A Multicenter, Randomized, Double-Blind, Parallel Group Phase II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of a Second Generation VIR-7831 Material in Non-Hospitalized Participants With Mild to Moderate Coronavirus Disease 2019 (COVID-19)
Phase: PHASE2
Conditions: Covid19
Sponsor: Vir Biotechnology, Inc.

 
 
 
 
Protocol 
 
Study ID:  216912 
 
Official Title of Study: A Multicenter, Randomized, Double-Blind, Parallel Group Phase 
II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of a Second Generation 
VIR-7831 Material in Non-Hospitalized Participants with Mild to Moderate Coronavirus 
Disease 2019 (COVID-19) 
 
NCT ID: NCT04779879 
 
IND Identifier: 149315 
 
EudraCT Identifier: 2021-000724-35 
 
 
Date of Document: 29-OCT-2021 
 
 

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Vir Biotechnology Inc. and GlaxoSmithKline group of companies 
216912 
 
 
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TITLE PAGE 
Protocol Title: A Multicenter, Randomized, Double-Blind, Parallel Group Phase II 
Study to Evaluate the Safety, Tolerability and Pharmacokinetics of a Second Generation 
VIR-7831 Material in Non-Hospitalized Participants with Mild to Moderate Coronavirus 
Disease 2019 (COVID-19) 
Protocol Number: GSK Study 216912 (VIR-7831-5006) / Amendment 05 
Compound Number 
or Name: 
VIR-7831 (GSK4182136, also known as sotrovimab) 
 
Brief Title: Safety, tolerability, pharmacokinetics, and pharmacodynamics of second 
generation VIR-7831 material administered intravenously (IV) and intramuscularly (IM) 
in non-hospitalized participants with mild to moderate coronavirus disease 2019 
(COVID-19) 
Study Phase: Phase II 
Acronym: COMET-PEAK (COVID-19 Monoclonal antibody Efficacy Trial – Patient 
safEty, tolerAbility, pharmacoKinetics)  
Sponsor Name and Legal Registered Address:  
Vir Biotechnology, Inc. 
499 Illinois Street, Suite 500 
San Francisco, CA 94158  
USA 
 
This study is sponsored by Vir Biotechnology Inc (Vir).  GlaxoSmithKline (GSK) is 
supporting Vir Biotechnology Inc. in the conduct of this study.  
Regulatory Agency Identifying Number(s):  
IND: 149315 
EudraCT: 2021-000724-35 
NCT: NCT04779879 
Approval Date: 29-OCT-2021 
Copyright 2021 Vir Biotechnology, Inc. and the GlaxoSmithKline group of companies.  
All rights reserved.  Unauthorised copying or use of this information is prohibited. 

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SPONSOR SIGNATORY: 
Protocol Title: A Multicenter, Randomized, Double-Blind, Parallel Group Phase II 
Study to Evaluate the Safety, Tolerability and Pharmacokinetics of a Second Generation 
VIR-7831 Material in Non-Hospitalized Participants with Mild to Moderate Coronavirus 
Disease 2019 (COVID-19) 
Protocol Number: 216912 / Amendment 05 
Compound Number 
or Name: 
VIR-7831 (GSK4182136, also known as sotrovimab)  
 
 
 
 
 
Elizabeth Alexander, MD, MSc 
Vice President, Clinical Research 
Vir Biotechnology Inc. 
 
Date 
 
The signed page is a separate document. 
 
 
 
 
 
Medical Monitor Name and Contact Information will be provided separately 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 05 
29-OCT-2021 
TMF-14113476 
Amendment 04 
18-MAY-2021 
TMF-12902987 
Amendment 03 
08-APR-2021 
TMF-11941318 
Amendment 02 
03-MAR-2021 
TMF-11814330 
Amendment 01 
19-JAN-2021 
TMF-11735674 
Original Protocol 
10-DEC-2020 
2020N457654_00 
Amendment 05: 29-OCT-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: Expanded the safety follow-up of all active 
participants through Week 36 (~5 half lives of sotrovimab).     

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Section # and Name 
Description of Change 
Brief Rationale 
Section 1:Brief Summary, 
Objective/Endpoints, Schema,  
SoA: Part A, Part B, Part C,  
2.3.1 Risk Assessment Table,  
3 Objectives/Endpoints, 
4.1 Overall Design, 4.2 Scientific 
Rationale for Study Design, 
4.4 End of Study Definition, 
5.1. Inclusion Criteria, 
8 Study assessments,  
8.4. Safety Assessments, 
 8.4.5 Active Monitoring of 
COVID-19 Progression,  
8.5.1 Time Period and 
Frequency for Collecting AE, and 
SAEs,  
8.5.6. Pregnancy 
8.5.8 Disease-Related Events 
and/or Disease-Related 
Outcomes not Qualifying as AE 
or SAE,  
8.5.9.4 Antibody-Dependent 
Enhancement, 9.4.3 Secondary 
Endpoints.  
Added a site phone call at 
Week 36 to all  to capture   
SAEs, AESIs, DREs, 
concomitant medication, 
COVID symptoms and 
pregnancy status.  
Added instructions for all 
WOCBP to continue 
contraception through Week 
36. 
Given that the half-life of 
sotrovimab is 
approximately 49 days a 
decision was made to 
expand the  safety follow-
up through Week 36 (~5 
half-lives). 
2.3.3. Overall Benefit:Risk 
Conclusion, 
6.1. Table 5 
Correction of a reference and 
clarification in the table to 
include Gen2 IM as a source.  
General administrative 
updates. 
Throughout document 
Other minor grammatical and 
typographical corrections. 
To improve readability 

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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY .......................................................................................... 8 
1.1. 
Synopsis ....................................................................................................... 8 
1.2. 
Schema ...................................................................................................... 19 
1.3. 
Schedule of Activities (SoA) ........................................................................ 20 
2. 
INTRODUCTION .................................................................................................... 23 
2.1. 
Study Rationale .......................................................................................... 23 
2.2. 
Background ................................................................................................ 27 
2.3. 
Benefit/Risk Assessment ............................................................................ 29 
2.3.1. 
Risk Assessment ......................................................................... 30 
2.3.2. 
Benefit Assessment ..................................................................... 36 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 37 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 37 
4. 
STUDY DESIGN .................................................................................................... 40 
4.1. 
Overall Design ............................................................................................ 40 
4.2. 
Scientific Rationale for Study Design .......................................................... 42 
4.3. 
Justification for Dose .................................................................................. 43 
4.4. 
End of Study Definition ............................................................................... 44 
5. 
STUDY POPULATION ........................................................................................... 44 
5.1. 
Inclusion Criteria ......................................................................................... 44 
5.2. 
Exclusion Criteria ........................................................................................ 46 
5.3. 
Lifestyle Considerations .............................................................................. 47 
5.4. 
Screen Failures........................................................................................... 48 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 48 
6.1. 
Study Intervention(s) Administered ............................................................. 48 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 50 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 50 
6.4. 
Study Intervention Compliance ................................................................... 51 
6.5. 
Dose Modification ....................................................................................... 51 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 52 
6.7. 
Treatment of Overdose ............................................................................... 52 
6.8. 
Concomitant Therapy.................................................................................. 52 
6.8.1. 
Medication Not Permitted During the Study ................................. 52 
6.8.2. 
Permitted Concomitant Medication .............................................. 53 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 53 
7.1. 
Discontinuation of Study Intervention .......................................................... 53 
7.1.1. 
Temporary Discontinuation .......................................................... 53 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 53 
7.3. 
Lost to Follow Up ........................................................................................ 54 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 54 

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8.1. 
Efficacy ....................................................................................................... 56 
8.2. 
Screening Period ........................................................................................ 56 
8.2.1. 
Medical History ............................................................................ 56 
8.2.2. 
Physical Examinations ................................................................. 56 
8.2.3. 
SARS-CoV-2 Diagnostic Testing ................................................. 56 
8.2.4. 
Secondary Contact Information .................................................... 57 
8.3. 
Virologic Assessments ................................................................................ 57 
8.4. 
Safety Assessments ................................................................................... 58 
8.4.1. 
Vital Signs .................................................................................... 58 
8.4.2. 
Electrocardiograms ...................................................................... 59 
8.4.3. 
Cardiac Monitoring ....................................................................... 60 
8.4.4. 
Hospitalization and Death Data Collection ................................... 60 
8.4.5. 
Active Monitoring of COVID-19 Progression ................................ 60 
8.4.6. 
Clinical Safety Laboratory Assessments ...................................... 60 
8.4.7. 
Pregnancy Testing ....................................................................... 61 
8.4.8. 
Local Injection Site Tolerability ..................................................... 61 
8.5. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 62 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 63 
8.5.2. 
Assessment of Severity ............................................................... 63 
8.5.3. 
Method of Detecting AEs and SAEs ............................................. 64 
8.5.4. 
Follow-up of AEs and SAEs ......................................................... 64 
8.5.5. 
Regulatory Reporting Requirements for SAEs ............................. 64 
8.5.6. 
Pregnancy ................................................................................... 64 
8.5.7. 
Cardiovascular and Death Events ................................................ 65 
8.5.8. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as AEs or SAEs ................................... 65 
8.5.9. 
Adverse Events of Special Interest .............................................. 66 
8.5.9.1. 
Infusion-Related Reactions and Serious 
Hypersensitivity .......................................................... 66 
8.5.9.2. 
Injection Site Reactions .............................................. 66 
8.5.9.3. 
Immunogenicity .......................................................... 67 
8.5.9.4. 
Antibody-Dependent Enhancement ............................ 67 
8.6. 
Pharmacokinetics ....................................................................................... 68 
8.7. 
Genetics ..................................................................................................... 69 
8.8. 
Biomarkers ................................................................................................. 69 
8.9. 
Health Economics ....................................................................................... 69 
8.10. 
Immunogenicity Assessments ..................................................................... 69 
8.11. 
Resistance Analyses .................................................................................. 70 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 70 
9.1. 
Statistical Hypotheses................................................................................. 70 
9.1.1. 
Part A Statistical Hypotheses ....................................................... 70 
9.1.2. 
Part B Statistical Hypotheses ....................................................... 70 
9.1.3. 
Part C Statistical Hypotheses....................................................... 70 
9.2. 
Sample Size Determination ........................................................................ 71 
9.2.1. 
Part A Sample Size Determination ............................................... 71 
9.2.2. 
Part B Sample Size Determination ............................................... 71 
9.2.3. 
Part C Sample Size Determination............................................... 71 
9.3. 
Analysis Sets .............................................................................................. 72 
9.3.1. 
Part A Analysis Sets .................................................................... 72 

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9.3.2. 
Part B and Part C Analysis Sets .................................................. 72 
9.4. 
Statistical Analyses ..................................................................................... 73 
9.4.1. 
General Considerations ............................................................... 73 
9.4.1.1. 
Part A, Part B, and Part C General 
Considerations ........................................................... 73 
9.4.2. 
Primary Endpoint(s) ..................................................................... 73 
9.4.2.1. 
Part A Primary Endpoint(s) ......................................... 73 
9.4.2.2. 
Part B and Part C Primary Endpoint(s) ....................... 74 
9.4.3. 
Secondary Endpoints ................................................................... 75 
9.4.3.1. 
Part A Secondary Endpoints ....................................... 75 
9.4.3.2. 
Part B and Part C Secondary Endpoints ..................... 75 
9.4.4. 
Exploratory Endpoints .................................................................. 76 
9.5. 
Interim Analysis .......................................................................................... 76 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 77 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 77 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 77 
10.1.2. 
Financial Disclosure ..................................................................... 77 
10.1.3. 
Informed Consent Process .......................................................... 78 
10.1.4. 
Data Protection ............................................................................ 78 
10.1.5. 
Committees Structure .................................................................. 79 
10.1.5.1. Joint Safety Review Team (JSRT) .............................. 79 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 79 
10.1.7. 
Data Quality Assurance ............................................................... 79 
10.1.8. 
Source Documents ...................................................................... 80 
10.1.9. 
Study and Site Start and Closure ................................................. 81 
10.1.10. Publication Policy ......................................................................... 82 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 83 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 84 
10.3.1. 
Definition of AE ............................................................................ 84 
10.3.2. 
Definition of SAE .......................................................................... 85 
10.3.3. 
Definition of Cardiovascular Events ............................................. 87 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 87 
10.3.5. 
Reporting of SAE to GSK ............................................................. 89 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ....................................... 91 
10.4.1. 
Definitions: ................................................................................... 91 
10.4.2. 
Contraception Guidance: ............................................................. 92 
10.5. 
Appendix 5: Local Injection Site Tolerability Assessment ............................ 94 
10.6. 
Appendix 6: Management of Local Injection Site Reactions and 
Systemic Symptoms (Anaphylaxis) ............................................................. 96 
10.7. 
Appendix 7: Country-specific Requirements ............................................... 98 
10.7.1. 
Germany ...................................................................................... 98 
10.7.2. 
Summary of Changes History for the Germany Country-
specific Protocol Amendment ....................................................... 99 
10.8. 
Appendix 8: Abbreviations and Trademarks .............................................. 101 
10.9. 
Appendix 9: Protocol Amendment History ................................................. 105 
11. REFERENCES ..................................................................................................... 120 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title 
A Multicenter, Randomized, Double-Blind, Parallel Group Phase II Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of a Second Generation VIR-7831 Material in 
Non-Hospitalized Participants with Mild to Moderate Coronavirus Disease 2019 
(COVID-19) 
Brief Title:  
Safety, tolerability, pharmacokinetics, and pharmacodynamics of second generation VIR-
7831 material administered intravenously (IV) and intramuscularly (IM) in non-
hospitalized participants with mild to moderate coronavirus disease 2019 (COVID-19) 
Rationale: 
There is an urgent medical need for therapeutics for the treatment of coronavirus disease 
2019 (COVID-19). 
Vir Biotechnology, Inc. (Vir) is developing VIR-7831 (also known as GSK4182136, 
sotrovimab) for the treatment and prophylaxis of COVID-19. VIR-7831 is a human 
immunoglobulin G (IgG1) monoclonal antibody (mAb) that binds to a highly conserved 
epitope on the spike protein receptor binding domain of severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2). 
As of 31 March 2021, approximately 1350 participants have been randomized to either 
VIR-7831 (500 mg dose) or placebo in two clinical studies: 1057 participants in a study 
evaluating VIR-7831 for the treatment of non-hospitalized individuals with mild to 
moderate COVID-19 (COMET-ICE [NCT04545060]) and 300 participants in a study that 
evaluated VIR-7831 for the treatment of individuals hospitalized with COVID-19 
(ACTIV-3-TICO [NCT04501978]). 
COMET-ICE, is a seamless first-in-human (FIH) Phase II/III study assessing the safety 
and efficacy of a single 500 mg intravenous dose of VIR-7831 for the early treatment of 
COVID-19 in non-hospitalized participants at high risk for progression and subsequent 
hospitalization. Participants were randomized in a 1:1 ratio to VIR-7831 or placebo. 
COMET-ICE started with a lead-in phase (N=21) in August 2020 to assess safety and 
tolerability. An Independent Data Monitoring Committee (IDMC) met 
23 September 2020 to review unblinded safety data after the 20th participant from the 
lead-in cohort completed Day 15 (1 participant was withdrawn). There were no deaths or 
serious adverse events reported up to this IDMC review. The IDMC recommended the 
study to proceed with the expansion-phase to enroll additional participants across each 
treatment group (~1300 participants total). 
Subsequently, the IDMC met to review available safety and tolerability data on 
28 January 2021. At the data cutoff of 22 January 2021, safety data was available from 

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526 participants (of 532 enrolled) including 405/532 (76%) who were at least 15 days 
post-dosing. Available data indicate that 99/526 (19%) participants experienced an 
adverse event (AE) with 10 (2%) participants experiencing an AE related to study 
treatment. One participant experienced a serious adverse event (SAE) of respiratory 
distress with onset 10 days after study drug infusion that led to patient discontinuation 
from the study follow up. This event occurred on Day 12 and resolved on Day 27, lasting 
16 days. In the validated dataset shared with the IDMC, there were 22 SAEs reported, the 
majority of which represented respiratory progression of COVID-19 disease leading to 
hospitalization (i.e. disease progression) which is also the primary efficacy endpoint. Of 
these, one participant of the 526 for whom safety data was available (<1%) experienced 
an SAE coded to Preferred Term Covid-19, which was later updated to Covid-19 
pneumonia, and was considered related. The IDMC recommended the study to continue 
with no adaptation. 
The IDMC subsequently met on 10 March 2021 for a planned interim analysis, with 
review of data from 583 participants. There was an 85% reduction in the primary 
endpoint of hospitalization or death in the VIR-7831 arm versus the placebo arm 
(p=0.002). The IDMC recommended that the study halt enrollment on the basis of 
overwhelming efficacy [Vir Biotechnology, 2021]. 
VIR-7831 was also being studied for the treatment of hospitalized participants with 
COVID-19 in Study 215149, also known as ACTIV-3-TICO, sponsored by the National 
Institute of Allergy and Infectious Diseases. The ACTIV-3-TICO study is a randomized, 
blinded, placebo-controlled platform study that allows investigational drugs to be added 
and dropped during the course of the study. The sub-study evaluating VIR-7831 started in 
December 2020 and aimed to enroll approximately 500 participants per treatment arm. 
A Data and Safety Monitoring Board (DSMB) review for ACTIV-3-TICO to include the 
VIR-7831 sub-protocol occurred on 25 January 2021. The DSMB reviewed data from 
148 participants who had been randomized to VIR-7831 or shared placebo. One 
potentially life-threatening allergic reaction (anaphylaxis) was reported during infusion in 
ACTIV-3-TICO in a participant who received VIR-7831. The time to onset was 
21 minutes after the start of infusion and the event was considered related to study 
treatment. The participant was treated for the allergic reaction and recovered. The DSMB 
recommended the VIR-7831 sub-study should continue as planned. 
The DSMB met on 01 March 2021 for a pre-planned safety and efficacy data review of 
ACTIV-3-TICO. While VIR-7831 met initial pre-specified criteria to continue to the next 
phase of the ACTIV-3 trial and there were no reported safety signals, sensitivity analyses 
of the available data raised concerns about the magnitude of potential benefit. The DSMB 
therefore recommended that the trial be closed to future enrollment [GlaxoSmithKline 
plc, 2021a]. 
To date, partial Phase 1 pharmacokinetics (PK) data from Lead-in subjects enrolled in 
COMET-ICE is available through Study Day 57. The mean maximum concentration 
(Cmax) of 500 mg VIR-7831 was 219 µg/mL following a 1 hour IV infusion. The mean 
serum level on Day 29 is 37.2 µg/mL for the Lead-in phase of COMET-ICE.  

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Vir partnered with WuXi Biologics to initiate manufacturing activities to enable rapid 
entry of VIR-7831 into the COMET-ICE (NCT04545060) study in non-hospitalized 
patients with mild to moderate disease in August 2020. Initially, two manufacturing 
batches were produced from a pool of cells (non-clonal) stably transfected to express the 
VIR-7831 sequences (Generation 1 [Gen1]). Additional cGMP drug substance has been 
produced at WuXi Biologics using a similar manufacturing process but from a clonal 
Master Cell Bank (MCB) derived from the original pool of transfectants (Generation 2 
[Gen2]). As Gen2 is from a clonally-derived cell bank, it will be the intended commercial 
product. 
COMET-ICE and ACTIV-3-TICO utilized Gen1 material. Analytical comparability 
studies evaluating Gen1 drug substance (DS) and drug product (DP) in relation to Gen2 
DS and DP have recently been completed. These studies included routine release analysis 
and extended characterization, and were designed and completed in alignment with 
International Council for Harmonisation (ICH) Q5E guidelines (comparability of 
biotechnological/biological products subject to changes in their manufacturing process). 
These confirm a high degree of analytical and bioanalytical comparability between Gen1 
and Gen2, thereby supporting the use of Gen2 in clinical studies.  
In addition, Gen2 IV material was used in combination with bamlanivimab, in one arm of 
the BLAZE-4 study (NCT04634409), a clinical trial with multiple arms evaluating anti-
SARS-CoV-2 mAbs from Eli Lilly and Company. In this arm, the combination of 
bamlanivimab with VIR-7831 was compared to placebo (randomized 1:1), for the 
treatment of mild to moderate COVID-19. Enrollment for this arm concluded at 
approximately 200 participants on 05 February 2021. As of 17 March 2021, no safety 
concerns have been identified. The BLAZE-4 study met the primary endpoint, with a 
70% (p<0.001) relative reduction in persistently high viral load (>5.27; cycle threshold 
value <27.5) at Day 7 compared with placebo for bamlanivimab 700 mg co-administered 
with VIR-7831 500 mg. Co-administration of bamlanivimab and VIR-7831 also 
demonstrated a statistically significant reduction in the key virologic secondary endpoints 
of mean change from baseline for SARS-CoV-2 viral load to Days 3, 5, and 7 compared 
with placebo [GlaxoSmithKline plc, 2021b]. 
Since Gen2 will be the commercial product, Vir is proposing this study to gain additional 
clinical experience with Gen2 administered both intravenously (IV) and via intramuscular 
(IM) injection in non-hospitalized patients with mild to moderate COVID-19, a patient 
population similar to that of COMET-ICE, to complement the analytical and 
bioanalytical data. This study will evaluate the safety, tolerability, immunogenicity, 
pharmacokinetics, and viral pharmacodynamics (PD) of both IV and IM formulations of 
VIR-7831 Gen2 (500 mg IV, 500 mg IM and 250 mg IM) when administered in this early 
treatment population. Part A of the study will evaluate VIR-7831 Gen2 and Gen1 500 mg 
administered via IV infusion. Part B will evaluate VIR-7831 Gen2 500 mg IV infusion 
and Gen2 500 mg IM injection, and Part C will evaluate VIR-7831 Gen2 500 mg IV 
infusion and Gen2 250 mg IM injection. Intramuscular injection of VIR-7831 will also be 
evaluated in the following planned studies: 
• A study evaluating efficacy, safety, and tolerability of VIR-7831 IM (250 mg and 
500 mg) versus VIR-7831 IV (500 mg) for treatment of mild/moderate COVID-

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19 in non-hospitalized participants at high risk for disease progression (VIR-
7831-5008 [GSK Study 217114] also known as COMET-TAIL) 
• Studies evaluating VIR-7831 IM (500 mg) as prophylaxis against SARS-CoV-2 
infection.  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
Safety (Part A) 
To evaluate the safety and tolerability 
profile of intravenous (IV) VIR-7831 Gen2 
and IV Gen1 
• Occurrence of adverse events (AEs) through 
Day 29 
• Occurrence of serious adverse events (SAEs) 
through Day 29 
• Occurrence of adverse events of special 
interest (AESIs) through Day 29 
• Occurrence of clinically significant abnormalities 
on 12-lead electrocardiogram (ECG) readings 
through Day 29 
• Occurrence of disease progression events (not 
classified as AEs) through Day 29 
Pharmacodynamics (Part B) 
To evaluate the virological response of 
VIR-7831 Gen2 administered IV (500 mg) 
and via intramuscular (IM) injection 
(500 mg) in the upper respiratory tract 
• Mean area under the curve (AUC) of SARS-
CoV-2 viral load as measured by quantitative 
reverse transcriptase polymerase chain 
reaction (qRT-PCR) from Day 1 to 
Day 8 (AUCD1-8) in nasopharyngeal swab 
samples 
Pharmacodynamics (Part C) 
To evaluate the virological response of 
VIR-7831 Gen2 administered IV (500 mg) 
and via IM injection (250 mg) in the upper 
respiratory tract 
• Mean area under the curve (AUC) of SARS-
CoV-2 viral load as measured by quantitative 
reverse transcriptase polymerase chain 
reaction (qRT-PCR) from Day 1 to 
Day 8 (AUCD1-8) in nasopharyngeal swab 
samples 
Secondary 
 
Safety (Part A) 
To evaluate the safety and tolerability 
profile of IV VIR-7831 Gen2 and IV Gen1 
• Occurrence of non-serious AEs through 
Week 12  
• Occurrence of SAEs through Week 36 
• Occurrence of AESIs through Week 36 

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Objectives 
Endpoints 
• Occurrence of clinically significant abnormalities 
on 12-lead ECG readings through Week 12 
• Occurrence of disease progression events (not 
classified as AEs) through Week 36 
Safety (Part B and C) 
To evaluate the safety and tolerability 
profile of VIR-7831 Gen2 administered via 
IV infusion and IM injection, through 
Day 29 
• Occurrence of adverse events (AEs) through 
Day 29  
• Occurrence of serious adverse events (SAEs) 
through Day 29  
• Occurrence of adverse events of special 
interest (AESIs) through Day 29  
• Occurrence of clinically significant abnormalities 
on 12-lead electrocardiogram (ECG) readings 
through Day 29  
• Occurrence of disease progression events (not 
classified as AEs) through Day 29  
Safety (Part B and C) 
To evaluate the safety and tolerability 
profile of VIR-7831 Gen2 administered 
via IV infusion and IM injection, through 
End of Study (EOS) 
• Occurrence of non-serious AEs through 
Week 12  
• Occurrence of SAEs through Week 36  
• Occurrence of AESIs through Week 36 
• Occurrence of clinically significant abnormalities 
on 12-lead ECG readings through Week 12 
• Occurrence of disease progression events (not 
classified as AEs) through Week 36  
Virology (Part A) 
To characterize the effect of VIR-7831 
Gen2 IV and Gen1 IV on the viral 
shedding profile in the upper respiratory 
tract 
• Change from baseline in viral load at all visits 
through Day 29 as measured by qRT-PCR from 
saliva and nasal mid-turbinate swabs samples 
Virology (Part B and C) 
To characterize the effect of VIR-7831 
Gen2 IV and Gen2 IM on the viral 
shedding profile in the upper respiratory 
tract 
• Change from baseline in viral load at all visits 
through Day 29 as measured by qRT-PCR from 
nasopharyngeal (NP) swab samples 
• Proportion of participants with undetectable 
viral load at all visits through Day 29 of the 
study as measured by qRT-PCR from NP swab 
samples 

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Objectives 
Endpoints 
• Mean area under the curve of SARS-CoV-2 
viral load as measured by qRT-PCR from Day 1 
to Day 5 (AUCD1-5) and Day 1 to 11 (AUCD1-11) 
Virology (Part B and C) 
To characterize the effect of VIR-7831 
Gen2 IV and IM on viral load clearance in 
the upper respiratory tract 
• Proportion of individuals with a persistently high 
viral load at Day 8 as assessed via qRT-PCR in 
NP swab samples (see Section 8.3) 
Pharmacokinetics (Part A, Part B, and 
Part C) 
To assess the pharmacokinetics (PK) of 
VIR-7831 Gen2 IV and IM and Gen1 IV in 
serum 
• Serum PK of VIR-7831  
Exploratory 
 
Resistance (Part A, Part B, and Part C) 
To monitor the presence at Baseline and 
the emergence of SARS-CoV-2 resistant 
mutants against VIR-7831 
• Presence at Baseline and emergence of SARS-
CoV-2 viral resistance mutants   
Immunogenicity (Part A, Part B , and 
Part C) 
To assess the immunogenicity of VIR-
7831 Gen2 IV and IM and Gen1 IV 
• Incidence and titers (if applicable) of serum 
anti-drug antibodies (ADA) to VIR-7831  
Immunology (Part A, Part B and 
Part C) 
To assess the effect of VIR-7831 Gen2 IV 
and IM and Gen1 IV on immune 
response 
• Incidence and titers (if applicable) of anti-
nucleocapsid (anti-N), anti-spike (anti-S) and 
anti-receptor binding domain (anti-RBD) SARS-
CoV-2 antibodies at baseline  
• Incidence and titers (if applicable) of anti-N 
SARS-CoV-2 antibodies at Day 29 
Overall Design: 
This study is a randomized, multi-center, parallel group phase II trial of VIR-7831, a 
monoclonal antibody (mAb) against SARS-CoV-2, in non-hospitalized patients with mild 
to moderate COVID-19, aged 18 years or older. The study is comprised of Parts A, B, 
and C.  

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Part A Design: 
Part A of the study is double-blind and participants will be randomized 3:1 to receive a 
single, 500 mg intravenous infusion of either Gen2 or equal volume Gen1 study material. 
A Gen1 study arm is included to maintain blinding of Gen1 versus Gen2 VIR-7831 
receipt during the conduct of the study, including for assessment of safety outcomes. 
Safety, tolerability, virology, immunogenicity, and PK will be evaluated.  
Part B Design: 
Part B of the study will be open-label and participants will be randomized 1:1 to receive a 
500 mg dose of Gen2 material by IV infusion or intramuscular (IM) injection. In Part B, 
viral load PD as assessed via upper respiratory samples, safety, tolerability, 
immunogenicity, and PK will be evaluated. Part B will include a Lead-in phase (n=20) 
with frequent assessments for injection site reactions (ISRs), infusion-related reactions 
(IRRs), and safety, along with PK sampling.  
A JSRT review on 13 May 2021 identified no serious safety concerns on review of 
66 participants enrolled in Part B (all of the Lead-in participants and some Expansion 
phase participants). Based on this safety review, the Joint Safety Review Team (JSRT) 
agreed with the proposal to reduce the post-dose monitoring time on Day 1 from 2 hours 
to 1 hour for Part B of the study. 
Part C Design: 
Part C of the study will be open-label and participants will be randomized 1:1 to receive a 
500 mg dose of Gen2 material by IV infusion or a 250 mg dose of Gen2 material by IM 
injection. Participants will be stratified by prior exposure to an authorized or approved 
SARS-CoV-2 vaccine. In Part C, viral load PD as assessed via upper respiratory samples, 
safety, tolerability, immunogenicity, and PK will be evaluated. Part C will include a 
Lead-in phase (n=20) with frequent safety assessments to allow for JSRT determination if 
the post-dose monitoring time can be shortened (from 1 hour to 30 minutes). The Lead-in 
phase will also include PK sampling.  
Brief Summary: 
This study will occur in 3 Parts (Part A, Part B, and Part C). The purpose of the study is 
to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and viral PD of 
the Gen2 VIR-7831 material. All participants will receive standard of care (SoC) for 
COVID-19 disease during this study, including admission to a hospital if deemed 
necessary by the responsible investigator.  
Enrollment for Part A of the study, which assesses intravenous (IV) Gen2, will 
commence first. Enrollment for Part B of the study, which assesses 500 mg IV and 
500 mg IM Gen2, will not be gated to Part A. Enrollment for Part C of the study, which 
will assess Gen2 500 mg IV and Gen2 250 mg IM, will not be gated to Part A or Part B. 

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Part A:   
• Treatment Duration: Single IV infusion on Day 1. 
• Day 1 monitoring: Approximately 9 hours for safety assessments and intensive 
PK sampling.  
• Study Duration: 36 weeks.  
• Blinded JSRT will review all available safety data at regular intervals. While the 
primary safety endpoint is through Day 29, safety assessments will continue 
during the study to end-of-study (EOS) (Week 36).  
After Day 1, subsequent visits for study activities and clinical monitoring will be 
conducted via clinic visits (except for Week 16 and Week 36, which will be a phone call).  
Part B: 
• Treatment Duration: Single-dose by IV infusion or IM injection on Day 1. 
• Day 1 monitoring: Approximately 2 hours post-dose in the Lead-in phase and 
1 hour post-dose in the Expansion phase (based on JSRT review) for safety 
assessments. 
• Study Duration: 36 weeks. 
• JSRT will review all available safety data at regular intervals. The JSRT will 
review unblinded aggregate safety and tolerability data by treatment arm through 
Day 3 for the Lead-in phase participants (n=20). Enrollment for Part B of the 
study will continue into the Expansion phase once the Lead-in (n=20) has been 
recruited, but Day 1 monitoring will remain at 2 hours post-dose for new 
participants until the JSRT provides a recommendation that this monitoring in the 
Expansion phase can be shortened to 1 hour post-dose. 
• After Day 1, subsequent visits for study activities and clinical monitoring will be 
conducted via home or clinic visits (except for Week 6,Week 16, and Week 36 for 
both the Lead-in phase and Expansion phase, and Week 8 for the Expansion 
phase, which will be phone calls).  
A JSRT review on 13 May 2021 identified no serious safety concerns on review of 
66 participants enrolled in Part B (all of the Lead-in participants and some Expansion 
phase participants). Based on this safety review, the JSRT agreed with the proposal to 
reduce the post-dose monitoring time on Day 1 from 2 hours to 1 hour for Part B of the 
study. 
Part C: 
• Treatment Duration: Single-dose by IV infusion or IM injection on Day 1. 
• Day 1 monitoring: Approximately 1 hour post-dose in the Lead-in phase and 
30 minutes post-dose in the Expansion phase (based on JSRT review) for safety 
assessments.  
• Study Duration: 36 Weeks.   
• The JSRT will review all available safety data at regular intervals. The JSRT will 
review unblinded aggregate safety and tolerability data by treatment arm through 

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Day 3 for the Lead-in phase participants (n=20). Enrollment for Part C of the 
study will continue into the Expansion phase once the Lead-in (n=20) has been 
recruited, but Day 1 monitoring will remain at 1 hour post-dose for new 
participants until the JSRT provides a recommendation that this monitoring in the 
Expansion phase can be shortened to 30 minutes post-dose. 
• After Day 1, subsequent visits for study activities and clinical monitoring will be 
conducted via home or clinic visits (except for Week 6,Week 16 and Week 36 for 
both the Lead-in phase and Expansion phase, and Week 8 for the Expansion 
phase, which will be phone calls).  
Number of Participants: 
Part A:  
Approximately 40 enrolled participants 18 years of age or older will be randomly 
assigned in a 3:1 (Gen2: Gen1) randomization scheme to study intervention. Any 
participant who receives the study intervention will be considered evaluable. 
Part B:  
Part B will enroll a total of approximately 150 participants 18 years to <70 years of age 
with a detectable viral load at baseline (Day 1).  
In the Lead-in phase of Part B, approximately 20 participants will be enrolled and 
randomly assigned (1:1) to receive either Gen2 500 mg IV or Gen2 500 mg IM. An 
unblinded review of injection site reactions (ISRs), infusion-related reactions (IRRs), and 
other safety and tolerability data through Day 3 will be performed by the JSRT.   
Enrollment for the Expansion phase will begin after completion of enrollment of the 
Lead-in phase; however, the change from 2 hours to 1 hour of monitoring post-injection 
or post-infusion did not occur until after the JSRT recommendation to reduce the 
monitoring time was received on 13 May 2021, following review of the Day 3 data from 
the Lead-in phase. In the Expansion phase, approximately 130 participants will be 
randomly (1:1) assigned to receive Gen2 500 mg IV or Gen2 500 mg IM. Any participant 
who receives the study intervention will be considered evaluable.  
A greater number of participants may be enrolled in the Part B Expansion phase if 
blinded assessments of baseline (Day 1) viral load data that are available from Part A of 
the study and the Lead-in phase of Part B (anticipated total of 40 to 60 baseline viral 
loads from the two parts combined) demonstrate that there are individuals with an 
undetectable viral load at baseline. If it is determined that additional participants will 
need to be enrolled, the expected total enrollment will be updated based on estimates of 
the percentage of participants with undetectable virus at baseline using data from 
participants in Part A and the Part B Lead-in phase. In this event, additional participants 
will be enrolled up to a maximum of 110 per arm (220 total for Part B) and randomized 
1:1 to Gen2 500 mg IV or IM to achieve approximately 75 participants per arm in Part B 
with a detectable viral load at baseline.  

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Part C:  
Part C will enroll a total of approximately 150 participants 18 years to <70 years of age 
with a detectable viral load at baseline (Day 1).  
In the Lead-in phase of Part C, approximately 20 participants will be enrolled and 
randomly assigned (1:1) to receive either Gen2 500 mg IV or Gen2 250 mg IM. An 
unblinded review of ISRs, IRRs, and other safety and tolerability data through Day 3 will 
be performed by the JSRT.   
Enrollment for the Part C Expansion phase will begin after completion of enrollment of 
the Lead-in phase; however, the change from 1 hour to 30 minutes of monitoring post-
injection or post-infusion will not occur until a recommendation to reduce monitoring 
time from the JSRT is received, following review of the Day 3 data from the Lead-in 
phase. In the Expansion phase, approximately 130 participants will be randomly (1:1) 
assigned to receive Gen2 500 mg IV or Gen2 250 mg IM. Any participant who receives 
the study intervention will be considered evaluable.  
A greater number of participants may be enrolled in the Part C Expansion phase if 
blinded assessments of baseline (Day 1) viral load data that are available from Part A of 
the study and the Lead-in phase of Part B (anticipated total of 40 to 60 baseline viral 
loads from the two Parts combined) demonstrate that there are individuals with an 
undetectable viral load at baseline. If it is determined that additional participants will 
need to be enrolled, the expected total enrollment will be updated based on estimates of 
the percentage of participants with undetectable virus at baseline using data from 
participants in Part A and the Part B Lead-in phase. In this event, additional participants 
will be enrolled up to a maximum of 110 per arm (220 total for Part C) and randomized 
1:1 to Gen2 500 mg IV or Gen2 250 mg IM to achieve approximately 75 participants per 
arm in Part C with a detectable viral load at baseline.  
Note: For all study Parts, "enrolled" means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study following completion of the 
informed consent process and screening. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not participate in the study, are not 
considered enrolled, unless otherwise specified by the protocol.  
Intervention Groups and Duration: 
Part A:  
Screening assessments will be performed within 1 day before the start of infusion. After 
completion of screening and baseline assessments, eligible participants will be 
randomized in a 3:1 ratio to VIR-7831 Gen2 or Gen1, by interactive response technology 
(IRT) in a blinded manner and treated with a single IV dose of the study intervention on 
Day 1. Screening may be performed on the same day as randomization and dosing 
(Day 1). All participants will receive SoC as per institutional protocols, in addition to the 
study intervention.   
 

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Part B: 
Screening assessments will be performed within 1 day before the start of the IV infusion 
or IM injections. After completion of screening and baseline assessments, eligible 
participants will be randomized in a 1:1 ratio to receive a single dose of VIR-7831 Gen2 
IV (500 mg) or Gen2 IM (500 mg), by IRT on Day 1. Part B will be open-label, and 
participants will only receive the intervention that he/she is randomized to receive (i.e., 
there is no additional placebo administered IV or IM). Screening may be performed on 
the same day as randomization and dosing (Day 1). All participants will receive SoC as 
per institutional protocols, in addition to the study intervention.   
Part C: 
Screening assessments will be performed within 1 day before the start of the IV infusion 
or IM injections. After completion of screening and baseline assessments, eligible 
participants will be randomized in a 1:1 ratio to receive a single dose of VIR-7831 Gen2 
IV (500 mg) or Gen2 IM (250 mg), by IRT on Day 1. Part C will be open-label, and 
participants will only receive the intervention that they are randomized to receive (i.e., 
there is no additional placebo administered IV or IM). Screening may be performed on 
the same day as randomization and dosing (Day 1). All participants will receive SoC as 
per institutional protocols, in addition to the study intervention.   
Joint Safety Review Team (JSRT):  
The JSRT, comprised of team members from clinical research, pharmacovigilance and 
statistics from Vir and GSK, will review blinded safety data from Part A of the study at 
regular intervals. For Parts B and C of the study, the JSRT will be unblinded, and data 
will be reviewed according to the Treatment-Sensitive Data Plan for Open-Label 
Randomized Study. There will be no routine in-stream review of aggregated safety data 
by treatment arm at any JSRT meeting other than at the two post-Day 3 JSRT meetings 
(one for Part B and one for Part C) that will determine if the monitoring time may be 
reduced. Additionally, any sharing of potential safety signals will reflect pooled data that 
is not separated by treatment arm. The Safety team may need to review single unblinded 
case reports to support regulatory reporting obligations and/or potential safety signals that 
may need to be reviewed by JSRT. The objective nature of the primary endpoint 
(virologic PD) further supports the central team and JSRT remaining unblinded. Details 
regarding the JSRT process will be available in relevant Safety Review Team (SRT) 
documents. 

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1.2. 
Schema 
 
 

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1.3. 
Schedule of Activities (SoA) 
Table 1 
Schedule of Activities: Part A 
 
 
 
W1 
W2 
W3 W4 W6 W8 W12 W16 W20 W24 W36 
Notes 
 
 
 Study Visit Day  Visit Window14 
Screening 
(Day 0/1) 
Day 1 
Day 2 
Day 5 
Day 8 
Day 11 
Day 15 ± 1d 
Day 22 ± 1d 
Day 29 ± 2d 
Day 43 ± 3d 
Day 57 ± 4d 
Day 85 ± 7d 
Day 113 ± 7d 
Day 141 ± 7d 
Day 169 ± 7d 
Day 253 ± 7d 
Site visit or call1 
Site Site Site Site Site Site Site Site Site Site Site Site Call1 Site Site 
Call 1. The site phone call may be replaced with a clinic visit at the 
discretion of the investigator.  
2. Data on the history of COVID-19 illness prior to enrollment should be 
collected in the specific eCRF. 
3. As per institution diagnostic protocols. 
4. All screening procedures must be completed within 1 day prior to 
dosing. Screening and dosing may take place on the same day.   
5. Including height and weight. 
6. If screening and dosing occur on the same day: full physical 
examination, pre-treatment vital signs, and pre-treatment safety lab 
assessments only need to be performed once, and only the triplicate 
ECGs prior to infusion are required; an additional single 12-lead ECG 
prior to infusion is not required. 
7. Record Day 1 vital signs: prior to dosing, then every 15 minutes 
during IV infusion, and at approximately 1, 2, 6, and 8 hours after end 
of infusion. Vital signs on other days should be performed once daily. 
8. Day 1: triplicate ECGs prior to infusion and within 30 minutes of end 
of infusion. All other timepoints are single 12-lead ECG once daily.  
9. Urine for albumin to creatinine ratio should be collected on Day 1 
(pre-dose) and on Day 2. Other safety labs on Day 1 should also be 
collected pre-dose. 
10. Urine or serum pregnancy test, as required by local guidelines. Refer 
to Section 8.4.7. 
11. On Day 1, sample collection will occur pre-dose, end of infusion and 
at approximately 1, 2, 6, and 8 hours following end of infusion. On 
other days, samples will be collected once daily. 
12. On Day 1, sample collection will occur pre-dose. 
13. At screening, only SAEs related to study participation or a GSK 
product will be reported.  
14. If participant withdraws early from the study prior to Week 24, then 
the W24 visit assessments will be performed as the EW visit. If the 
participant withdraws early from the study after Week 24, the W36 
visit assessments will be performed as the EW visit.  
Screening only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Disease History2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (incl. comorbidities 
and tobacco use) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 diagnostic test (if not 
previously confirmed)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessments 
Full physical examination 
X5,6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 signs/symptoms review 
 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, PR, RR, 
temperature and oxygen 
saturation) 
X6 
X7 X 
X 
X X 
X 
X 
X 
 
 
 
 
 
X 
 
12-lead ECG8 
X6 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
Sample collection 
Safety lab assessments 
X6 
X9 X9 X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample for PK analysis11 
 
X11 X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
Blood sample for anti-drug 
antibody 
 
X12 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Nasal mid-turbinate swab for 
virology 
 
X12 X 
X 
X X 
X 
X 
X 
 
 
 
 
 
 
 
Saliva sampling for virology 
 
X12 X 
X 
X X 
X 
X 
X 
 
 
 
 
 
 
 
Blood sample for Anti-SARS-CoV-
2 antibody (serum) 
 
X12 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
AE review 
 
<============= X ==================> 
 
 
 
 
SAE review 
X13 
 
<================== X ======================> 
AESI, disease-related events, and 
concomitant medication review 
 
 
<===================== X ======================> 
 

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Table 2 
Schedule of Activities: Part B 
 
 
 
W1 
W2 
W3 W4 W6 W8 W12 W16 W20 W24 W36 
Notes 
 
 
 
Study Visit Day  Visit Window17 
Screening (Day 
0/1) 
Day 1 
Day 2 
Day 3 
Day 5 
Day 8 
Day 11 
Day 15 ± 1d 
Day 22 ± 1d 
Day 29 ± 2d 
Day 43 ± 3d 
Day 57 ± 4d 
Day 85 ± 7d 
Day 113 ± 7d 
Day 141 ± 7d 
Day 169 ± 7d 
Day 253 ± 7d 
 
1. Visits other than Screening and Day 1 may take place at home, where local 
home nursing support is available. 
2. Phone calls may be replaced by a visit at investigator’s discretion.  
3. Week 8/Day 57 must be an in-person visit for the Lead-in phase, but may be a 
phone call for the Expansion phase. 
4. Data on the history of COVID-19 illness prior to enrollment should be collected 
in the specific eCRF. 
5. As per institution diagnostic protocols. 
6. All screening procedures must be completed within 1 day prior to dosing. 
Screening and dosing may take place on the same day. 
7. Including height and weight. 
8. If screening and dosing occur on the same day: full physical examination, pre-
treatment vital signs, and pre-treatment safety lab assessments are only 
performed once, and the single screening ECG is not required (pre- and post-
dose triplicate11 ECGs are still required). 
9. For Lead-in and Expansion phases prior to JSRT recommendation: Record 
Day 1 vital signs within 1 hour prior to dosing, and at the end of infusion (IV 
infusion only) then approximately 30 minutes, 1 hour and 2 hours after dosing. 
For Expansion phase after the 13 May 2021 JSRT review: Record Day 1 vital 
signs within 1 hour prior to dosing, and at the end of infusion (IV infusion only) 
then approximately 30 minutes and 1 hour after dosing. For both phases: Vital 
signs on other days should be performed once daily.  
10. For Lead-in and Expansion phases prior to JSRT recommendation: Local 
injection site tolerability assessment on Day 1 at approximately 1 and 2 hours 
post-dose and on Days 2 and 3 for all participants. Expansion phase after the 
13 May 2021 JSRT review: Local injection site tolerability assessment on Day 
1 at approximately 1 hour post-dose, those with severe ISRs on Day 1 need to 
be assessed in-person at Day 2 or 3. All ISRs to be followed by PI to 
resolution.  
11. Day 1: triplicate ECGs prior to dosing and within 30 minutes  of end of infusion 
or post-injection. All other timepoints are single 12-lead ECGs.  
12. Day 1 safety labs should be collected pre-dose. Urine for albumin to creatinine 
ratio should be collected on Day 1 (pre-dose) and on Day 2.  
13. Urine or serum pregnancy test, as per local guidelines. See 8.4.7. 
14. Day 1, sample collection will occur pre-dose (IM and IV) and at end of infusion 
(IV only). On other days, samples will be collected once daily. 
15. On Day 1, sample collection will occur pre-dose. 
16. At screening, only SAEs related to study participation or a GSK product will be 
reported. 
17. If participant withdraws early from the study prior to Week 24, then the W24 
visit assessments will be performed as the EW visit. If the participant withdraws 
early from the study after Week 24, the W36 visit assessments will be 
performed as the EW visit. 
 
Site visit1, home visit1, or call2 
Visit Visit Visit1 Visit1 Visit1 Visit1 Visit1 Visit1 Visit1 Visit1 Call Visit1/ 
Call3 Visit1 Call Visit1 Visit1 Call 
Screening only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Disease History4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (incl. comorbidities and 
tobacco use) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 diagnostic test (if not 
previously confirmed)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessments 
Full physical examination 
X7,8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 signs/symptoms review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, PR, RR, temperature 
and oxygen saturation) 
X8 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Local injection site tolerability 
assessment (IM injections only) 
 
X10 X10 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG11 
X8 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
Sample collection 
Safety lab assessments 
X8 
X12 X12 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
Pregnancy test13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample for PK analysis (Lead-in 
phase)14 
 
X14 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
Blood sample for PK analysis 
(Expansion phase)14 
 
X14 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
Blood sample for anti-drug antibody 
 
X15 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Nasopharyngeal swab for virology 
 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Blood sample for Anti-SARS-CoV-2 
antibody (serum) 
 
X15 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
AE review 
 
<================== X ==================> 
 
 
 
 
 
SAE review 
X16 
 
<=========================== X ===========================> 
 
AESI, disease-related events, and 
concomitant medication review 
 
 
<=========================== X ===========================> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 3 
Schedule of Activities: Part C 
 
 
 
W1 
W2 
W3 W4 W6 W8 W12 W16 W20 W24 W36 
Notes 
 
 
Study Visit Day  Visit Window17 
Screening (Day 
0/1) 
Day 1 
Day 2 
Day 3 
Day 5 
Day 8 
Day 11 
Day 15 ± 1d 
Day 22 ± 1d 
Day 29 ± 2d 
Day 43 ± 3d 
Day 57 ± 4d 
Day 85 ± 7d 
Day 113 ± 7d 
Day 141 ± 7d 
Day 169 ± 7d 
Day 253 ± 7d 
 
1. Visits other than Screening and Day 1 may take place at home, where local 
home nursing support is available. 
2. Phone calls may be replaced by a visit at investigator’s discretion.  
3. Week 8/Day 57 must be an in-person visit for the Lead-in phase, but may be a 
phone call for the Expansion phase. 
4. Data on the history of COVID-19 illness prior to enrollment should be collected 
in the specific eCRF. 
5. As per institution diagnostic protocols. 
6. All screening procedures must be completed within 1 day prior to dosing. 
Screening and dosing may take place on the same day. 
7. Including height and weight. 
8. If screening and dosing occur on the same day: full physical examination, pre-
treatment vital signs, and pre-treatment safety lab assessments are only 
performed once, and the single screening ECG is not required (pre- and post-
dose triplicate11 ECGs are still required). 
9. For Lead-in and Expansion phases prior to JSRT recommendation: Record 
Day 1 vital signs within 1 hour prior to dosing and at the end of infusion (IV 
infusion only) and then approximately 30 minutes and 1 hour after dosing. For 
Expansion phase if JSRT recommend reduced 30-minutes post-dose 
monitoring: Record Day 1 vital signs within 1 hour prior to dosing, at the end of 
infusion (IV infusion only), and approximately 30 minutes after dosing. For both 
phases: Vital signs on other days should be performed once daily.  
10. For Lead-in and Expansion phases prior to JSRT recommendation: Local 
injection site tolerability assessment on Day 1 at approximately 1 hour post-
dose and on Days 2 and 3 for all participants. Expansion phase if JSRT 
recommend reduced 30-minutes monitoring: Local injection site tolerability 
assessment on Day 1 at approximately 30 minutes post-dose, those with 
severe ISRs on Day 1 need to be assessed in-person at Day 2 or 3. All ISRs to 
be followed by PI to resolution.  
11. Day 1: triplicate ECGs prior to dosing and within 30 minutes of end of infusion 
or post-injection. All other timepoints are single 12-lead ECGs.  
12. Day 1 safety labs should be collected pre-dose. Urine for albumin to creatinine 
ratio should be collected on Day 1 (pre-dose) and on Day 2.  
13. Urine or serum pregnancy test, as per local guidelines. See 8.4.7. 
14. Day 1, sample collection will occur pre-dose (IM and IV) and at end of infusion 
(IV only). On other days, samples will be collected once daily. 
15. On Day 1, sample collection will occur pre-dose. 
16. At screening, only SAEs related to study participation or a GSK product will be 
reported. 
17. If participant withdraws early from the study prior to Week 24, then the W24 
visit assessments will be performed as the EW visit. If the participant withdraws 
early from the study after Week 24, the W36 visit assessments will be 
performed as the EW visit. 
 
Site visit1, home visit1, or call2 
Visit Visit Visit1 Visit1 Visit1 Visit1 Visit1 Visit1 Visit1 Visit1 Call Visit1/ 
Call3 Visit1 Call Visit1 Visit1 Call 
Screening only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Disease History4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (incl. comorbidities and 
tobacco use) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 diagnostic test (if not 
previously confirmed)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessments 
Full physical examination 
X7,8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 signs/symptoms review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, PR, RR, temperature 
and oxygen saturation) 
X8 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Local injection site tolerability 
assessment (IM injections only) 
 
X10 X10 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG11 
X8 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
Sample collection 
Safety lab assessments 
X8 
X12 X12 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
Pregnancy test13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample for PK analysis (Lead-in 
phase)14 
 
X14 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
Blood sample for PK analysis 
(Expansion phase)14 
 
X14 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
Blood sample for anti-drug antibody 
 
X15 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Nasopharyngeal swab for virology 
 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Blood sample for Anti-SARS-CoV-2 
antibody (serum) 
 
X15 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
AE review 
 
<================== X ==================> 
 
 
 
 
 
SAE review 
X16 
 
<=========================== X ===========================> 
 
AESI, disease-related events, and 
concomitant medication review 
 
 
<=========================== X ===========================> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2. 
INTRODUCTION 
2.1. 
Study Rationale  
There is an urgent medical need for therapeutics for the treatment of coronavirus disease 
2019 (COVID-19). A highly potent neutralizing monoclonal antibody (mAb) given as 
early treatment in outpatients with mild to moderate disease could prevent the need for 
hospitalization in patients at high risk of disease progression. Vir Biotechnology, Inc. 
(Vir) is developing VIR-7831 (also known as GSK4182136, sotrovimab) for the 
treatment and prophylaxis of COVID-19. VIR-7831 is a human immunoglobulin G 
(IgG1) monoclonal antibody (mAb) that binds to a highly conserved epitope on the spike 
protein receptor binding domain of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2). VIR-7831 has an Fc-modification (“LS”) that is designed to improve 
bioavailability in the respiratory mucosa and increase half-life [Hope, 2020; Ko, 2014]. 
As of 31 March 2021, approximately 1350 participants have been randomized to either 
VIR-7831 (500 mg dose) or placebo in two clinical studies: 1057 participants in a study 
evaluating VIR-7831 for the treatment of non-hospitalized individuals with mild to 
moderate COVID-19 (COMET-ICE [NCT04545060]) and 300 participants in a study that 
evaluated VIR-7831 for the treatment of individuals hospitalized with COVID-19 
(ACTIV-3-TICO [NCT04501978]). 
COMET-ICE, is a seamless first-in-human (FIH) Phase II/III study assessing the safety 
and efficacy of a single 500 mg intravenous dose of VIR-7831 for the early treatment of 
COVID-19 in non-hospitalized participants at high risk for progression and subsequent 
hospitalization. Participants were randomized in a 1:1 ratio to VIR-7831 or placebo. 
COMET-ICE started with a lead-in phase (N=21) in August 2020 to assess safety and 
tolerability. An Independent Data Monitoring Committee (IDMC) met 23 September 
2020 to review unblinded safety data after the 20th participant from the lead-in cohort 
completed Day 15 (1 participant was withdrawn). There were no deaths or serious 
adverse events reported up to this IDMC review. The IDMC recommended the study to 
proceed with the expansion-phase to enroll additional participants across each treatment 
group (~1300 participants total). 
Subsequently, the IDMC met to review available safety and tolerability data on 28 
January 2021. At the data cutoff of 22 January 2021, safety data was available from 526 
participants (of 532 enrolled) including 405/532 (76%) who were at least 15 days post-
dosing. Available data indicate that 99/526 (19%) participants experienced an AE with 10 
(2%) participants experiencing an AE related to study treatment. One participant 
experienced an SAE of respiratory distress with onset 10 days after study drug infusion 
that led to patient discontinuation from the study follow up. This event occurred on Day 
12 and resolved on Day 27, lasting 16 days. In the validated dataset shared with the 
IDMC, there were 22 SAEs reported, the majority of which represented respiratory 
progression of COVID-19 disease leading to hospitalization (i.e. disease progression) 
which is also the primary efficacy endpoint. Of these, one participant of the 526 for 
whom safety data was available (<1%) experienced an SAE coded to Preferred Term 
Covid-19, which was later updated to Covid-19 pneumonia, and was considered related. 
The IDMC recommended the study to continue with no adaptation. 

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The IDMC subsequently met on 10 March 2021 for a planned interim analysis, with 
review of data from 583 participants. There was an 85% reduction in the primary 
endpoint of hospitalization or death in the VIR-7831 arm versus the placebo arm 
(p=0.002). The IDMC recommended that the study halt enrollment on the basis of 
overwhelming efficacy [Vir Biotechnology, 2021]. 
VIR-7831 was also being studied for the treatment of hospitalized participants with 
COVID-19 in Study 215149, also known as ACTIV-3-TICO, sponsored by the National 
Institute of Allergy and Infectious Diseases. The ACTIV-3-TICO study is a randomized, 
blinded, placebo-controlled platform study that allows investigational drugs to be added 
and dropped during the course of the study. The sub-study evaluating VIR-7831 started in 
December 2020 and aimed to enroll approximately 500 participants per treatment arm. 
A Data and Safety Monitoring Board (DSMB) review for ACTIV-3-TICO to include the 
VIR-7831 sub-protocol occurred on 25 January 2021. The DSMB reviewed data from 
148 participants who had been randomized to VIR-7831 or shared placebo. One 
potentially life-threatening allergic reaction (anaphylaxis) was reported during infusion in 
ACTIV-3-TICO in a participant that received VIR-7831. The time to onset was 21 
minutes after the start of infusion and the event was considered related to study treatment. 
The participant was treated for the allergic reaction and recovered. The DSMB 
recommended the VIR-7831 sub-study should continue as planned. 
The DSMB met on 01 March 2021 for a pre-planned safety and efficacy data review. 
While VIR-7831 met initial pre-specified criteria to continue to the next phase of the 
ACTIV-3 trial and there were no reported safety signals, sensitivity analyses of the 
available data raised concerns about the magnitude of potential benefit. The DSMB 
therefore recommended that the trial be closed to future enrollment [GlaxoSmithKline 
plc, 2021a]. 
Partial blinded serum PK through Study Day 57 from the Lead-in phase of COMET-ICE 
is available to date. PK sampling will continue for 6 months for all participants in 
COMET-ICE. The preliminary pharmacokinetic (PK) profile and PK parameters for 
VIR-7831, based on nominal times are presented in Figure 1 and Table 4, respectively. 
The mean maximum concentration (Cmax) of 500 mg VIR-7831 was 219 µg/mL following 
a 1 hour IV infusion. The mean serum level on Day 29 is 37.2 µg/mL. Based on the 
partial data available to date, >20% of the AUC is being extrapolated and the observation 
range for λz spans <2 half-lives in all except one subject, so summary statistics for 
clearance (CL), apparent volume of distribution (V), terminal elimination half-life (t1/2), 
and the area under the serum concentration-time curve from zero to infinity (AUCinf) will 
be reported once sufficient data are available.   
 

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Figure 1 
Preliminary Mean Concentration vs Time Profile of VIR-7831 in 
Serum: COMET-ICE Intensive Lead-in Pharmacokinetics 
 
Note: Concentrations are displayed as mean ± standard deviation. 
 
Table 4 
Preliminary VIR-7831 Pharmacokinetic Parameters Following a 
Single 500 mg Intravenous Dose 
Parameter 
Dose 500 mg 
(N=9a) 
Cmax, µg/mL  
 219 (45.5) 
Tmax, hour  
1.0 (1.0, 1.0) 
Clast,  µg/mL  
24.1 (19.7) 
Tlast, day 
56.0 (56.0, 56.0) 
CD29, µg/mL  
37.2 (7.6) 
AUCD1-29, day*µg/mL  
1550 (10.1) 
AUClast, day*µg/mL  
2350 (9.64) 
%AUCexp, % 
39.1 (29.5) 
AUCinf, day*µg/mL  
TBDb 
CL (mL/day)  
TBDb 
Vz, L  
TBDb 
t1/2, day  
TBDb 
Abbreviations: AUCD1-29 = Area under the serum concentration-time curve, from Day 1 to day 29; AUClast = area under 
the curve from the time of dosing to the time of the last measurable (positive) concentration; AUCinf = area under 
the serum concentration-time curve from zero to infinity; %AUCexp = The extrapolated portion of AUCinf; CD29 = 
observed concentration on Day 29 (28 days post-dose); Clast = concentration  at last quantifiable timepoint; Cmax 
= maximum observed concentration; CL = clearance; t1/2 = terminal elimination half-life; Tlast = time of the last 
quantifiable concentration; Tmax = time to reach Cmax; TBD = to be determined; Vz = apparent volume of 
distribution during the elimination phase. 
Parameters are reported as mean (%CV) except for Tmax, Tlast and t1/2, which are presented as median (Q1,Q3).   
a. 
N=9 for Cmax, Tmax, Clast, Tlast; CD29;  N=8 for AUCD1-29, AUClast, AUC % Extrapolated.  
b. 
Final summary statistics for AUCinf, as well as CL,V, and t1/2 will be reported when sufficient data are available 
so that ≤20% of the AUCinf is extrapolated observation range for λz spans >2 half-lives. 

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Partial sparse serum PK through Day 29 from 176 participants in the Expansion phase of 
COMET-ICE is available to date. PK sampling will continue for 6 months for all 
participants. The mean serum concentration of VIR-7831 on Day 29 in the Expansion 
phase of COMET-ICE is 34.6 µg/mL. 
Vir partnered with WuXi Biologics to initiate manufacturing activities to enable rapid 
entry of VIR-7831 into the COMET-ICE study in August 2020. Initially, two 
manufacturing batches were produced from a pool of cells (non-clonal) stably transfected 
to express the VIR-7831 sequences (Generation 1 [Gen1]). Additional cGMP drug 
substance has been produced at WuXi Biologics using a similar manufacturing process 
but from a clonal Master Cell Bank (MCB) derived from the original pool of transfectants 
(Generation 2 [Gen2]). 
COMET-ICE and ACTIV-3-TICO utilized Gen1 material. Analytical comparability 
studies evaluating Gen1 drug substance (DS) and drug product (DP) in relation to Gen2 
DS and DP have recently been completed. These studies included routine release analysis 
and extended characterization and were designed and completed in alignment with 
International Council for Harmonisation (ICH) Q5E guidelines (comparability of 
biotechnological/biological products subject to changes in their manufacturing process). 
These confirm a high degree of analytical and bioanalytical comparability between Gen1 
and Gen2, thereby supporting the use of Gen2 in clinical studies.  
In addition, Gen2 IV material was used in the BLAZE-4 study (NCT04634409), a 
clinical trial with multiple arms evaluating anti-SARS-CoV-2 mAbs from Eli Lilly and 
Company. One arm compared the combination of bamlanivimab with VIR-7831 to 
placebo (randomized 1:1) for the treatment of mild to moderate COVID-19. Enrollment 
for this arm concluded at approximately 200 participants on 05 February 2021, with no 
safety concerns identified as of 17 March 2021. The BLAZE-4 study met the primary 
endpoint, with a 70% (p<0.001) relative reduction in persistently high viral load (>5.27; 
cycle threshold value <27.5) at Day 7 compared with placebo for bamlanivimab 700 mg 
co-administered with VIR-7831 500 mg. Co-administration of bamlanivimab and VIR-
7831 also demonstrated a statistically significant reduction in the key virologic secondary 
endpoints of mean change from baseline for SARS-CoV-2 viral load to Days 3, 5, and 7 
compared with placebo [GlaxoSmithKline plc, 2021b]. 
Since Gen2 will be the commercial product, Vir is proposing this study to gain clinical 
experience with Gen2 administered both intravenously (IV) and via IM injection in non-
hospitalized patients with mild to moderate COVID-19, a patient population similar to 
that of COMET-ICE, to complement the analytical and bioanalytical data. This study will 
evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and viral PD of both 
IV and IM formulations of VIR-7831 Gen2 (500 mg IV, 500 mg IM, and 250 mg IM) 
when administered in this early treatment population. Part A of the study will evaluate 
Gen2 and Gen1 500 mg administered via IV infusion. Part B will evaluate Gen2 500 mg 
via IV infusion and 500 mg via IM injection. Part C will evaluate Gen2 500 mg via IV 
infusion and 250 mg via IM injection. Intramuscular injection of VIR-7831 will also be 
evaluated in the following planned studies: 

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• A study evaluating efficacy, safety, and tolerability of VIR-7831 IM (250 mg and 
500 mg) versus VIR-7831 IV (500 mg) for treatment of mild/moderate COVID-
19 in non-hospitalized participants at high risk for disease progression (VIR-
7831-5008 [GSK Study 217114] also known as COMET-TAIL) 
• Studies evaluating VIR-7831 IM (500 mg) as prophylaxis against SARS-CoV-2 
infection.  
2.2. 
Background 
A novel beta-coronavirus causing severe pneumonia was first reported in December 2019 
in Wuhan, China. Since that time, severe acute respiratory syndrome coronavirus-2 
(SARS-CoV-2) has spread throughout the world. As of 09 May 2021, there have been 
approximately 157.8 million confirmed cases and >3.2 million deaths globally with 
approximately 32.7 million cases and 581,659 deaths in the United States [Johns Hopkins 
COVID Dashboard, 2021].  
The spectrum of symptomatic COVID-19 disease ranges from mild disease without 
pneumonia to critical disease requiring hospitalization in an intensive care unit (ICU). A 
comprehensive report from the Chinese Center for Disease Prevention and Control which 
included nearly 45,000 confirmed cases estimated that the vast majority of patients, 81%, 
were classified as having mild disease with no or mild pneumonia [Wu, 2020]. In the 
same study, 14% were classified as having severe disease, and 5% as having critical 
disease. Risk factors for severe disease and/or death include older age and certain 
comorbidities such as cardiovascular disease, diabetes mellitus, obesity, respiratory 
disease (e.g., chronic obstructive pulmonary disease), tobacco use, and chronic kidney 
disease. The current estimated infection fatality rate increases exponentially with age, 
from 0.004% in individuals younger than 35 to 28.3% in the population 85 years and 
older [Levin, 2020]. 
In the United States, data on the proportion of patients with symptomatic disease 
requiring hospitalization have ranged from 21% overall to as high as 40% in those with at 
least one pre-existing health condition [CDC, 2020]. The median time for COVID-19 
related hospital admission has been reported to be 7 to 11 days and the median time to 
clinical deterioration, 9 to 12 days [Huang, 2020; Zheng, 2020; Zhou, 2020].  
Complications are common among hospitalized patients, including respiratory failure 
with acute respiratory distress syndrome (ARDS); cardiomyopathy; thromboembolic 
disease with pulmonary embolism and/or stroke; shock; and multiorgan dysfunction 
[Wang, 2020; Klok, 2020; Arentz, 2020]. Multisystem inflammatory syndrome (MIS), a 
hyperinflammatory syndrome with involvement of multiple organ systems and often 
requiring ICU-level support, has also been recently described in adults [Morris, 2020]. 
While long-term complications of COVID-19 have been described mostly in the 
hospitalized population, there are increasing data demonstrating significant long-term 
sequelae in patients with mild to moderate disease not requiring hospitalization, including 
long-term disability and prolonged duration of illness before a return to baseline 
functioning [Tenforde, 2020]. 

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Monoclonal antibodies directed against SARS-CoV-2 have the potential to both be used 
for prevention and treatment of COVID-19 [Marovich, 2020]. Indeed, given 
developmental consideration [Kelley, 2020], mAbs could serve as an important bridge 
until vaccines are widely available. Specifically, neutralizing mAbs, given as early 
treatment in outpatients with mild to moderate COVID-19 disease could prevent need for 
hospitalization due to disease progression in patients at risk for complications such as 
respiratory compromise, respiratory failure, or other organ failure. Additionally, an 
efficacious neutralizing mAb given early in the disease course could ameliorate the 
severity and duration of COVID-19 and potentially reduce transmission. Given data 
demonstrating that viral loads are highest early in the course of disease [Wölfel, 2020; 
Zheng, 2020], the non-hospitalized patient population at high risk for disease progression 
may in particular benefit from early intervention with a mAb. 
There are limited specific treatment options for patients with COVID-19, particularly for 
the outpatient population where the mainstay of treatment is monitoring and supportive 
care. In the US, an Emergency Use Authorization (EUA) was granted on 
21 November 2020 for casirivimab and imdevimab (to be administered together) and on 
09 February 2021 for bamlanivimab and etesevimab (to be administered together) for the 
treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age 
and older and weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral 
testing who are at high risk for progressing to severe COVID-19 and/or hospitalization 
[FDA News Release, 2020; FDA News Release, 2021]. Early reports from studies of 
mAbs in non-hospitalized patients with COVID-19 at high risk of progression to severe 
disease, as well as the recent EUAs for bamlanivimab/etesevimab and 
casirivimab/imdevimab, support the utility of mAbs in the treatment of COVID-19 in 
outpatients [Chen, 2021; Eli Lilly and Company, 2020; FDA News Release, 2020; FDA 
News Release, 2021].  
Given that these mAbs are currently indicated for intravenous administration, a mAb that 
is able to be administered via IM injection would be of particular benefit in the outpatient 
setting where there are significant logistical challenges to IV administration. For 
example, most clinics require a dedicated infusion center with appropriate infection 
prevention and control measures to administer these mAbs to patients with early SARS-
CoV-2 infection, as well as targeted allocation of resources and personnel for the close 
monitoring that is required during and post-infusion. A mAb that is able to be 
administered via IM injection would be able to be provided in a substantially greater 
number of outpatient clinics that are currently not equipped for administration and 
monitoring of IV infusions, as well as possibly in the home care setting. Administration 
by an IM route also enables the potential to treat patients at high risk for poor outcomes 
in geographic areas where medical infrastructure is weak and the capacity to administer 
IV infusion is inadequate, including rural and underdeveloped regions. In addition, being 
able to provide an efficacious 250 mg IM dose of mAb via deltoid injection would allow 
for ease of administration across a considerably larger number of settings for high-risk 
patients, including pharmacies. Lastly, a shorter required duration for monitoring post-
administration (e.g., 30 minutes) would improve the ease of delivery for clinics, 
pharmacies, and other sites where non-hospitalized patients would be able to receive 
treatment. 

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Given the high degree of analytical and bioanalytical comparability between Gen1 and 
Gen2 material, a formal clinical comparability study will not be conducted. However, Vir 
proposes to gain clinical experience with Gen2 material across multiple clinical studies, 
including this study in non-hospitalized patients with mild to moderate COVID-19. Gen2 
material is also anticipated to be used in future planned studies of VIR-7831 in various 
patient populations (i.e., hospitalized patients, patients requiring prophylaxis). 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of VIR-7831 may be found in the IB.  

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2.3.1. 
Risk Assessment 
All the potential clinical risks of VIR-7831 are based on theoretical and known concerns associated with the mAbs class of therapeutics in 
general. The potential risk monitoring and mitigation strategy for the administration of VIR-7831 in this protocol is outlined below: 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention: VIR-7831 
Infusion-related reactions including serious 
hypersensitivity reactions (HSR) 
While VIR-7831 is a human immunoglobulin G1 (IgG1) 
mAb, infusion-related reactions (IRRs) 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 
mAbs or any of the excipients present in the 
investigational product. 
Monitoring:  
• 
Guidelines for monitoring relevant AEs 
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. 
• 
Infusion time can be extended at the 
discretion of the Investigator or Sponsor 
based on local infusion-related symptoms 
or other safety findings. 
• 
Vital signs in Part A of the study will be 
monitored every 15 minutes over the 1-
hour IV infusion and at 1, 2, 6, and 8 hours 
in the post-infusion period. Vital signs in 
the Lead-in phase of Part B of the study 
will be monitored before and at the end of 
the 15 minute IV infusion, and at 30 
minutes, 1 hour, and 2 hours post-infusion. 
Vital signs in the Lead-in phase of Part C of 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
the study will be monitored before and at 
the end of the 15 minute IV infusion, and at 
30 minutes and 1 hour post-infusion. 
• 
IRRs are categorized as adverse events of 
special interest (AESI). 
• 
The Joint Safety Review Team (JSRT) will 
review blinded safety data of this study at 
regular intervals to determine if a 
significant safety concern for severe 
hypersensitivity reaction is identified.  
Mitigation:  
• 
General guidance on management of 
hypersensitivity reactions is provided in 
Section 8.5.9.1 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 intravenous (IV) infusions for 
participants who develop Grade 3 or higher 
infusion reactions using the division of 
acquired immune-deficiency syndrome 
(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 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
investigator’s discretion, and/or after 
symptomatic treatment (e.g. 
antihistamines, IV fluids).  
• 
IV infusion will be administered in the clinic 
with staff trained in emergency care & 
resuscitation procedures & emergency 
care kit on hand during the infusion & post 
therapy observation periods. 
Injection Site Reaction (ISR) 
VIR-7831 will be administered via intramuscular injection.  
A similar human immunoglobulin G1 (IgG1) mAb specific to 
influenza A (VIR-2482) has been studied in a recent Phase I 
trial (NCT04033406). Intramuscular injection of this IgG1 
mAb, including at similar volumes as planned for the current 
study, was well-tolerated with minimal injection site 
reactions [Sager, 2020]. Specifically, dosing was well 
tolerated, with 6/100 participants experiencing mild injection 
site reactions that generally resolved within 48 hours. 
Through 12 weeks post-dosing, the majority (124/126) of 
AEs were mild to moderate in nature, no SAEs were 
reported, and no subjects discontinued due to an AE. 
Injection site reactions will be monitored very closely 
in the Lead-in phase of Part B of the study in 20 
participants (N=10 in the Gen2 VIR-7831 IV arm; 
N=10 in the Gen2 VIR-7831 IM arm) for 2 hours and 
for 1 hour in the Lead-in phase of Part C (N=10 in 
the Gen2 VIR-7831 IV arm; N=10 in the Gen2 VIR-
7831 IM arm). Monitoring will also be performed for 
systemic symptoms post-dosing (e.g., fever, chills, 
malaise). Local injection site tolerability assessment 
data was evaluated by the JSRT prior to decreasing 
the monitoring time to 1 hour for the Expansion 
phase of Part B and will be assessed by the JSRT 
prior to decreasing the monitoring time to 
30 minutes for Part C. 
Immunogenicity 
While VIR-7831 is a  human IgG1 mAb, 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. 
Monitoring: This study will include participant 
follow-up for a period of 24 weeks to assess for the 
potential of immunogenicity (measurement of ADA) 
as well as if ADA is potentially causally associated 
with specific safety concerns. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Antibody-dependent enhancement (ADE) 
due to sub-neutralizing levels of VIR-7831 
enhancing fusion or leading to Fc Gamma 
Receptor (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 re-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 re-
infection 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 FcR-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 36 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 re-infection as well 
as the severity of disease will be performed by the 
JSRT to assess for rates of re-infection or severe 
disease above what is clinically expected. 
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 endothelial, renal or 
cardiovascular (CV) 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]. 
Monitoring: 
• 
In this study, periodic review of AEs which are 
potential clinical signs and symptoms of 
COVID-19, clinical chemistry, other AEs, end-
organ disease, cardiac assessments, and 
histopathological diagnoses (as available per 
routine care) observed through to Week 36 will 
be performed by the Joint Safety Review 
Team (JSRT) at regular intervals to identify 
potential cases of immune complex disease 
(e.g., worsening of COVID-19-related end-
organ complications and/or greater than 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 anti-viral 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]. 
VIR-7831 shows potent binding as well as neutralization of 
pseudovirus and live virus in vitro, thus this risk is deemed 
to be low. 
VIR-7831 Clinical experience: A total of 21 subjects were 
enrolled in the Lead-In phase of the COMET-ICE study. 
Patients were randomized 1:1 to VIR-7831 or placebo. As 
of the Day 15 follow-up (data cut 28 September 2020), no 
safety signals have been observed, and no subjects died or 
discontinued the study due to AEs to date. No evidence of 
ADE with SARS-CoV-2 per IDMC criteria has been 
observed.  
On 30 September 2020, the IDMC recommended initiation 
of the Expansion study phase based on safety assessment 
expected incidence of end-organ 
complications [Chen, 2020]). 
• 
Additional monitoring in the event a participant 
develops signs or symptoms of cardiac 
complications (See Section 8.5.7). 
• 
Assessments of the overall duration and 
severity of COVID-19 will be performed by the 
JSRT to assess for greater than expected 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
of unblinded Lead-In data. Enrollment in the Expansion 
phase is ongoing. 
Subsequently, the IDMC met to review available safety and 
tolerability data on 28 January 2021. At the data cutoff of 
22 January 2021, safety data was available from 526 
participants (of 532 enrolled) including 405/532 (76%) who 
were at least 15 days post-dosing. Available data indicate 
that 99/526 (19%) participants experienced an AE with 10 
(2%) participants experiencing an AE related to study 
treatment. One participant experienced an SAE of 
respiratory distress with onset 10 days after study drug 
infusion that led to patient discontinuation from the study 
follow up. This event occurred on Day 12 and resolved on 
Day 27, lasting 16 days. In the validated dataset shared 
with the IDMC, there were 22 SAEs reported, the majority 
of which represented respiratory progression of COVID-19 
disease leading to hospitalization (i.e. disease progression) 
which is also the primary efficacy endpoint. Of these, one 
participant of the 526 for whom safety data was available 
(<1%) experienced an SAE coded to Preferred Term 
Covid-19, which was later updated to Covid-19 pneumonia, 
and was considered related. The IDMC recommended the 
study to continue with no adaptation. 
The IDMC subsequently met on 10 March 2021 for a 
planned interim analysis, with review of data from 
583 participants. No serious safety concerns were 
identified, and the IDMC recommended to halt enrollment 
based on overwhelming efficacy. 
 

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2.3.2. 
Benefit Assessment 
There is a biologic rationale to support the use of VIR-7831, an antiviral mAb, in the 
early treatment of COVID-19 to prevent disease progression. The mainstay of outpatient 
treatment of COVID-19 is supportive care and monitoring. Recent EUAs were also 
granted for the mAbs bamlanivimab/etesevimab in combination and 
casirivimab/imdevimab in combination for the treatment of mild to moderate COVID-19 
in adults and pediatric patients (12 years of age and weighing 40 kg) who are at high 
risk for progressing to severe COVID-19 and/or hospitalization FDA News Release, 
2020; FDA News Release, 2021. Specific treatments for COVID-19 in the non-
hospitalized patient population remain limited.  
VIR-7831 has been demonstrated in vitro to be a highly potent human IgG1 neutralizing 
SARS-CoV-2 antibody with additional antibody effector functions. The non-clinical 
pharmacology, pharmacokinetics and toxicology results support the evaluation of VIR-
7831 in humans for the treatment of COVID-19 infection. VIR-7831 has the potential to 
be an effective therapeutic in mild to critically ill patients with COVID-19 infection.  
The study population to be enrolled in this study are non-hospitalized patients with mild 
to moderate COVID-19, a population that has a high unmet medical need. The safety and 
tolerability of Gen1 material has been assessed in 21 patients in the lead-in phase of the 
COMET-ICE study in non-hospitalized patients with mild to moderate COVID-19 at 
high risk for progression, with a safe to proceed recommendation issued by the IDMC 
after meeting 23 September 2020 following Day 15 data review (data cut off: 
28 September 2020). Subsequently, the IDMC met to review available safety and 
tolerability data on 28 January 2021. At the data cutoff of 22 January 2021, safety data 
was available from 526 participants (of 532 enrolled) including 405/532 (76%) who were 
at least 15 days post-dosing. The IDMC recommended the study to continue with no 
adaptation.   
Importantly, the IDMC subsequently met on 10 March 2021 for a planned interim 
analysis, with review of data from 583 participants. There was an 85% reduction in the 
primary endpoint of hospitalization or death in the VIR-7831 arm versus the placebo arm 
(p-value=0.002). The IDMC recommended that the study halt enrollment on the basis of 
overwhelming efficacy [Vir Biotechnology, 2021]. 
VIR-7831 was also being studied for the treatment of hospitalized participants with 
COVID-19 in Study 215149, also known as ACTIV-3-TICO, sponsored by the National 
Institute of Allergy and Infectious Diseases. The DSMB reviewed ACTIV-3-TICO 
including the VIR-7831 sub-protocol on 25 January 2021. The DSMB reviewed data 
including a potentially life-threatening allergic reaction (anaphylaxis) that was reported 
during infusion of VIR-7831 in ACTIV-3-TICO. The DSMB recommended the VIR-
7831 sub-study should continue as planned.  
The DSMB subsequently met on 01 March 2021 for a pre-planned safety and efficacy 
data review. While VIR-7831 met initial pre-specified criteria to continue to the next 
phase of the ACTIV-3 trial and there were no reported safety signals, sensitivity analyses 
of the available data raised concerns about the magnitude of potential benefit. The DSMB 

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therefore recommended that the trial be closed to future enrollment [GlaxoSmithKline 
plc, 2021a]. 
A high degree of analytical and bioanalytical comparability has been shown between 
Gen1 and Gen2. VIR-7831 (Gen1 or Gen2) may or may not improve the time to clinical 
response or overall clinical outcome in an individual participant with mild to 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 
(both Gen1 and Gen2 material) 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. 
No clinical studies of VIR-7831 have been completed to date. There is prior clinical 
experience with VIR-7831 in the setting of the early treatment of COVID-19 (COMET-
ICE and BLAZE-4) and hospitalized treatment in ACTIV-3-TICO. In the COMET-ICE 
study, there have been no significant safety concerns identified at the IDMC reviews 
conducted to date. As of 17 March 2021, there have been no safety concerns identified in 
the BLAZE-4 study. In the ACTIV-3-TICO study, one case of anaphylaxis was reported 
during infusion of VIR-7831 which resolved with treatment.  
VIR-7831 has the potential to be an effective therapeutic in mild to critically ill patients 
with COVID-19. This benefit has been demonstrated in the interim analysis of the 
COMET-ICE study of participants with mild to moderate COVID-19 at high risk of 
disease progression, a similar non-hospitalized population as for the COMET-PEAK 
study [Vir Biotechnology, 2021]. Human-derived mAbs with similar Fc modifications as 
VIR-7831, have a well-established safety profile [Gaudinski, 2018]. Considering the 
measures taken to minimize risk to participants in this study, including close monitoring 
for IRRs in Part A of the study and for ISRs and IRRs in the Lead-in phase of Parts B and 
C of the study (Gen2 IV and IM), and the limited disease directed therapeutic options for 
non-hospitalized patients with mild to moderate COVID-19, the overall benefit-risk 
assessment of this study is considered favorable based on the available data.  
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
Safety (Part A) 
To evaluate the safety and tolerability 
profile of intravenous (IV) VIR-7831 Gen2 
and IV Gen1 
• Occurrence of adverse events (AEs) through 
Day 29 
• Occurrence of serious adverse events (SAEs) 
through Day 29 

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Objectives 
Endpoints 
• Occurrence of adverse events of special 
interest (AESIs) through Day 29 
• Occurrence of clinically significant abnormalities 
on 12-lead electrocardiogram (ECG) readings 
through Day 29 
• Occurrence of disease progression events (not 
classified as AEs) through Day 29 
Pharmacodynamics (Part B) 
To evaluate the virological response of 
VIR-7831 Gen2 administered IV (500 mg) 
and via intramuscular (IM) injection 
(500 mg) in the upper respiratory tract 
• Mean area under the curve (AUC) of SARS-
CoV-2 viral load as measured by quantitative 
reverse transcriptase polymerase chain 
reaction (qRT-PCR) from Day 1 to 
Day 8 (AUCD1-8) in nasopharyngeal swab 
samples 
Pharmacodynamics (Part C) 
To evaluate the virological response of 
VIR-7831 Gen2 administered IV (500 mg) 
and via IM injection (250 mg) in the upper 
respiratory tract 
• Mean area under the curve (AUC) of SARS-
CoV-2 viral load as measured by quantitative 
reverse transcriptase polymerase chain 
reaction (qRT-PCR) from Day 1 to 
Day 8 (AUCD1-8) in nasopharyngeal swab 
samples 
Secondary 
 
Safety (Part A) 
To evaluate the safety and tolerability 
profile of IV VIR-7831 Gen2 and IV Gen1 
• Occurrence of non-serious AEs through 
Week 12  
• Occurrence of SAEs through Week 36 
• Occurrence of AESIs through Week 36 
• Occurrence of clinically significant abnormalities 
on 12-lead ECG readings through Week 12 
• Occurrence of disease progression events (not 
classified as AEs) through Week 36 
Safety (Part B and C) 
To evaluate the safety and tolerability 
profile of VIR-7831 Gen2 administered via 
IV infusion and IM injection, through 
Day 29 
• Occurrence of adverse events (AEs) through 
Day 29  
• Occurrence of serious adverse events (SAEs) 
through Day 29  
• Occurrence of adverse events of special 
interest (AESIs) through Day 29  

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Objectives 
Endpoints 
• Occurrence of clinically significant abnormalities 
on 12-lead electrocardiogram (ECG) readings 
through Day 29  
• Occurrence of disease progression events (not 
classified as AEs) through Day 29  
Safety (Part B and C) 
To evaluate the safety and tolerability 
profile of VIR-7831 Gen2 administered 
via IV infusion and IM injection, through 
End of Study (EOS) 
• Occurrence of non-serious AEs through 
Week 12  
• Occurrence of SAEs through Week 36  
• Occurrence of AESIs through Week 36  
• Occurrence of clinically significant abnormalities 
on 12-lead ECG readings through Week 12 
• Occurrence of disease progression events (not 
classified as AEs) through Week 36  
Virology (Part A) 
To characterize the effect of VIR-7831 
Gen2 IV and Gen1 IV on the viral 
shedding profile in the upper respiratory 
tract 
• Change from baseline in viral load at all visits 
through Day 29 as measured by qRT-PCR from 
saliva and nasal mid-turbinate swabs samples 
Virology (Part B and C) 
To characterize the effect of VIR-7831 
Gen2 IV and Gen2 IM on the viral 
shedding profile in the upper respiratory 
tract 
• Change from baseline in viral load at all visits 
through Day 29 as measured by qRT-PCR from 
nasopharyngeal (NP) swab samples 
• Proportion of participants with undetectable 
viral load at all visits through Day 29 of the 
study as measured by qRT-PCR from NP swab 
samples 
• Mean area under the curve of SARS-CoV-2 
viral load as measured by qRT-PCR from Day 1 
to Day 5 (AUCD1-5) and Day 1 to 11 (AUCD1-11) 
Virology (Part B and C) 
To characterize the effect of VIR-7831 
Gen2 IV and IM on viral load clearance in 
the upper respiratory tract 
• Proportion of individuals with a persistently high 
viral load at Day 8 as assessed via qRT-PCR in 
NP swab samples (see Section 8.3) 
Pharmacokinetics (Part A, Part B, and 
Part C) 
• Serum PK of VIR-7831  

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Objectives 
Endpoints 
To assess the pharmacokinetics (PK) of 
VIR-7831 Gen2 IV and IM and Gen1 IV in 
serum 
Exploratory 
 
Resistance (Part A, Part B, and Part C) 
To monitor the presence at Baseline and 
the emergence of SARS-CoV-2 resistant 
mutants against VIR-7831 
• Presence at Baseline and emergence of SARS-
CoV-2 viral resistance mutants   
Immunogenicity (Part A, Part B , and 
Part C) 
To assess the immunogenicity of VIR-
7831 Gen2 IV and IM and Gen1 IV 
• Incidence and titers (if applicable) of serum 
anti-drug antibodies (ADA) to VIR-7831  
Immunology (Part A, Part B and 
Part C) 
To assess the effect of VIR-7831 Gen2 IV 
and IM and Gen1 IV on immune 
response 
• Incidence and titers (if applicable) of anti-
nucleocapsid (anti-N), anti-spike (anti-S) and 
anti-receptor binding domain (anti-RBD) SARS-
CoV-2 antibodies at baseline  
• Incidence and titers (if applicable) of anti-N 
SARS-CoV-2 antibodies at Day 29 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study is a randomized, multi-center, parallel group phase II trial of VIR-7831, a 
monoclonal antibody (mAb) against SARS-CoV-2 for the prevention of progression of 
mild to moderate COVID-19 in non-hospitalized patients. This study will be conducted in 
three Parts (Parts A, B, and C). 
Part A:  
Participants with early mild to moderate COVID-19 will be randomized 3:1 to receive a 
single, 500 mg intravenous infusion of either Gen2 or Gen1 study material. Safety, 
tolerability, virology, immunogenicity, and PK will be evaluated. Part A is double-
blinded. 
• Screening assessments will be performed within 1 day before the start of infusion. 
Eligible participants will be treated in a blinded manner with a single IV dose on 
Day 1 and followed up to 36 weeks. Participants will be monitored for 

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approximately 9 hours on Day 1 for safety assessments and intensive PK 
sampling.  
Part B:  
Participants with early mild to moderate COVID-19 will be randomized 1:1 to receive a 
500 mg dose of Gen2 study material by IV infusion or IM injection. In Part B, viral load 
pharmacodynamics (PD) as assessed via upper respiratory samples, safety, tolerability, 
immunogenicity, and PK will be evaluated. Part B is open-label. Part B will include a 
Lead-in phase with frequent assessments for injection site reactions (ISRs) and safety, 
along with intensive PK sampling. 
Screening assessments will be performed within 1 day before the start of infusion or IM 
injection. Lead-in phase safety data (e.g., ISRs) through Day 3 for 20 participants 
(10 receiving IV Gen2 and 10 receiving IM Gen2) will be reviewed in an unblinded 
manner by the JSRT. In the Lead-in phase, participants will be monitored for a period of 
2 hours post-injection or post-infusion for ISRs and IRRs. Once participants for the Lead-
in phase (n=20) have been recruited, new participants will be enrolled into the Expansion 
phase. However, the post-dose monitoring period for the Expansion phase will remain at 
2 hours until a recommendation to shorten monitoring to 1 hour is issued by the JSRT, 
based on a review of unblinded aggregate safety data through Day 3 of the Lead-in phase, 
including ISRs and IRRs. 
A JSRT review on 13 May 2021 identified no serious safety concerns on review of 
66 participants enrolled in Part B (all of the Lead-in participants and some Expansion 
phase participants). Based on this safety review, the JSRT agreed with the proposal to 
reduce the post-dose monitoring time on Day 1 from 2 hours to 1 hour for Part B of the 
study. 
Part C:  
Participants with early mild to moderate COVID-19 will be randomized 1:1 to receive a 
500 mg dose of Gen2 study material by IV infusion or a 250 mg dose of Gen2 study 
material by IM injection. Participants will be stratified by prior exposure to an authorized 
or approved SARS-CoV-2 vaccine. Prior exposure includes any of the following 
scenarios: one dose of a one-dose series; first dose of a two-dose series; or second dose of 
a two-dose series. 
In Part C, viral load PD as assessed via upper respiratory samples, safety, tolerability, 
immunogenicity, and PK will be evaluated. Part C is open label. Part C will include a 
Lead-in phase with assessments for safety to inform the JSRT review of data through 
Day 3 and subsequent decision on whether the Day 1 monitoring time can be decreased 
(from 1 hour to 30 minutes), along with intensive PK sampling. 
Screening assessments will be performed within 1 day before the start of infusion or IM 
injection. Lead-in phase safety data (e.g., ISRs) through Day 3 for 20 participants 
(10 receiving 500 mg IV Gen2 and 10 receiving 250 mg IM Gen2) will be reviewed in an 
unblinded manner by the JSRT. In the Lead-in phase, participants will be monitored for a 
period of 1 hour post-injection or post-infusion for ISRs and IRRs. Once participants for 
the Lead-in phase (n=20) have been recruited, new participants will be enrolled into the 
Expansion phase. However, the post-dose monitoring period for the Expansion phase will 

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remain at 1 hour until a recommendation to shorten monitoring to 30 minutes is issued by 
the JSRT, based on a review of unblinded aggregate safety data through Day 3 of the 
Lead-in phase, including ISRs and IRRs. 
4.2. 
Scientific Rationale for Study Design 
Vir has completed analytical comparability testing for the changes from the WuXi 2k 
Gen1 DS and DP to the WuXi 2k Gen2 DS and DP. A high degree of analytical and 
bioanalytical comparability has been demonstrated between Gen1 and Gen2, supporting 
the use of Gen2 in clinical trials. While a dedicated clinical comparability study is not 
planned, because Gen2 will be the commercial product, Vir proposes to gain clinical 
experience with Gen2 material across multiple clinical studies, including in non-
hospitalized patients with mild to moderate COVID-19. The study will include non-
hospitalized patients with mild to moderate SARS-CoV-2 infection as confirmed by local 
laboratory tests and/or point of care tests. A single dose level of Gen1 or Gen2 material 
designed to provide potential therapeutic benefit will be studied and will be delivered via 
IV infusion (Gen1 and Gen2) or IM injection (Gen2). Participants will receive the 
infusion or IM injection in a clinic/study unit where they will be monitored closely for 
adverse events in the post-infusion or post-injection period. 
Subsequent visits for study activities and clinical monitoring will be conducted via home 
nursing (Part B and Part C only) or clinic visits (except for Week 16 for Part A; Weeks 6 
and 16 for the Part B and Part C Lead-in phases; and Weeks 6, 8, 16, and 36 for the Part 
B and Part C Expansion phases, which will be conducted via phone call). A double-blind 
design as implemented for Part A is a standard methodology for randomized, controlled 
studies to minimize bias. A Gen1 study arm is included to maintain blinding of Gen1 
versus Gen2 VIR-7831 study material receipt during the conduct of the study. This 
blinding will minimize bias that may occur during study assessments, including during 
evaluation of AEs and disease-related safety outcomes. Given that there has been 
substantial previous Gen1 clinical experience in COMET-ICE, a randomization ratio of 
3:1 for Gen2 to Gen1 was selected to increase the number of participants that will receive 
Gen2 study material. There is no placebo in this study because the primary aim is to 
evaluate safety and tolerability of Gen2 material. 
Parts B and C of the study will be open-label, as administering placebo IV infusion to 
participants receiving Gen2 IM injection or placebo IM injection to participants receiving 
Gen2 IV infusion would unduly impose excess risk from requiring an additional mode of 
delivery of placebo. In addition, it may be difficult to appropriately attribute an AE or 
SAE that occurs during study drug administration to VIR-7831 or placebo if participants 
receive both active and placebo agents at the same visit. Given the open-label design, 
investigators, site study staff, and participants will not be blinded. The central study team 
and the JSRT will also be unblinded as some adverse events of special interest (AESIs) 
are specific to route of administration, i.e., injection site reactions for IM administration 
and infusion-related reactions for IV administration, and maintaining blinding in this 
circumstance would be very difficult. Differences in study assessments (e.g., timing) for 
IM versus IV administration, and other logistical considerations, also support the central 
team and JSRT remaining unblinded. The objective nature of the primary endpoint 
(virologic PD) further supports the central team and JSRT remaining unblinded. 

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Blinded safety data will be reviewed regularly by the JSRT through Week 36 for Part A 
of the study. For Parts B and Part C of the study, the JSRT will be unblinded, and data 
will be reviewed through Week 36 according to the Treatment-Sensitive Data Plan for 
Open-Label Randomized Study. There will be no routine in-stream review of aggregated 
safety data by treatment arm at any JSRT meeting other than at the two post-Day 3 JSRT 
meetings (one for Part B and one for Part C) that will determine if the monitoring time 
may be reduced. Additionally, any sharing of potential safety signals will reflect pooled 
data that is not separated by treatment arm. The Safety team may need to review single 
unblinded case reports to support regulatory reporting obligations. All participants will 
receive standard of care for COVID-19 disease during this study, including admission to 
a hospital if deemed necessary by the responsible investigator. 
4.3. 
Justification for Dose 
The single 500 mg IV dose of VIR-7831 to be evaluated in Parts A, B and C was selected 
based on extensive nonclinical data and expected human PK extrapolated from 
cynomolgus monkeys. This IV dose is currently being evaluated in ongoing clinical trials 
COMET-ICE (NCT04545060), ACTIV-3-TICO (NCT04501978) and BLAZE-4 
(NCT04634409), with approximately 1550 participants randomized to either VIR-7831 
(500 mg dose) or placebo to date. 
The IM doses to be evaluated in Part B (500 mg IM) and Part C (250 mg IM) of this 
study were selected based on in vitro neutralization data, in vitro resistance data, and 
simulated IM PK based on preliminary IV PK from the 500 mg dose being evaluated in 
ongoing clinical studies (COMET-ICE, ACTIV-3-TICO, BLAZE-4). VIR-7831 
neutralized SARS-CoV-2 live virus with an average 90% effective concentration (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, 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, E340A was identified as a monoclonal antibody-resistant mutant (MARM) 
conferring a >100-fold reduction in susceptibility to VIR-7831. Notably, E340 is 99.9% 
conserved among available SARS-CoV-2 sequences. Due to the binary nature of the 
resistance selection results, a specific inhibitory quotient was not informed by the 
resistance profiling. 
Based on preliminary IV PK data from the Lead-in phase of an ongoing clinical study 
evaluating VIR-7831 in the early treatment of COVID-19 (COMET-
ICE; NCT04545060), the mean Day 29 serum concentration of VIR-7831 following a 
single 500 mg IV dose is 37.2 µg/mL (N=9). Based on the PK data available to date, 
>20% of the AUC is being extrapolated so final CL, V, AUC and t1/2 have not been 
determined; however, a preliminary estimate of the median half-life of VIR-7831 is 
approximately 47 days. 
Intramuscular doses of 250 mg and 500 mg were selected to ensure that the VIR-7831 
concentrations in lung are maintained at or above levels anticipated to be neutralizing for 
the duration of the treatment window. 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 

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(assumed conservative value of 0.25; reported range 0.25 to 0.68 for whole lung and 
interstitial fluid, respectively; Baxter, 1994, Covell, 1986, Datta-Mannan, 2019, Lobo, 
2004), and assuming 70% bioavailability following intramuscular administration, 
IM doses of 250 mg and 500 mg are expected to maintain serum levels at or above 5x and 
10x lung tissue adjusted EC90 through the Day 29 primary endpoint, respectively.  
Prior clinical experience with a 500 mg IV dose of VIR-7831 has been gained in the 
setting of the early treatment of COVID-19 (COMET-ICE and BLAZE-4) and 
hospitalized treatment in ACTIV-3-TICO. In the COMET-ICE study, there have been no 
significant safety concerns identified at the IDMC reviews conducted to date. 
Furthermore, an interim analysis of data from 583 high-risk patients demonstrated an 
85% (p=0.002) reduction in hospitalization or death in patients receiving VIR-7831 
compared to placebo [Vir Biotechnology, 2021]. In ACTIV-3-TICO, one case of 
anaphylaxis was reported during infusion of VIR-7831 which resolved with treatment. In 
the BLAZE-4 study, there have been no safety concerns identified as of 17 March 2021. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
phases of the respective Part of the study to which he/she was enrolled (Part A, Part B, or 
Part C) through to Week 36 follow up. The end of the study is defined as the date of the 
last contact of the last participant in the study. 
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: 
Age 
1. Part A: Participant must be aged 18 years or older at the time of obtaining 
informed consent. 
Part B and C: Participant must be aged 18 years to <70 years at the time of 
obtaining informed consent. The additional age restriction of <70 years for Part B 
and C is for logistical purposes such that this study and the COMET-TAIL study 
(a study administering VIR-7831 via IM injection for which planning is currently 
ongoing), which are enrolling similar populations (non-hospitalized patients with 
mild to moderate COVID-19), can utilize many of the same sites for participant 
enrollment. The COMET-TAIL study, which requires that a participant is at high 
risk for progression to severe disease and/or 55 years of age, will be enriching 
enrollment for participants 70 years of age or older. 
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Type of Participant and Disease Characteristics 
2. Participants who have a positive SARS-CoV-2 test result (by any validated test 
e.g. RT-PCR on any respiratory type) 7 days prior to enrollment  
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 
7 days from onset of symptoms 
Sex and Contraceptive/Barrier Requirements 
3. No gender restrictions 
4. 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. 
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 36 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 8.4.7 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. 

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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. 
Informed Consent 
5. Capable of giving signed informed consent as described in Section 10.1.3 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. 
Other Inclusion Criteria 
6. For South Korea only: Age 19 years of age at the time of obtaining informed 
consent. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Currently hospitalized or judged by the investigator as likely to require 
hospitalization in the next 24 hours. 
Note: For Participants at Sites in South Korea refer to Exclusion Criteria 16. 
2. Symptoms consistent with severe COVID-19 as defined by shortness of breath at 
rest or respiratory distress or requiring supplemental oxygen.  
3. Participants who, in the judgement of the investigator are likely to die in the next 
7 days. 
4. Severely immunocompromised participants including but not limited to cancer 
patients receiving immunosuppressive chemotherapy or immunotherapy, those 
with a solid organ transplant or allogeneic stem cell transplant within the last 
3 months, any history of heart or lung transplant or high dose long-term systemic 
corticosteroids (equivalent to 20 mg a day of prednisone or the systemic 
equivalent for over 2 weeks). 
5. Known hypersensitivity to any constituent present in the investigational product. 
6. Previous anaphylaxis or hypersensitivity to a monoclonal antibody. 
7. For Part B and Part C of the study – Participant has any condition that would 
prohibit receipt of intramuscular injections in the investigator’s opinion, such as 
coagulation disorder, bleeding diathesis, or thrombocytopenia. 

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Prior/ Concurrent Clinical Study Experience 
8. 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.  
9. Enrollment in any trial of an investigational vaccine for SARS-CoV-2. 
Other Exclusions 
10.  The following exclusions related to vaccination are applicable:  
a. Part A and Part B only: Prior receipt of a SARS-CoV-2 vaccine at any 
time. Vaccination with an authorized or approved SARS-CoV-2 vaccine 
will not be allowed for 90 days after dosing. 
NOTE FOR PART C: Previous receipt of an authorized or approved 
SARS-CoV-2 vaccine is NOT an exclusion criteria. 
b.  Part A, Part B, and Part C: Receipt of any vaccine within 48 hours prior to 
enrollment. Vaccination will not be allowed for 90 days after dosing.  
11. Receipt of convalescent plasma from a recovered COVID-19 patient or anti-
SARS-CoV-2 mAb within the last 3 months. 
12. Participants who, in the judgment of the investigator, will be unlikely or unable to 
comply with the requirements of the protocol through Day 29. 
13. For Germany only: Participants of legal age who are incapable of comprehending 
the nature, significance and implications of the clinical trial according to §41 
paragraph 3 no. 3, according to German Medicinal Products Act (AMG). 
14. For Germany only: Participants who have been committed to an institution by 
virtue of an order issued either by the judicial or the administrative authorities, 
according to §40 paragraph 1 sentence 3 no. 4, German Medicinal Products Act 
(AMG). 
15. For Germany only: Participants must not be in a dependent relationship with the 
site, investigator or sponsor, according to §40 paragraph 1 sentence 3 no. 3 letter 
b) and c), German Medicinal Products Act (AMG). 
16. For South Korea only: Patients with mild to moderate COVID-19 who are 
hospitalized purely for public health/quarantine purposes in South Korea are not 
excluded. 
5.3. 
Lifestyle Considerations 
Lifestyle considerations are not applicable to this study. 

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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 
SAEs. Re-screening will be permitted once for each subject during study conduct. 
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 
Table 5 
Overview of Study Intervention  
ARM Name 
VIR-7831 Gen1 
IV (Part A only) 
VIR-7831 Gen2 
IV (Parts A, B, 
and C) 
VIR-7831 Gen2 
IM (Part B only) 
VIR-7831 Gen2 
IM (Part C only) 
Intervention 
Name 
VIR-7831 Gen1 
VIR-7831 Gen2 
VIR-7831 Gen2 
VIR-7831 Gen2 
Type  
Biologic 
Biologic 
Biologic 
Biologic 
Dose 
Formulation  
Solution in single 
use vial 
(25 mg/mL) 
Solution in single 
use vial 
(62.5 mg/mL) 
Solution in single 
use vial 
(62.5 mg/mL) 
Solution in single 
use vial 
(62.5 mg/mL) 
Unit Dose 
Strength(s)  
250 mg 
Dilution will be 
with normal 
saline to achieve 
equal volume for 
administration 
500 mg 
Dilution will be 
with normal 
saline to achieve 
equal volume for 
administration 
500 mg 
500 mg 
Dosage Level(s) 500 mg 
500 mg 
500 mg 
250 mg 
Route of 
Administration 
IV infusion 
IV infusion 
IM injection 
IM injection 

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ARM Name 
VIR-7831 Gen1 
IV (Part A only) 
VIR-7831 Gen2 
IV (Parts A, B, 
and C) 
VIR-7831 Gen2 
IM (Part B only) 
VIR-7831 Gen2 
IM (Part C only) 
Duration of 
Infusion 
1 hour 
Part A: 1 hour  
Parts B and C: 
15 minutes 
Not applicable 
Not applicable 
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
VIR-7831 Gen1 
will be provided 
centrally by the 
sponsor/ 
designee  
VIR-7831 Gen2 
will be provided 
centrally by the 
sponsor/ 
designee 
VIR-7831 Gen2 
will be provided 
centrally by the 
sponsor/ 
designee 
VIR-7831 Gen2 
will be provided 
centrally by the 
sponsor/ 
designee 
Packaging and 
Labeling 
VIR-7831 Gen1 
study 
intervention will 
be provided in a 
single-use vial 
and labeled as 
required per 
country 
requirement. 
VIR-7831 Gen2 
study 
intervention will 
be provided in a 
single-use vial 
and labeled as 
required per 
country 
requirement. 
VIR-7831 Gen2 
study 
intervention will 
be provided in a 
single-use vial 
and labeled as 
required per 
country 
requirement. 
VIR-7831 Gen2 
study 
intervention will 
be provided in a 
single-use vial 
and labeled as 
required per 
country 
requirement. 
Current/Former 
Name(s) or 
Alias(es) 
VIR-7831, 
GSK4182136, 
sotrovimab 
Gen1 
VIR-7831, 
GSK4182136, 
sotrovimab 
Gen2 
VIR-7831, 
GSK4182136, 
sotrovimab 
Gen2 
VIR-7831, 
GSK4182136, 
sotrovimab 
Gen2 
 
In Part A of the study, IV infusion of Gen1 and Gen2 VIR-7831 study material will be 
administered over a 1-hour period. The COMET-ICE and ACTIV-3-TICO studies 
administered Gen1 VIR-7831 over a 1-hour period. However, in Part B and C of the 
study, IV infusion of Gen2 VIR-7831 study material will be administered over 
15 minutes, in part to reflect what is expected for the commercial product infusion time. 
Previous experience for a shorter time of infusion has been gained from the BLAZE-4 
study, where no serious infusion-related reactions were noted with a 30-minute infusion 
time.  
In Part B of the study, the 500 mg IM injection will be performed as two 4 mL injections, 
one in each dorsogluteal muscle.  
In Part C of the study, the 250 mg IM dose will be given either as a single 250 mg (4 mL) 
injection in the dorsogluteal muscle or as two 2 mL injections, one in each deltoid 
muscle.  

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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 must receive study intervention and only 
authorized site staff must 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. 
Part A:  
Participants will be randomized in a 3:1 ratio to receive an IV infusion of VIR-7831 
Gen2 or Gen1 material. In Part A of the study, 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. 
For Part A of the study, 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 
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date and reason that the blind was broken must be recorded in the source documentation 
and case report form, as applicable. 
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. 
Part B: 
Participants will be randomized in a 1:1 ratio to receive VIR-7831 Gen2 material by IV 
infusion or IM injection. As noted in Section 4.2, Part B will be open-label; therefore, no 
blinding is required. 
Part C: 
Participants will be randomized in a 1:1 ratio to receive a VIR-7831 Gen2 500 mg IV 
infusion or 250 mg IM injection. As noted in Section 4.2, Part C will be open-label; 
therefore, no blinding is required. 
Participants will be stratified based on their prior exposure to an approved or authorized 
SARS-CoV-2 vaccine. 
6.4. 
Study Intervention Compliance 
Participants will receive VIR-7831 Gen1 or Gen2 directly from the investigator or 
designee, under medical supervision. The date and start and stop times of the IV dose and 
the date and administration time of the IM dose 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 
Since this is a single dose study, dose modifications are not applicable. See Section 7.1 
for instructions to discontinue study treatment for safety reasons.  

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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 treating 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 AEs/SAEs and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdosing in 
the case report form (CRF). 
6.8. 
Concomitant Therapy 
Any vaccine or medication (including over-the-counter or prescription medicines, 
recreational drugs, vitamins, and/or herbal supplements) that the participant is receiving 
at the time of enrolment or receives during the study must be recorded in the electronic 
case report form (eCRF), along with: 
• reason for use 
• 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 with the 
exception of patients with rheumatoid arthritis or systemic lupus erythematosus who are 
on hydroxychloroquine as a maintenance medication. 
Receipt of convalescent plasma from a recovered COVID-19 patient, anti-SARS-CoV-2 
mAb, or intravenous immunoglobulin (IVIG) is also not permitted during the study. 
Receipt of any vaccine is not permitted within 90 days after dosing. Receipt of any 
investigational (not authorized or approved) SARS-CoV-2 vaccine is not permitted 
during the study.  

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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. 
Receipt of any authorized or approved SARS-CoV-2 vaccine is permitted following 
90 days post-dosing for participants in any Part of the study (Part A, B, or C).  
For participants in Part C of the study who have not received a SARS-CoV-2 vaccine 
prior to enrollment, receipt of the first dose of approved SARS-CoV-2 vaccine is 
permitted following 90 days post-dosing. For those participants who entered Part C of the 
study following receipt of the first dose of a two-dose vaccine series, the second dose will 
also be permitted following 90 days post-dosing. Participants 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. 
Any concerns regarding the acceptability of potential treatments should be discussed with 
the medical monitor(s). 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
For IV administration, a participant will be permanently discontinued from completion of 
drug infusion if they experience a Grade 3 or 4 IRR (for example, life-threatening, 
infusion-related reactions including severe allergic or hypersensitivity reactions or severe 
cytokine release syndrome). 
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 
For IV administration, 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. antihistamines, 
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 legally authorized representative (LAR) 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. 

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• 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. 
Refer to Section 10.7.1 for additional Germany-specific information regarding participant 
discontinuation or withdrawal from the study. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to adhere to 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to complete a follow-up 
assessment. 
• 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 
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. 
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).  

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• As most of the follow-up visits include blood collections as noted in the Schedule 
of Activities, these follow-up assessments may be performed as a home nursing 
visit (Part B and C) or at the clinic. The Week 16 and Week 36 follow-up visits 
will be conducted via a site phone call for Part A. For the Part B and Part C Lead-
in phases, the Week 6, Week 16, and Week 36 follow-up visits will be conducted 
via a site phone call. For the Part B and Part C Expansion phases, the Week 6, 
Week 8, Week 16, and Week 36 follow-up visits will be conducted via a site 
phone call. Site phone calls may be replaced with a home nursing visit (Part B or 
Part C) or a clinic visit at the discretion of the investigator. 
• 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 the informed consent form 
(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 

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auditors, as required) assigned to a given site can view the Source 
Documents remotely. 
8.1. 
Efficacy 
Not Applicable. 
8.2. 
Screening Period 
Informed consent must be obtained before conducting any study procedures. Screening 
will be performed within 1 day prior to dosing and include the assessments outlined in 
the Schedule of Activities (Section 1.3).  
The Screening visit and the Day 1 visit may occur on the same day. 
8.2.1. 
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.  
COVID-19 disease history, including date of onset and signs and symptoms of COVID-
19 as detailed in the eCRF will be collected. 
8.2.2. 
Physical Examinations 
A complete physical examination will be performed at Screening and on Day 1. The 
physical exam only needs to be performed once if Screening and dosing occur on the 
same day. 
• 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. 
8.2.3. 
SARS-CoV-2 Diagnostic Testing 
Documentation of laboratory-confirmed SARS-CoV-2 infection via a validated molecular 
diagnostic test (e.g. RT-PCR) 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).  

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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 7 days.  
8.2.4. 
Secondary Contact Information 
In order to minimize the potential for missing data related to the safety assessments 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. 
8.3. 
Virologic Assessments 
Part A:  
Saliva samples and nasal (mid-turbinate) swabs from participants will be collected for 
qRT-PCR for virologic assessments at timepoints noted in the Schedule of Activities 
(Days 1, 2, 5, 8, 11, 15, 22, and 29) (Section 1.3). 
For the purpose of resistance surveillance analysis, next generation sequencing analysis 
of the spike protein of SARS-CoV-2 will be performed on all Day 1 (baseline) mid-
turbinate swabs and at the last timepoint with virus above the limit for the sequencing 
assay for all participants up to Day 8 and an additional timepoint will be sequenced up to 
Day 29 if still above the limit for the sequencing assay. Other time points may also be 
subjected to sequence analysis as needed. Susceptibility of suspected resistant variants 
will be analyzed in a pseudo-virus phenotype assay. 
A blood sample for anti-SARS-CoV-2 antibody testing will also be collected on Day 1 
pre-dose to allow for exploratory sub-analysis of the virologic endpoints stratified based 
on antibody response at baseline. A post-baseline blood sample at Day 29 will also be 
collected to investigate the effect of VIR-7831 on the development of anti-N SARS-CoV-
2 antibody. 
Part B and Part C: 
Nasopharyngeal (NP) swabs from participants will be collected for qRT-PCR for 
virologic assessments at timepoints noted in the Schedule of Activities (Days 1, 2, 3, 5, 8, 
11, 15, 22, and 29) (Section 1.3). 
For the purpose of resistance surveillance analysis, next generation sequencing analysis 
of the spike protein of SARS-CoV-2 will be performed on all Day 1 (baseline) NP swabs 
and at the last timepoint with virus above the limit for the sequencing assay for all 
participants. Other time points may also be subjected to sequence analysis as needed. 

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Susceptibility of suspected resistant variants will be analyzed in a pseudo-virus 
phenotype assay. 
For the secondary endpoint of “Proportion of individuals with a persistently high viral 
load at Day 8 as assessed via qRT-PCR in nasopharyngeal swab samples”, a persistently 
high viral load will be defined using data from the COMET-ICE study. Viral load data 
from the COMET-ICE study will be examined and a value and time period for the 
persistently high viral load will be determined. 
A blood sample for anti-SARS-CoV-2 antibody testing will also be collected on Day 1 
pre-dose to allow for exploratory sub-analysis of the virologic endpoints stratified based 
on antibody response at baseline. A post-baseline blood sample at Day 29 will also be 
collected to investigate the effect of VIR-7831 on the development of anti-N SARS-CoV-
2 antibody. 
8.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).  
Part A:  
While the primary safety endpoint is through Day 29, given that this is when the majority 
of AEs/AESIs (e.g., IRRs) would be expected to occur, safety assessments will continue 
through Week 36.  
Part B and Part C:  
Secondary safety endpoints will be through Day 29 and End of Study (Week 36).  
8.4.1. 
Vital Signs 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(see Section 1.3). 
Part A:  
Vital signs will be monitored within 1 hour prior to and every 15 minutes over the 1 hour 
IV infusion. Vital signs will also be monitored at approximately 1, 2, 6, and 8 hours after 
infusion. 
Part B:  
Vital signs will be monitored within 1 hour prior to administration of study intervention 
(IM injection or the 15 minute IV infusion). For the Lead-in phase, vital signs will be 
monitored at end of infusion (IV infusion only) and approximately 30 minutes, 1 hour, 
and 2 hours after administration of study intervention (infusion or IM injection). For the 
Expansion phase after the JSRT recommendation that was received on 13 May 2021 to 
reduce monitoring time, vital signs will be monitored at the end of infusion (IV infusion 

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only) and approximately 30 minutes and 1 hour after administration of study intervention 
(infusion or IM injection).  
Part C: 
Vital signs will be monitored within 1 hour prior to administration of study intervention 
(IM injection or the 15 minute IV infusion). For the Lead-in phase, vital signs will be 
monitored at end of infusion (IV infusion only) and at approximately 30 minutes and 
1 hour after administration of study intervention (infusion or IM injection). For the 
Expansion phase, pending JSRT recommendation to reduce monitoring time, vital signs 
will be monitored at the end of infusion (IV infusion only) and approximately 30 minutes 
after administration of study intervention (infusion or IM injection). 
8.4.2. 
Electrocardiograms 
For Parts A, B, and C of the study, electrocardiograms will be performed locally as 
outlined in the Schedule of Activities (see Section 1.3). The review of the ECG printed at 
the time of collection must be documented. Any new clinically relevant finding on ECGs 
should be reported as an AE. 
Twelve-lead ECGs will be obtained at each planned ECG assessment during the study 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTcF intervals.  
Before each ECG test, the participant should be at rest for approximately 10 minutes. The 
participant should be in the semi-recumbent or supine position; the same position must be 
used for all subsequent ECG tests. 
At Screening, a single 12-lead ECG is required.  
On the day of administration of study intervention, a 12-lead triplicate ECG will be 
performed before the infusion or injection and within 30 minutes post-injection or the end 
of infusion:   
• Twelve-lead ECGs will be performed with the participant in a semi-supine 
position after being at rest for at least 10 minutes.  
• At each time point at which triplicate ECGs are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession but no more than 
2 minutes apart. The full set of triplicates should be completed over a brief (e.g., 
5 to 10 minutes) recording period. 
If Screening occurs on the same day as the infusion, only the 12-lead triplicate ECGs 
need to be performed.  
At all other time points a single 12-lead ECG will be performed.  
Triplicate 12-lead ECGs should be performed as clinically indicated throughout the 
study, if an ECG abnormality is detected post baseline.  

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8.4.3. 
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 myocardial infarction 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. 
8.4.4. 
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 safety endpoints. Data from the hospitalization and/or 
death should be captured in the EDC system including but not limited to: 
1. Serious Adverse Event (SAE) form 
2. Dates that the participant is hospitalized and discharged 
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 
8.4.5. 
Active Monitoring of COVID-19 Progression  
Following study intervention administration, study participants will be followed up as 
noted in the Schedule of Activities (Section 1.3) via home nursing (Part B and Part C 
only) or clinic visits for all visits except Week 16 and Week 36 for Part A; Week 6, Week 
16, and Week 36 for the Part B and Part C Lead-in phases; and Week 6, Week 8,  Week 
16, and Week 36 for the Part B and Part C Expansion phases; which will be conducted 
via site phone calls. During these assessments, participants will be monitored 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 home nurse 
and/or site will direct the participant to seek medical attention. In addition, any healthcare 
encounters or new concomitant medications will be recorded. 
Participants will also be monitored during these visits/phone calls for subsequent 
COVID-19 illness (potential re-infection) after Day 29. These assessments will determine 
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. 
8.4.6. 
Clinical Safety Laboratory Assessments 
• See Section 10.2 for the list of clinical laboratory tests to be performed and the 
Schedule of Activities (Section 1.3) for the timing and frequency.  
• Laboratory assessments for safety purposes will be performed as noted in the 
Schedule of Activities (Section 1.3). 

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• To ensure timely safety management of the participants, laboratory assessments 
will be performed more frequently during Week 1 as outlined in the Schedule of 
Activities. 
• Urine will be collected on Day 1 (pre-dose) and Day 2 for analysis of albumin to 
creatinine ratio.  
• All protocol-required laboratory tests performed, 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 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 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), then the results 
must be recorded. 
8.4.7. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at Screening to confirm eligibility and at Week 24 or the 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. 
8.4.8. 
Local Injection Site Tolerability 
For IM injections in Part B and Part C of the study, a local injection site tolerability 
assessment will be performed per the Schedule of Activities (Section 1.3). Injection sites 
should be monitored for pain/tenderness, swelling, redness, bruising, and pruritus. A local 
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At the discretion of the investigator, unscheduled visits are permitted as needed for 
follow up of any unresolved local injection site tolerability symptoms. Management 
guidelines for these symptoms are provided in Section 10.6. 
Part B: 
For the Part B Lead-in phase, the injection sites will be marked and mapped for later 
observation and should be documented. The tolerability assessment will be performed 
approximately 1 hour and 2 hours following study drug administration and at 
Days 2 and 3 per the Schedule of Activities (Section 1.3).  
For the Part B Expansion phase after the JSRT recommendation that was received on 
13 May 2021 to reduce the monitoring time for Part B, a local injection site tolerability 
assessment will be performed approximately 1 hour after injection. Any ISRs will need to 
be followed by the principal investigator (PI) for resolution. If the participant had a 
severe ISR on Day 1, the participant should be assessed on Day 2 or Day 3 by the 
investigator. 
Part C: 
For the Part C Lead-in phase, the injection sites will be marked and mapped for later 
observation and should be documented. The tolerability assessment will be performed 
approximately 1 hour following study drug administration and at Days 2 and 3 per the 
Schedule of Activities (Section 1.3).  
For the Part C Expansion phase, a local injection site tolerability assessment will be 
performed approximately 30 minutes after injection, pending JSRT recommendation to 
reduce monitoring time. Any ISRs will need to be followed by the PI for resolution. If the 
participant had a severe ISR on Day 1, the participant should be assessed on Day 2 or 
Day 3 by the investigator. 
8.5. 
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). 
Hospitalization will be collected and reported as SAEs as delineated in Section 8.5.1 
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 counted as SAEs with the exception of hospitalization for: 

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• elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE as noted in Section 10.3, or 
• adverse events related to expected progression, signs, or symptoms of COVID-19 
as noted in Section 8.5.8. 
All deaths, regardless of cause, will be reported and collected as SAEs. 
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 8.4.4 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. 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All AEs will be collected through Week 12 post-dose. SAEs and AESIs will be 
collected from dose administration through the Week 36 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 the 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. 
8.5.2. 
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.  

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8.5.3. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  
8.5.4. 
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 8.5.9), 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. 
8.5.5. 
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. 
8.5.6. 
Pregnancy 
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until Week 36 or the Early Withdrawal visit. 
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. The 
investigator will collect follow-up information on the participant and the neonate/child 
for 8 weeks after the birth 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 8.5.1. 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. 
8.5.7. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3.3 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 Medical 
Dictionary for Regulatory Activities (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. 
8.5.8. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs  
Adverse events related to expected progression, signs, or symptoms of COVID-19, unless 
more severe than expected for the participant’s current clinical status and medical history, 
should not be reported as an AE or SAE. These should be collected as disease-related 
events in the specific eCRF and through Week 36 (EOS). 
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the clinical course of the disease and/or the patient’s clinical 
status, or if the investigator considers that there was a causal relationship between 
treatment with study treatment(s) or protocol design/procedures and the disease 
progression, then this must be reported as an AE or SAE. 
For example, the following constitute events NOT meeting the AE definition and that 
should be collected as disease-related events:  
• hypoxemia due to COVID-19 requiring supplemental oxygen 

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• hypoxemia due to COVID-19 requiring non-invasive ventilation or high flow 
oxygen devices 
• respiratory failure due to COVID-19 requiring invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO) 
NOTE: If either of the following conditions apply, then the event must be recorded and 
reported as an AE or SAE (instead of a disease-related event): 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the natural history of the disease, or 
• 
The investigator considers that there is a reasonable possibility that the event 
was related to treatment with study treatment(s). 
Any death should be recorded and reported as an SAE, and not as a disease-related event. 
8.5.9. 
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 
• Injection site reactions (ISRs) 
• Immunogenicity related adverse drug reactions 
• Adverse events potentially related to antibody-dependent enhancement of disease 
8.5.9.1. 
Infusion-Related Reactions and Serious Hypersensitivity 
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. Investigators will be 
provided with general guidance on management of serious 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. 
8.5.9.2. 
Injection Site Reactions  
Part B: 
Any ISRs occurring within 2 hours in the Part B Lead-in phase or the Expansion phase 
prior to JSRT recommendation to reduce the monitoring time, or within 1 hour post-dose 

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in the Expansion phase after the JSRT recommendation to reduce the monitoring time 
(received on 13 May 2021), will be considered as solicited AEs and will be reported as 
clinical events. ISRs occurring after 2 hours post-dose in the Lead-in phase or the 
Expansion phase prior to JSRT recommendation to reduce the monitoring time, or after 1 
hour post-dose in the Expansion phase after the JSRT recommendation to reduce the 
monitoring time (received on 13 May 2021), will be considered as unsolicited AEs and 
will be reported as described in Section 10.3.1. 
Part C:  
Any ISRs occurring within 1 hour in the Part C Lead-in phase or the Expansion phase 
prior to JSRT recommendation to reduce the monitoring time, or within 30 minutes post-
dose in the Expansion phase after the JSRT recommendation to reduce the monitoring 
time, will be considered as solicited AEs and will be reported as clinical events. ISRs 
occurring after 1 hour post-dose in the Lead-in phase or the Expansion phase prior to 
JSRT recommendation to reduce the monitoring time, or after 30 minutes post-dose in the 
Expansion phase after the JSRT recommendation to reduce the monitoring time, will be 
considered as unsolicited AEs and will be reported as described in Section 10.3.1. 
 
8.5.9.3. 
Immunogenicity 
Therapeutic proteins, including mAbs, have the potential to induce an unwanted immune 
response (immunogenicity) in humans. 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 24 weeks to assess for the development of ADA and potential impacts on 
safety, PK and/or efficacy. 
8.5.9.4. 
Antibody-Dependent Enhancement 
ADE of disease theoretically can occur via one of three previously described 
mechanisms: 
• By facilitating viral entry into host cells and enhancing viral replication in these 
cells; 
• By increasing viral fusion with target host cells, enhancing viral replication in 
these cells; 
• 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 
36 Weeks 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 

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viral replication. This may manifest as acute deterioration in clinical status temporally 
associated with VIR-7831 infusion or as increased severity or duration of illness in VIR-
7831-treated participants compared to what would be clinically expected. 
As described in Section 2.3.1, AEs potentially related to ADE of the disease will be 
reviewed by the JSRT to assess if there is a greater than expected incidence of re-
infection or disease severity. 
8.6. 
Pharmacokinetics 
Blood samples for serum PK will be collected from predose Day 1 to Day 169 as detailed 
in the Schedule of Activities (Section 1.3) and Table 6. 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 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. 
• 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. 
Table 6 
Timeline of Sample Collection for Pharmacokinetic Analysis 
 
 
W1 
W2 
W3 W4 W6 W8 W12 W16 W20 W24 
Study Part 
Screening 
(Day 0/1) 
Day 1 
Day 2 
Day 3 
Day 5 
Day 8 
Day 11 
Day 15 ± 1d 
Day 22 ± 1d 
Day 29 ± 2d 
Day 43 ± 3d 
Day 57 ± 4d 
Day 85 ± 7d 
Day 113 ± 7d 
Day 141 ± 7d 
Day 169 ± 7d 
Part A 
 
Xa 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
Part B Lead-in phase 
 
Xb 
X 
X X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Part B Expansion phase 
 
Xb 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Part C Lead-in phase 
 
Xb 
X 
X X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Part C Expansion phase 
 
Xb 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
a. 
On Day 1, sample collection will occur pre-dose, end of infusion, and at approximately 1, 2, 6, and 8 hours 
following end of infusion. On other days, samples will be collected once daily. 
b. 
On Day 1, sample collection will occur pre-dose (IM and IV) and at end of infusion (IV only). On other days, 
samples will be collected once daily. 
 
For intensive PK in Part A and the Lead-in phases of Parts B and C, PK parameters will 
be computed using standard noncompartmental methods. Parameters may include, but are 
not limited to Cmax, Clast, Tmax, Tlast, AUCD1-29, AUCinf, AUClast, %AUCexp, t1/2, λz, Vz 
(IV), apparent volume of distribution at steady state (Vss; IV), apparent volume (V/F; 
IM), apparent clearance (CL/F; IM), bioavailability (F) and will be listed and summarized 

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using descriptive statistics. Other parameters may be calculated, if deemed necessary. 
Definitions of PK parameters, methods for estimation and details of PK analyses for each 
study Part will be included in the analysis plan. 
Serum concentrations may be combined with data from other studies evaluating VIR-
7831 for the purpose of population PK model development. 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 Population PK analysis plan. 
8.7. 
Genetics 
Not applicable. 
8.8. 
Biomarkers 
Not applicable. 
8.9. 
Health Economics 
Not applicable. 
8.10. 
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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8.11. 
Resistance Analyses  
In order to monitor for potential resistance to VIR-7831, resistance surveillance will be 
conducted for all participants at baseline and certain follow-up specimens (nasal mid-
turbinate in Part A, and NP in Parts B and C). Deep sequence analysis of the SARS-CoV-
2 spike gene may be attempted on nasopharyngeal or nasal mid-turbinate samples to 
determine amino acid variants. For identified substitutions that qualify for phenotypic 
analysis, the antiviral activity of VIR-7831 will be evaluated in vitro using a SARS-CoV-
2 spike pseudovirus system. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
9.1.1. 
Part A Statistical Hypotheses 
The primary objective of Part A of the study is to evaluate the safety and tolerability of 
VIR-7831 Gen2 material. Secondary objectives are to evaluate the pharmacokinetics and 
virologic profile of VIR-7831. There are no formal hypothesis tests associated with these 
objectives and no formal significance tests or comparisons will be made between the two 
treatment groups.  
9.1.2. 
Part B Statistical Hypotheses 
The primary objective of Part B of the study is to evaluate the viral pharmacodynamics of 
VIR-7831 Gen2 material administered via IV infusion and IM injection, specifically via 
assessments of log10 SARS-CoV2 viral load AUC(D1-8) following a single dose of 500 mg 
IV or a single dose of 500 mg IM. The time period of 8 days has been selected to 
optimize the sensitivity of the AUC signal given the propensity for negative PCR results 
in the majority of trial participants by Day 28 [Chen, 2021]. Secondary objectives include 
evaluating the safety, tolerability, and pharmacokinetics of VIR-7831 Gen2 material 
administered via IM injection.  
9.1.3. 
Part C Statistical Hypotheses 
The primary objective of Part C of the study is to evaluate the viral pharmacodynamics of 
VIR-7831 Gen2 500 mg IV compared to Gen2 250 mg IM, specifically via assessments 
of log10 SARS-CoV2 viral load AUC(D1-8) following a single dose of 500 mg IV or a single 
dose of 250 mg IM. Similar to Part B, the time period of 8 days has been selected to 
optimize the sensitivity of the AUC signal given the propensity for negative PCR results 
in the majority of trial participants by Day 28 [Chen, 2021]. Secondary objectives include 
evaluating the safety, tolerability, and pharmacokinetics of VIR-7831 Gen2 material 
administered via IM injection. 

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9.2. 
Sample Size Determination 
9.2.1. 
Part A Sample Size Determination 
Approximately 40 participants will be randomized in a 3:1 ratio to VIR-7831 Gen2 or 
Gen1 material.  
The sample size is based on practical considerations, i.e., experience with similar types of 
studies that allow for reasonable qualitative data. No formal sample size calculations 
were performed; however, a sample size of 40 subjects (30 Gen2, 10 Gen1) should 
provide suitable assessment of the descriptive safety, tolerability and PK profile for VIR-
7831 Gen2. Table 7 shows examples of the precision in the estimated AE rate on the 
Gen2 arm. 
Table 7 
Precision in the Estimated AE Rate (Gen2) for Part A 
Number of Gen2 participants with 1 AE (N=30) 
AE Rate 
Exact 95% CI 
3 
10% 
2.1%, 26.5% 
6 
20% 
7.7%, 38.6% 
15 
50% 
31.3%, 68.7% 
 
9.2.2. 
Part B Sample Size Determination 
Approximately 150 participants will be randomized in a 1:1 ratio to VIR-7831 Gen2 IV 
or IM. The sample size is based on enabling a comparison of log10 SARS-CoV2 viral 
load AUC(D1-8) following a single dose of 500 mg IV or a single dose of 500 mg IM that 
will be made based on the treatment ratio 90% confidence interval falling within 
pharmacological equivalence bounds of 0.5 to 2.0 and assumed coefficient of variation of 
200% and the true ratio is 1. The margin of 0.5 to 2.0 is deemed appropriate for the 
comparison of viral load due to the endpoint being a variable PD endpoint. Table 8 
presents the sensitivity of power for different values of coefficient of variations, given the 
same sample size of 75 participants per arm. 
Table 8 
Sample Size Sensitivity Assessment for Part B 
Equivalence Bound 
Range 
Sample Size Per 
Arm 
Coefficient of 
Variation (%) 
Power (%) 
0.5-2.0 
75 
150 
98 
180 
94 
200 
91 
220 
88 
250 
83 
9.2.3. 
Part C Sample Size Determination 
Approximately 150 participants will be randomized in a 1:1 ratio to VIR-7831 Gen2 
500 mg IV or 250 mg IM. The sample size is based on enabling a comparison of log10 

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SARS-CoV2 viral load AUC(D1-8) following a single dose of 500 mg IV or a single dose of 
250 mg IM that will be made based on the treatment ratio 90% confidence interval falling 
within pharmacological equivalence bounds of 0.5 to 2.0 and assumed coefficient of 
variation of 200% and the true ratio is 1. The margin of 0.5 to 2.0 is deemed appropriate 
for the comparison of viral load due to the endpoint being a variable PD endpoint. Table 
9 presents the sensitivity of power for different values of coefficient of variations, given 
the same sample size of 75 participants per arm. 
Table 9 
Sample Size Sensitivity Assessment for Part C 
Equivalence Bound 
Range 
Sample Size Per 
Arm 
Coefficient of 
Variation (%) 
Power (%) 
0.5-2.0 
75 
150 
98 
180 
94 
200 
91 
220 
88 
250 
83 
 
9.3. 
Analysis Sets 
9.3.1. 
Part A Analysis Sets 
Participant Analysis Set 
Description 
Randomized 
All participants who were randomly assigned to study intervention 
in the study.  
Data should be reported according to the randomized intervention. 
Safety 
All randomized participants who are exposed to study intervention. 
Participants will be analyzed according to the intervention they 
actually received. 
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). 
Participants will be analyzed according to the intervention they 
actually received. 
Virology 
All participants in the Safety analysis set with a central lab 
confirmed quantifiable nasal mid-turbinate and/or saliva swab at 
baseline.  
Data should be reported according to the intervention they actually 
received. 
 
9.3.2. 
Part B and Part C Analysis Sets 
Participant Analysis Set 
Description 
Randomized 
All participants who were randomly assigned to study intervention 
in the study.  
Data should be reported according to the randomized intervention. 

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Participant Analysis Set 
Description 
Safety 
All randomized participants who are exposed to study intervention. 
Participants will be analyzed according to the intervention they 
actually received. 
Viral Pharmacodynamic 
(PD) 
All participants in the Safety analysis set who had a baseline 
(Day 1) quantifiable viral load as assessed using qRT-PCR from 
NP swabs. 
Data should be reported according to the intervention they actually 
received. 
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). 
Participants will be analyzed according to the intervention they 
actually received. 
 
9.4. 
Statistical Analyses 
9.4.1. 
General Considerations 
9.4.1.1. 
Part A, Part B, and Part C General Considerations 
The statistical analysis plans for Part A, Part B and Part C will include a more detailed 
description of the statistical analyses described in this section. Results from these three 
Parts will be reported separately. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary and key secondary endpoints. 
9.4.2. 
Primary Endpoint(s) 
9.4.2.1. 
Part A Primary Endpoint(s) 
Adverse events (AEs) will be coded using the standard GSK dictionary, Medical 
Dictionary for Regulatory Activities (MedDRA), and grouped by body system. The 
number and percentage of subjects experiencing at least one AE of any type, AEs within 
each body system and AEs within each preferred term will be presented for each 
treatment group. Separate summaries will be provided for all AEs, drug-related AEs, fatal 
AEs, non-fatal SAEs, adverse events of special interest (AESIs) and AEs leading to 
withdrawal from study, through to Day 29. Deaths and SAEs, if applicable, will be 
documented in case narrative format. Occurrence of clinically significant ECG 
abnormalities through Day 29 will also be summarized. 
As part of regular safety assessments during conduct of the study, events deemed by the 
investigator to be related to expected COVID-19 disease progression and therefore not 
classified as an AE or SAE (see Section 8.5.8) will also be summarized. Further detail 
will be provided in the analysis plan. 
Possible intercurrent events include withdrawal of consent, lost-to-follow-up and use of 
non-study therapy for COVID-19. The strategy for analysis for these intercurrent events, 
will be to use the treatment policy strategy, with data analyzed as collected. The complete 

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descriptions for intercurrent events and estimand strategies with further details will be 
provided in the analysis plan. 
The primary estimand strategy for primary safety endpoint is provided in Table 10. 
Table 10 
Primary Estimand Strategy for Primary Safety Endpoint 
Primary Estimand 
 
Objective 
Evaluate safety and tolerability of VIR-7831 Gen2 material 
Variable/Endpoints 
1 event (AE, SAE, AESI, ECG abnormality) through Day 29 
Participant Analysis Set  
Safety 
Intercurrent Event Strategy 
Data analyzed as collected (treatment policy strategy) 
Population Level Summary 
Measure 
Descriptive summary: proportion of participants with 1 
event through Day 29 
 
9.4.2.2. 
Part B and Part C Primary Endpoint(s) 
The primary endpoints of Part B and Part C will be analyzed separately using different 
ANCOVA models as stated in this section. The mean of log-transformed AUC of SARS-
CoV-2 viral load as measured by qRT-PCR from Day 1 to Day 8 (AUCD1-8) in NP swab 
samples will be assessed using an ANCOVA Model with treatments, prior exposure to an 
authorized or approved SARS-CoV-2 vaccine (for Part C only), and baseline viral load as 
covariates. The estimated geometric mean ratios and 90% CI of 500 mg IV:500 mg IM in 
Part B and 500 mg IV:250 mg IM in Part C after back-transformation will also be 
presented. Further details will be provided in the analysis plan. 
The primary estimand strategy for primary PD endpoint is provided in Table 11. 
Table 11 
Primary Estimand Strategy for Primary PD Endpoint 
Primary Estimand 
 
Objective 
Evaluate the virological response of VIR-7831 Gen2 in the 
upper respiratory tract administered by different routes and 
doses as planned by Parts B and C separately, without 
combining the data. 
Variable/Endpoints 
Log-transformed AUCD1-8 of SARS-CoV-2 viral load as 
measured by qRT-PCR in nasopharyngeal swab samples. 
Participant Analysis Set  
Pharmacodynamic 
Intercurrent Event Strategy 
Intercurrent events: Death and Use of other COVID-19 
therapies.  
Strategy for Death: Composite strategy, where subjects who 
die prior to Day 8, their AUCD1-8 viral load value will be 

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Primary Estimand 
 
imputed using the worst AUC viral load value from other 
subjects in the same treatment arm.  
The strategy for all the other intercurrent events (as 
applicable for this endpoint) will be treatment policy where 
data will be reported as captured. 
Population Level Summary 
Measure 
Geometric mean ratios and 90% CI 
9.4.3. 
Secondary Endpoints 
9.4.3.1. 
Part A Secondary Endpoints 
Full details of all analysis methods for the PK endpoints will be provided in the analysis 
plan. 
AEs and clinically significant ECG abnormalities (through Week 12), SAEs, and AESIs 
through EOS (Week 36) will be summarized in a similar manner as noted for the primary 
endpoint above. 
As part of regular safety assessments during conduct of the study, events deemed by the 
investigator to be related to expected COVID-19 disease progression (i.e., disease-related 
events) and therefore not classified as an AE or SAE (see Section 8.5.8) through Week 36 
will also be summarized. Further detail will be provided in the analysis plan. 
The virology endpoint specific to Part A is the change from baseline in viral load at all 
visits through Day 29 as measured by qRT-PCR from saliva and nasal mid-turbinate 
swab samples. Summaries of mean viral load and change from baseline will be presented 
on the log10 scale for Gen1 and Gen2-treated patients at each visit. Further details of the 
analysis methods for the virology endpoints will be provided in the analysis plan. 
9.4.3.2. 
Part B and Part C Secondary Endpoints 
Full details of all analysis methods for the PK endpoints will be provided in the analysis 
plan. The secondary endpoints in Parts B and C will also be reported separately, without 
combining the data. 
AEs, SAEs, and AESIs through Day 29 and EOS (Week 36 for all except Week 12 for 
non-serious AEs and clinically significant ECG abnormalities) will be summarized in a 
similar manner as noted for the primary endpoint analysis of Part A above. 
As part of regular safety assessments during conduct of the study, events deemed by the 
investigator to be related to expected COVID-19 disease progression (i.e., disease-related 
events) and therefore not classified as an AE or SAE (see Section 8.5.8) through Day 29 
and Week 36 will also be summarized. Further detail will be provided in the analysis 
plan. 
The virology endpoints for Part B and C are the change from baseline in viral load at all 
visits through Day 29 as measured by qRT-PCR from NP swab samples, the proportion 

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of participants with undetectable viral load at all visits through Day 29 as measured by 
qRT-PCR from NP swab samples, the proportion of participants with a persistently high 
viral load at Day 8 as measured by qRT-PCR from NP swab samples, and the mean area 
under the curve of SARS-CoV-2 viral load as measured by qRT-PCR from NP swab 
samples from Day 1 to Day 5 (AUCD1-5) and Day 1 to 11 (AUCD1-11). In each Part of the 
study, separate summaries of mean viral load and change from baseline will be presented 
on the log10 scale by treatments at each visit. Further details of the analysis methods for 
the virology endpoints will be provided in the analysis plan.  
9.4.4. 
Exploratory Endpoints 
For Parts A, B and C, incidence and titers (if applicable) of serum anti-drug antibodies 
(ADA) to VIR-7831 will be assessed. Incidence and titers (if applicable) of serum anti-N 
SARS-CoV-2 antibodies at Day 29 will also be assessed. Incidence and titers (if 
applicable) of anti-N, anti-S and anti-RBD SARS-CoV-2 antibodies at baseline will also 
be assessed. Further details of the analysis methods for the exploratory endpoints will be 
provided in the analysis plan. 
Emergence of SARS-CoV-2 viral resistance mutants will also be assessed. Further details 
of the analysis methods for the resistance endpoint will be provided in the analysis plan. 
9.5. 
Interim Analysis 
No interim analyses will be conducted in this study.  
However, in all Parts, once the last participant recruited completes the primary 
assessment, the data will be analyzed for a readout of the primary and selected secondary 
endpoints. Data from different Parts of the study will not be combined for analysis and 
separate study reports will be prepared, as appropriate. Participants will continue to 
complete the remaining scheduled assessments. 
 

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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 
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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. 
GSK (alone or working with others) may use 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 
10.1.5.1. 
Joint Safety Review Team (JSRT) 
The JSRT, comprised of team members from clinical research, pharmacovigilance, and 
statistics from Vir and GSK, will review blinded safety data from Part A of the study at 
regular intervals. For Parts B and C of the study, the JSRT will be unblinded, and data 
will be reviewed according to the Treatment-Sensitive Data Plan for Open-Label 
Randomized Study. There will be no routine in-stream review of aggregated safety data 
by treatment arm at any JSRT meeting other than at the two Post-Day 3 JSRT meetings 
(one for Part B and one for Part C) that will determine if the monitoring time may be 
reduced. Additionally, any sharing of potential safety signals will reflect pooled data that 
is not separated by treatment arm. The Safety team may need to review single unblinded 
case reports to support regulatory reporting obligations. Details regarding the JSRT 
process will be available 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. 
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 

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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.  
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. 

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• 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 
• 
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 
Refer to 10.7.1 for additional Germany-specific information regarding study and site 
termination. 

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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. 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Section 1.3 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. 
Table 12 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
 
Hematocrit 
ABO typing1 
Urine albumin to creatinine ratio2 
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 
Creatinine3 
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) 
1 ABO grouping: If done during the current or previous medical encounter, that data can be used, no 
additional blood draw should be performed 
2 Repeat if >500 mg/g 
3 Repeat if above 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 
• 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 
• An unsolicited adverse event is an adverse event that was not solicited using a diary 
or form with pre-specified criteria. Unsolicited adverse events are obtained either 
by asking a general question or unprompted by a participant who has signed the 
informed consent. Unsolicited AEs include serious and non-serious AEs. 
• 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. 
• 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. 
• Solicited AEs are predefined local at the injection site and systemic events for 
which the participant is specifically questioned when indicated by the protocol, 
such as those collected in the Local Injection Site Tolerability Assessment and 
monitoring of COVID-19 disease progression. 
 
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. 

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• 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. 
• Clinically significant changes in laboratory assessments. 
 
Events NOT Meeting the AE Definition  
• 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. 
o For example, hypoxemia due to COVID-19 requiring supplemental oxygen, 
hypoxemia due to COVID-19 requiring non-invasive ventilation or high 
flow oxygen devices and respiratory failure due to COVID-19 requiring 
invasive mechanical ventilation or ECMO 
• 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. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 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: 
a. Results in death 
b. 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. 

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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• 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 AEs. 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. 
• Hospitalization for the following are not considered an AE: 
o elective treatment of a pre-existing condition that did not worsen from 
baseline, or  
o adverse events related to expected progression, signs, or symptoms of 
COVID-19 (as noted in Section 8.5.8). 
d. Results in persistent or significant disability/incapacity 
• Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person's ability to 
conduct normal life functions. 
• 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. 
e. Is a congenital anomaly/birth defect 
f. 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. 
o 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. 
 

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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: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• 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. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. 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 to GSK. 
• 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 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.  

T M F -1 4 1 1 3 4 7 6  
C O N FI D E N TI A L  
 
 
 
2 1 6 9 1 2  
 
 
Pr ot o c ol A m e n d m e nt 5  
 
8 8  
 
T he f u ncti o nal ta ble b el o w s h o ul d be use d t o gra d e t he se verit y of a n A E t h at is n ot 
s pecificall y i de ntifie d i n t he gra di n g ta ble. I n a d diti o n,
are 
t o be classifie d as Gra de 5. 
A n e ve nt is defi ne d as ‘s eri o us’ w he n it meets at least 1 of t he pre defi n e d o utc o mes as 
descri be d i n t he d efi niti o n of a n  S A E as per Secti o n  1 0. 3. 2 , N O T w he n it is rate d as 
se vere. 
 
T a bl e 1 3  
D AI D S T a bl e f or Gr a di n g t h e S e v erit y of A d ult a n d P e di atri c A d v er s e 
E v e nt s  
P A R A M E T E R  Gr a de 1  
Mil d  
Gr a de 2  
M o der ate  
Gr a de 3  
Se vere  
Gr a de 4  
P ote nti all y 
life-
t hre ate ni n g 
 
A s s e ss m e nt  of C a u salit y  
•  
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n 
a n d eac h occ urre n ce of eac h A E/ S A E.  
•  A "reas o na bl e p ossi bilit y" of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca us al  relati o ns hi p, rat her t ha n a rel ati o ns hi p ca n n ot 
be r ule d o ut.  
•  T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
•  Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her 
ris k fact ors, as well as t h e te m p oral r elati o ns hi p of t he e ve nt t o st u d y i nter ve nti o n 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate 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 CI

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• 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 GSK. 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 GSK. 
• 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. 
 
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 GSK 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 

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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. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual (SRM). 
 
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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10.4. 
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. 
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: 

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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. 
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 
o oral 

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CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
o intravaginal 
o transdermal 
o 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
o oral 
o 
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. 
 
 
 

T M F -1 4 1 1 3 4 7 6  
C O N FI D E N TI A L  
 
 
 
2 1 6 9 1 2  
 
 
Pr ot o c ol A m e n d m e nt 5  
 
9 4  
 
1 0. 5.  
A p p e n di x 5: L o c al I nj e cti o n Sit e T ol er a bilit y A s s e s s m e nt  
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.

T M F -1 4 1 1 3 4 7 6  
C O N FI D E N TI A L  
 
 
 
2 1 6 9 1 2  
 
 
Pr ot o c ol A m e n d m e nt 5  
 
9 5  
 
 
 
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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10.6. 
Appendix 6: Management of Local Injection Site Reactions 
and Systemic Symptoms (Anaphylaxis) 
A. 
Local Injection Site Reactions 
Signs and Symptoms 
Management 
Redness, soreness or 
swelling at the injection 
site 
Apply a cold compress to the injection site(s) 
Consider giving an analgesic (e.g., ibuprofen, acetaminophen, 
paracetamol) 
Itching and redness 
Consider giving an anti-pruritic (e.g., diphenhydramine) 
Observe patient closely for the development of generalized symptoms 
Slight bleeding 
Apply pressure and an adhesive compress 
Continuous bleeding 
Place gauze pads over the site and maintain direct and firm pressure 
If a subject has evidence of necrosis/ulceration, the subject should be referred to a higher 
level of acute care (e.g., hospital Emergency Department) for appropriate management.  
 
B. 
Systemic Reactions/Anaphylaxis 
As with any antibody, allergic reactions to study drug are possible. Therefore, appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  
Diagnosis of Anaphylaxis 
The most common signs and symptoms of anaphylaxis are cutaneous (e.g., sudden onset 
of generalized urticaria, angioedema, flushing, pruritis). However, 10-20% of patients 
have no skin findings. 
Danger Signs include: 
• Rapid progression of symptoms 
• Evidence of respiratory distress (stridor, wheezing, dyspnea, increased work 
of breathing, persistent cough, cyanosis) 
• Vomiting 
• Abdominal pain 
• Hypotension 
• Dysrhythmia 
• Chest pain 
• Collapse 

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Management of Anaphylaxis 
The following procedures should be followed in the event of a suspected anaphylactic 
reaction:  
1. Call for additional medical assistance; activate emergency medical services 
2. Ensure appropriate monitoring is in place, such as continuous ECG and pulse 
oximetry 
3. First-line treatment: 
Administer epinephrine (1.0 mg/ml) aqueous solution (1:1000 dilution) – 0.5 
mg (0.5ml) IM in the anterolateral thigh 
If using an epinephrine auto-injector – use 0.3 mg IM into the anterolateral 
thigh 
May be repeated every 5-15 minutes up to 3 times 
4. Optional treatment (antihistamine): 
Diphenhydramine 50 mg oral/IV/IM 
OR 
Hydroxyzine 25 mg oral/IM 
5. Give oxygen (8-10 L/minute) via facemask, as needed 
6. Normal saline rapid bolus – treat hypotension with rapid infusion of 1-2 liters IV 
7. Monitor patient until emergency medical services arrive. 
References 
1. Medical Management of Vaccine Reactions in Adults in a Community Setting, 
Immunization Action Coalition, https://www.immunize.org/catg.d/p3082.pdf 
2. Preventing and Managing Adverse Reactions, General Best Practice Guidelines 
for Immunization: Best Practices Guidance of the Advisory Committee on 
Immunization Practices (ACIP) 
3. Sampson HA Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, 
Branum A, et al, Second symposium on the definition and management of 
anaphylaxis: Summary report—Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol 2006; 117:391-7 
 
 
 

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10.7. 
Appendix 7: Country-specific Requirements 
10.7.1. 
Germany 
7.2 Participant Discontinuation/Withdrawal from the Study 
The following additional participant discontinuation criterion applies: 
i. 
Participants are to be excluded from further participation if the COVID-19 disease 
requires hospitalization or treatment with non-permitted medication (please refer to 
Section 6.8.1 of the protocol), according to §40 paragraph 1 sentence 3 no. 2 German 
Medicinal Products Act (AMG). 
Safety Criteria for Withdrawal of Individual from Study 
The criteria leading to termination of a subject or withdrawal of study intervention are 
provided in Section 7 of the protocol, and include the following: 
• AEs: For IV administration, 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. If study intervention is permanently discontinued, the 
participant will remain in the study to be evaluated for follow-up assessments.  
• Grade 2 IRRs: For IV administration, 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. antihistamines, IV fluids). 
• Withdrawal of consent: A participant may withdraw from the study at any time 
at his/her own request, at the request of their LAR, 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. 
• Lost to follow-up: A participant will be considered lost to follow-up if he or she 
repeatedly fails to adhere to scheduled visits and is unable to be contacted by the 
study site. Further details are provided in Section 7.3 of the protocol. 
 
10.1.9 Study and Site Start and Closure 
The following additional study termination reason applies: 
ii. The study shall also be terminated if the favorable opinion or approval is revoked, 
according to §42a paragraph 4 in conjunction with paragraph 1, 2 and 4a, German 
Medicinal Products Act (AMG). 
Safety Criteria for Termination of Study 
Further information on the reasons for study and/or site termination are provided in 
Section 10.1.9 of the protocol and includes the following: 

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• 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 
• 
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 
In addition to the above, a JSRT will review safety data from Part A, Part B and Part C of 
the study on a regular basis and if the JSRT identifies any serious safety concerns for any 
Part of the study, including those that may require study termination, these will be 
escalated to an internal Safety Review Committee, and any actions will be distributed to 
sites and investigators promptly.   
10.7.2. 
Summary of Changes History for the Germany Country-specific 
Protocol Amendment 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 03/DEU-01 
23-APR-2021 
TMF-12551962 
Amendment 03 
08-APR-2021 
TMF-11941318 
Amendment 02 
03-MAR-2021 
TMF-11814330 
Amendment 01 
19-JAN-2021 
TMF-11735674 
Original Protocol 
10-DEC-2020 
2020N457654_00 
Amendment 03/DEU-1: 23-APR-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: To add country-specific information that was 
requested by the Germany Ethics Committee.  

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Section # and Name 
Description of Change 
Brief Rationale 
10.7. Appendix 7: Country-
specific Requirements 
Added Germany-specific 
exclusion criteria; clarified 
participant discontinuation 
criteria and reasons for study 
termination 
Added information 
requested by the 
Germany Ethics 
Committee 
 

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10.8. 
Appendix 8: Abbreviations and Trademarks 
Term 
Definition 
ADA 
Anti-drug antibodies 
ADE 
Antibody dependent enhancement 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine Aminotransferase 
AMG 
Medicinal Products Act 
Anti-N 
Anti-nucleocapsid 
Anti-RBD 
Anti-receptor binding domain 
Anti-S 
Anti-spike 
ARDS 
Acute respiratory distress syndrome 
AUC 
Area under the curve 
AUCDX-Y 
Area under the curve from Day X to Day Y 
AUCinf 
Area under the serum concentration-time curve extrapolated from zero to infinity 
AUClast 
Area under the curve from the time of dosing to the time of the last measurable (positive) 
concentration 
%AUCexp 
The extrapolated portion of AUCinf  
BP 
Blood pressure 
BMI 
body mass index 
Clast 
Concentration at last quantifiable timepoint. 
Cmax 
Maximum observed concentration 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
CL/F 
Apparent clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CONSORT 
Consolidated Standards of Reporting Trials 
CoV 
Coronavirus 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CSR 
Clinical study report 
CV 
Cardiovascular 
DAIDS 
Division of acquired immune-deficiency syndrome 

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Term 
Definition 
DP 
Drug Product 
DS 
Drug Substance 
DSMB 
Data and Safety Monitoring Board 
EC90 
90% effective concentration 
ECG 
Electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
EU 
European Union 
EW 
Early withdrawal 
F 
Bioavailability 
FcR 
Fc Gamma Receptor 
FIH 
First-in-human 
FPFV 
First patient first visit 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GSK 
GlaxoSmithKline 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormone replacement therapy 
HSR 
Hypersensitivity reactions 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent data monitoring committee 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IgG1 
Immunoglobulin G1 
IM 
Intramuscular 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRR 
Infusion related reaction 

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Term 
Definition 
IRT 
Interactive response technology 
ISR 
Injection site reaction 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
IWRS 
Interactive Web Response System 
L 
Liter 
JSRT 
Joint safety review team 
LAR 
Legally authorized representative 
g 
microgram 
mg 
milligram 
mAb 
Monoclonal antibody 
MARM 
Monoclonal antibody-resistant mutant 
MCB 
Master Cell Bank 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
MSDS 
Material safety data sheet 
NP 
Nasopharyngeal  
NQ 
Non-quantifiable 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PR 
Pulse rate 
qRT-PCR 
Quantitative reverse transcriptase polymerase chain reaction 
QTLs 
Quality tolerance limits 
RBC 
Red blood cell count 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
RSV 
Respiratory syncytial virus 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SARS 
Severe acute respiratory syndrome 

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Term 
Definition 
SoA 
Schedule of activities 
SoC 
Standard of care 
SRM 
Study reference manual 
SRT 
Safety review team 
SUSAR 
Suspected unexpected serious adverse reactions 
t1/2 
Terminal elimination half-life 
Tlast 
Time of the last quantifiable concentration 
Tmax 
Time to reach Cmax 
ULN 
Upper limit of normal 
US 
United States 
V 
Apparent volume of distribution 
V/F 
Apparent volume 
Vir 
Vir Biotechnology, Inc. 
Vss 
Apparent volume of distribution at steady state 
Vz 
Apparent volume of distribution during the elimination phase 
λz 
Apparent terminal elimination rate constant, calculated by linear regression of the 
terminal linear portion of the log concentration vs. time curve. 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
Cepheid Gene Xpert Xpress 
 
 
MedDRA 
 
 

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10.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 04: 18 May 2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: Protocol changes have been made to add a third 
part (Part C) to this study to assess the safety, tolerability, immunogenicity, 
pharmacokinetics, and viral pharmacodynamics of a 250 mg dose of VIR-7831 
administered by intramuscular (IM) injection. Changes were made throughout the 
protocol to add information necessary for conducting Part C procedures. Additionally, the 
post-dose monitoring time for Part B has been reduced to 1 hour after Joint Safety 
Review Team (JSRT) review on 13 May 2021. Other changes include: moving resistance 
analysis to an exploratory objective, providing updated data, clarification of inclusion and 
exclusion criteria, incorporated information from the Germany-specific protocol 
amendment, and other clarifications throughout the protocol. 

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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis, 1.2. Schema, 
1.3. Schedule of Activities (SoA), 
2.1. Study Rationale, 2.2. Background, 
2.3.1. Risk Assessment, 2.3.3. Overall 
Benefit: Risk Conclusion, 
3. Objectives and Endpoints, 
4.1. Overall Design, 4.2. Scientific 
Rationale for Study Design, 
4.3. Justification for Dose, 4.4. End of 
Study Definition, 5.1. Inclusion 
Criteria, 5.2. Exclusion Criteria, 
6.1. Study Intervention(s) 
Administered, 6.3. Measures to 
Minimize Bias: Randomization and 
Blinding, 6.8.2. Permitted Concomitant 
Medication, 8. Study Assessments 
and Procedures, 8.3. Virologic 
Assessments, 8.4. Safety 
Assessments, 8.4.1. Vital Signs, 
8.4.2 Electrocardiograms, 
8.4.5. Active Monitoring of COVID-19 
Progression, 8.4.8. Local Injection Site 
Tolerability, 8.5.9.2. Injection Site 
Reactions, 8.6. Pharmacokinetics, 
8.11. Resistance Analyses, 9.1.3. 
Part C Statistical Hypotheses, 
9.2.3. Part C Sample Size 
Determination, 9.3.2. Part B and 
Part C Analysis Sets, 9.4.1.1. Part A, 
Part B, and Part C General 
Considerations, 9.4.2.2. Part B and 
Part C Primary Endpoint(s), 9.4.3.2. 
Part B and Part C Secondary 
Endpoints, 9.4.4. Exploratory 
Endpoints, 9.5. Interim Analysis, 
10.1.5.1. Joint Safety Review Team 
(JSRT), 10.7.1. Germany 
Added information 
regarding the Part C 
endpoints, objectives, 
rationale, background, 
inclusion and exclusion 
criteria, number of 
participants, intervention 
groups and duration, 
JSRT, study design, study 
procedures, dose rationale, 
risk assessment, and 
statistical analyses to 
applicable sections. 
Updated the study schema 
and added a Schedule of 
Activities table for Part C. 
Added study Part C to 
gain clinical experience 
with 250 mg VIR-7831 
administered via IM 
injection  
1.1. Synopsis, 1.3. Schedule of 
Activities (SoA), 4.1. Overall Design, 
8.4.1. Vital Signs, 8.4.8. Local 
Injection Site Tolerability, 8.5.9.2. 
Injection Site Reactions 
Updated with JSRT 
recommendation to reduce 
Part B post-dose 
monitoring to 1 hour.  
Updated based on the 
13 May 2021 JSRT 
recommendation to 
reduce the post-dose 
monitoring time for 
Part B to 1 hour. 

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Section # and Name 
Description of Change 
Brief Rationale 
5.2. Exclusion Criteria 
Updated Exclusion Criteria 
number 10 to clarify when 
SARS-CoV-2 vaccine is 
permitted for each Part of 
the study. 
To clarify exclusion 
criteria 
5.1. Inclusion Criteria, 5.2. Exclusion 
Criteria 
Added South Korea- and 
Germany-specific inclusion 
and exclusion criteria. 
Added country-specific 
inclusion and exclusion 
criteria into the main 
body of the global 
protocol 
7.2. Participant 
Discontinuation/Withdrawal from the 
Study, 10.1.9. Study and Site Start 
and Closure, 10.7. Appendix 7: 
Country-specific Requirements; 
10.7.1. Germany, 10.7.2. Summary of 
Changes History for the Germany 
Country-specific Protocol Amendment 
Incorporated Germany-
Specific language into the 
global protocol.  
To provide information 
from the Germany 
country-specific 
amendment in the global 
protocol 
6.8.1. Medication Not Permitted 
During the Study, 6.8.2. Permitted 
Concomitant Medication 
Further described the 
permitted and prohibited 
receipt of SARS-CoV-2 
vaccines during each Part 
of the study. 
To clarify the permitted 
and prohibited receipt of 
SARS-CoV-2 vaccines  
1.1. Synopsis, 1.2. Schema, 3. 
Objectives and Endpoints, 
9.4.3.1. Part A Secondary Endpoints, 
9.4.3.2. Part B and Part C Secondary 
Endpoints, 9.4.4. Exploratory 
Endpoints 
Resistance analysis was 
moved from a secondary to 
an exploratory objective 
and removed from the 
schematic. 
Given the small number 
of expected events for 
this endpoint, resistance 
analysis was moved 
from a secondary 
objective to an 
exploratory objective 
1.1. Synopsis, 3. Objectives and 
Endpoints 
Added ‘presence at 
baseline’ to the endpoint 
for the resistance 
objective. 
Added detail to the 
resistance endpoint to 
match the objective 
10.3.4. Recording and Follow-Up of 
AE and SAE 
Changed assessment of 
severity to Division of 
Acquired Immune-
Deficiency Syndrome 
(DAIDS) grading. 
Corrected information  

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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis, 1.2. Schema, 4.1. 
Overall Design, 4.2. Scientific 
Rationale for Study Design, 
10.1.5.1. Joint Safety Review Team 
(JSRT) 
Clarified the JSRT data 
review for Parts B and C. 
To clarify JSRT review of 
data 
7.1. Discontinuation of Study 
Intervention 
Specified that participants 
should be permanently 
discontinued from study 
drug intervention if they 
experience a Grade 3 or 4 
infusion-related reaction. 
To clarify study 
intervention 
discontinuation 
8.3. Virologic Assessments 
Added details regarding 
the timepoints for 
sequencing analysis for 
Part A.  
To clarify virologic 
assessments 
1.1. Synopsis, 8.4.1. Vital Signs 
Updated wording of Part B 
study procedures. 
To clarify study 
procedures and for 
consistency throughout 
the document 
8.5. Adverse Events (AEs), Serious 
Adverse Events (SAEs) and Other 
Safety Reporting 
Used bullet points for the 
exceptions to reporting 
hospitalization as an SAE. 
To clarify when 
hospitalization is not 
considered an SAE 
10.3.2. Definition of an SAE 
Added the exceptions to 
reporting hospitalization as 
an SAE. 
To align with Section 8.5.  
8.5. Adverse Events (AEs), Serious 
Adverse Events (SAEs) and Other 
Safety Reporting, 8.5.8. Disease-
Related Events and/or Disease-
Related Outcomes Not Qualifying as 
AEs or SAEs 
Added text to clarify that all 
deaths are considered 
SAEs. 
To clarify that all deaths 
should be considered 
SAEs 
10.3.1. Definition of AE 
Updated the descriptions 
of solicited and unsolicited 
adverse events. 
Updated the descriptions 
for solicited and 
unsolicited adverse 
events because 
participant diaries are 
not used in this study 

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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis, 2.1. Study Rationale; 
2.2. Background, 2.3.2. Benefit 
Assessment, 2.3.3. Overall Benefit: 
Risk Conclusion, 4.3. Justification for 
Dose 
Provided updated 
information from BLAZE-4 
and COMET-ICE. Provided 
updated numbers for 
COVID-19 cases and 
deaths. Removed 
bamlanivimab from the list 
of monoclonal antibodies 
that have emergency use 
authorization for COVID-
19. Provided updated 
information about other 
planned studies for IM VIR-
7831. 
To provide the most 
current information 
Title Page, Sponsor Signatory Page, 
1.1. Synopsis, 2.1. Study Rationale, 
6.1. Study Intervention(s) 
Administered 
Added sotrovimab to the 
list of names for the 
investigational product. 
Added the international 
nonproprietary name 
6.1. Study Intervention(s) 
Administered 
Corrected GSK compound 
number. 
Corrected typographical 
error 
9.4.2.2. Part B and Part C Primary 
Endpoint(s) 
Updated intercurrent 
events.  
To align with the 
statistical analysis plan 
9.4.2.2. Part B and Part C Primary 
Endpoint(s) 
Changed model from 
ANOVA to ANCOVA. 
Corrected typographical 
error 
9.4.3.1. Part A Secondary Endpoints, 
9.4.3.2. Part B and Part C Secondary 
Endpoints 
“Disease-progression 
events’ was changed to 
“disease-related events” 
Corrected wording 
9.4.1.1. Part A, Part B, and Part C 
General Considerations, 9.5. Interim 
Analysis 
Provided details regarding 
the planned data readouts 
for Parts A, B, and C and 
specified that results from 
each Part will be reported 
separately.  
Clarified the data 
readout plan and 
reporting 
8.6. Pharmacokinetics 
Specified which 
parameters are to be 
assessed for intravenous 
infusions and 
intramuscular injections. 
To clarify 
pharmacokinetic 
assessments 

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Section # and Name 
Description of Change 
Brief Rationale 
10.7. Appendix 7: Country-specific 
Requirements 
Added level 3 numbered 
headings.  
Headings added to 
improve readability  
10.7. Appendix 7: Country-specific 
Requirements 
Removed country-specific 
inclusion and exclusion 
criteria from this section.  
Country-specific 
inclusion and exclusion 
criteria were moved to 
Section 5.1. and Section  
5.2., respectively 
10.7. Appendix 7: Country-specific 
Requirements 
Removed South Korea 
from Appendix 7. 
All South Korea-specific 
information has been 
incorporated into Section 
5.1. and Section 5.2 
8.4.2. Electrocardiograms 
Changed a statement from 
“on the day of infusion” to 
“on the day of 
administration of study 
intervention”. 
Updated for clarity 
because this statement 
applies to both IV and IM 
administration of study 
intervention 
10.8. Appendix 8: Abbreviations and 
Trademarks 
Added additional 
abbreviations. 
Updated abbreviation list 
to match abbreviations 
used in-text 
11. References 
Added and removed 
references. 
Updated the reference 
list to match in-text 
citations 
All sections 
Other minor grammatical 
and typographical 
corrections. 
To improve readability 
 
Amendment 03: 08-APR-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: Adding measurement of anti-SARS-CoV-2 
antibody at baseline and Day 29 to the study procedures to allow for exploratory analysis 
of immune response. Removing the requirement that at least 15 participants are enrolled 
in Part A before enrollment in Part B can begin so that Part B can begin without delay. 

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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis, 1.3. Schedule of 
Activities, 3. Objectives and 
Endpoints, 8.3 Virologic 
Assessments, 9.4.4. Exploratory 
Endpoints 
Added measurement and 
analyses of anti-SARS-CoV-2 
antibody at baseline and Day 29 
to study Parts A and B. Added 
an exploratory objective and 
endpoints to assess the effect of 
VIR-7831 on immune response. 
To allow for exploratory 
sub-analysis of virologic 
endpoints based on 
antibody response at 
baseline.  
To evaluate the effect of 
VIR-7831 on 
development of antibody 
(immune response) at 
Day 29. 
1.1. Synopsis, 3. Objectives and 
Endpoints 
Clarified that the secondary 
objective to monitor for 
emergence of resistance 
mutants to VIR-7831 will also 
monitor presence at baseline. 
To clarify the intention of 
the secondary objective 
to monitor resistance. 
1.1. Synopsis, 1.2 Schema, 2.1. 
Study Rationale, 4.1. Overall 
Design 
Removed the requirement that 
at least 15 participants are 
enrolled in Part A before 
enrollment in Part B can begin. 
To permit selected sites 
to begin enrolling to Part 
B without delay.  
5.1 Inclusion Criteria 
Updated wording of inclusion 
criteria 1 to state that the age 
restriction for Part B is for 
logistical purposes related to 
study COMET-TAIL instead of 
COMET ICE. 
COMET-ICE is no longer 
enrolling patients, but 
COMET-TAIL will enroll 
a similar population as 
COMET PEAK. 
1.1. Synopsis, 2.1. Study 
Rationale, 2.3.1. Risk 
Assessment, 2.3.2. Benefit 
Assessment, 2.3.3. Overall 
Benefit: Risk Conclusion, 4.3. 
Justification for Dose, 6.1. Study 
Intervention(s) Administered 
Provided updated information 
from the COMET-ICE, BLAZE-4, 
and ACTIV-3 studies 
Provided updated 
information.  
1.1. Synopsis, 2.1. Study 
Rationale, 2.3.2 Benefit 
Assessment, 6.1. Study 
Intervention(s) Administered 
Changed language regarding 
enrollment, randomization, and 
VIR-7831 administration in the 
COMET-ICE and ACTIV-3-TICO 
studies to past tense.  
COMET-ICE and ACTIV-
3-TICO are no longer 
enrolling participants. No 
new administration of 
VIR-7831 will occur in 
COMET-ICE or ACTIV-3-
TICO.  

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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Specified that Part B will enroll 
participants 18 to <70 years of 
age. 
Corrected wording to 
match the inclusion 
criteria. 
8.6. Pharmacokinetics 
Added ‘approximately;’ to 
footnote a for Table 5.  
Corrected footnote to 
match the corresponding 
footnote in the Schedule 
of Activities table.  
Title page, 1.1. Synopsis 
Defined abbreviations IV, IM, 
and COVID-19 in the brief title. 
To clarify the brief title. 
All sections 
Other minor grammatical and 
typographical corrections. 
To improve readability. 
 
Amendment 02: 03-MAR-2021 
Overall Rationale for the Amendment: Protocol changes have been made to add a 
second part (Part B) to this study to assess intramuscular (IM) injection of VIR-7831 
Gen2 material. The original treatment arms evaluating Gen2 and Gen1 material 
administered IV is designated Part A. Changes were made throughout the protocol to add 
information necessary for conducting Part B and to differentiate Part A and Part B 
procedures. Other changes include: removal of home nursing option for Part A study 
visits, an additional endpoint for the secondary safety objective for Part A, updates to 
endpoint wording for Part A, the addition of resistance analyses, updated background 
information based on new data, and clarifications throughout the protocol.  

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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis, 1.2. Schema, 1.3. 
Schedule of Activities, 2.1. Study 
Rationale, 2.2. Background, 2.3.1. Risk 
Assessment, 2.3.2. Benefit Assessment, 
2.3.3. Overall Benefit: risk Assessment, 
3. Objectives and Endpoints, 4.1. Overall 
Design, 4.2. Scientific Rationale for 
Study Design; 4.3. Justification for Dose, 
4.4. End of Study Definition, 5.1 
Inclusion Criteria, 5.2. Exclusion Criteria, 
6.1. Study Intervention(s) Administered, 
6.3. Measures to Minimize Bias: 
Randomization and Blinding, 6.4. Study 
Intervention Compliance, 8. Study 
Assessments and Procedures, 8.3. 
Virologic Assessments, 8.4. Safety 
Assessments; 8.4.1. Vital Signs; 8.4.2. 
Electrocardiograms, 8.4.5. Active 
Monitoring of COVID-19 Progression 
8.4.8. Local Injection Site Tolerability, 
8.6. Pharmacokinetics, 9.1. Statistical 
Hypotheses, 9.2. Sample Size 
Determination, 9.3. Analysis Sets, 9.4.1. 
General Considerations, 9.4.2. Primary 
Endpoints, 9.4.3 Secondary endpoints, 
9.4.4 Exploratory Endpoints, 9.5 Interim 
Analysis, 10.1.5.1. Joint Safety Review 
Team (JSRT) 
Separated study into Parts 
A and B. Added information 
regarding the Part B 
endpoints, objectives, 
rationale, number of 
participants, intervention 
groups and duration, Joint 
Safety Review Team, study 
design, study procedures, 
background, risk 
assessment, exclusion 
criteria, study interventions, 
and statistical analyses to 
applicable sections. 
Updated the study schema 
and added schedule of 
Activities tables for the 
Lead-in and Expansion 
phases of Part B. Added 
language to differentiate 
Part A from Part B. 
Added study Part B to 
gain clinical 
experience with Gen2 
administered via 
intramuscular (IM) 
injection.  
5.2. Exclusion Criteria, 6.8.1. Medication 
Not Permitted During the Study 
Changed time after dosing 
before vaccinations are 
permitted to 90 days.  
Updated to be 
consistent with CDC 
guidelines on timing 
of approved COVID-
19 vaccines. 

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Section # and Name 
Description of Change 
Brief Rationale 
8.4.8. Local Injection Site Tolerability, 
8.5.9. Adverse Events of Special 
Interest, 8.5.9.2. Injection Site 
Reactions, 10.5. Appendix 5: Local 
Injection Site Tolerability Assessment, 
10.6. Appendix 6: Management of Local 
Injection Site Reactions and Systemic 
Symptoms (Anaphylaxis) 
Added injection site 
reactions as an adverse 
event of special interest 
(AESI), and procedures for 
assessing local injection site 
tolerability. Added 
Appendices for local 
injection site tolerability 
assessment and 
management of local 
injection site reactions and 
systemic symptoms. 
Added because of the 
addition of IM 
injections to the 
protocol. 
Synopsis, 3. Objectives and Endpoints 
9.1 Statistical Hypotheses, 9.4.3. 
Secondary Endpoints, 9.4.4. Exploratory 
Endpoints  
Updated language of 
secondary pharmacokinetic 
(PK) endpoint, added 
occurrence of non-serious 
AEs through Week 12 and 
changed ECG endpoint to 
Week 12 for the Part A 
secondary safety objective. 
Moved the virology endpoint 
from Part A to a secondary 
endpoint. Added resistance 
endpoint. Updated statistical 
analyses sections to match 
changes. 
Updated PK endpoint 
wording to generalize 
to Parts A and B. 
Added Week 12 non-
serious AE endpoint  
and updated 
secondary ECG 
endpoint to match 
reporting as 
described in the 
protocol. Made Part A 
virology endpoint a 
secondary endpoint. 
Added a resistance 
endpoint to monitor 
for potential 
development of 
resistance to VIR-
7831. 
Protocol Brief Title 
Updated to add 
pharmacodynamics and add 
routes of study drug 
administration. 
Updated brief study 
title to reflect addition 
of Part B. 
8.11. Resistance Analyses 
Added section for 
resistance surveillance. 
Added to monitor for 
potential development 
of resistance to VIR-
7831. 

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Section # and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Activities (SoA) 
Removed home nursing 
option for study visits in Part 
A and specified that safety 
labs on Day 1 should be 
collected pre-dose. Clarified 
that screening procedures 
that are redundant with 
dosing procedures do not 
need to be performed twice 
if screening and dosing 
occur on the same day. 
Added AESI, disease-
related events, and 
concomitant medication 
review to the Schedule of 
Activities. Clarified that 
phone call visits can be 
performed at site. Updated 
footnote numbering. 
Updated Part A study 
procedures to remove 
home nursing option 
as all sites selected 
site visits. Clarified 
study procedures. 
8.2.2. Physical examination, 8.4.2. 
Electrocardiograms 
Clarified that screening 
procedures that are 
redundant with dosing 
procedures do not need to 
be performed twice if 
screening and dosing occur 
on the same day. 
Clarified study 
procedures.  
6.1. Study Intervention(s) Administered 
Specified that the IV 
infusion duration for Part A 
is 1 hour and is 15 minutes 
for Part B. Added row to 
Table 4 to clarify infusion 
times. 
Clarified infusion 
times for Part A and 
Part B. 
6.8.1. Medication Not Permitted During 
the Study 
Added that intravenous 
immunoglobulin (IVIG) is a 
not permitted during the 
study. 
Added because a 
question was asked 
about IVIG in another 
study. 
8.5.1. Time Period and Frequency for 
Collecting AE and SAE Information 
Added AESI collection. 
Clarification of AESI 
reporting. 

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Section # and Name 
Description of Change 
Brief Rationale 
9.3. Analysis Sets, 9.3.1. Part A Analysis 
Sets, 9.3.2. Part B Analysis Sets 
Added definition of Virology 
analysis set and clarified 
wording of Part A 
randomized Analysis set. 
Updated to match 
statistical analysis 
plan. 
9.4.4. Exploratory Endpoints 
Added description of 
immunogenicity analyses. 
Updated to provide 
details of analyses for 
exploratory 
endpoints. 
8.3 Virologic Assessments 
Section renamed from 
Exploratory Assessments to 
Virologic Assessments and 
subheading removed. 
Updated section 
name because 
virology is no longer 
an exploratory 
assessment. 
1.1. Synopsis, 2.1. Study Rationale; 
2.3.2. Benefit Assessment, 2.3.3. Overall 
Benefit: Risk Conclusion; 4.3. 
Justification for Dose, 6.1. Study 
Interventions Administered 
Added relevant information 
from the BLAZE-4, COMET-
ICE, and ACTIV-3-TICO 
studies. 
Updated to include 
the most recent 
available data from 
ongoing studies. 
4.3. Justification for Dose 
Added information from 
COMET-ICE, ACTIV-3-
TICO, and resistance 
analyses and added 
information regarding IM 
injections. 
Updated to include 
the most recent 
available data and 
provide information 
relevant to IM 
injections.  
7.1. Discontinuation of Study 
intervention, 7.1.1. Temporary 
Discontinuation 
Specified which 
discontinuation procedures 
are specific to IV infusion. 
Clarification of which 
procedures are 
specific to IV 
administration. 
5.4. Screen Failures 
Clarified that re-screening 
will be permitted once 
during study conduct. 
Clarification of study 
procedures 
Synopsis, 4.1. Overall Design, 8.2. 
Screening Period 
Changed wording for 
screening period from ’24 
hours’ to ‘1 day’ prior to 
dosing. 
Updated for 
consistency with the 
Schedule of Activities 

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Section # and Name 
Description of Change 
Brief Rationale 
2.2. Background 
Updated number of COVID-
19 cases and deaths. 
Updated fatality estimates. 
Updated to include 
most recent COVID-
19 data. Removed 
European Centre for 
Disease Prevention 
and Control statistics 
because the Johns 
Hopkins COVID-19 
tracker includes 
global data that are 
more recently 
updated. 
2.2. Background, 2.3.2. Benefit 
Assessment 
Added 
bamlanivimab/etesevimab 
to monoclonal antibodies 
that have received 
Emergency Use 
Authorization in the US. 
Updated to include 
the most current 
available treatment 
options. 
8.5.8. Disease-Related Events and/or 
Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
Specified that disease-
related events should be 
recorded in the specific 
eCRF and reported through 
Week 24 (EOS). 
Clarification of the 
reporting method for 
disease-related 
events. 
10.7. Appendix 7: Country-specific 
Requirements 
Added Appendix. 
Added to address 
requirements specific 
to South Korea. 
2.3.1 Risk Assessment, 8.5.9.3. 
Immunogenicity, 8.5.9.4. Antibody-
Dependent Enhancement,  
Removed mention of 
approximate number of half-
lives. 
Removed extraneous 
information.  
10.8. Appendix 8: Abbreviations and 
Trademarks, 11. References 
Added and removed 
references and 
abbreviations as applicable 
to changes made in the 
protocol. Updated 
references for accuracy and 
consistent formatting.  
Updated to match 
changes in the 
protocol text and for 
accuracy/consistency. 
All sections 
Other minor grammatical 
and typographical 
corrections. 
To improve 
readability. 
 
 

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Amendment 01: (19-JAN-2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment 
Protocol changes have been made to include nasal mid-turbinate swabs and resistance 
testing at the request of regulatory agencies. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, Section 
3 
Objectives/Endpoints, 
Section 8.3.1 
Virologic Measures,  
and,   
9.4.4 Exploratory 
Endpoints 
Nasal mid-turbinate swab 
added to exploratory endpoint. 
At the request of regulatory agencies. 
1.3 Schedule of 
Activities 
Nasal mid-turbinate swab 
added to activities. 
At the request of regulatory agencies. 
2.2 Background 
Included Emergency Use 
Authorization (EUA) for 
Regeneron mAbs.  
Updated to include the most current 
available treatment options.  
2.3.2 Benefit 
Assessment, and 
2.3.3 Overall Benefit  
IDMC data review from 
COMET-ICE added. 
Updated to include the most recent 
available data from ongoing studies.   
6.8.2 Permitted 
Concomitant 
Medications 
Language included to permit 
use of COVID-19 vaccines 
following 90 days post dosing.  
Updated to align with other studies in 
the program to the timing of approved 
COVID-19 vaccines. 
8.3.1 Virologic 
Measures 
Included language for the 
purpose of resistance 
surveillance analysis, next 
generation sequencing analysis 
of the spike protein of SARS-
CoV-2 will be performed.  
At the request of regulatory agencies. 

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Section # and Name 
Description of Change 
Brief Rationale 
8.5.8. Disease-
Related Events 
and/or Disease-
Related Outcomes 
Not Qualifying as 
AEs or SAEs 
Updated to clarify the collection 
of disease related events.  
Clarification of previous text.  
 

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11. 
REFERENCES 
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