-7831 
versus placebo in preventing 
hospitalization from non-respiratory 
complications of COVID-19 
• Proportion of participants hospitalized 
due to non-respiratory complications of 
COVID-19 (cardiac, renal, neurologic, 
hematologic events) by Day 8, Day 15, 
Day 22, and Day 29 
• Monitor on-treatment emergence of 
SARS-CoV-2 resistant mutants against 
VIR-7831  
• Emergence of viral resistance mutants to 
mAb by SARS-CoV-2  
• Evaluate the efficacy of VIR-7831 
versus placebo in reducing duration of 
SARS-CoV-2 viral shedding and 
viremia 
• Detection of SARS-CoV-2 in nasal 
secretions by RT-PCR at baseline and 
during follow-up period through Day 29  
• Detection of SARS-CoV-2 in blood by 
RT-PCR at baseline and during follow-up 
period through Day 29 
• Evaluate the efficacy of VIR-7831 
versus placebo in reducing SARS-
CoV-2 viral load 
• Change from baseline in viral load in 
nasal secretions by qRT-PCR during 
follow-up period through Day 29 
• Evaluate the incidence of respiratory 
co-infection with SARS-CoV-2 
• Respiratory pathogen detection in nasal 
secretions by PCR on Day 1 
• Evaluate the effect of VIR-7831 versus 
placebo on potential biomarkers of 
host response to SARS-CoV-2 
• Evaluation of host immune responses and 
exploratory biomarkers related to SARS-
CoV-2 and/or VIR-7831, including 
genetic, cellular, transcriptomic, and 
proteomic parameters  
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• Measure the impact of VIR-7831 
treatment on health-related quality of 
life and time away from work due to 
COVID19 
• 
 Change from baseline in Work 
Productivity and Activity Impairment 
(WPAI) questionnaire 
• 
 Change from baseline for health-related 
quality of life according to the SF-12 
hybrid questionnaire 
• Evaluate the impact of VIR-7831 
versus placebo on the duration and the 
severity of COVID-19 clinical 
symptoms 
• 
Mean change in FLU-PRO Plus total score 
(AUC through Days 14, 21) and Domain 
scores (AUC through Days 7, 14, 21) 
comparing Vir-7831 vs. Placebo 
• 
The proportion of participants with 
symptom alleviation using the FLU-PRO 
Plus at Days 7, 14, 21 
 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study is a randomized, double-blind, multi-center, placebo-controlled trial of 
VIR-7831, a monoclonal antibody (mAb) against SARS-CoV-2 for the prevention of 
progression of mild/moderate COVID-19 in high risk participants, with interim 
monitoring to allow early stopping for futility, efficacy, or safety. Participants with early, 
mild/moderate COVID-19 who are at high risk for progression of disease will be 
randomized 1:1 to receive a single, intravenous infusion of either VIR-7831 or equal 
volume saline placebo. Comparisons of safety and efficacy will be based on data from 
concurrently randomized participants.  
Screening assessments will be performed within 24 hours before the first dose. Eligible 
participants will be treated in a blinded manner with a single IV dose on Day 1 and 
followed up to 24 weeks. 
The Lead-In phase of this study will serve as the first-in-human assessment and will 
include 20 non-hospitalized participants who have early, mild/moderate COVID-19 and 
are at high risk of disease progression. These participants will be given a single 
intravenous infusion of VIR-7831 and confined for 7 days for safety monitoring. 
Following a safety assessment of unblinded data by an IDMC, the expansion phase will 
progress, where additional participants with early, mild/moderate COVID-19 and who are 
at high risk of disease progression will be enrolled. 
4.2. 
Scientific Rationale for Study Design 
This study is a two-phase (FIH to phase 2/3) randomized, placebo-controlled study to 
evaluate the safety, tolerability, PK, immunogenicity, and efficacy of VIR-7831 
compared to placebo in the treatment of early mild/moderate COVID-19 in adults at high 
risk of medical complications from COVID-19, including but not limited to older adults 
(age ≥ 55 years) and all individuals age 18 or older with comorbidities associated with 
worse outcomes, including diabetes, obesity (BMI>30), chronic kidney 
disease, congestive heart failure, chronic obstructive pulmonary disease, and moderate to 
severe asthma. The study will include outpatients with SARS-CoV-2, the virus that 
causes COVID-19, as confirmed by local laboratory tests and/or point of care tests. 
The study will include a Lead-In phase to assess the safety of VIR-7831 compared to 
placebo (10 participants per arm). A single dose level designed to provide potential 
therapeutic benefit will be studied and will be delivered via IV infusion. Participants will 
be admitted to a study unit and monitored closely for adverse events, changes in 
laboratory parameters and progression (or improvement) in disease signs 
and symptoms. This approach is appropriate given the theoretical risk for antibody 
dependent enhancement of disease, including immune complex formation and deposition 
in tissues, in patients with high viral burden [Liu 2019]. 
Following review of available unblinded safety data through Day 15 by the IDMC, the 
study will expand to enroll additional participants. The purpose of the Expansion phase 
will be to evaluate the safety and efficacy of VIR-7831 in comparison to the placebo 
control arm. Two interim analyses at approximately 41% of participants enrolled and 
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approximately 64% of participants enrolled will be conducted to evaluate futility, 
efficacy, and safety based on data through Day 29 for these participants. To date, there 
are no approved treatments for mild/moderate COVID-19. A placebo control is required 
to distinguish the safety and tolerability of VIR-7831 from the background signs and 
symptoms of COVID-19 and to evaluate its potential benefit on clinical outcomes. The 
use of a placebo arm allows for a valid evaluation of any changes in efficacy and safety 
attributable to VIR-7831 versus those attributable to background supportive care given 
during the study. 
A double-blind design is a standard methodology for randomized, controlled studies to 
avoid bias. Unblinded safety and efficacy data will be reviewed regularly by an IDMC. 
The primary endpoint to assess efficacy of treatment is progression of mild/moderate 
COVID-19 defined by hospitalization >24 hours for acute management of illness or death 
within 29 days of randomization. The transition from outpatient status without 
hypoxemia or oxygen requirement to hospitalization for acute care or death is a clinically 
significant milestone. It is considered to be clinically important to participants and 
physicians alike. A 29-day period to assess the primary endpoint is appropriate as the 
median time for COVID-19 related hospital admission has been reported to be 7-11 days 
and the median time to clinical deterioration, 9-12 days (Zhou 2020, Huang 2020). 
The most significant of the secondary endpoints is evaluation of whether VIR-7831 can 
shorten the duration or lessen the severity of COVID-19. Demonstration of an 
improvement in the severity of disease following administration of VIR-7831 would be 
considered highly clinically meaningful. Other efficacy endpoints related to decrease in 
viral shedding, mortality, and health resource utilization – length of hospital stay, ICU 
stay, time ventilated – are also highly clinically relevant and recommended in COVID-19 
trial guidelines (NICE 2020; WHO 2020; FDA 2020). 
4.3. 
Justification for Dose 
4.3.1. 
VIR-7831 
A single dose of 500 mg was selected for the study based on in vitro neutralization data, 
in vitro resistance data, expected human PK extrapolated from a study in cynomolgus 
monkeys, and the results of the GLP monkey toxicology study. 
VIR-7831 neutralized SARS-CoV-2 live virus with an average EC90 value of 
186.3 ng/mL (range: 125.8 – 329.5 ng/mL) (PC-7831-0105). In resistance analyses, no 
viral breakthrough was observed through 10 passages at fixed concentrations of antibody 
even at the lowest dose tested (~10x EC50), indicating the potential for VIR-7831 to have 
a high barrier to resistance (PC-7831-0109). 
Using an increasing concentration selection method to force resistance emergence, 
modest fold changes in EC50 were observed during viral selection (5-to 6-fold change in 
EC50) for some passages (PC-7831-0109). Sequencing and testing of spike variants from 
these passages using a pseudotyped virus system did not identify causal variants for this 
modest shift in potency. One passage of virus did demonstrate a >10 fold shift in EC50 
which correlated with an E340A mutation. Further assessment has identified E340A to be 
a monoclonal antibody-resistant mutant (MARM) that confers a >100-fold reduction in 
susceptibility to VIR-7831. Notably, E340 is 100% conserved among available 
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SARS-CoV-2 sequences. Due to the binary nature of the resistance selection results, a 
specific inhibitory quotient (IQ) was not informed by the resistance profiling. However, 
as our understanding of the biology of SARS-CoV-2 is currently still limited and very 
few strains are available to directly assess breadth of coverage, a conservative IQ (>10) is 
appropriate in this case. 
The cynomolgus monkey PK from study PK-7831-0115 was fit to a 2 compartment PK 
model. Human PK parameters were scaled from the cynomolgus monkey using an 
allometric scaling approach for fully human IgGs (allometric coefficient of 0.85 and 1 for 
CL and V, respectively; Deng 2011). The predicted serum clearance of VIR-7831 in 
humans is estimated to be 141 mL/day and estimated volume of distribution is 6500 mL 
(~93 mL/kg) assuming human weight of 70 kg. The projected human terminal 
elimination half-life is approximately 32 days.  
In order to reduce risk to patients (treatment failure, resistance), the dose was selected to 
ensure that VIR-7831 concentrations in lung are maintained at or above levels anticipated 
to be protective of SARS-CoV-2 infection for the duration of the 28-day treatment 
window. A dose of 500 mg is expected to maintain serum levels at or above 38.5 µg/mL 
for the duration of the 28-day treatment period. Based on the EC90 (0.33 μg/mL) from the 
highest end of the EC90 range (PC-7831-0105), and accounting for the lung:serum ratio 
for IgG (assumed conservative value of 0.25; reported range 0.25-0.68 for whole lung 
and interstitial fluid, respectively; Baxter 1994, Covell 1986, Datta-Mannan 2019, Lobo 
2004) the serum trough concentration following a 500 mg dose is expected to result in 
lung concentrations associated with maximal (> 99%) antiviral activity; > 29 x tissue-
adjusted EC90 for the duration of the 28 day treatment period. This conservative 
inhibitory quotient (29) in lung is believed to be appropriate to increase potential for 
treatment success and reduce risk for resistance. 
Additionally, a 500 mg dose is anticipated to result in protective levels of VIR-7831 in 
nasopharyngeal secretions (>5 x tissue adjusted EC90 assuming NPS:serum ratio of 0.05, 
Lim 2017) which could potentially reduce transmission.  
The NOAEL for VIR-7831 was 500 mg/kg, the highest dose tested, when VIR-7831 was 
administered via IV infusion once a week for 2 weeks in cynomolgus monkeys 
(TX-7831-0102). At this NOAEL, preliminary Cmax and AUC0-t (AUC from time 0 to 
168hr post-end of infusion following the 2nd dose) were 13500 μg/mL and 
48200 μg•day/mL, respectively. The human equivalent dose (HED) (HED calculated via 
direct mg/kg conversion according to FDA guidance on proteins administered 
intravascularly with Mr > 100,000 daltons; FDA 2005) is 500 mg/kg or a 30,000 mg 
fixed dose (using human body weight of 60 kg). Using a safety factor of 10, the 
maximum recommended starting dose in humans is approximately 50 mg/kg or a 
3,000 mg fixed dose. Based on the proposed 500 mg human dose, the margins based on 
the HED, Cmax, and AUC (conservative AUC margin based on partial AUC0-t from 
TX-7831-0102 and expected AUCinf in humans) are 60-, 87-, and 13.6-fold, respectively, 
supporting the proposed clinical dose of 500 mg. 
4.3.2. 
Placebo 
There is no established treatment for non-hospitalized patients with mild to moderate 
COVID-19, hence a placebo control is required to distinguish the safety and tolerability 
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of VIR-7831 from the background signs and symptoms of severe or critical COVID-19 
and to evaluate its potential benefit on clinical outcomes 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
phases of the study through to Week 24. The end of the study is defined as the date of the 
last contact of the last participant in the study. 
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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
5.1.1. 
Age and Risk Factors 
1. Participant must be aged 18 years or older AND at high risk of progression of 
COVID-19 based on presence of one or more of the following risk factors: 
diabetes (requiring medication), obesity (BMI>35), chronic kidney disease  
(i.e., eGFR <60 by MDRD), congestive heart failure (NYHA class II or more), 
chronic obstructive pulmonary disease (history of chronic bronchitis, chronic 
obstructive lung disease, or emphysema with dyspnea on physical exertion), and 
moderate to severe asthma (participant requires an inhaled steroid to control 
symptoms or has been prescribed a course of oral steroids in the past year) 
OR 
2. Participant ≥ 55 years old, irrespective of co-morbidities. 
a. Note: target enrollment of ~15% of participants >70 years old 
5.1.2. 
Type of Participant and Disease Characteristics 
3. Participants who have a positive SARS-CoV-2 test result (by any validated 
diagnostic test e.g. RT-PCR, antigen based testing on any specimen type) 
AND 
Oxygen saturation ≥94% on room air  
AND 
Have COVID-19 defined by one or more of the following symptoms: fever, chills, 
cough, sore throat, malaise, headache, joint or muscle pain, change in smell or 
taste, vomiting, diarrhea, shortness of breath on exertion 
AND 
Less than or equal to 5 days from onset of symptoms 
5.1.3. 
Sex and Contraceptive/Barrier Requirements 
4. No gender restrictions 
5. Female participants must meet and agree to abide by the following contraceptive 
criteria. Contraception use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
 
A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and one of the following conditions applies: 
a. Is a woman of non-childbearing potential (WONCBP) as defined in 
Section 10.4. 
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OR 
b. Is a WOCBP and using a contraceptive method that is highly effective, with a 
failure rate of <1%, as described in Section 10.4 of the protocol during the 
study intervention period and for up to 24 weeks after the last dose of study 
intervention. The investigator should evaluate potential for contraceptive 
method failure (e.g., noncompliance, recently initiated) in relationship to the 
first dose of study intervention. 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) before the first dose of study intervention. 
See Section 8.3.7 Pregnancy Testing of the protocol. 
− If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive. 
− Additional requirements for pregnancy testing during and after study intervention 
are located in Section 1.3 of the protocol. 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy 
5.1.4. 
Informed Consent 
6. Capable of giving signed informed consent as described in Section 10.1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
OR 
If participants are not capable of giving written informed consent, alternative 
consent procedures will be followed as described in Section 10.1.3. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. 
Medical Conditions 
7. Currently hospitalized or judged by the investigator as likely to require 
hospitalization in the next 24 hours 
8. Symptoms consistent with severe COVID-19 as defined by shortness of breath at 
rest or respiratory distress or requiring supplemental oxygen.  
9. Participants who, in the judgement of the investigator are likely to die in the next 
7 days. 
10. Severely immunocompromised participants, including but not limited to cancer 
patients actively receiving immunosuppressive chemotherapy or immunotherapy, 
those with a solid organ transplant or allogeneic stem cell transplant within the 
last 3 months, or those having conditions requiring the use of systemic 
corticosteroids equivalent to ≥ 0.5 mg/kg of body weight per day of prednisone 
within 6 weeks of randomization 
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11. Known hypersensitivity to any constituent present in the investigational product 
12. Previous anaphylaxis or hypersensitivity to a monoclonal antibody 
5.2.2. 
Prior/Concurrent Clinical Study Experience 
13. Enrollment in any investigational vaccine study within the last 180 days or any 
other investigational drug study within 30 days prior to Day 1 or within 
5 half-lives of the investigational compound, whichever is longer.  
14. Enrollment in any trial of an investigational vaccine for SARS-CoV-2 . 
5.2.3. 
Other Exclusions 
15. Receipt of any vaccine within 48 hours prior to enrollment. Receipt of a 
SARs-CoV-2 vaccine prior to randomization at any timepoint. Vaccination 
(including vaccination for SARS-CoV-2) will not be allowed for 4 weeks after 
dosing. 
16. Receipt of convalescent plasma from a recovered COVID-19 patient or 
anti-SARS-CoV-2 mAb within the last 3 months. 
17. Participants who, in the judgment of the investigator, will be unlikely or unable to 
comply with the requirements of the protocol through Day 29 
5.3. 
Lifestyle Considerations 
Lifestyle considerations are not applicable to this study. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
serious adverse events (SAEs). 
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6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study Intervention(s) Administered 
Overview of study interventions is provided in Table 3. Detailed instructions for the 
administration of study drug will be provided in a separate pharmacy manual 
Table 3: 
Overview of Study Intervention 
Arm Name 
VIR-7831 
Placebo 
Intervention Name 
VIR-7831 
Placebo to VIR-7831 
Type  
Biologic 
Placebo to Biologic 
Dose Formulation 
Solution in single-use vial 
(25 mg/mL) 
Sterile 0.9% (w/v) sodium chloride 
solution 
Unit Dose 
Strength(s) 
250 mg/vial (250 mg/10 mL) 
Not applicable 
Dosage Level(s) 
500 mg once 
Once 
Route of 
Administration 
IV infusion 
IV infusion 
IMP and NIMP 
IMP 
IMP 
Sourcing 
VIR-7831 will be provided 
centrally by the Sponsor.  
Saline for placebo will be provided 
centrally by Sponsor. 
Dosing instructions 
Approximately 1-hour infusion 
time will be used to administer 
the total dose volume. 
Approximately 1-hour infusion 
time will be used to administer the 
total dose volume. 
Packaging and 
Labelling 
Study intervention will be 
provided in a single-use vial in 
an individual carton and 
labelled as required per country 
requirement. 
Saline will be provided in a single-
use vial and labelled as required 
per country requirement 
Current/Former 
Name(s) or Alias(es) 
VIR-7831, GSK4182136 
Not applicable 
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6.2. 
Preparation/Handling/Storage/Accountability 
Instructions for the preparation of study drug will be provided in a separate pharmacy 
manual. 
1. The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions 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 site staff. 
3. The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the pharmacy manual.  
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, medical monitor and/or Sponsor 
study contact. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally randomized using an Interactive Web Response System 
(IWRS). Before the study is initiated, the log in information and directions for the IWRS 
will be provided to each site. 
Participants will be randomized in a 1:1 ratio to receive study intervention. Investigators 
will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. In order to maintain this blind, the study pharmacist will be 
responsible for the reconstitution and dispensation of all study intervention and will 
endeavor to ensure that there are no differences in time taken to dispense following 
randomization. 
The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participants’ intervention assignment is warranted. Participant safety must always be the 
first consideration in making such a determination. If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact the Sponsor 
prior to unblinding a participant’s intervention assignment unless this could delay 
emergency intervention of the participant. If a participant’s intervention assignment is 
unblinded, the Sponsor must be notified within 24 hours after breaking the blind. The 
date and reason that the blind was broken must be recorded in the source documentation 
and case report form, as applicable. 
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Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to unblinded study intervention records at the site(s) to verify that 
randomization/dispensing has been done accurately. 
A participant may continue in the study if that participant’s intervention assignment is 
unblinded 
GlaxoSmithKline’s (GSK’s) Pharma Safety staff may unblind the intervention 
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the participant’s intervention assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy. 
6.4. 
Study Intervention Compliance 
Participants will receive VIR-7831 or placebo directly from the investigator or designee, 
under medical supervision. The date and start and stop times of the dose administered 
will be recorded in the source documents. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study intervention. 
6.5. 
Dose Modification 
This is a single dose study and dose modifications are not applicable. See Section 7.1 for 
instructions to discontinue study treatment for safety reasons. 
6.6. 
Continued Access to Study Intervention after the End of the 
Study 
COVID-19 is an acute illness and participants are not expected to need continued access 
to VIR-7831 after the end of the study 
6.7. 
Treatment of Overdose 
No specific treatment is recommended for an overdose. The treatment physician may 
provide supportive measures depending on the symptoms.  
In the event of an overdose, the treating physician should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
recreational drugs, vitamins, and/or herbal supplements) or other specific categories of 
interest that the participant is receiving at the time of enrollment or receives during the 
study must be recorded along with: 
• reason for use 
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• dates of administration including start and end dates 
• dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.8.1. 
Medication Not Permitted During the Study 
Given accumulating evidence around the risks associated with the use of 
hydroxychloroquine and chloroquine and absence of defined benefit, these will NOT be 
considered standard of care, and are prohibited over the course of the study. 
Receipt of convalescent plasma from a recovered COVID-19 patient or 
anti-SARS-CoV-2 mAb is also not permitted during the study.  
Receipt of any vaccine is not permitted within 4 weeks after dosing. Receipt of any 
investigational or approved SARS-CoV-2 vaccine is permitted following Week 4. 
Patients should consult with the primary investigator and their primary care physician on 
local guidelines for vaccine administration and guidance on the risks associated with 
administration of a SARS-CoV-2 vaccine while on study.  
6.8.2. 
Permitted Concomitant Medication 
All medication that the participant is receiving as local, established standard of care for 
acute COVID-19 is permitted. 
Any concerns regarding the acceptability of potential treatments should be discussed with 
the medical monitor(s). 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
A participant will be permanently discontinued from completion of drug infusion if they 
experience life-threatening, infusion-related reactions including severe allergic or 
hypersensitivity reactions or severe cytokine release syndrome. 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for follow-up assessments. See the Schedule of 
Activities in Section 1.3 for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
7.1.1. 
Temporary Discontinuation 
If a participant experiences a Grade 2 IRR, investigators will be instructed to pause the 
infusion. The infusion may subsequently resume at a slower pace at the investigator’s 
discretion, and/or after symptomatic treatment (e.g. anti-histamines, IV fluids). 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, at the 
request of their LAR (legally authorized representative), or may be withdrawn at any 
time at the discretion of the investigator for safety, behavioral, or compliance reasons. 
This is expected to be uncommon. 
• At the time of withdrawal from the study, if possible, an early withdrawal (EW) visit 
should be conducted, as shown in the Schedule of Activities (Section 1.3). 
Participants may be contacted by phone. See Schedule of Activities for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• If the participant withdraws consent or the LAR requests that the participant is 
withdrawn for disclosure of future information, the sponsor/designee may retain and 
continue to use any data collected before such a withdrawal of consent. 
• If the participant withdraws from the study, he/she or the LAR may request 
destruction of any samples taken and not tested, and the investigator must document 
this in the site study records. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
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assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• If participants cannot be reached after 3 telephone calls at least 24 hours apart, their 
listed secondary contact person(s) or health care provider will be contacted. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are described in 
Section 10.1.9.  
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
This section lists the parameters of each planned study assessment. 
• Study procedures and their timing are summarized in Section 1.3 (Schedule of 
Activities).  
• Select follow-up visits as noted in the Schedule of Activities are planned to be phone 
call from site to participants. Follow-up visits that include only blood collections may 
be performed at the clinic or as a home visit.  
• Protocol waivers or exemptions are not allowed.  
• Immediate safety concerns should be discussed with the medical monitor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for screening 
or baseline purposes provided the procedure met the protocol-specified criteria and 
was performed within the time frame defined in the Schedule of Activities. 
• PK or ADA analysis results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• Validated and secure electronic access will be granted to Clinical Research 
Associates to review the participants’ electronic records to verify that the information 
in the records matches the information entered in the Electronic Data Capture (EDC) 
system. If required, in the event of a Quality Assurance audit, auditor(s) may be 
granted access to electronic records. 
− In cases where validated and secure electronic access to the participant’s 
electronic records is not available, unredacted Source Documents (including ICF, 
Regulatory Documents and Source data) will be uploaded into a regulatory and 
data privacy-compliant cloud environment, generating certified copies of source 
documents (as per ICH/GCP guidelines) to be verified by the Clinical Research 
Associate against the information entered in the Electronic Data Capture (EDC). 
As per ICH/GCP guidelines, the Principal Investigator and site staff users remain 
in control of the Source Documents, only site personnel can upload or invalidate 
source data, while only Clinical Research Associates (or auditors, as required) 
assigned to a given site can view the Source Documents remotely. 
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8.1. 
Screening Period 
Informed consent must be obtained before conducting any study procedures. Participant’s 
informed consent will be obtained via a validated and secure e-consent system where 
available. Screening will be performed no more than 24 hours prior to randomization and 
include the assessments outlined in the Schedule of Activities (Section 1.3).  
Screening visit and Day 1 visit may occur on the same day. 
8.1.1. 
Medical History 
Relevant medical history within the last three years, as determined by the Investigator, 
should be reported. Details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing will be collected for all participants and should be 
updated prior to dosing.  
8.1.2. 
SARS-CoV-2 Diagnostic Testing 
Documentation of laboratory-confirmed SARS-CoV-2 infection via a validated 
diagnostic test (e.g. RT-PCR or antigen based testing) from any respiratory specimen 
collected ≤ 7 days prior to study entry must be confirmed for eligibility. This can include 
tests conducted in a Clinical Laboratory Improvement Amendments (CLIA) certified 
laboratory or equivalent or from a validated CLIA-waived platform (e.g. Cepheid Gene 
Xpert Xpress SARS-CoV-2 assay).  
Participants with a negative test prior to screening, who are tested again at screening and 
are positive for SARS-CoV-2 can be included as long as the participant has had 
symptoms ≤ 5 days.  
8.1.3. 
Secondary Contact Information 
In order to minimize the potential for missing data related to the primary endpoint of 
mortality or need for hospitalization, sites should collect participant contact information 
for two secondary contacts (e.g., caregiver, family member, friend). The site may also 
request health care provider contact information and medical care facilities the participant 
is likely to go to if they get sick.  
Contact information for secondary contacts or health care provider will not be recorded in 
any eCRF. Contact information should be reviewed and updated at each clinic visit, home 
visit, and during site phone calls.  
8.2. 
Efficacy Assessments 
8.2.1. 
Hospitalization and Death Data Collection 
A hospitalization event and the clinical care that is received during a hospitalization as 
well as death are components of primary, secondary, and exploratory endpoints. Data 
from the hospitalization and/or death should be captured in the electronic data capture 
(EDC) system including but not limited to: 
1. Serious Adverse Event (SAE) form 
2. Dates that the participant is hospitalized and discharged 
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3. Dates that the participant is admitted to an intensive care unit 
4. Ventilatory support that the participant received 
5. Date, time, and cause of death 
8.2.2. 
Active Monitoring of COVID-19 Progression Phone Call 
8.2.2.1. 
Lead-In Phase 
During the Lead-In phase of the study, participants will be admitted to a study unit and 
monitored closely for 7 days after dosing for adverse events, changes in laboratory 
parameters and progression (or improvement) in disease signs and symptoms. If they do 
not show signs and symptoms of progression after 7 days, they will be discharged from 
the study unit. 
During Week 2, the participants will be called by the study site daily (except on in-clinic 
visit days) to monitor for progression of disease. This will include questions regarding 
serious or life-threatening conditions such as dyspnea at rest or severe dyspnea on 
exertion, hemoptysis, cyanosis, or mental status changes. If a participant exhibits any of 
these symptoms, the site will direct the participant to seek medical attention. In addition, 
any healthcare encounters or new concomitant medications will be recorded. 
8.2.2.2. 
Expansion Phase 
During the Expansion portion of the study, the participants will be called by the study site 
daily (except on in-clinic visit days) for 14 days post-infusion to monitor for progression 
of disease. This will include questions regarding serious or life-threatening conditions 
such as dyspnea at rest or severe dyspnea on exertion, hemoptysis, cyanosis, or mental 
status changes. If a participant exhibits any of these symptoms, the site will direct the 
participant to seek medical attention. In addition, any healthcare encounters or new 
concomitant medications will be recorded. 
8.2.3. 
Phone Call for Subsequent COVID-19 Illness 
In order to monitor participants for subsequent COVID-19 illness after Day 29, 
participants will be called every 4 weeks through Week 20. This phone call will assess 
whether the participant was diagnosed again with COVID-19 and whether this illness 
resulted in any healthcare encounters. Any medications given as a result of this illness 
will also be recorded. 
8.2.4. 
Participant Reported Outcome Assessments 
All questionnaires are planned to be administered using an electronic device where 
available. Details of the participant reported outcome assessment analyses will be 
provided in the analysis plan. 
8.2.4.1. 
FLU-PRO Plus Questionnaire  
In both the lead-in and expansion phases, participants will complete self-reported 
presence and severity of COVID-19 symptoms using a COVID-19 adapted FLU-PRO 
Plus questionnaire. 
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The questionnaire will be completed where available, once daily with a 24-hour recall, 
from Day 1 through Day 21, Day 29, Week 8 and Week 12 as outlined in the Schedule of 
Activities (Section 1.3). 
8.2.4.2. 
Health-related Quality of Life (SF-12 Hybrid) 
In the expansion phase, the SF-12 hybrid questionnaire will be used to measure 
self-reported functional health and well-being where available. Participants will complete 
the questionnaire with a 24-hour recall on Day 1, Day 15, and Day 29. Starting on Week 
8, participants will complete the questionnaire monthly through Week 24 as outlined in 
the Schedule of Activities (Section 1.3). 
8.2.4.3. 
Work Productivity and Activity Impairment (WPAI) 
The WPAI is a validated, patient-reported, quantitative assessment of absenteeism (work 
time missed), presenteeism (reduced on-the-job effectiveness), work productivity loss 
and activity impairment due to a specific health problem. In the expansion phase, where 
available participants will complete the 6-item questionnaire via an electronic device on 
Day 1, Day 15 and Day 29. Starting on Week 8, participants will complete the 
questionnaire monthly as outlined in the Schedule of Activities (Section 1.3). 
To assess the impact of local shelter-in-place and/or lockdown policies, questions related 
to social distancing, ability to work on-site / remotely will be asked prior to the WPAI 
questionnaire.  
8.2.5. 
Long COVID Assessment 
To monitor for subsequent development of long COVID during the EOS visit, 
participants will be asked a series of questions to evaluate a range of symptoms after first 
being infected with the SARS-CoV-2. These questions will assess whether the participant 
experienced persistent symptoms since the COVID-19 diagnosis, type of symptoms, 
frequency, change over time, and impact on social functioning. The questions can be 
asked and completed via phone call or during the in-clinic visit (see Section 10.6). 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.3.1. 
Physical Examinations 
A complete physical examination will be performed on Day 1. For all other visits the 
physical examination will be symptom-directed as outlined in the Schedule of Activities. 
• A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, and Abdominal systems.  
• Height and weight will also be measured and recorded at Screening. Body mass index 
(BMI) will be calculated from these measurements.  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
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8.3.2. 
Vital Signs 
Lead-In Phase 
During dose administration, vital signs will be monitored every 15 minutes over the 
1-hour IV infusion. Vital signs will also be monitored at 1, 2 and 6 hours after infusion. 
After the first 6 hours after infusion, vital signs will be monitored every 8 hours while the 
participant is in-clinic.  
Expansion Phase 
During dose administration, vital signs will be monitored every 15 minutes over the 
1-hour IV infusion. Vital signs will also be monitored at 1 hour and 2 hours after 
infusion. 
• Vital sign measurements will include blood pressure, pulse rate, temperature (oral 
preferred), respiratory rate, and oxygen saturation. 
• Blood pressure and pulse measurements will be assessed while participant is 
semi-supine or sitting with a completely automated device. Manual techniques will be 
used only if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones). 
8.3.3. 
Electrocardiograms 
Electrocardiogram will be performed locally. Recording should be reviewed on-site by 
the investigator.  
• For the lead-in phase, 12-lead ECG will be obtained as outlined in the Schedule of 
Activities (see Section 1.3) using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. 
• For the expansion phase, 12-lead ECG will be obtained prior to dose administration 
on Day 1. 
8.3.4. 
Cardiac Monitoring 
Given the potential for direct myocardial involvement by SARS-CoV-2, it is possible that 
ADE of disease could manifest as cardiac toxicity (Huang 2020). To monitor this, for 
participants who develop new or worsening cardiac symptoms, signs or ECG findings 
suggestive of an acute MI or cardiac failure, cardiology consultation will be 
recommended to guide further cardiac work up and assessment of potential cardiac 
events. Event details should be captured in the appropriate EDC forms. 
8.3.5. 
Virologic Measures 
Samples for virological analysis will be collected in accordance with the laboratory 
manual and Schedule of Activities (Section 1.3).  
• Nasopharyngeal swabs will be collected for SARS-CoV-2 RT-PCR 
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• Nasopharyngeal swab on Day 1 will include respiratory viral panel to asses 
coinfection 
• Blood samples will be collected for quantitative SARS-CoV-2 RT-PCR  
Samples may also be used for resistance surveillance analysis. 
8.3.6. 
Clinical Safety Laboratory Assessments 
• See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) for the timing and frequency.  
• Laboratory assessments at Screening visit for the Lead-In phase and Expansion phase 
will be performed locally at the clinical site. 
• To ensure timely safety management of the participants, local laboratory assessments 
per standard of care at the clinical site will be performed for the in-patient portion of 
the Lead-In phase as outlined in the Schedule of Activities. 
• In the Lead-In phase only, urine will be collected on Day 1 (pre-dose) and Day 2 for 
analysis of albumin to creatinine ratio conducted locally.  
• All protocol-required laboratory test performed centrally, as defined in Section 10.2, 
must be conducted in accordance with the laboratory manual and Schedule of 
Activities (Section 1.3) 
− The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
− Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
− All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 2 days after the last dose of study 
intervention should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor.  
− If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified and 
the sponsor notified. 
• If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.3.7. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
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• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at Screening to confirm eligibility and at Week 24 or Early Withdrawal 
visit. 
• Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study. 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of adverse events (AE) or serious adverse events (SAEs) can be found in 
Section 10.3. 
The definitions of unsolicited and solicited adverse events can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
Since hospitalization or death are SAEs and they are included in the primary endpoint, 
they will be collected and reported as SAEs as delineated in Section 8.4.1 below. Since it 
will not be possible to delineate in a single participant whether the hospitalization is 
directly related to COVID-19 complications or could be related to VIR-7831 causing 
more severe disease due to ADE, all hospitalizations regardless of cause will be included 
in the primary endpoint and will also be counted as serious adverse events (with the 
exception of elective treatment of a pre-existing condition that did not worsen from 
baseline as noted in Section 10.3). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). As noted in 
Section 8.2.1 data on hospitalization or death should additionally be recorded in the 
eCRF for all relevant sections. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
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8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
• All AEs will be collected through Week 12 post-dose. SAEs will be collected from 
dose administration through the Week 24 follow-up visit at the time points specified 
in the Schedule of Activities (Section 1.3). However, any SAEs assessed as related to 
study participation (e.g., study intervention, protocol-mandated procedure, invasive 
tests or change in existing therapy) will be recorded from the time participant 
consents to participate in the study.  
• Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions not as AEs. 
• All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Section 10.3. The 
investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of it being available. 
• Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor or designee. 
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8.4.2. 
Assessment of Severity 
Standard toxicity grading according to the DAIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events, version 2.1 (July 2017) will be used to grade all AEs.  
8.4.3. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
8.4.4. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AEs of special 
interest (as defined in Section 8.4.8), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Section 10.3. 
8.4.5. 
Regulatory Reporting Requirements for SAEs 
GlaxoSmithKline (GSK) is acting on behalf of Vir for the purposes of global safety 
reporting for this study. 
• Prompt notification by the investigator to GSK of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.  
• GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical 
investigation. GSK will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and GSK policy and 
forwarded to investigators as necessary. 
8.4.6. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until Week 24. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to sponsor or designee within 24 hours of learning of 
the female participant pregnancy. While pregnancy itself is not considered to be an 
AE or SAE, any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an AE or SAE. 
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• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The participant will be followed to determine the outcome of the pregnancy and for 
up to 1 year after birth. The investigator will collect follow-up information on the 
participant and the neonate/child and the information will be forwarded to the sponsor 
or designee. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor or designee as 
described in Section 8.4.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
8.4.7. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.4.8. 
Adverse Events of Special Interest 
Adverse events of special interest are defined in the study protocol as relevant known 
toxicities of other therapeutic mAbs or as a result of signals observed from previous 
studies in the nonclinical programs of VIR-7831 that will be monitored by the Sponsor 
either during or at the end of the study. These will be updated during the course of the 
study based on accumulating safety data. 
AESI include: 
• Infusion-related reactions (IRR) including hypersensitivity reactions; reactions on 
same day as infusion 
• Immunogenicity related adverse drug reactions 
• Adverse events potentially related to antibody dependent enhancement of disease 
8.4.8.1. 
Infusion-Related Reactions and Serious Hypersensitivity 
Pleae refer to local or institutional guidelines for monitoring relevant adverse events 
encompassing hypersensitivity, angioedema, anaphylaxis, acute anaphylactic shock and 
minor allergic episodes. Pre-medications will be permitted at the investigator’s discretion 
and will be appropriately documented. 
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8.4.8.2. 
Immunogenicity 
Unwanted immunogenicity is an immune response by an organism against a therapeutic 
protein. This reaction leads to production of anti-drug-antibodies (ADA) which may 
inactivate the therapeutic effects of the treatment and, in rare cases, induce adverse 
events. This study will include participant follow-up for a period of 5 half-lives to assess 
for the development of ADA and potential impacts on safety, PK and/or efficacy. 
8.4.8.3. 
Antibody Dependent Enhancement 
Antibody-dependent enhancement (ADE) of disease theoretically can occur via one of 
three previously described mechanisms: 
1. By facilitating viral entry into host cells and enhancing viral replication in these 
cells;  
2. By increasing viral fusion with target host cells, enhancing viral replication in 
these cells. 
3. By enhancing disease pathology from viral antigen-antibody related immune 
complex deposition or complement activation and immune cell recruitment in 
target organs;  
The first two mechanisms are hypothesized to occur at sub-neutralizing antibody 
concentrations (Arvin 2020). This study will include participant follow-up for a period of 
5 half-lives to assess for the potential of enhanced disease in the context of waning 
VIR-7831 levels, which may manifest as an increased incidence of re-infection or 
increased severity of re-infections after recovery from initial illness. The third mechanism 
is hypothesized to occur at high levels of antigen (i.e., viral load) and antibody potentially 
leading to immune complex deposition and complement activation in tissue sites of high 
viral replication. This may manifest as acute deterioration temporally associated with 
VIR-7831 infusion or as increased severity or duration of illness in VIR-7831-treated 
participants vs. placebo-treated participants. 
As described in Section 2.3.1, AEs potentially related to ADE of the disease will be 
reviewed by the IDMC to see if there is an imbalance in incidence or severity between 
the treatment groups. 
8.5. 
Pharmacokinetics 
Blood samples for serum PK will be collected as detailed in the Schedule of Activities 
(Section 1.3). Instructions for the collection and handling of biological samples will be 
provided by the sponsor or designee in the laboratory manual. 
• The actual date and time (24-hour clock time) of each sample will be recorded. 
• Samples collected for analyses of VIR-7831 serum concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the 
study. 
• At visits during which whole blood samples are collected to obtain serum endpoints 
other than PK VIR-7831, one sample of sufficient volume can be used. 
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• VIR-7831 serum concentration information that would unblind the study will not be 
reported to investigative sites or blinded personnel until the study has been unblinded. 
For the intensive sub-study in the Lead-In phase, pharmacokinetic parameters will be 
computed using standard noncompartmental methods. Parameters may include, but not be 
limited to Cmax, Clast, Tmax, Tlast, AUCinf, AUClast, %AUCexp, t1/2, λz, Vz, Vss, CL, and will 
be listed and summarized using descriptive statistics. Other parameters may be 
calculated, if deemed necessary. Definitions of PK parameters and methods for 
estimation will be included in the analysis plan. 
For the Expansion Phase, serum concentrations may be combined with data from the 
Lead-In Phase in addition to other studies evaluating VIR-7831 for the purpose of 
population PK model development. Pharmacokinetic analyses may be conducted to 
explore exposure-response relationships between PK parameters and selected antiviral 
variables. These analyses may include graphical plots, tabular summaries, and various 
linear and/or nonlinear analyses. Details of the PK analyses will be provided in the 
analysis plan. 
8.6. 
Genetics 
A 2.5 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Sequencing of 
four genomic polymorphisms in FCGR2A, FCGR2B, FCGR3A, and IGHG1 loci will be 
performed on whole blood samples collected pre-dosing in all participants. Participation 
is optional. Participants who do not wish to participate in the genetic research may still 
participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
Samples will be collected in accordance with the laboratory manual and Schedule of 
Activities (Section 1.3). 
8.7. 
Biomarkers 
Multiple immunology/biomarker samples will be collected from participants to evaluate 
host immune responses and exploratory biomarkers related to SARS-CoV-2 and/or 
VIR-7831, including genetic, cellular, transcriptomic, virologic, and proteomic 
parameters. 
Whole blood samples will be collected for RNAseq to evaluate cellular populations and 
transcriptomes at early timepoints after treatment. This is an optional test requiring 
consent from patients. Serum will be collected throughout the course of the study to 
evaluate changes in serum biomarkers and cytokines at early timepoints following 
treatment (including but not limited to inflammatory cytokines and chemokines, such as 
IL-6, IFN-alpha, IL-1, IL-3, TNF-alpha, as available), as well as to evaluate the host 
antibody response to SARS-CoV-2 antigens over the duration of the study. In a 
sub-study, PBMCs will be collected to assess the frequency and function of SARS-CoV-
2 specific T cells. 
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Samples will be collected in accordance with the laboratory manual and Schedule of 
Activities (Section 1.3). 
Sponsor may store samples for up to 15 years after the end of the study to achieve study 
objectives.  
8.7.1. 
Resistance Analyses 
In order to monitor for resistance, resistance surveillance will be conducted for all 
participants who are randomized and dosed. Deep sequence analysis of the SARS-CoV-2 
spike gene will be attempted on baseline and post-baseline (from participants who do not 
experience a decline in viral load or who experience virologic rebound) nasopharyngeal 
samples to identify substitutions in the mAb epitope or substitutions outside the epitope 
that arise during treatment. Virologic rebound will be defined as participants who 
experience an increase of >1 log10 copies/mL in viral load for 2 consecutive visits, or 
viral load becomes quantifiable for 2 consecutive visits after having been below the limit 
of quantification. For identified substitutions that qualify for phenotypic analysis, in vitro 
phenotypic analysis of the antiviral activity of VIR-7831 using a SARS-CoV-2 spike 
pseudovirus system will be attempted and analysed for reduced susceptibility to VIR-
7831. 
8.8. 
Immunogenicity Assessments 
Antibodies to VIR-7831 will be evaluated in serum samples collected from all 
participants according to the Schedule of Activities (Section 1.3). Additionally, serum 
samples should also be collected at the final visit from participants who discontinued 
study intervention or were withdrawn from the study. These samples will be tested by the 
sponsor or designee. 
Serum samples will be screened for antibodies binding to VIR-7831 and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify 
the stability of antibodies to VIR-7831 and/or further characterize the immunogenicity of 
VIR-7831. 
The detection and characterization of antibodies to VIR-7831 will be performed using a 
validated assay method by or under the supervision of the sponsor or designee. All 
samples collected for detection of antibodies to study intervention will also be evaluated 
for VIR-7831 serum concentration to enable interpretation of the antibody data. 
Antibodies may be further characterized and/or evaluated for their ability to neutralize the 
activity of the study intervention(s). Samples may be stored for a maximum of 15 years 
(or according to local regulations) following the last participant’s last visit for the study at 
a facility selected by the sponsor/designee to enable analysis of immune responses to 
VIR-7831 as described. 
Samples will be collected in accordance with the laboratory manual and Schedule of 
Activities (Section 1.3). 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary objective of this study is to evaluate the efficacy or VIR-7831 versus 
placebo in preventing the progression of COVID-19. 
The primary endpoint is proportion of participants who have progression of COVID-19 
through Day 29 as defined by hospitalization > 24 hours for acute management of illness 
or death.  
If we denote the proportion of participants with progression of COVID-19 in the 
VIR-7831 arm as PA, and the proportion of participants with progression of COVID-19 in 
the placebo arm as PB, the following null and alternative hypothesis for superiority is as 
follows: 
H0: PA = PB  
H1: PA ≠ PB 
9.2. 
Sample Size Determination 
VIR-7831 and placebo will be randomized in a 1:1 ratio. 
The study will utilize a group sequential design with two interim analyses to asses both 
futility due to lack of efficacy and overwhelming efficacy. A Lan-DeMets alpha-spending 
function to control the type I error will be used, using a Pocock analogue rule for futility 
and a Hwang-Shih-DeCani (with parameter γ = 1) analogue for efficacy [Hwang 1990]. 
The expected sample size is 680 participants per arm No sample size re-estimation is 
planned. 
Approximately 1360 (680 per arm) participants will be randomly assigned to study 
intervention. A total sample size of 1360 will provide approximately 90% power to detect 
a 37.5% relative efficacy in reducing progression of COVID-19 through Day 29 at the 
overall two-sided 5% significance level with assumed progression of COVID-19 rates of 
16% in the placebo arm and 10% in the VIR-7831 arm, respectively. The minimal 
detectable efficacy for this design at the final efficacy analysis is approximately 25% if 
disease progression rates is 16% in the placebo arm. 
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9.3. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Intent-to-Treat 
All participants who were randomized according to the 
intervention they were randomized to. This will be the primary 
analysis set. 
Safety 
All randomized participants who are exposed to study 
intervention. Participants will be analyzed according to the 
intervention they actually received. 
Per-Protocol 
All participants in the ITT analysis set for whom there were no 
major protocol deviations that impact the primary analyses. 
Data should be reported according to the intervention a 
participate was randomized to. 
Specific details of major protocol deviations that would exclude 
participants from the PP analysis will be defined in the analysis 
plan 
Pharmacokinetic 
All participants in the Safety analysis set who had at least 1 
non-missing PK assessment (Non-quantifiable [NQ] values will 
be considered as non-missing values) 
Virology 
All participants who were randomized according to the 
intervention they were randomized to and with a central lab 
confirmed quantitative nasopharyngeal swab at Day 1. This will 
be the primary analysis set for virology. 
 
Defined Analysis Data Sets Description 
Analysis set for all efficacy 
estimands 
All randomized participants. For participants who discontinue 
study intervention and/or receive rescue therapy, all post 
discontinuation or post rescue observations will be included in 
the analysis set. 
Analysis set for all safety 
estimands 
All randomized participants. For participants who discontinue 
study intervention and/or receive rescue therapy, all post 
discontinuation or post rescue observations will be included in 
the analysis set. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to unblinding for the first IDMC and it 
will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
Any change to the data analysis methods described in the protocol will require an 
amendment only if it changes a principal feature of the protocol. Any other change to the 
data analysis methods described in the protocol and the justification for making the 
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change will be described in the statistical analysis plan. Additional exploratory analyses 
of the data will be conducted as deemed appropriate. 
9.4.1. 
General Considerations 
In the case of a difference between the stratification assigned at the time of randomization 
and the data collected in the eCRF, the analyses will be performed based on the 
calculated stratum at randomization.  
Confidence intervals will use the 95% levels unless otherwise specified. 
9.4.2. 
Primary Endpoint(s) 
The primary endpoint will be proportion of participants who have progression of 
COVID-19 as defined by hospitalization > 24 hours for acute management of illness or 
death through Day 29. 
The primary analysis will be the comparison of progression rate within 29 days between 
VIR-7831 and placebo using generalized linear model (GLM) with log binomial link, 
adjusted for treatment (VIR-7831 vs. placebo), duration of symptoms (≤3 days vs. 
4-5 days) , age (≤70 vs. >70 years old) and gender (female vs. male) to test for 
superiority of VIR-7831 versus placebo. If the GLM does not converge then it will be 
approximated by a Poisson regression model with a robust sandwich estimator, adjusted 
for the same covariates of GLM. If the P-value from the GLM (or from Poisson 
regression model if GLM does not converge) is less than the adjusted significance 
level02446, a statistically significant advantage in favor of VIR-7831 will be declared. 
Relative risk of VIR-7831 versus placebo and its 95% confidence interval (CI) will be 
estimated. At each of the interim and final efficacy analysis, appropriate CI based on 
the adjusted significance level will also be provided.  
Possible intercurrent events are withdrawal of consent and lost-to-follow-up on or before 
Day 29. The strategy for analysis for these intercurrent events, will be to use the 
treatment policy strategy, with data analyzed as collected. It is expected missing data will 
be minimal and most will be lost to follow up data after discharge and this along with 
intermittent data will be imputed using multiple imputation under the missing at random 
assumption. Every effort will be made to reduce missing data (refer to Section 7) . 
Supplemental estimand strategies and missing data sensitivities will be performed and 
further details will be provided in the analysis plan. 
9.4.3. 
Secondary Endpoint(s) 
Full details of all analysis methods for the secondary endpoints will be provided in the 
analysis plan. 
9.4.4. 
Exploratory Endpoint(s) 
Full details of all analysis methods for the exploratory endpoints will be provided in the 
analysis plan. 
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9.4.5. 
Safety Analysis 
For safety data, no formal hypotheses will be tested. Occurrence of AEs, non-COVID-19-
related AEs, SAEs, non-COVID 19 relate SAEs, and AESIs, including laboratory tests, 
vital signs, and ECG abnormalities will be displayed in the form of listings, frequencies, 
summary statistics, graphs, and statistical analyses where appropriate. Interpretation will 
be aided by clinical expertise.  
As noted in Section 8.4, since it will not be possible to delineate in a single participant 
whether the hospitalization is directly related to COVID-19 complications or could be 
related to VIR-7831 causing more severe disease due to ADE, all hospitalizations 
regardless of cause will be included in the primary endpoint and will also be counted as 
serious adverse events. To inform on the number and nature of non-COVID-19 adverse 
events and serious adverse events, additional safety analyses will be performed in which 
select, pre-specified terms consistent with known progression of COVID-19 disease will 
be excluded. Details of these and all analyses, including example outputs, will be 
documented in the analysis plan. 
9.4.6. 
Other Analysis 
Full details of all analysis methods of immunogenicity and population pharmacokinetics 
will be provided in the analysis plan. 
9.5. 
Interim Analysis 
Interim analysis will be used to assess safety (due to harm), futility due to lack of efficacy 
and efficacy. A non-binding statistical framework for evaluating number of events of 
interest will be provided to aide the IDMC to make recommendations based upon 
the totality of available safety data from the study. 
Full details of timing of analyses and all stopping criteria will be given in the IDMC 
charter. 
Interim analyses to assess efficacy and futility are planned when approximately 41% and 
64% of the required number of participants have reached Day 29 visit. The analysis of the 
primary endpoint at the interim analyses will be the same as that described for the 
primary endpoint. Group sequential techniques will be used to adjust stopping boundaries 
to reflect the actual number of participants with available data for primary endpoint at the 
time of each interim analysis. The full decision criteria for the futility due to lack of 
efficacy and efficacy rules along with additional information to be presented to the IDMC 
will be defined in the IDMC charter and associated documents, as well as the analysis 
plan.  
The Joint Safety Review Team (JSRT) comprising individuals from Vir and GSK will 
review blinded safety data at regular intervals throughout the conduct of the study and 
determine if a safety concern based on instream blinded data review needs to be escalated 
to the IDMC. Details of the JSRT process is recorded in relevant SRT documents. 
Following all participants completing the final follow-up visit at Week 24, a final safety 
analysis will be performed. 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
− Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU Clinical Trials 
Directive 2001/20/EC or Regulation (EU) No. 536/2014 (if applicable), and all 
other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor or designee with sufficient, 
accurate financial information as requested to allow the sponsor/designee to submit 
complete and accurate financial certification or disclosure statements to the appropriate 
regulatory authorities. Investigators and sub-investigators are responsible for providing 
information on financial interests during the course of the study and for 1 year after 
completion of the study. 
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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or their legally authorized representative and answer all questions 
regarding the study.  
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A signed copy of the ICF(s) must be provided to the participant or their legally 
authorized representative.  
Vir (alone or working with others) may use the participant’s coded study data and 
samples and other information to carry out this study; understand the results of this study; 
learn more about VIR-7831 or about the study disease; fulfill legal and regulatory 
obligations, including reporting safety information about VIR-7831, this study, and the 
results of this study to regulatory authorities; provide information about the safety and 
use of VIR-7831 to investigators and institutions that plan to administer VIR-7831 to 
patients; publish the results of these research efforts; work with government agencies or 
insurers to have VIR-7831 approved for medical use or approved for payment coverage.  
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor/designee. Any 
participant records or datasets that are transferred to the sponsor/designee will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor/designee in accordance with local data protection law. The level of 
disclosure must also be explained to the participant, who will be required to give 
consent for their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor/designee, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
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10.1.5. 
Committees Structure 
Independent Data Monitoring Committee (IDMC) 
An IDMC will actively monitor interim unblinded safety (Lead-In Phase) and interim 
unblinded safety and efficacy data (Expansion Phase) to make recommendations to Vir as 
detailed in the IDMC Charter. The IDMC members will include at least 2 physicians with 
relevant medical training and one statistician. Details regarding the IDMC process will be 
available in relevant IDMC documents. 
Details of the structure and function of the IDMC, and analysis plan for IDMC reviews 
are outlined in the IDMC Charter, which is available upon request.  
Joint Safety Review Team 
The Joint Safety Review Team (JSRT) comprised of individuals from Vir and GSK will 
review blinded safety data at regular intervals throughout the conduct of the study and 
determine if a safety concern based on instream blinded data review needs to be escalated 
to the IDMC. Details of the JSRT process is recorded in relevant SRT documents. 
10.1.6. 
Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report. The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a sponsor site or other 
mutually-agreeable location. 
• Sponsor or designee will also provide all investigators who participated in the study 
with a summary of the study results and will tell the investigators what treatment their 
study participants received. The investigator(s) is/are encouraged to share the 
summary results with the study participants, as appropriate. 
• Under the framework of the SHARE initiative, the sponsor intends to make 
anonymized participant-level data from this trial available to external researchers for 
scientific analyses or to conduct research that can help advance medical science or 
improve patient care. This helps ensure the data provided by trial participants are used 
to maximum effect in the creation of knowledge and understanding. Requests for 
access may be made through www.clinicalstudydatarequest.com. 
• Sponsor or its designee will provide the investigator with the randomization codes for 
their site only after completion of the full statistical analysis. 
• The procedures and timing for public disclosure of the protocol and results summary 
and for development of a manuscript for publication for this study will be in 
accordance with GSK Policy. 
• A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
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10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.  
• Guidance on completion of CRFs will be provided in the data entry guidelines. 
• Quality Tolerance limits (QTLs) will be pre-defined in the Integrated Quality Risk 
Management Plan to identify systematic issues that can impact participant safety 
and/or reliability of study results. These pre-defined parameters will be monitored 
during and at the end of the study, and all deviations from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Monitoring details describing strategy including definition of study critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are provided 
in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals  
(e.g., Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the 
sponsor.  
• As hospitalization and mortality are both primary study endpoints and serious adverse 
events, instream data cleaning including updating and reconciliation of hospitalization 
events between the safety dataset and efficacy dataset will be performed throughout 
the study duration and any changes or updates to the SAEs of hospitalization or 
mortality will be reflected in the efficacy dataset. 
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10.1.8. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the printed CRFs or entered in the electronic eCRFs that are 
transcribed from source documents must be consistent with the source documents or 
the discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
• Definition of what constitutes source data and its origin can be found in [Source Data 
Acknowledgment]. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study/Site Termination 
Vir reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of Vir. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
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• Inadequate or no recruitment of participants (evaluated after a reasonable amount of 
time) by the investigator 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or suspension, 
as specified by the applicable regulatory requirements. The investigator shall 
promptly inform the participant(s) and should assure appropriate participant therapy 
and/or follow-up 
10.1.10. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary information 
and to provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site 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. 
10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 4 will be performed by either the central laboratory or the site 
local laboratory.  
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
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Table 4: 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
 
Hematocrit 
ABO typing2 
Urine albumin to creatinine ratio3 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Clinical 
Chemistry 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total and direct 
bilirubin 
 
Creatinine6 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
Glucose (non-
fasting) 
Calcium 
Alkaline phosphatase 
Gamma-glutamyl 
transferase (GGT) 
 
Carbon 
dioxide/bicarbonate 
Chloride 
Lactate dehydrogenase 
(LDH) 
Albumin 
 
Amylase 
Lipase 
 
 
Coagulation 
parameters 
International 
Normalized Ratio 
(INR) time 
Prothrombin 
time (PT) 
Partial thromboplastin 
time (PTT) / Activated 
PTT (aPTT) 
 
Pregnancy 
testing 
Highly sensitive (Serum/plasma or urine) human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential) 
Inflammatory 
Markers1 
C-reactive protein1, 5 
Ferritin1, 5 
IL-61, 5 
 
Respiratory 
Pathogens4 
Respiratory viral 
panel by PCR4 
 
 
 
1 Parameters not included in local laboratory assessments performed at Screening visit 
2 Screening visit only to be performed locally 
3Lead-In phase only: Day 1 (pre-dose) and Day 2 to be performed locally.  
4 Day 1 only and performed by central laboratory  
5 Day 1, 15 and 29 visits only and performed by central laboratory  
6 Repeat if above the normal range 
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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
a. An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to the 
study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a study intervention. 
 
Definition of Unsolicited and Solicited AE 
b. An unsolicited adverse event is an adverse event that was not solicited using a Participant 
Diary and that is communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and non-serious AEs. 
c. Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses requiring 
a hospitalization, or emergency room visit, or visit to/by a health care provider). The 
participants will be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant concern. Detailed information about reported unsolicited AEs will be collected 
by qualified site personnel and documented in the participant’s records. 
d. Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during interview with the participants and by review of available medical 
records at the next visit. 
e. Solicited AEs are predefined local at the infusion site and systemic events for which the 
participant is specifically questioned, and which are noted by the participant in their diary.  
 
Events Meeting the AE Definition 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
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Events Meeting the AE Definition 
• Clinically significant changes in laboratory assessments. 
 
Events NOT Meeting the AE Definition  
1. Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
2. The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
3. Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
4. Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
5. Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
1) Results in death 
2) Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
3) Requires inpatient hospitalization or prolongation of existing hospitalization 
Appendix A. 
In general, hospitalization signifies that the participant has been 
admitted (usually involving at least an overnight stay) at the hospital or 
emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be 
considered serious. 
Appendix B. 
Hospitalization for elective treatment of a pre-existing condition that did 
not worsen from baseline is not considered an AE. 
4) Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
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An SAE is defined as any serious adverse event that, at any dose: 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
5) Is a congenital anomaly/birth defect 
6) Other medically significant situations: 
• 
Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% direct 
bilirubin) or international normalized ratio (INR) >1.5 must be reported as SAE 
• 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
− 
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
a. Myocardial infarction/unstable angina 
b. Congestive heart failure 
c. Arrhythmias 
d. Valvulopathy 
e. Pulmonary hypertension 
f. Cerebrovascular events/stroke and transient ischemic attack 
g. Peripheral arterial thromboembolism 
h. Deep venous thrombosis/pulmonary embolism 
i. Revascularization 
 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
a. 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
b. 
The investigator will then record all relevant AE/SAE information. 
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AE and SAE Recording 
c. 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to sponsor in lieu of completion of the required form. 
d. 
There may be instances when copies of medical records for certain cases are 
requested by GSK Pharma Safety staff. In this case, all participant identifiers, with 
the exception of the participant number, will be redacted on the copies of the 
medical records before submission. 
e. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
• 
The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor with a copy of any post-mortem findings 
including histopathology.  
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of receipt of 
the information. 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the relationship 
of each SAE to IP/study participation (causality) within 72 hours of SAE entry into the 
eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the SAE coordinator by telephone. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• 
Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the SAE coordinator. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
 
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10.3.6. 
Expedited Reporting to Health Authorities, Investigators and Ethics 
Committees 
Expedited Reporting 
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events to identify and expeditiously communicate new safety findings to investigators, IRBs, 
ECs, and health authorities based on applicable legislation. 
 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the VIR-7831 Investigator’s Brochure.  
10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.  
− Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
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If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following (for 
the purpose of this study): 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
2. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
• Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
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10.4.2. 
Contraception Guidance: 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)  
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or medical 
history interview.) 
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 
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10.5. 
Appendix 5: Genetics 
10.5.1. 
USE/ANALYSIS OF DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis. 
• DNA samples will be used for research related to VIR-7831 mechanism of action in 
SARS-CoV-2 and related diseases. They may also be used to develop tests/assays 
(including diagnostic tests) related to VIR-7831 and related mAb therapeutics for 
SARS-CoV-2 and related diseases. Genetic research may consist of the analysis of 
one or more candidate genes or the analysis of genetic markers throughout the 
genome. 
• DNA samples will be analyzed for genomic polymorphisms in FCGR2A, FCGR2B, 
FCGR3A, and IGHG1 loci.  
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to VIR-7831 or study interventions of this class. The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• The samples will be retained while research on VIR-7831 (or study interventions of 
this class) or SARS-CoV-2 continues but no longer than 15 years after the last 
participant last visit or other period as per local requirements. 
 
 
 
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10.6. 
Appendix 6: Long COVID Questionnaire  
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with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-
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Jan 30;: PMID: 31986264; PMCID: PMC7159299. 
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human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. 
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Hwang IK, Shih WJ, DeCani JS, Statistics In Medicine. Dec 1990 (Volume9, Issue 12 , 
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Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H Thromb Res. 2020; 
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Haase AT, Rao SS, Blumberg RS, Mascola JR, Nabel GJ. 2014. Enhanced neonatal Fc 
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JY, Xing X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, 
Jin L, Yang R, Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, 
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Pelletier I, Girard J, Kulkarni P, Newton E, Tavel JA. A Phase 1, Randomized, Double-
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Liu Y, Yan LM, Wan L, Xiang TX, Le A, Liu JM, Peiris M, Poon LLM, Zhang W.. Viral 
dynamics in mild and severe cases of COVID-19. Lancet Infect Dis 2020;doi: 
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Pablo N Perez-Guzman, Anna Daunt, Sujit Mukherjee et al. Clinical characteristics and 
predictors of outcomes of hospitalised patients with COVID-19 in a London NHS Trust: 
a retrospective cohort study (2020), doi: https://doi.org/10.25561/78613 
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Petrilli et al, medrxiv N=1999 (hosp) OpenSAFELY (NHS data) N=5683 Deaths REF: 
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Pinto D, Park Y, Beltramello M et al. Cross-neutralization of SARS-CoV-2 by a human 
monoclonal SARS-CoV antibody. Nature. Published online May 18, 2020. 
https://doi.org/10.1038/s41586-020-2349-y 
Polack FP, Teng MN, Collins PL, Prince GA, Exner M, Regele H, Lirman DD, Rabold 
R, Hoffman SJ, Karp CL, Kleeberger SR, Wills-Karp M, Karron RA. A role for immune 
complexes in enhanced respiratory syncytial virus disease. J Exp Med. 2002 Sep 
16;196(6):859-65. doi: 10.1084/jem.20020781. PMID: 12235218; PMCID: 
PMC2194058. 
Powers JH, Bacci ED, Leidy NK, Poon JL, Stringer S, Memoli MJ, et al. Performance of 
the inFLUenza Patient-Reported Outcome (FLU-PRO) Diary in Patients with Influenza-
Like Illness (ILI). PLoS One. 2018 Mar 22;13(3):e0194180. doi: 
10.1371/journal.pone.0194180. eCollection 2018. 
Powers JH, Bacci ED, Guerrero ML, Leidy NK, Stringer S, Kim K, Memoli MJ, et al. 
Reliability, Validity, and Responsiveness of InFLUenza Patient-Reported Outcome 
(FLU-PRO©) Scores in Influenza-Positive Patients. Value Health. 2018 Feb;21(2):210-
218. doi: 10.1016/j.jval.2017.04.014. Epub 2017 Jun 7. 
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, 
and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City 
Area. JAMA. Published online April 22, 2020. doi:10.1001/jama.2020.6775. 
Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized 
patients with COVID-2019. Nature. 2020 Apr 01. https://doi.org/10.1038/s41586-020-
2196-x 
Wu JT, Ma ES, Lee CK, Chu DK, Ho PL, Shen AL, Ho A, Hung IF, Riley S, Ho LM, 
Lin CK, Tsang T, Lo SV, Lau YL, Leung GM, Cowling BJ, Malik Peiris JS. The 
infection attack rate and severity of 2009 pandemic H1N1 influenza in Hong Kong. Clin 
Infect Dis. 2010 Nov 15;51(10):1184-91. doi: 10.1086/656740. PMID: 20964521; 
PMCID: PMC3034199. 
Yang H, et al. O0814 Phase IIb study evaluating the efficacy and safety of anti-influenza 
A monoclonal antibody, CT-P27, in subjects with acute uncomplicated Influenza A 
Infection. 29th European Congress of Clinical Microbiology and Infectious Diseases. 
Amsterdam, Netherlands. 2019 Apr 13-16. Poster presentation. 
Yu J, Powers JH 3rd, Vallo D, Falloon J. Evaluation of Efficacy Endpoints for a Phase 
IIb Study of a Respiratory Syncytial Virus Vaccine in Older Adults Using Patient-
Reported Outcomes with Laboratory Confirmation. Value Health. 2020 Feb;23(2):227-
235. doi: 10.1016/j.jval.2019.09.2747. Epub 2019 Nov 21. 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, 
Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk 
factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective 
cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-
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6736(20)30566-3. Epub 2020 Mar 11. Erratum in: Lancet. 2020 Mar 
28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038. PubMed PMID: 32171076. 
Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, Yu J, Kang M, Song Y, Xia J, 
Guo Q, Song T, He J, Yen HL, Peiris M, Wu J. SARS-CoV-2 Viral Load in Upper 
Respiratory Specimens of Infected Patients. N Engl J Med. 2020 Mar 19;382(12):1177-
1179. doi: 10.1056/NEJMc2001737. Epub 2020 Feb 19. PubMed PMID: 32074444. 
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SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
Study ID:  214367 
 
Official Title of Study: A randomized, multi-center, double-blind, placebo-controlled 
study to assess the safety and efficacy of monoclonal antibody VIR-7831 for the early 
treatment of coronavirus disease 2019 (COVID-19) in outpatients. 
 
NCT ID: NCT04545060 
 
 
Date of Document: 29-JAN-2021 
 
 


 
CONFIDENTIAL 
 
Vir Biotechnology, Inc and GlaxoSmithKline group of companies 
 (GSK Study 214367) 
 
VIR-7831-5001 
1 
 
Division 
: Worldwide Development 
Information Type 
: Statistical Analysis Plan (SAP) 
Title Page 
Protocol Title: A randomized, multi-center, double-blind, placebo-controlled study to 
assess the safety and efficacy of monoclonal antibody VIR-7831 for the early treatment 
of coronavirus disease 2019 (COVID-19) in outpatients 
Protocol Number: VIR-7831-5001 (GSK Study 214367) Original 
Compound Number: VIR-7831 (GSK4182136) 
Short Title: VIR-7831 for the early treatment of COVID-19 in outpatients 
Sponsor Name: This study is sponsored by Vir Biotechnology, Inc. 
GlaxoSmithKline is supporting Vir Biotechnology, Inc. in the conduct of this study. 
Vir Biotechnology, Inc. 
 499 Illinois Street, Suite 500 
 San Francisco, CA 94158 
 USA 
 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
IND:  
EudraCT:   
NCT: 
 
IND-149315 
2020-002871-36 
NCT04545060 
 
Copyright 2021 the Vir Biotechnology, Inc and GlaxoSmithKline group of companies. 
All rights reserved.  Unauthorised copying or use of this information is prohibited 
 
 
 
 


 
C O N FI D E N TI A L  
 
 
 
2 1 4 3 6 7 (VI R -7 8 3 1 -5 0 0 1 ) 
2  
 
S A P  A ut h or(s):  
A ut h or  
D ate  
  
2 9 J A N  2 0 2 1  
Statistics Lea der, Bi ostatistics, 
Gla x o S mit h Kli ne  
 
S A P  Te a m Re vie w C o nfir m ati o ns  ( E-m ail C o nfir m ati o n) : 
A p pr o ver  
D ate of E -m ail 
C o nfir m ati o n  
 
2 9 J A N 2 0 2 1  
, Cli nical Researc h, Vir 
Bi otec h n ol o g y I n c.  
 
2 9 J A N 2 0 2 1  
 P har m a Safet y, Gla x o S mit h Kli ne 
 
2 9 J A N 2 0 2 1  
Pr o gra m mer/ A nal yst, Cli nical Pr o gra mi n g, 
Gla x o S mit h Kli ne  
Cli nic al St atistics Li ne A p pr o v al  (E -M ail ): 
A p pr o ver  
D ate  
 
2 9 J A N 2 0 2 1  
, Bi o metri cs, Vir Bi otec h n ol o g y I n c 
 
2 9 J A N 2 0 2 1  
, Bi ostatistics, Gla x o S mit h Kli ne  
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
CONFIDENTIAL 
 
 
 
214367(VIR-7831-5001) 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 7 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
1.2. 
Objectives, Endpoints and Estimands ........................................................... 8 
1.2.1. 
Objectives and Endpoints .............................................................. 8 
1.2.2. 
Estimands .................................................................................... 11 
1.3. 
Study Design .............................................................................................. 17 
2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA .......................................... 19 
2.1. 
Multiple Comparisons and Multiplicity ......................................................... 19 
3. 
SAMPLE SIZE DETERMINATION ......................................................................... 21 
4. 
ANALYSIS SETS ................................................................................................... 21 
4.1. 
Protocol Deviations ..................................................................................... 22 
4.1.1. 
Definitions for Per Protocol Analysis Set ...................................... 23 
5. 
STATISTICAL ANALYSES ..................................................................................... 23 
5.1. 
General Considerations .............................................................................. 23 
5.1.1. 
General Methodology .................................................................. 23 
5.1.2. 
Baseline Definition ....................................................................... 24 
5.1.3. 
Multicenter Studies ...................................................................... 24 
5.1.4. 
Intercurrent Events ...................................................................... 24 
5.1.5. 
Missing Data Handling Rules ....................................................... 25 
5.2. 
Primary Endpoint Analyses ......................................................................... 25 
5.2.1. 
Definition of Endpoint ................................................................... 25 
5.2.2. 
Main Analytical Approach ............................................................ 25 
5.2.2.1. 
Decision Criteria ......................................................... 26 
5.2.3. 
Sensitivity Analyses ..................................................................... 27 
5.2.4. 
Supplementary Analyses ............................................................. 27 
5.2.5. 
Subgroup Analyses ...................................................................... 27 
5.3. 
Secondary Endpoints Analyses .................................................................. 28 
5.3.1. 
Definition of Endpoints ................................................................. 28 
5.3.1.1. 
Safety and tolerability ................................................. 28 
5.3.1.2. 
Immunogenicity of VIR-7831 ...................................... 28 
5.3.1.3. 
Pharmacokinetics of VIR-7831 ................................... 29 
5.3.1.4. 
Proportion of Participants Who Have 
Progression of COVID-19 ........................................... 29 
5.3.1.5. 
Proportion of Participants Who Progress to 
Develop Severe or Critical Respiratory COVID-
19 ............................................................................... 29 
5.3.1.6. 
Severity and Duration of COVID-19 Clinical 
Symptoms .................................................................. 30 
5.3.1.7. 
Reduction in SARS-CoV-2 Viral Load. ........................ 30 
5.3.1.8. 
All-cause Mortality ...................................................... 30 
5.3.2. 
Main Analytical Approach ............................................................ 31 
5.3.2.1. 
Binary Endpoints ........................................................ 31 
5.3.2.2. 
Continuous Endpoints ................................................ 31 
5.3.2.3. 
Time to Event Endpoints ............................................ 32 


 
CONFIDENTIAL 
 
 
 
214367(VIR-7831-5001) 
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5.3.3. 
Sensitivity Analyses ..................................................................... 32 
5.3.4. 
Supplementary Analyses ............................................................. 32 
5.3.5. 
Subgroup Analyses ...................................................................... 32 
5.4. 
Exploratory Endpoints Analyses ................................................................. 32 
5.4.1. 
Definition of Endpoints ................................................................. 32 
5.4.1.1. 
Total Number of Ventilator Days ................................. 32 
5.4.1.2. 
Total Intensive Care Length of Stay ............................ 33 
5.4.1.3. 
Total Hospital Length of Stay ...................................... 33 
5.4.1.4. 
Reduction in the Duration of SARS-CoV-2 Viral 
Shedding. ................................................................... 33 
5.4.1.5. 
Proportion of Participants Hospitalized Due to 
Non-Respiratory Complications of COVID-19 ............. 33 
5.4.1.6. 
On-treatment Emergence of SARS-CoV-2 
Resistant Mutants Against VIR-7831 .......................... 33 
5.4.1.7. 
Host Immune Responses and Exploratory 
Biomarkers ................................................................. 33 
5.4.1.8. 
Severity and Duration of COVID-19 Clinical 
Symptoms .................................................................. 34 
5.4.1.9. 
Work Productivity and Activity Impairment 
(WPAI) ........................................................................ 34 
5.4.1.10. Health-Related Quality of Life According to the 
SF-12 Hybrid .............................................................. 34 
5.4.2. 
Main Analytical Approach ............................................................ 34 
5.4.2.1. 
Binary Endpoints ........................................................ 34 
5.4.2.2. 
Continuous Endpoints ................................................ 34 
5.4.2.3. 
Time-to-event endpoints ............................................. 35 
5.5. 
Safety Analyses .......................................................................................... 35 
5.5.1. 
Extent of Exposure ...................................................................... 36 
5.5.2. 
Adverse Events............................................................................ 36 
5.5.2.1. 
Adverse Events of Special Interest ............................. 38 
5.5.3. 
Additional Safety Assessments .................................................... 39 
5.5.3.1. 
Laboratory Data .......................................................... 39 
5.5.3.2. 
Vital Signs .................................................................. 39 
5.5.3.3. 
Oxygen Saturation ...................................................... 40 
5.5.3.4. 
ECG ........................................................................... 40 
5.6. 
Other Analyses ........................................................................................... 40 
5.6.1. 
Population Pharmacokinetics ....................................................... 40 
5.7. 
Interim Analyses ......................................................................................... 41 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 42 
6.1. 
Appendix 1 Abbreviations and Trademarks ................................................. 42 
6.1.1. 
List of Abbreviations .................................................................... 42 
6.1.2. 
Trademarks ................................................................................. 43 
6.2. 
Appendix 2: Changes to Protocol-Planned Analyses .................................. 44 
6.3. 
Appendix 3: Statistical Modelling ................................................................ 45 
6.3.1. 
Multiple Imputation ....................................................................... 45 
6.3.2. 
Count Data Model Checking ........................................................ 46 
6.3.3. 
Continuous Data Model Checking ................................................ 46 
6.4. 
Appendix 4: Flu-PRO Plus responder definition .......................................... 47 
7. 
REFERENCES ....................................................................................................... 49 
 


 
CONFIDENTIAL 
 
 
 
214367(VIR-7831-5001) 
5 
 
Version history 
This Statistical Analysis Plan (SAP) for study VIR-7831-5001 (GSK Study 214367) is 
based on the original protocol dated 27-JUL-2020 and protocol amendment dated 23-
DEC-2020.  
Table 1 
SAP Version History Summary 
SAP 
Version 
Approval 
Date 
Change 
Rationale 
3.0 
Current 
Version 
The key changes include: 
• Amendment of the hierarchy 
strategy for the secondary 
endpoints for FluPRO Plus 
• Clarification of handling of 
missing data for FluPRO Plus  
Following partial use of 
paper PROs, additional 
clarification around 
handling of missing data 
required.   
2.0 
14-Jan-
2021 
The key changes include: 
• Amendment of the alpha-
spending function from O’Brien 
Flemming to Hwang-Shih-
DeCani (γ = 1) rules for 
overwhelming efficacy 
following emergent data on 
neutralising mAbs 
• Due to increasing importance of 
gender as a prognostic factor for 
progression, switching from a 
stratified CMH test to a log-
binomial model including age, 
duration of symptoms, region 
and gender as covariates 
• Amendment of the hierarchy 
strategy for the secondary 
endpoints following emergent 
data on neutralising mAbs 
• Inclusion of a patient reported 
symptoms sustained response 
based on the adapted Flu-PRO 
Plus 
• Other minor, grammatical and 
Update to SAP in 
response to regulatory 
feedback, clarifications 
and emergent data in the 
early treatment of 
COVID-19 with 
neutralising mAbs 


 
CONFIDENTIAL 
 
 
 
214367(VIR-7831-5001) 
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typographical corrections to 
improve readability 
1.0 
 
Not Applicable 
Original version 
 
 


 
CONFIDENTIAL 
 
 
 
214367(VIR-7831-5001) 
7 
 
1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Study VIR-7831-5001. Details of the planned interim analyses, in 
addition to the final Day 29 efficacy analyses and 24-Week Safety Follow-Up analyses, 
are provided. 
Descriptive study population analyses, such as summary of demography and baseline 
characteristics, and additional detail with regards to data handling conventions and the 
specification of data displays will be provided in the Output and Programming 
Specification (OPS) document. 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the planned statistical analysis specified in the 
protocol amendment 1 (Dated: 22-DEC-2020). 
 


 
CONFIDENTIAL 
 
 
 
214367(VIR-7831-5001) 
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1.2. 
Objectives, Endpoints and Estimands 
1.2.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• Evaluate the efficacy of VIR-7831 versus 
placebo in preventing the progression of 
mild/moderate COVID-19 
• Proportion of participants who have 
progression of COVID-19 through Day 29 
as defined by: 
 1. Hospitalization > 24 hours for acute 
management of illness 
OR 
2. Death  
Secondary 
 
Safety 
• Determine the safety and tolerability of 
VIR-7831 compared to placebo 
 
• Occurrence of adverse events (AEs) 
• Occurrence of serious adverse events 
(SAEs)  
• Occurrence of adverse events of special 
interest (AESI) 
• Assess the immunogenicity of VIR-7831 
• Incidence and titers (if applicable) of 
serum ADA to VIR-7831 
Pharmacokinetics 
• Assess the pharmacokinetics (PK) of 
VIR-7831 in serum 
 
• VIR-7831 pharmacokinetics (PK) in 
serum 
Efficacy 
• 
Evaluate the efficacy of VIR-7831 versus 
placebo in preventing the progression of 
mild/moderate COVID-19 
Proportion of participants who have 
progression of COVID-19 through Day 29 as 
defined by: 
1. 
 Visit to a hospital emergency room for 
management of illness  
OR 
2. 
Hospitalization for acute management of 
illness 
OR 
Death  
• Evaluate the impact of VIR-7831 versus 
placebo on the duration and the severity 
• Mean change in FLU-PRO Plus total 
score comparing Vir-7831 vs. Placebo 


 
CONFIDENTIAL 
 
 
 
214367(VIR-7831-5001) 
9 
 
Objectives 
Endpoints 
of COVID-19 clinical symptoms 
(AUC through Day 7) 
• Time to symptom alleviation using the 
FLU-PRO Plus 
• Evaluate the efficacy of VIR-7831 versus 
placebo in reducing SARS-CoV-2 viral 
load 
• Change from baseline in Viral load in 
nasal secretions by qRT-PCR at Day 8 
• Evaluate the efficacy of VIR-7831 versus 
placebo in preventing COVID-19 
respiratory disease progression  
• Proportion of participants who progress to 
develop severe and/or critical respiratory 
COVID-19 as manifest by requirement for 
and method of supplemental oxygen at 
Day 8, Day 15, Day 22, or Day 29 
• Evaluate the efficacy of VIR-7831 versus 
placebo in preventing mortality 
• 29-day, 60-day, and 90-day all-cause 
mortality 
Exploratory 
 
• Evaluate the impact of VIR-7831 versus 
placebo on incidence and duration of time 
on a ventilator, ICU length of stay (LOS), 
and total hospital LOS 
• Total number of ventilator days from 
randomization through 90 days 
• Total intensive care length of stay (LOS) 
• Total hospital LOS 
• Evaluate the efficacy of VIR-7831 versus 
placebo in preventing hospitalization from 
non-respiratory complications of COVID-
19 
• Proportion of participants hospitalized 
due to non-respiratory complications of 
COVID-19 (cardiac, renal, neurologic, 
hematologic events) by Day 8, Day 15, 
Day 22, and Day 29 
• Monitor on-treatment emergence of 
SARS-CoV-2 resistant mutants against 
VIR-7831  
Emergence of viral resistance mutants to 
mAb by SARS-CoV-2  
• Evaluate the efficacy of VIR-7831 versus 
placebo in reducing duration of SARS-
CoV-2 viral shedding and viremia 
• Detection of SARS-CoV-2 in nasal 
secretions by RT-PCR at baseline and 
during follow-up period through Day 29 
• Detection of SARS-CoV-2 in blood by 
qRT-PCR RT-PCR at baseline and during 
follow-up period through Day 29 
• Evaluate the efficacy of VIR-7831 versus 
placebo in reducing SARS-CoV-2 viral 
load 
• Change from baseline in viral load in 
nasal secretions and blood by qRT-PCR 
• Evaluate the incidence of respiratory viral 
co-infection with SARS-CoV-2 
• Respiratory pathogen detection in nasal 
secretions by PCR on Day 1 
• Evaluate the effect of VIR-7831 versus 
placebo on potential biomarkers of host 
response to SARS-CoV-2 
• Evaluation of host immune responses 
and exploratory biomarkers related to 
SARS-CoV-2 and/or VIR-7831, including 
genetic, cellular, transcriptomic, and 
proteomic parameters 
• Measure the impact of VIR-7831 
treatment on health-related quality of life 
• Change from baseline in Work 
Productivity and Activity Impairment 


 
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Objectives 
Endpoints 
and time away from work due to COVID-
19 
(WPAI) questionnaire 
• Change from baseline for health-related 
quality of life according to the SF-12 
hybrid questionnaire 
• Evaluate the impact of VIR-7831 versus 
placebo on the duration and the severity 
of COVID-19 clinical symptoms 
• Mean change in FLU-PRO Plus Total 
score (AUC through Days 14, 21) and 
Domain scores (AUC through Days 7, 14, 
21) comparing Vir-7831vs. Placebo 
• The proportion of participants with 
symptom alleviation using the FLU-PRO 
Plus at Days 7, 14, 21 
 


 
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1.2.2. 
Estimands 
Each study objective is presented below with additional information, including prespecified estimands with related attributes. 
Table 2 
Estimands 
Objective 
Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Analysis Set 
Intercurrent Event 
Strategy 
Population Level 
Summary Measure 
Primary Objective:  
Evaluate the efficacy of 
VIR-7831 versus 
placebo in preventing 
the progression of 
mild/moderate COVID-
19 disease 
Primary  
Proportion of 
participants who 
have 
progression of 
COVID-19 
through Day 29 
as defined by: 
1. 
Hospitalization 
> 24 hours for 
acute 
management of 
illness 
OR 
2. Death 
Entire trial 
population 
randomized (ITT) 
Data analyzed as collected 
(treatment policy strategy) 
Relative Risk 
 
Supplementary Proportion of 
participants who 
Entire trial 
population 
Missing treated as 
Relative Risk 


 
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Objective 
Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Analysis Set 
Intercurrent Event 
Strategy 
Population Level 
Summary Measure 
have 
progression of 
COVID-19 
through Day 29 
as defined by: 
 1. 
Hospitalization 
> 24 hours for 
acute 
management of 
illness 
OR 
2. Death 
randomized (ITT) 
progressions 
(composite strategy) 
 
Supplementary Proportion of 
participants who 
have 
progression of 
COVID-19 
through Day 29 
as defined by: 
 1. 
Hospitalization 
Per-Protocol 
Data analyzed as collected 
(treatment policy strategy) 
Relative Risk 


 
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Objective 
Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Analysis Set 
Intercurrent Event 
Strategy 
Population Level 
Summary Measure 
> 24 hours for 
acute 
management of 
illness 
OR 
2. Death 
Secondary Objective: 
Evaluate the efficacy of 
VIR-7831 versus 
placebo in preventing 
the progression of 
mild/moderate 
COVID-19 
Secondary  
Proportion of 
subjects who 
have 
progression of 
COVID-19 as 
defined by visit 
to a hospital 
emergency 
room for 
management of 
illness, 
hospitalization 
>24 hrs or death 
at Day 8, Day 
15, Day 22 or 
Day 29 
ITT 
Data analyzed as collected 
(treatment policy strategy) 
Relative Risk 


 
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Objective 
Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Analysis Set 
Intercurrent Event 
Strategy 
Population Level 
Summary Measure 
Secondary Objective: 
Evaluate the efficacy of 
VIR-7831 versus 
placebo in preventing 
COVID-19 respiratory 
disease progression  
Secondary  
Proportion of 
participants who 
progress to 
develop severe 
or critical 
respiratory 
COVID-19 as 
manifest by 
requirement for 
and method of 
supplemental 
oxygen at Day 
8, Day 15, Day 
22, or Day 29 
ITT 
Participants who die will 
be considered to have 
progressed to severe or 
critical respiratory 
COVID-19 by 
requirement for and 
method of supplemental 
oxygen  
For all other intercurrent 
events data will be 
analyzed as collected 
(treatment policy strategy) 
Relative Risk 
Secondary Objective:  
Evaluate the impact of 
VIR-7831 versus 
placebo in the duration 
and severity of COVID-
19 clinical symptoms 
Secondary  
Mean change in 
FLU-PRO Plus 
total score 
comparing Vir-
7831 vs. Placebo 
(AUC through 
Day 7) 
ITT 
Data analyzed as collected 
(treatment policy strategy) 
Difference in Average 
 
 
Time to symptom 
alleviation using 
the FLU-PRO 
ITT 
Data analyzed as collected 
(treatment policy strategy)  
Kaplan Meier 
Estimates 


 
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Objective 
Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Analysis Set 
Intercurrent Event 
Strategy 
Population Level 
Summary Measure 
Plus 
Secondary Objective: 
Evaluate the efficacy of 
VIR-7831 versus 
placebo in reducing 
duration of SARS-CoV-
2 viral shedding 
Secondary  
Change from 
baseline in viral 
load in nasal 
secretions by 
qRT-PCR at Day 
8 
ITT 
Data analyzed as collected 
(treatment policy strategy) 
Difference in Average 
Secondary Objective: 
Evaluate the efficacy of 
VIR-7831 versus 
placebo in preventing 
mortality 
Secondary  
29-day, 60-day, 
and 90-day all-
cause mortality 
ITT 
Data analyzed as collected 
(treatment policy strategy) 
Kaplan Meier 
Estimates 
Secondary Objective: 
Determine the safety and 
tolerability of VIR-7831 
compared to placebo 
Secondary  
Occurrence of 
adverse events 
(AEs) 
 
Safety 
Data analyzed as collected 
(treatment policy strategy) 
Frequency and 
Percentage of 
Participants 
 
Secondary  
Occurrence of 
serious adverse 
events (SAEs)  
 
Safety 
Data analyzed as collected 
(treatment policy strategy) 
Frequency and 
Percentage of 
Participants 


 
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Objective 
Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Analysis Set 
Intercurrent Event 
Strategy 
Population Level 
Summary Measure 
 
Secondary  
Occurrence of 
adverse events 
of special 
interest (AESI) 
Safety 
Data analyzed as collected 
(treatment policy strategy) 
Frequency and 
Percentage of 
Participants 
 


 
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1.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design Features • 
This study is a randomized, double-blind, multi-center, placebo-
controlled group-trial of VIR-7831, a monoclonal antibody 
(mAb) against SARS-CoV-2 for the prevention of progression of 
mild/moderate COVID-19 in high risk participants, with interim 
monitoring to allow early stopping for futility, efficacy, or safety.  
• 
The study will comprise two parts: lead-in phase and expansion 
phase. 
• 
The lead-in phase will enrol 20 non-hospitalized participants who 
have early, mild/moderate COVID-19 and are at high risk of 
disease progression.  These participants will be given a single 
intravenous infusion of VIR-7831 and confined in the in-patient 
setting for 7 days for safety monitoring.  
• 
Following a safety assessment of unblinded data by an IDMC, the 
expansion phase will progress, where an additional 1340 
participants with early, mild/moderate COVID-19 and who are at 
high risk of disease progression will be enrolled. 
• 
Unblinded safety and efficacy data will be reviewed regularly by 
an IDMC. 
• 
The first safety review during the expansion phase will include 
available safety and tolerability data though Day 15 from a total 
of 60 patients (30 per arm). If deemed necessary, an additional 
safety review will be conducted after approximately 100 
additional participants are enrolled (50 per arm) to review safety 
and tolerability data through Day 15. IDMC members will also 
review all SAEs via draft CIOMS prior to each IDMC review 


 
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Overview of Study Design and Key Features 
meeting.  
• 
Two interim analyses will be conducted at approximately 41% of 
participants enrolled (280 per arm) and approximately 64% of 
participants enrolled (435 per arm) to evaluate safety, futility, and 
efficacy based on data through Day 29 for these participants. 
Study 
intervention 
• 
VIR-7831 500mg or Placebo, single intravenous infusion  
• 
All participants will receive SoC as per institutional protocols, in 
addition to the study intervention.   
Study 
intervention 
Assignment 
• Participants with early, mild/moderate COVID-19 who are at high 
risk for progression of disease will be randomized 1:1 to receive a 
single, intravenous infusion of either VIR-7831 or equal volume 
saline placebo.  
• Participants will be stratified by age (≤70 vs. >70 years old), 
symptom duration (≤3 days vs. 4-5 days) and region (North 
America, South America, Europe, Asia, Rest of World (RoW). 
• All participants will be centrally randomized using an Interactive 
Web Response System (IWRS). 
• 
Investigators will remain blinded to each participant’s assigned 
study intervention throughout the course of the study. In order to 
maintain this blind, the study pharmacist will be responsible for 
the reconstitution and dispensation of all study intervention and 
will endeavor to ensure that there are no differences in time taken 
to dispense following randomization. 
Interim 
Analyses 
• 
An IDMC will actively monitor interim unblinded safety (Lead-
In phase) and interim unblinded safety and efficacy data 
(Expansion phase) to make recommendations to Vir regarding 
ongoing study conduct as detailed in the IDMC Charter. 
• 
Interim analysis will be used to assess safety (due to harm), 
futility due to lack of efficacy and efficacy. Safety stopping rules 
will be put in place for the IDMC to stop the study if there is an 
excess risk of mortality or other events of interest.  Full details of 
timing of analyses and all stopping criteria will be given in the 
IDMC charter. 
• 
Interim analyses to assess efficacy and futility are planned when 
approximately 41% and 64% of the required number of 
participants have reached Day 29 visit.  
• 
The analysis of the primary endpoint at the interim analyses will 
be the same as that described for the primary endpoint at the final 
Day 29 analysis. Group sequential techniques will be used to 
adjust stopping boundaries to reflect the actual number of 
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Overview of Study Design and Key Features 
of each interim analysis.  
• 
The full decision criteria for the futility due to lack of efficacy 
and efficacy rules along with additional information to be 
presented to the IDMC will be defined in the IDMC charter and 
associated documents, as well as the analysis plan.  
• 
The Joint Safety Review Team (JSRT) comprised of team 
members from clinical research, pharmacovigilance and statistics 
will review blinded safety data at regular intervals throughout the 
conduct of the study and determine if a safety concern based on 
instream blinded data review needs to be escalated to the IDMC.  
Details of the JSRT process is recorded in relevant SRT 
documents. 
• 
Following all participants completing the final follow-up visit at 
Week 24, a final safety analysis will be performed. 
 
2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA 
The primary objective of this study is to evaluate the efficacy or VIR-7831 versus 
placebo in preventing the progression of COVID-19 disease. 
The primary endpoint is proportion of participants who progression of COVID-19 as 
defined by hospitalization > 24 hours or death through Day 29.  
If we denote the proportion of participants with progression of COVID-19 in the VIR-
7831 arm as PA, and the proportion of participants with progression of COVID-19 in the 
placebo arm as PB, the following null and alternative hypothesis for superiority is as 
follows: 
H0: PA = PB  
H1: PA ≠ PB 
2.1. 
Multiple Comparisons and Multiplicity 
The study will utilize a group sequential design with two interim analyses to asses both 
futility due to lack of efficacy and overwhelming efficacy.  A Lan-DeMets [Lan, 1983] 
alpha-spending function to control the type I error for the primary endpoint will be used, 
using a Pocock analogue rule for futility and a Hwang-Shih-DeCani (γ = 1) analogue  
rule for efficacy [Hwang, 1990].   
Secondary endpoints will only be formally analyzed at the final Day 29 analysis, 
secondary endpoints will be tested with alpha level of 5% (two-sided).  The testing of 
secondary endpoints is adjusted for multiplicity by using the following hierarchy:  
 


 
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As such the full alpha is transferred down between each endpoint/hypothesis.  All 
secondary endpoints in the testing hierarchy will present the nominal p-value of the 
analysis, and an overall summary of progress through each stage of the testing 
hierarchy will be provided. 
 
 


 
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3. 
SAMPLE SIZE DETERMINATION 
The expected sample size is up to 680 participants per arm.  
The study will utilize a group sequential design with two interim analyses to asses both 
futility due to lack of efficacy and overwhelming efficacy. A Lan-DeMets alpha-spending 
function to control the type I error will be used, using a Pocock analogue rule for futility 
and Hwang-Shih-DeCani (γ = 1) analogue rule for efficacy [Lan, 1983, Hwang, 1990]. 
Approximately 1360 (680 per arm) participants will be randomly assigned to study 
introversion. A total sample size of 1360 will provide approximately 90% power to detect 
a 37.5% relative efficacy in reducing progression of COVID-19 through Day 29 at the 
overall two-sided 5% significance level with assumed progression of COVID-19 rates of 
16% in the placebo arm and 10% in the VIR-7831 arm, respectively. The minimal 
detectable efficacy for this design at the final efficacy analysis is approximately 25% if 
disease progression rates is 16% in the placebo arm. 
4. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
All participants who were screened for 
eligibility 
Study Population 
Enrolled 
All participants who entered the study 
Note screening failures (who never 
passed screening even if rescreened) and 
participants screened are excluded from 
the Enrolled analysis set as they did not 
enter the study 
Study Population 
Intent-to-Treat 
 
All participants who were randomly 
assigned to study intervention in the 
study. Data should be reported according 
to the randomized treatment 
Study Population 
Efficacy 
Safety 
All participants who received at least one 
dose of study intervention. 
Data should be reported according to the 
actual treatment received 
Study Population 
Safety 
Per-Protocol  
(PP) 
All participants in the ITT analysis set for 
whom there were no important protocol 
deviations that impact the primary 
analyses. 
Data should be reported according to the 
randomized treatment. 
Specific details of important protocol 
deviations that would exclude participants 
from the PP analysis set are provided in 
Efficacy 
The PP set will generally 
not be used for analyses if 
this analysis set 
comprises more than 95% 
or less than 75% of the 
ITT analysis set. 


 
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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Section 4.1.1 
Pharmacokinetic 
(PK) 
All participants in the Safety analysis set 
who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] 
values will be considered as non-missing 
values). 
Data should be reported according to the 
actual treatment 
PK 
Virology 
All participants in the ITT analysis set 
with a central lab confirmed quantifiable 
baseline nasopharyngeal swab.  
Data should be reported according to 
the randomized treatment.  
Efficacy (Virology) 
 
4.1. 
Protocol Deviations 
Important protocol deviations are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject's rights, safety, or well-being. For example, important 
protocol deviations may include enrolling subjects in violation of key eligibility criteria 
designed to ensure a specific subject population or failing to collect data necessary to 
interpret primary endpoints, as this may compromise the scientific value of the trial. 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
Data will be reviewed prior to unblinding and freezing the final Day 29 efficacy database 
to ensure all important deviations are captured and categorized in the protocol deviations 
SDTM dataset.  
This dataset will be the basis for the summaries of important protocol deviations. 
A separate summary of all inclusion/exclusion criteria deviations will also be provided. 
This summary will be based on data as recorded on the inclusion/exclusion page of the 
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4.1.1. 
Definitions for Per Protocol Analysis Set 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized and listed. 
All protocol deviations deemed important will result in exclusion from the Per Protocol 
analysis population.  These will be reviewed in a blinded manner during the course of the 
study; any additional important deviations deemed to result in exclusion from the Per-
Protocol analysis set will be documented prior to unblinding of the study (Refer to 
Protocol Deviation Management Plan). 
5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations 
5.1.1. 
General Methodology 
The ITT Analysis Set will be used for all Study Population analyses and Efficacy 
analyses, unless otherwise specified.  Safety Analysis Set will be used for selected Study 
Population summarises and all safety analyses.  The PK Analysis Set will be used for all 
PK analyses. 
In the case of a difference between the stratification assigned at the time of randomization 
and the data collected in the eCRF, the analyses will be performed based on the data 
collected in the eCRF, not the assigned stratum at randomization.  All analyzes will be 
adjusted for duration of symptoms (≤3 days vs. 4-5 days), age (≤70 vs. >70 years old) and 
region (North America, South America, Europe, Asia, RoW) and also gender (male, 
female).   
If there are convergence issues, duration of symptoms and age will be fitted as 
continuous rather than categorical covariates for primary and all secondary/exploratory 
analyses, as applicable.  Should one randomisation region dominate the interim analysis 
then region may be considered for removal from the model to aid convergence issues. 
Confidence intervals will use 95% confidence levels unless otherwise specified.  
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (std), median, minimum and maximum. Log-
transformed data descriptive statistics will also present the geometric mean and 
coefficient of variation for data that is transformed back to the original scale. Categorical 
data will be summarized as the number and percentage of participants in each category. 
Efficacy data will be reported according to nominal time of clinical visits.  
Hospitalization status, oxygen supplementation and healthcare resource utilization use 
will be slotted against the clinical visit date for summaries and analyses by visit.   
All data will be reported according to the nominal time of clinic visits and assessments as 
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• 
Day 15, Day 18, Day 22, where data within ±1 days of the target day may be 
used if data is not recorded on the actual day 
• 
Day 29, where data within ±2 days of the target day may be used if data is not 
recorded on the actual day 
• 
Day 43, where data within ±3 days of the target day may be used if data is not 
recorded on the actual day 
• 
Day 57, where data within ±4 days of the target day may be used if data is not 
recorded on the actual day 
• 
Day 85, Day 113, Day 141, Day 169 where data within ±7 days of the target day 
may be used if data is not recorded on the actual day 
Laboratory assessments will be analyzed based on the timepoint information recorded in 
the eCRF.  Data for unscheduled visits, will be assigned to a scheduled visit if the visit 
date falls within the corresponding visit window as specified below.   
5.1.2. 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits and the screening visit. If time is 
not collected, Day 1 assessments are assumed to be taken prior to first dose and used as 
baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.1.3. 
Multicenter Studies 
It is anticipated that patient accrual will be spread thinly across centers and summaries of 
data by center would unlikely be informative and will not, therefore, be provided.   
Summaries by region (North America, South America, Europe, Asia, RoW as 
applicable). 
5.1.4. 
Intercurrent Events 
In general, the following may be considered intercurrent events/events leading to missing 
data if not part of the endpoint definition: 
• 
Withdrawal of consent or lost-to-follow up 
• 
Use of approved or authorized COVID-19 therapy 
• 
Death  
• 
Hospital Discharge  
• 
Transfer to other facilities 
• 
Admittance to ICU 


 
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The intercurrent event handling strategies are described in Table 2 Estimands and further 
expanded upon in Section 5.2 and Section 5.3. 
In general, unless otherwise specified, the handling strategy for all these intercurrent 
events will be based on a treatment policy approach; specifically, the effects estimated 
will be based on initial randomized treatment arm regardless of whether the participant 
had experienced an intercurrent event. If possible, data will continue to be collected 
after the occurrence of the intercurrent event, until the participant either completes the 
study or withdraws from the study before completion.   
5.1.5. 
Missing Data Handling Rules  
Unless otherwise stated the following rules will be applied to all endpoints:  
• 
If a participant experiences an intercurrent event but data continues to be 
collected, their data will be analyzed per their original randomized intervention.   
• 
Missing data can occur due to study withdrawal or participants lost to follow-
up before the completion of the study or due to intermittent missing values (i.e. 
data between two non-missing assessments).  
• 
Missing data will be imputed under a missing at random (MAR) assumption using 
a multiple imputation (MI) model. The MI model will include covariates; 
treatment, duration of symptoms (≤3 days vs. 4-5 days), age group (≤70 vs. >70 
years old), region (North America, South America, Europe, Asia and RoW), 
gender (male, female) and baseline of the variable of interest (if 
appropriate). More details will be provided in Appendix 3.  
5.2. 
Primary Endpoint Analyses 
5.2.1. 
Definition of Endpoint 
The primary endpoint will be proportion of participants who have progression of 
COVID-19 as defined as hospitalization > 24 hours for acute management of illness (i.e. 
excludes hospitalization for observation only, hospitalization for elective surgeries and 
procedures, etc.) status or mortality status (death) through Day 29.   
5.2.2. 
Main Analytical Approach 
The primary endpoint will be summarized using counts and proportions of the number of 
participants who have progression of COVID-19 and will be analyzed using a log-
binomial regression model adjusting for duration of symptoms (≤3 days vs. 4-5 days), age 
(≤70 vs. >70 years old), region (North America, South America, Europe, Asia and RoW) 
and gender (male, female). 
The relative risk of progression will be calculated from the log-binomial generalised 
linear model.  Should there be issues with model convergence then duration of symptoms 
and age (10 year increments) will be fitted as continuous covariates.  Should one 
randomization region dominate the interim analysis then region may be considered for 
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still fails to converge, then an exact Poisson regression model with robust sandwich 
estimators will be utilized.    
At each of the interim and final efficacy analysis, appropriate CI based on the adjusted 
significance level will also be provided. For example, if the remaining alpha for the final 
analysis is 0.024, 97.6% CI will be provided for the final efficacy analysis.  
As patients may attend their Day 29 visit up to 2 days prior or following the planned date, 
the protocol defined visit windows will be used to define the endpoint.  Further details on 
analysis windows will be provided in the Output and Programming Specification (OPS). 
5.2.2.1. 
Decision Criteria 
Guidelines for stopping the study for futility (e.g. lack of efficacy) or overall success (e.g. 
evidence of efficacy) based on the primary endpoint are detailed below. 
Futility due to lack of efficacy and study success due to overwhelming benefit of 
treatment will formally be assessed 29 days after approximately 280/arm and 435/arm 
participants have been randomised and followed for 29 days. 
Study stopping criteria have been defined using group sequential design methodology, 
using an alpha-spending function to control the type I error with two interim analyses for 
futility, using Pocock analogue rules; and two for efficacy, using the Hwang-Shih-
DeCani (γ = 1) analogue rules [Hwang, 1990]. 
Table 3 gives the stopping boundaries based on p-values (one-sided) from the planned 
interim analysis and on the Z score scale. The p-values or Z scores at each interim 
analysis will be plotted against the boundaries and if either the futility or efficacy success 
boundary is crossed the study should be recommended to stop. 
The boundaries are based on the estimated amount of information at each interim. If the 
amount included in the interim analysis differs from these values, the actual boundaries 
will be re-determined based on the exact amount of information at the time of the interim 
analyses.  Exact amount of information will be determined from the number of 
participants randomised at 29 days prior to data cut.   
Boundaries will be determined using PASS 2019, using the group sequential tests for two 
proportions (simulation procedure) with the following criteria: 2-sided overall 5% 
significance level (symmetric), equal allocation, 3 planned stages at actual and planned 
(future) information proportions (minimum 5 decimal places), no continuity correction, 
0.1 zero count adjustment added to zero cells only and non-binding futility boundaries 
and hold-out efficacy boundaries. 


 
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Table 3 
Planned Formal Stopping Rules for Efficacy Success and Efficacy 
Futility 
Stage/Formal 
Analysis 
 
Target 
Sample 
Size to 
D29 
 
Efficacy Success Boundaries 
Efficacy Futility Boundaries 
p-value 
Z-Score 
p-value 
Z-score 
Lower 
Upper 
Lower 
Upper 
Lower 
Upper 
Lower 
Upper 
1 
560 
<0.01335 
<0.01335 
-
2.2159 
2.2159 
>0.21147 
>0. 
21147 
-
0.8013 
0.8013 
2 
870 
<0.00973 
<0.00973 
-
2.3367 
2.3367 
>0.09363 
>0.09363 
-
1.3187  
1.3187  
Final (D29) 
1360 
<0.01103 
<0.01103 
-
2.2894 
2.2894 
>0.01103 
>0.01103 
-
2.2894 
2.2894 
 
5.2.3. 
Sensitivity Analyses 
As a sensitivity to the missing data, a tipping point analyses will be performed. 
The underlying response rate among those subjects with missing response status in each 
arm will be tested ranging between 0 and 1. This analysis will be two-dimensional, i.e. 
will allow for assumptions about the assumed response rate (and thus missing outcomes) 
in the two arms to vary independently, furthermore they will include scenarios where 
dropouts on VIR-7831 have worse outcomes than dropouts on placebo. For combinations 
of the assumed response rates in the two arms, the number of additional responders 
among subjects with missing response will be imputed multiple times by drawing from a 
binomial distribution. The risk ratio and associated standard error for each imputed 
dataset will be calculated and results combined using Rubin’s rules to calculate the test 
statistic and the corresponding p-value. Results will be presented via a heatmap. 
5.2.4. 
Supplementary Analyses 
A supplementary analysis for the primary endpoint will also be conducted on the Per-
Protocol analysis set, if this comprises more than 95% or less than 75% of the ITT 
analysis set. 
As a supplementary analysis, a composite estimand, where withdrawals will be treated as 
having progressed, will be presented as a supplementary estimand.   
Further estimand strategies may be investigated and will be described in a separate 
technical document. 
5.2.5. 
 Subgroup Analyses 
Subgroup analyses of the duration of symptoms (≤3 days vs. 4-5 days), age (≤70 vs. >70 
years old), gender and region will be performed using the same methodology as the 


 
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primary endpoint. Results will be presented as per primary analyses and, in addition, a 
forest plot of the relative risk ratios and the corresponding 95% CIs will be generated. 
If there are insufficient numbers of participants in each category to be able to perform the 
analyses, then categories may be combined, or the analyses may not be performed if there 
is not an appropriate grouping. 
Additional subgroup analyses may be performed and will be described in a separate 
technical document. 
5.3. 
Secondary Endpoints Analyses 
Secondary endpoints will be summarized for the IDMC reviews, and only analyzed at the 
final Day 29 analysis.  The estimands are described in Table 2. 
Confirmatory secondary endpoints are those secondary endpoints for which a label claim 
is pursued as part of the confirmatory hypotheses for which the type 1 error is controlled 
(multiplicity adjustment). 
5.3.1. 
Definition of Endpoints 
5.3.1.1. 
Safety and tolerability 
Adverse events analyses including the analysis of adverse events (AEs), Serious AEs 
(SAEs) and other significant AEs will be based on GSK Core Data Standards.  
An overview summary of AEs, including counts and percentages of participants with 
• 
any AE 
• 
any SAE 
will be provided as outlined in Section 5.5.2. 
Since it will not be possible to delineate in a single participant whether the hospitalization 
is directly related to COVID-19 complications or could be related to VIR-7831 causing 
more severe disease due to ADE, all hospitalizations regardless of cause will be included 
in the primary endpoint and will also be counted as serious adverse events.  To inform on 
the number and nature of non-COVID-19 adverse events and serious adverse events, 
additional safety summaries will be performed in which select, pre-specified terms 
consistent with known progression of COVID-19 disease will be excluded.  The 
MedDRA terms to be excluded will be pre-defined and documented in the study OPS. 
5.3.1.2. 
Immunogenicity of VIR-7831 
The incidence and titers (if applicable) of serum ADA to VIR-7831 will be listed and 
summarized for the Week 24 safety summary. 
Additional immunologic analyses may be conducted and will be documented in a 
separate technical document. 


 
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5.3.1.3. 
Pharmacokinetics of VIR-7831 
Serum pharmacokinetic concentrations and parameters will be listed and summarized by 
visit. 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times, and will be listed and summarized using descriptive statistics.  PK 
parameters may include, but not be limited to Cmax, Clast, CD29, tmax, tlast, AUCinf, AUClast, 
AUCD1-D29, %AUCexp, t1/2, Vz, Vss, CL.  Inclusion of PK parameters in summaries will be 
at the discretion of the PK scientist.  Any parameters not included in summaries should 
be flagged in the individual listings with an explanation for the exclusion. 
5.3.1.4. 
Proportion of Participants Who Have Progression of COVID-19 
Defined as per primary endpoint, see Section 5.2.1 plus additional emergency room visits 
(inpatient or out-patient visits of any duration). 
5.3.1.5. 
Proportion of Participants Who Progress to Develop Severe or Critical 
Respiratory COVID-19 
Participants are defined as progressing to develop severe respiratory COVID-19 if they 
require supplemental oxygen either by nasal cannula, face mask, high-flow oxygen 
devices, or non-invasive ventilation. 
Participants are defined as progression to critical respiratory COVID-19 if they require 
invasive mechanical ventilation or ECMO. 
Participants who die prior to Day 29 without first having received supplemental oxygen 
will be considered to have met the endpoint (composite estimands strategy). 
Further detail on the severity of respiratory COVID-19 based on the proportion of 
participants meeting each tier of the Vir modified version of the NIAID Ordinal Scale for 
Clinical Improvement (below) will be summarized.  


 
C O N FI D E N TI A L  
 
 
2 1 4 3 6 7( VI R -7 8 3 1 -5 0 0 1 ) 
3 0  
 
T a bl e 4  
Or di n al S c al e f or Cli ni c al I m pr o v e m e nt  
5. 3. 1. 6.  
S e v erit y a n d D ur ati o n  of C O VI D -1 9 C li ni c al S y m pt o m s  
Se verit y a n d d urati o n of C O VI D -1 9 cli nical  s y m pt o ms of C O VI D -1 9 -relat e d ill ness will 
be deter mi ne d fr o m  a vera ge d c h a n ge  ( A U C as det er mi ne d b y t he tra p ez oi dal r ule ) t h o u g h 
7  da ys i n t he t otal a n d d o mai n sc ores ( n os e, t hr oat, e yes, c hest/res pirat or y, 
gastr oi ntesti nal  a n d b o d y/s yste mic) fr o m t he F L U -P R O Pl us patie nt -re p orte d o utc o me 
i nstr u me nt a n d will als o c o m bi ne a d diti o nal sc ores f or s mell/taste . 
I n a d diti o n, ti me-t o s ustai ne d ( > = 4 8 h o urs) s y m pt o m alle viati o n as meas ure d b y th e 
F L U -P R O Pl us o ver first 2 1 da ys  will be c o m pare d .  T he defi niti o n of s ustai ne d 
s y m pt o m alle viati o n is i ncl u de d i n A p pe n di x 4 .   
C O VI D -1 9 Cli nical S y m pt o ms  a nal yses will be pr o vi de d f or t he p o p ulati o n, a n d i n t he 
s u b gr o u p of partici pa nts w h o re p orte d at least t w o m o derate s y m pt o ms at baseli ne.  
5. 3. 1. 7.  
R e d u cti o n i n S A R S -C o V -2 Vir al L o a d .  
Re d ucti o n of S A R S -C o V 2 viral s he d di n g will be deter mi ne d b y t he c h a n ge fr o m baseli ne 
of S A R S -C o V 2 nasal viral l oa d at Da y 8.  Viral l oa d will be l o g 1 0 -tra nsf or me d pri or t o 
s u m mar y a n d a nal ysis. 
5. 3. 1. 8.  
All -c a u s e M ort alit y  
Partici pa nts will meet t he e n d p oi nt if t he y h a ve die d d ue t o a n y ca us e pri or t o Da y 2 9, 
Da y 6 0 a n d D a y 9 0 .  Da y 6 0 a n d Da y 9 0 all -ca use m ortalit y will be pres e nte d i n t he 
Wee k 2 4 Safet y A nal ysis.  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
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5.3.2. 
Main Analytical Approach 
5.3.2.1. 
Binary Endpoints 
The binary endpoints: 
• 
Participants who have progression of COVID-19  
• 
Participants who progress to develop severe or critical respiratory COVID-19 
Binary secondary endpoints will be analysed as per Section 5.2.2 
5.3.2.2. 
Continuous Endpoints 
The following secondary endpoints will be analysed as continuous endpoints: 
• 
Severity of participant-reported symptoms of COVID-19-related illness using Flu-
PRO Plus (Average Change from Baseline) 
• 
Reduction of SARS-CoV-2 viral shedding using qRT-PCR 
Flu-PRO Plus (AUC) will be analysed using analysis of covariance adjusted for baseline 
value, age group, time to onset of symptoms, gender and region at each visit.   
Possible intercurrent events are withdrawal of consent and lost-to-follow-up on or before 
Day 29.  The strategy for analysis for intercurrent events, will be to use the treatment 
policy strategy, with data analyzed as collected.  
It is expected that missing data questions within the Flu-PRO Plus will be limited to 
paper PROs due to the set-up of ePRO devices.  The scoring of the Flu-PRO Plus domain 
scores limits the extent of missed questions permitted when determining a domain score; 
the total score requires all domain scores to be calculated prior to determining the total 
score.   
Thus, it is expected missing data will be due to incomplete paper PROs or lost to follow 
up data after discharge, and this will be imputed using a modified last-observation carried 
forward (mLOCF) approach for the final assessment only, due to the assumption 
incomplete paper PROs are not missing at random.  That is if the Day 7 Flu-PRO Plus 
score is missing or incomplete, the last non-missing value will be carried forward for the 
calculation of average change from baseline through to Day 7; no other missing scores 
would be imputed. 
SARS-CoV-2 viral load will be analysed using a mixed model repeated measures 
(MMRM) adjusted for baseline value, baseline value by visit, age group, time to onset of 
symptoms, gender and region.  
It is expected missing data for SARS-CoV-2 qRT-PCR results will be due to invalid 
qRT-PCT test, or lost to follow up data after discharge, and thus are assumed missing at 
random within the analysis. 


 
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5.3.2.3. 
Time to Event Endpoints 
The following secondary endpoints will be analyzed as time to event endpoints: 
• All-cause mortality 
• 
Sustained (>=48h) symptom alleviation as measured by adapted Flu-PRO Plus 
It is expected that missing data questions within the Flu-PRO Plus will be limited to 
paper PROs due to the set-up of ePRO devices.  Incomplete paper PROs are assumed to 
be missing not at random, thus symptom alleviation will use a LOCF approach for 
missing data. That is, questions will first be checked for imputation of missing questions 
using LOCF when determining whether symptom alleviation has been achieved; if a 
symptom alleviation cannot be determined missing symptom alleviation (yes/no) will be 
imputed using LOCF. 
Time to event endpoints will be analyzed using nonparametric survival analysis methods, 
using Kaplan-Meier methods for summarizing data and analyzed using the log-rank test.  
5.3.3. 
Sensitivity Analyses 
Sensitivity analyses as per Section 5.2.3 may be performed on the binary endpoints. 
5.3.4. 
Supplementary Analyses 
Other estimands strategies may be investigated and will be described in a separate 
technical document. 
5.3.5. 
Subgroup Analyses 
Subgroup analyses will be performed on the secondary endpoints detailed in Section 2.1 
per Section 5.2.5 and will use the methods described above. 
5.4. 
Exploratory Endpoints Analyses 
5.4.1. 
Definition of Endpoints 
5.4.1.1. 
Total Number of Ventilator Days  
A participant is defined as being on a ventilator if have received invasive mechanical 
ventilation or ECMO as a form of oxygen therapy.  A participant may have more than 
one period of ventilation during the analysis time-point follow-up included in the total 
number of ventilator days. 
Participants who die prior to Day 29/Day 90 without being on a ventilator will be 
considered to have met the endpoint (composite estimands strategy). 


 
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5.4.1.2. 
Total Intensive Care Length of Stay 
A participant is defined as requiring intensive care if they received an intensive care unit 
in-patient healthcare encounter of any duration.  A participant may have more than one 
period of intensive care stays included in the total intensive care length of stay. 
Participants who die prior to Day 29/Day 90 without being admitted to intensive care will 
be considered to have met the endpoint (composite estimands strategy). 
5.4.1.3. 
Total Hospital Length of Stay 
A participant is defined as requiring hospital stay if they received any in-patient 
healthcare (A&E, general ward or ICU) encounter of any duration.  A participant may 
have more than one period of hospital stay included in the total hospital length of stay. 
Participants who die prior to Day 29/Day 90 without being admitted to hospital will be 
considered to have met the endpoint (composite estimands strategy). 
5.4.1.4. 
Reduction in the Duration of SARS-CoV-2 Viral Shedding.  
Duration of SARS-CoV2 viral shedding will be determined by the time to obtain a 
confirmed negative PCR test for SARS-CoV-2 by Day 29.  A confirmed negative PCR is 
defined as first of two or more consecutive negative (no SARS-CoV2 detected) PCR 
tests.  If the first negative PCR occurs at Day 29, this will be regarded as confirmed for 
analysis purposes. 
Reduction of SARS-CoV2 viral shedding (nasal secretions and blood) will be determined 
by the change from baseline of SARS-CoV2 obtained in a PCR test at each visit.  Time 
weighted average change from baseline though the first 7 days will also be presented.  
Viral load will be log10-transformed for summary and analysis purposes. 
5.4.1.5. 
Proportion of Participants Hospitalized Due to Non-Respiratory 
Complications of COVID-19 
A participant is defined as hospitalized due to non-respiratory complications of COVID-
19 for if the primary reason was for hospitalization was due to cardiac, renal, neurologic, 
hematologic events. 
Participants who die prior to Day 29 without being admitted to hospital will be 
considered to have met the endpoint (composite estimand strategy). 
5.4.1.6. 
On-treatment Emergence of SARS-CoV-2 Resistant Mutants Against 
VIR-7831  
Summaries of viral resistance mutations will be provided based on frequency counts. 
5.4.1.7. 
Host Immune Responses and Exploratory Biomarkers 
Further details on genetic, cellular, transcriptomic, and proteomic parameters will be 
provided in a supplemental analysis plan. 


 
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5.4.1.8. 
Severity and Duration of COVID-19 Clinical Symptoms 
Severity and duration of COVID-19 clinical symptoms of COVID-19-related illness will 
be determined from averaged change (AUC as determined by the trapezoidal rule) though 
14 and 21 days in the total and domain scores (nose, throat, eyes, chest/respiratory, 
gastrointestinal and body/systemic) from the Flu-PRO Plus patient-reported outcome 
instrument and will also combine additional scores for smell/taste.  
In addition, the proportion of participants achieving sustained (>=48 hours) symptom 
alleviation as measured by the FLU-PRO Plus will be presented.  The definition of 
sustained symptom alleviation is included in Appendix 4. 
COVID-19 Clinical Symptoms will be provided for the population, and in the subgroup 
of participants who reported at least two moderate symptoms as baseline. 
5.4.1.9. 
Work Productivity and Activity Impairment (WPAI) 
At Baseline, participants were queried as to whether they were able to socially distance 
and either work on-site or remotely. 
Mean change in the WPAI scores for absenteeism (work time missed), presenteeism 
(impairment at work / reduced on-the-job effectiveness), work productivity loss (overall 
work impairment / absenteeism plus presenteeism) and activity impairment will be 
assessed at each visit. 
5.4.1.10. 
Health-Related Quality of Life According to the SF-12 Hybrid 
Mean change in the Health Status SF-12 plus the full SF-36 domains of vitality and 
physical role will be completed.  The total score, the physical component summary (PCS), 
mental component summary (MCS) and the SF-36 domain scores for vitality and 
physical role will be assessed at each visit. 
5.4.2. 
Main Analytical Approach 
5.4.2.1. 
Binary Endpoints 
The following exploratory endpoints will be analysed as continuous endpoints: 
• 
Proportion of participants hospitalized due to non-respiratory complications of 
COVID-19 
• 
Proportion of participants with sustained (>= 48 hours) symptom alleviation 
Binary secondary endpoints will be analysed as per Section 5.2.2. 
The strategy for missing data in derivation of symptom alleviation based on Flu-PRO 
Plus is as described in Section 5.3.2.3. 
5.4.2.2. 
Continuous Endpoints 
The following exploratory endpoints will be analysed as continuous endpoints: 


 
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• 
Total number of ventilator days from randomization through 90 days 
• 
Total intensive care length of stay 
• 
Total hospital length of stay 
• 
Reduction in SARS-CoV2 viral load (nasal secretions and blood) 
• 
Severity and Duration of COVID-19 Clinical Symptoms as measured by Flu-
PRO Plus. 
• 
Work Productivity and Activity Impairment (WPAI) 
• 
Health-related quality of life according to the SF-12 hybrid 
SARS-CoV-2 viral load will be analysed using a mixed model repeated measures 
(MMRM) adjusted for baseline value, baseline value by visit, age group, time to onset of 
symptoms, gender and region as described in Section 5.3.2.2.  
All other continuous endpoints will be analyzed using analysis of covariance adjusted for 
age group, time to onset of symptoms, region and gender at each visit.  Additionally, for 
Flu-PRO Plus and SF-12 the baseline measurement will be included. 
The strategy for handling intercurrent events and missing data for SARS-CoV-2 viral 
load and Flu-PRO Plus is as described in Section 5.3.2.2. 
Continuous endpoints will be summarised using the trimmed means approach (Permutt, 
2017) where the proportion of data to be trimmed will be determined by the amount of 
missing data due to death or lost-to-follow up/consent withdrawn.  For hospital and 
ICU/Ventilation use, the trimmed means will only be utilized if at least 10% of subjects 
overall have the event of interest. 
Descriptive statistics (n, arithmetic mean, standard deviation [SD] standard error [SE], 
95% CI, minimum, median and maximum) will be calculated by treatment. Total number 
of ventilator days, total intensive care length of stay and total hospital length of stay will 
only be analyzed if at least 10% of participants have one or more recorded event of 
interest. 
5.4.2.3. 
Time-to-event endpoints 
The following exploratory endpoints will be analyzed as time to event endpoints: 
• 
Time to undetectable nasal SARS-CoV2 viral load 
Time to event endpoints will be analyzed using nonparametric survival analysis methods, 
using Kaplan-Meier methods for summarizing data and analyzed using the log-rank test. 
5.5. 
Safety Analyses 
The safety analyses will be based on the “Safety” Analysis Set, unless otherwise 
specified. 


 
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5.5.1. 
Extent of Exposure 
As this is a single dose study, summaries of exposure will be limited to the number of 
participants exposed and the number of participants with Interruptions or Infusion 
stopped early and not completed. 
This will be presented with Subject Disposition. 
5.5.2. 
Adverse Events 
Adverse events analyses including the analysis of adverse events (AEs), Serious AEs 
(SAEs) and other significant AEs will be based on GSK Core Data Standards.  
An overview summary of AEs will be produced, including counts and percentages of 
participants with: 
• 
 AEs 
• 
AEs related to study intervention 
• 
AEs leading to permanent discontinuation of study intervention,  
• 
AEs leading to temporary interruption of study intervention 
• 
Grade 3 and 4 AEs  
• 
Grade 3 and 4 AEs related to study intervention,  
• 
Grade 3 and 4 AEs leading to permanent discontinuation of study intervention,  
• 
Grade 3 and 4 AEs leading to temporary interruption of study intervention 
• 
SAEs,  
• 
SAEs related to study intervention,  
• 
Fatal SAEs 
• 
Fatal SAEs related to study intervention will be produced. 
In addition, an overall summary of safety criteria will be produced, including counts and 
percentages of participants with:  
• All-cause mortality 
• SAEs 
• Renal events 
• Cardiac events 
• Pulmonary events 
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary) and graded by the investigator according to the DAIDS 
2017 v2.1. 
The frequency and percentage of AEs (all grades) will be summarized and displayed in in 
descending order by System Organ Class (SOC) and Preferred Term (PT). In the SOC 


 
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row, the number of participants with multiple events under the same SOC will be counted 
once.   
A summary of number and percentage of participants with any adverse events by 
maximum grade will also be produced. AEs will be sorted by PT in descending order. 
The summary will use the following algorithms for counting the participant: 
• 
Preferred term row: Participants experiencing the same AE preferred term 
several times with different grades will only be counted once with the maximum 
grade. 
• 
Any event row: Each participant with at least one adverse event will be counted 
only once at the maximum grade no matter how many events they have. 
A separate summary will be provided for study intervention-related AEs (all grades). A 
study intervention-related AE is defined as an AE for which the investigator classifies the 
possible relationship to study intervention as “Yes”. A worst-case scenario approach will 
be taken to handle missing relatedness data, i.e. the summary table will include events 
with the relationship to study intervention as ‘Yes’ or missing. The summary table will be 
displayed by SOC and PT. Similarly, a summary of study intervention-related AEs by 
maximum grade will also be produced. The summary table will be displayed by PT only. 
Other summaries of AEs to be produced will include: 
• 
AEs/study intervention related AEs leading to permanent discontinuation from 
study,  
• 
Most common AEs/ study intervention related AEs/ Grade 3 to 4 AEs/ study 
intervention related Grade 3 to 4 AEs, with common AE defined as any AE (PT) 
with an incidence of at least 5% in any of the treatment group 
• 
All AEs excluding events related to COVID-19 
• 
All AEs for subjects who received approved COVID-19 vaccination 
 
All SAEs will be tabulated based on the number and percentage of participants who 
experienced the event. The summary tables will be displayed by SOC and PT.  Separate 
summaries will also be provided for study intervention related SAEs. The summary 
tables will be displayed by PT.   
A study intervention-related SAE is defined as an SAE for which the investigator 
classifies the relationship to study intervention as “Yes”. A worst-case scenario approach 
will be taken to handle missing data, i.e. the summary table will include events with the 
relationship to study intervention as ‘Yes’ or missing. 
Relative risks based on observed frequencies, for the proportions of participants with 
common (>=5% in either treatment group) AEs will be calculated for VIR-7831 versus 
placebo. 
Relative risks with Exact unconditional confidence intervals will be presented 
graphically. Exact confidence limits will be computed by inverting two separate one 


 
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sided exact tests that are based on score statistic. Relative risks will not be calculated if 
there are no events in either of the two treatment arms being compared. The relative risks 
and exact confidence interval will be plotted on log base 10 scale. 
The adverse events with calculated relative risks will be presented in decreasing order. 
The full list of planned AE/SAE summaries will be as described in Section 4 of the study 
OPS. 
5.5.2.1. 
Adverse Events of Special Interest 
The following will be considered adverse events of special interest (AESI) for the 
purpose of analyses:  
• 
Infusion related reactions (IRR) including hypersensitivity reactions; reactions 
on same day as infusion 
• 
Immunogenicity related adverse drug reactions 
• 
Adverse events potentially related to antibody dependent enhancement of 
disease 
The summary of event characteristics will be provided for each AESI respectively, 
including: 
• 
number of participants with any event,  
• 
number of events,  
• 
number of Grade 3/4 events,  
• 
number of participants with any event that is serious,  
• 
number of participants with any event that is related to study intervention,  
• 
number of occurrences (One, Two, Three or more),  
• 
maximum grade,  
• 
maximum grade for events related to study intervention,  
• 
outcomes and the action taken for the event.  
The percentage will be calculated in two ways, one with number of participants with 
event as the denominator and the other with total number of participants as the 
denominator.  The worst-case approach will be applied at participant level for the 
maximum grade, i.e. a participant will only be counted once as the worst case from all the 
events experienced by the participant. For action taken to an event, a participant will be 
counted once under each action, e.g. if a participant has an event leading to both study 
intervention discontinuation and dose reduction, the participants will be counted once 
under both actions. 
The time to onset and duration of first event will also be summarized descriptively. 


 
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5.5.3. 
Additional Safety Assessments 
5.5.3.1. 
Laboratory Data 
Summaries of worst-case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by DIAIDs 2017 v2.1. These summaries will display the 
number and percentage of subjects with a maximum post-baseline grade increasing from 
their baseline grade. Any increase in grade from baseline will be summarized along with 
any increase to a maximum grade of 2, any increase to a maximum grade of 3 and any 
increase to a maximum grade of 4. Missing baseline grade will be assumed as grade 0. 
For laboratory tests that are graded for both low and high values, summaries will be done 
separately and labelled by direction, e.g., sodium will be summarized as hyponatremia 
and hypernatremia separately. 
For lab tests that are not gradable by DAIDS 2017 v2.1, summaries of worst-case 
changes from baseline with respect to normal range will be generated. Decreases to low, 
changes to normal or no changes from baseline, and increases to high will be summarized 
for the worst-case post-baseline. If a subject has a decrease to low and an increase to high 
during the same time interval, then the subject is counted in both the “Decrease to Low” 
categories and the “Increase to High” categories.  
Separate summary tables for haematology, and chemistry laboratory tests will be 
produced. Liver function laboratory tests will be included with chemistry lab tests.   
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above. Possible Hy’s law cases are 
defined as any elevated alanine aminotransferase (ALT)>3×upper limit of normal (ULN), 
total bilirubin≥2×ULN and alkaline phosphatase (ALP)<3×ULN/missing. Total 
bilirubin≥2×ULN can be within 28 days following the ALT elevation and if direct 
bilirubin is available on the same day, it must be ≥ 35% of total bilirubin. 
ALP<3×ULN/missing means it is satisfied unless the ALP is 3xULN at the time of 
bilirubin elevation. The summary will be produced for worst case post baseline only.  A 
plot for maximum post-baseline Total Bilirubin against ALT will also be produced, and 
will be repeated with the values standardized with respect to baseline, instead of ULN. 
This is to account for the individual variation at baseline 
5.5.3.2. 
Vital Signs 
Summaries of grade increase in systolic blood pressure (SBP) and diastolic blood 
pressure (DBP) will be provided separately. These summaries will display the number 
and percentage of participants with any grade increase, increase to Grade 2 and increase 
to Grade 3 for worst case post-baseline only. The grade definition for SBP is: Grade 0 
(<120), Grade 1 (120-139), Grade 2 (140-159), Grade 3 (>=160). The grade definition for 
DBP is: Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), Grade 3 (>=100). The 
summaries will be produced for worst case post baseline only. 
In addition, summaries of respiratory rate, heart rate and temperature will be provided. 


 
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5.5.3.3. 
Oxygen Saturation 
Summaries of actual and changes in blood oxygen saturation (Sp02) and proportion of 
subjects administered oxygen at each visit will be provided separately.  Summaries of 
worst-case actual changes in FiO2  and Sp02/Fi02 ratios will be summarised for those 
administered supplemental oxygen.  Where FiO2 is not collected, this will be estimated 
from the oxygen flow rate and device providing supplemental oxygen. 
For participants administered supplemental oxygen, additional summary tables will 
display the number and percentage of participants with %SpO2 <92 and/or SpO2/FiO2 < 
315 at each visit and worst-case post-baseline.   
Changes in requirement for respiratory support according to the following categories: 
1. Room air 
2. Low flow nasal canulae/face mask  
3. Non-re-breather mask or high flow nasal cannulae/ non-invasive ventilation 
(including continuous positive airway pressure support) 
4. Mechanical ventilation / extra-corporeal membrane oxygenation 
Changes in requirement for respiratory support will be summarized using counts and 
proportions of the number of participants in each category. 
In addition, a shift table from baseline to the level of respiratory support will be produced 
and the proportion of participants in each category will be summarised at each visit using 
a stacked bar chart.  Individual subject profiles showing the time course of respiratory 
support will also be produced. 
5.5.3.4. 
ECG 
A summary of the number and percentage of participants with ECG findings will be 
summarized by treatment. The ECG findings to be summarized are the ECG 
interpretation, clinical significance of abnormal ECGs, and whether there was a clinically 
significant change from baseline. Participants with missing baseline values will be 
excluded from this summary. 
5.6. 
Other Analyses 
5.6.1. 
Population Pharmacokinetics  
Sparse PK samples will be analysed using population PK approach.  Parameters may 
include, but not be limited to Cmax, Clast, tmax, tlast, AUCinf, AUClast, AUC0-D28, %AUCexp, 
t1/2, Vz/F, CL/F, and will be listed and summarized using descriptive statistics.   
A two-compartment IV bolus population pharmacokinetic model will be used to describe 
VIR-7831 pharmacokinetics. The model will fit concentration data in the log-domain 
with additive residual and takes the general form: 
Log(CONC) = LNDV = log(Dose) + log(A exp(-ALPHA*TIME) + B*exp(-
BETA*TIME)) + eps 


 
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Since infusion duration is very short compared to both distribution, ALPHA- and 
elimination BETA-phases, the bolus assumption is valid for monoclonal antibody 
administration. A physiological parameterisation of A, B, ALPHA and BETA will be 
used in terms of clearance (CL), inter-tissue peripheral clearance (Q), central volume 
(V1) and peripheral volume (V1). These physiological parameters will be related to 
bodyweight using conventional allometry (standardised to 70 kg), with fixed bodyweight 
powers of 0.75 for clearance and 1.00 for volume and subject to additional random 
effects (b1, b2). Observed sample times will be used for analysis and units will be days. 
Should convergence not be achieved by default Gaussian quadrature, the firo first-order 
method will be implemented instead.  
5.7. 
Interim Analyses  
Interim analysis will be used to assess safety (due to harm), futility due to lack of efficacy 
and efficacy.  Safety stopping rules will be put in place for the IDMC to stop the study if 
there is an excess risk of harm (see IDMC Charter for further details.) 
Interim analyses to assess efficacy and futility are planned when approximately 41% and 
64% of the required number of participants have reached Day 29 visit. The analysis of the 
primary endpoint at the interim analyses will be the same as that described for the 
primary endpoint. Group sequential techniques will be used to adjust stopping boundaries 
to reflect the actual number of participants with available data for primary endpoint at the 
time of each interim analysis. The timing of the efficacy interim analyses and stopping 
rules are provided in Section 5.2.2.1. 
Details of the interim analyses and required outputs are provided in the IDMC Charter 
and IDMC Analyses Plan. 
The Joint Safety Review Team (JSRT) comprising physicians and scientists from Vir and 
GSK will review blinded safety data at regular intervals throughout the conduct of the 
study and determine if a safety concern based on instream blinded data review needs to 
be escalated to the IDMC.  Details of the JSRT process is recorded in relevant SRT 
documents. 
Following all participants completing the final follow-up visit at Week 24 a final safety 
analysis will be performed. 
 


 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Abbreviations and Trademarks 
6.1.1. 
List of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
A&E 
Accident and Emergency 
ADA 
Antidrug Antibosy 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
APX 
Analysis Population Exclusion 
AUC 
Area Under the Curve 
AST 
Aspartate Aminotransferase 
BiPAP 
Bilevel Positive Airway Pressure 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel 
COVID-19 
Corona Virus Disease 2019 
CPAP 
Continuous Positive Airway Pressure 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBP 
Diastolic Blood Pressure 
DBR 
Database Release 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation  
eCRF 
Electronic Case Record Form 
FiO2 
Concentration of Inspired Oxygen 
Flu-PRO 
Influenza-Patient Reported Outcome 
GSK 
GlaxoSmithKline 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web-based Randomisation System 
JSRT 
Joint Safety Review Team 
LOS 
Length of Stay 
mAb 
monoclonal antibody 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MCS 
Mental Component Score 
MI 
Mutliple Imputation 


 
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Abbreviation 
Description 
NIAID 
National Institute of Allergy and Infectious Diseases 
OPS 
Output and Programming Specification 
PCI 
Potential Clinical Importance 
PCR 
Polymerase chain reaction 
PCS 
Physical Component Score 
PD 
Protocol Deviation   
PK 
Pharmacokinetic 
PP 
Per Protocol 
qRT 
Quantitative Reverse Transcription  
RoW 
Rest of World 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SBP 
Systolic Blood Pressure 
SD/SE 
Standard Deviation / Standard Error 
SF-12 
12-item short form survey 
Sp02 
Blood Oxygen Saturation 
ULN 
Upper Limit Normal 
WPAI 
Work Productivity and Activity Impairment  
 
6.1.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
None 
 


 
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6.2. 
Appendix 2: Changes to Protocol-Planned Analyses 
There are no changes to the protocol-planned analyses. 


 
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6.3. 
Appendix 3: Statistical Modelling 
6.3.1. 
Multiple Imputation 
Multiple imputation will be utilized to impute data that is missing following withdrawal 
of the subject from the study. Each data type will use one set of imputations with all 
endpoints that depend on that data type being derived from the intermediate dataset. 
The statistical model used for the multiple imputation data generation will use one of two 
approaches depending on data type: 
• 
Continuous endpoints will use the Markov Chain Monte Carlo (MCMC) method 
with adjustment for covariates. 
• 
Binary and ordinal endpoints will use a two-stage approach: 
• 
1. First intermittent missing data will be imputed using MCMC followed by 
adaptive rounding [Carpenter, 2012] step to create a monotone structure. 
• 
2. Second a monotone logistic regression imputation will be performed to 
impute data post-study withdrawal, in addition to the analyses covariates this 
model will include a parameter for COVID-19 progression (Progressed/Not 
Progressed). If logistic regression step fails to converge the following back-
up options including: 
• 
i. A discriminant function [Brand, 1999] may be used in place of logistic. 
• 
ii. MCMC with adaptive rounding. 
A sufficient number of imputations will be performed to ensure the stability of the 
estimates. The results of analysis from each complete imputed dataset will be combined 
using Rubin’s rule. 
Table 5 
  details the models, covariates and the seed to be used for the analyses. 
Table 5 
Multiple Imputation Specifications 
Endpoint 
Model 
Covariates 
Post-Baseline 
Timepoints 
Included in 
Prediction Model 
Initial Seed 
Proportion of 
participants who 
have progression 
of COVID-19 at 
Day 8, Day 15, 
Day 22, or Day 
29 
Monotone Binary 
Logistic 
Regression 
Treatment, Age 
Group at 
Baseline, 
Duration of 
Symptoms  
Day 8, Day 15, 
Day 22, or Day 
29 
6862 
Proportion of 
participants who 
progress to 
Monotone Binary 
Logistic 
Regression 
Treatment, Age 
Group at 
Baseline, 
Day 8, Day 15, 
Day 22, or Day 
29 
376 


 
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Endpoint 
Model 
Covariates 
Post-Baseline 
Timepoints 
Included in 
Prediction Model 
Initial Seed 
develop severe or 
critical respiratory 
COVID-19 
Duration of 
Symptoms  
29-day, 60-day, 
and 90-day all-
cause mortality 
Monotone Binary 
Logistic 
Regression 
Treatment, Age 
Group at 
Baseline, 
Duration of 
Symptoms  
Day 29, 60 & 90 
7371 
 
The seeds were generated using the following code: 
DATA seeds; 
DO i=1 to 3; 
seed=int(10000*ranuni(214366)); 
OUTPUT; 
END; 
RUN; 
If additional seeds are required, then the initial seed as specified will be incremented by 
1. 
6.3.2. 
Count Data Model Checking 
Distributional assumptions underlying the model used for analysis will be checked. If 
there are any departures from the distributional assumptions, alternative models may be 
explored. 
6.3.3. 
Continuous Data Model Checking 
Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption of 
the model respectively) to gain confidence that the model assumptions are reasonable. 
If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 


 
C O N FI D E N TI A L  
 
 
2 1 4 3 6 7( VI R -7 8 3 1 -5 0 0 1 ) 
4 7  
 
6. 4.  
A p p e n di x 4: Fl u -P R O Pl u s r e s p o n d er d efi niti o n  
I n Septe m b er 2 0 2 0, F D A releas e d G ui da nce  
(htt ps:// w w w.f da. g o v/ me dia/ 1 4 2 1 4 3/ d o w nl oa d ) e nc o ura gi n g t he de v el o p me nt a n d use b y 
s p o ns ors of a res p o n d er defi niti o n. T o de vel o p t his res p o n der defi niti o n Fl u -P R O  Pl us  
ite ms ha ve bee n ma p p e d  o nt o t he ite m s u g geste d b y t he F D A i n t heir g ui da nce.  T he 
ma p pi n g is as f oll o ws:  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
2 1 4 3 6 7( VI R -7 8 3 1 -5 0 0 1 ) 
4 8  
 
 
A r e s p o n d er will b e d efi n e d a s  
•  
Ite ms 
 a n d 
 s c ori n g 
 
•  
Ite ms 
 sc ori n g n o m or e t ha n “ 
” i n se v erit y 
•  
Ite ms 
 sc ori n g 
 
•  
Ite ms 
 sc ori n g  
 or 
 
 
A s ustai ne d res p o nse is d efi ne d as s ustai ne d f or > = 4 8 hrs.  
      
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


 
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7. 
REFERENCES 
Brand, J. P. L. Development, Implementation, and Evaluation of Multiple Imputation 
Strategies for the Statistical Analysis of Incomplete Data Sets. Ph.D. thesis, Erasmus 
University 1999. 
Carpenter, J.R. & Kenward M.G. Multiple Imputation and its Applications. Wiley 2012 
Hwang IK, Shih WJ, DeCani JS, Statistics In Medicine. Dec 1990 (Volume9, Issue 12, 
1439-1445) Group sequential designs using a family of type I error probability spending 
functions. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63. 
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat 2017;16: 
20-8. 
Sanofi. Press release. https://www.sanofi.com/en/media-room/press-releases/2020/2020-
04-27-12-58-00. 
Van Buuren, S. Multiple Imputation of Discrete and Continuous Data by Fully 
Conditional Specification. Statistical Methods in Medical Research 2007; 16:219–242. 
Vir Document: VIR-7831-5001 Original Protocol (GSK Study ID 214367). A 
randomized, multi-center, double-blind, placebo-controlled study to assess the safety and 
efficacy of monoclonal antibody VIR-7831 for the early treatment of coronavirus disease 
2019 (COVID-19) in non-hospitalized patients. Effective Date: 27 July 2020