A Phase 3 Randomized, Multi-center, Open Label Study to Assess the Efficacy, Safety, and Tolerability of Monoclonal Antibody VIR-7831 (Sotrovimab) Given Intramuscularly Versus Intravenously for the Treatment of Mild/Moderate Coronavirus Disease 2019 (COVID-19) in High-risk Non-hospitalized Patients; Safety Substudy Assessing the Safety and Tolerability of Single Ascending Dose Monoclonal Antibody VIR-7831
Phase: PHASE3
Conditions: Covid19
Sponsor: Vir Biotechnology, Inc.

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 1 
 
SAFETY SUBSTUDY CLINICAL STUDY PROTOCOL 
A Phase 3 randomized, multi-center, open label study to assess the efficacy, safety, and 
tolerability of monoclonal antibody VIR-7831 (sotrovimab) given intramuscularly versus 
intravenously for the treatment of mild/moderate coronavirus disease 2019 (COVID-19) in high-
risk non-hospitalized patients; Safety Substudy assessing the safety and tolerability of single 
ascending dose monoclonal antibody VIR-7831 
Protocol Number: VIR-7831-5008 (GSK Study 217114) 
Compound Number or Name: 
VIR-7831 (sotrovimab; GSK4182136) 
Protocol Version & Date: Amendment #4, 27 MAY 2022 
Brief Substudy Title: Intravenous single ascending dose VIR-7831 (sotrovimab) for 
mild/moderate COVID-19 
Study Phase: Phase 3  
 
Acronym: COMET-TAIL (COVID-19 Monoclonal antibody Efficacy Trial– Treatment of 
Acute COVID-19 with Intramuscular monocLonal antibody) 
Sponsor Name and Legal Registered Address:  
This study is sponsored by Vir Biotechnology, Inc. 
GlaxoSmithKline is supporting Vir Biotechnology, Inc. in the conduct of this study. 
 
Vir Biotechnology, Inc. 
499 Illinois Street, Suite 500 
San Francisco, CA 94158 
USA 
 
Regulatory Agency Identifying Number(s): 
IND: 149315 
EudraCT: 2021-000623-13 
NCT: NCT04913675 
 
Copyright 2022 Vir Biotechnology, Inc. and the GlaxoSmithKline group of companies. All 
rights reserved. Unauthorized copying or use of this information is prohibited. 
 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 2 
INVESTIGATOR SIGNATURE PAGE 
 
VIR BIOTECHNOLOGY, INC 
499 ILLINOIS STREET SUITE 500 
SAN FRANCISCO, CA 94158 
 
STUDY ACKNOWLEDGMENT 
 
Title:  
A Phase 3 randomized, multi-center, open label study to assess the efficacy, safety, and 
tolerability of monoclonal antibody VIR-7831 (sotrovimab) given intramuscularly versus 
intravenously for the treatment of mild/moderate coronavirus disease 2019 (COVID-19) in high-
risk non-hospitalized patients; Safety Substudy assessing the safety and tolerability of single 
ascending dose monoclonal antibody VIR-7831 
 
This protocol has been approved by Vir Biotechnology, Inc. The following signature documents 
this approval.  
, MD 
Vir 
  
 
{See Appended Electronic Signature Page} 
Printed Name 
 
Signature and Date 
 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.  
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Vir Biotechnology, Inc. I will discuss this material with them to ensure 
they are fully informed about the drugs and the study.  
 
 
 
Principal Investigator Printed Name 
 
Signature 
 
 
 
 
 
Date 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD
PPD
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 3 
TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ............................................................................................8 
1.1. 
Synopsis ........................................................................................................................8 
1.2. 
Study Schema .............................................................................................................14 
1.3. 
Schedule of Activities .................................................................................................15 
2. 
INTRODUCTION ......................................................................................................17 
2.1. 
Study Rationale ...........................................................................................................17 
2.2. 
Background .................................................................................................................18 
2.2.1. 
Clinical Experience with Sotrovimab .........................................................................19 
2.3. 
Benefit/Risk Assessment ............................................................................................19 
2.3.1. 
Risk Assessment .........................................................................................................20 
2.3.2. 
Benefit Assessment: ....................................................................................................26 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................27 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................28 
4. 
STUDY DESIGN .......................................................................................................30 
4.1. 
Overall Design ............................................................................................................30 
4.2. 
Scientific Rationale for Study Design ........................................................................32 
4.3. 
Justification for Dose ..................................................................................................33 
4.3.1. 
Sotrovimab ..................................................................................................................33 
4.4. 
End of Study Definition ..............................................................................................34 
5. 
STUDY POPULATION: ............................................................................................35 
5.1. 
Inclusion Criteria ........................................................................................................35 
5.1.1. 
Age and Risk Factors ..................................................................................................35 
5.1.2. 
Type of Participant and Disease Characteristics ........................................................35 
5.1.3. 
Sex and Contraceptive/Barrier Requirements ............................................................35 
5.1.4. 
Informed Consent .......................................................................................................36 
5.2. 
Exclusion Criteria .......................................................................................................36 
5.2.1. 
Medical Conditions .....................................................................................................36 
5.2.2. 
Prior/Concurrent Clinical Study Experience ..............................................................37 
5.2.3. 
Other Exclusions .........................................................................................................37 
5.3. 
Pre-Screening ..............................................................................................................37 
5.4. 
Screen Failures ............................................................................................................37 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 4 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................38 
6.1. 
Study Intervention(s) Administered ...........................................................................38 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................38 
6.3. 
Randomization ............................................................................................................39 
6.4. 
Study Intervention Compliance ..................................................................................39 
6.5. 
Dose Modification ......................................................................................................39 
6.6. 
Continued Access to Study Intervention after the End of the Study ..........................39 
6.7. 
Treatment of Overdose ...............................................................................................39 
6.8. 
Concomitant Therapy .................................................................................................39 
6.8.1. 
Medication Not Permitted During the Study ..............................................................40 
6.8.2. 
Permitted Concomitant Medication ............................................................................40 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................41 
7.1. 
Discontinuation of Study Intervention........................................................................41 
7.1.1. 
Temporary Discontinuation ........................................................................................41 
7.2. 
Participant Discontinuation/Withdrawal from Study .................................................41 
7.3. 
Lost to Follow Up .......................................................................................................41 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................43 
8.1. 
Screening Period .........................................................................................................43 
8.1.1. 
Medical History ..........................................................................................................43 
8.1.2. 
SARS-CoV-2 Diagnostic Testing ...............................................................................44 
8.1.3. 
Secondary Contact Information ..................................................................................44 
8.2. 
Efficacy Assessments .................................................................................................44 
8.2.1. 
Hospitalization and Death Data Collection ................................................................44 
8.2.2. 
Phone Call for Subsequent COVID-19 Illness ...........................................................44 
8.3. 
Safety Assessments .....................................................................................................45 
8.3.1. 
Physical Examinations ................................................................................................45 
8.3.2. 
Vital Signs ..................................................................................................................45 
8.3.3. 
Electrocardiograms .....................................................................................................45 
8.3.4. 
Virologic Measures .....................................................................................................45 
8.3.5. 
Resistance Analyses ....................................................................................................46 
8.3.6. 
Clinical Safety Laboratory Assessments ....................................................................46 
8.3.7. 
Pregnancy Testing ......................................................................................................47 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 5 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting ....................................................................................................................47 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................47 
8.4.2. 
Assessment of Severity ...............................................................................................48 
8.4.3. 
Method of Detecting AEs and SAEs ..........................................................................48 
8.4.4. 
Follow-up of AEs and SAEs .......................................................................................48 
8.4.5. 
Regulatory Reporting Requirements for SAEs ...........................................................48 
8.4.6. 
Pregnancy ...................................................................................................................49 
8.4.7. 
Cardiovascular and Death Events ...............................................................................49 
8.4.8. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ...............................................................................................................50 
8.4.9. 
Adverse Events of Special Interest .............................................................................50 
8.4.9.1. 
Systemic Reactions and Hypersensitivity Reactions ..................................................50 
8.4.9.2. 
Immunogenicity ..........................................................................................................51 
8.4.9.3. 
Antibody Dependent Enhancement ............................................................................51 
8.5. 
Pharmacokinetics ........................................................................................................51 
8.6. 
Immunogenicity Assessments ....................................................................................52 
9. 
STATISTICAL CONSIDERATIONS .......................................................................53 
9.1. 
Statistical Hypotheses .................................................................................................53 
9.2. 
Sample Size Determination ........................................................................................53 
9.3. 
Analysis Sets ...............................................................................................................55 
9.4. 
Statistical Analyses .....................................................................................................55 
9.4.1. 
Primary Endpoints ......................................................................................................55 
9.4.2. 
Secondary Endpoint(s) ................................................................................................56 
9.4.3. 
Exploratory Endpoint(s) .............................................................................................56 
9.4.4. 
Other Safety Analysis .................................................................................................56 
9.4.5. 
Other Analysis ............................................................................................................56 
9.5. 
Interim Analysis ..........................................................................................................56 
9.6. 
Multiple Comparisons and Multiplicity......................................................................56 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................57 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................57 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................57 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 6 
10.1.2. 
Financial Disclosure ...................................................................................................57 
10.1.3. 
Informed Consent Process ..........................................................................................58 
10.1.4. 
Data Protection ...........................................................................................................58 
10.1.5. 
Joint Safety Review Team ..........................................................................................59 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................59 
10.1.7. 
Data Quality Assurance ..............................................................................................59 
10.1.8. 
Source Documents ......................................................................................................60 
10.1.9. 
Study and Site Start and Closure ................................................................................61 
10.1.9.1. 
First Act of Recruitment .............................................................................................61 
10.1.9.2. 
Study/Site Termination ...............................................................................................61 
10.1.10. 
Publication Policy .......................................................................................................61 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................62 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................64 
10.3.1. 
Definition of AE .........................................................................................................64 
10.3.2. 
Definition of SAE .......................................................................................................65 
10.3.3. 
Definition of Cardiovascular Events ..........................................................................66 
10.3.4. 
Recording and Follow-Up of AE and SAE ................................................................67 
10.3.5. 
Reporting of SAEs ......................................................................................................68 
10.3.6. 
Expedited Reporting to Health Authorities, Investigators and Ethics 
Committees .................................................................................................................68 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................69 
10.4.1. 
Definitions ..................................................................................................................69 
10.4.1.1. 
Woman of Nonchildbearing Potential (WONCBP) ...................................................69 
10.4.1.2. 
Woman of Childbearing Potential (WOCBP) ............................................................69 
10.4.2. 
Contraception Guidance .............................................................................................70 
11. 
REFERENCES ...........................................................................................................72 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 7 
LIST OF TABLES  
Table 1: 
Overview of Study Intervention .................................................................................38 
Table 2: 
Precision of Estimated Event Rate .............................................................................54 
Table 3: 
Protocol-Required Safety Laboratory Tests ...............................................................63 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 8 
1. 
PROTOCOL SUMMARY  
1.1. 
Synopsis  
Protocol Title:  
A Phase 3 randomized, multi-center, open label study to assess the efficacy, safety, and 
tolerability of monoclonal antibody VIR-7831 (sotrovimab) given intramuscularly versus 
intravenously for the treatment of mild/moderate coronavirus disease 2019 (COVID-19) in high-
risk non-hospitalized patients; Safety Substudy assessing the safety and tolerability of single 
ascending dose monoclonal antibody VIR-7831 
Rationale:  
There is an urgent medical need for therapeutics for the treatment of Severe Acute Respiratory 
Syndrome coronavirus-2 (SARS-CoV-2) infection, the cause of coronavirus disease 2019 
(COVID-19). Early treatment of mild and moderate disease in participants could prevent the 
more severe sequelae of COVID-19 requiring hospitalization, such as respiratory failure, 
thromboembolic disease leading to pulmonary embolism and stroke, arrhythmias, and shock. 
Furthermore, a potent treatment given early in disease could ameliorate the severity and duration 
of COVID-19 and potentially reduce transmission.  
Vir Biotechnology, Inc. (Vir) has developed a fully human neutralizing anti-SARS-CoV-2 
antibody (Pinto 2020), sotrovimab (also known as VIR-7831; GSK4182136), which has an 
Fc -modification (“LS”) that is designed to increase half-life (Ko 2014).  Sotrovimab, 
administered intravenously, has been evaluated in a Phase 3 randomized, multi-center study to 
assess the safety and efficacy for the early treatment of COVID-19 in non-hospitalized 
participants (VIR-7831-5001; GSK study 214367; COMET-ICE). The COMET-ICE study used 
the first-generation formulation of sotrovimab (Gen1) which could only be given intravenously. 
On 10 Mar 2021, the independent data monitoring committee of COMET-ICE recommended 
that the study be stopped for enrollment due to evidence of clinical efficacy. This was based on 
an interim analysis of data from 583 participants which demonstrated an 85% (p=0.002) 
reduction in hospitalization or death in participants receiving sotrovimab compared to placebo 
(Vir 2021). 
The COMET-TAIL study was then designed to assess the efficacy, safety, and tolerability of 
intramuscular (IM) sotrovimab versus intravenous (IV) sotrovimab when given to high-risk 
participants for the treatment of mild/moderate COVID-19. This study evaluated the clinical 
efficacy of two dose levels of IM sotrovimab compared with IV sotrovimab in preventing 
progression of COVID-19 by utilizing a non-inferiority (NI) design. Enrollment was completed 
on 19-AUG-2021 and the day 29 analysis indicated the following: in the IM administration 
(500mg) arm of the trial, there was a 2.7% rate of progression to hospitalization for more than 
24 hours or death through Day 29 of the trial, compared to 1.3% in the IV administration arm 
(also 500 mg). The adjusted difference between the IM and IV arms of the trial was 1.11% with a 
95% confidence interval (CI) of -1.24% to 3.45%. The upper bound of the 95% CI was within 
the predetermined 3.5% non-inferiority margin set for the trial’s primary endpoint in consultation 
with the US Food and Drug Administration (FDA). 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Page 9 
Since then, several factors have contributed to the need for evaluation of different doses of 
sotrovimab. First, the development of the Omicron variant and its sublineages has caused the 
landscape to evolve substantially as described in the COVID-19 treatment guidelines from the 
NIH (COVID-19 Treatment Guidelines Panel 2022). Understanding the safety and tolerability of 
sotrovimab across a broader dose range will provide the data should a higher dose of sotrovimab 
be required to treat a variant that is less susceptible to sotrovimab in the future. Additionally, 
evaluation of sotrovimab across a range of doses will allow for additional clinical pharmacology 
evaluation of population PK parameters.  
Thus, this study will now consist of two parts, the original protocol and the safety substudy. In 
the safety substudy, the aim will be to evaluate the safety and tolerability of a single ascending 
dose of sotrovimab when given for the treatment of mild/moderate COVID-19 to participants at 
high risk of disease progression. It will also evaluate the safety and tolerability of different 
infusion times. The existing non-clinical and clinical safety data support the evaluation of 
sotrovimab across the range of doses in this substudy. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 10 
Objectives and Endpoints (Safety Substudy):  
Objectives  
Endpoints 
Primary 
 
Safety 
Describe the safety and tolerability up through 
Day 8 of high dose ascending intravenous 
sotrovimab  
 
• 
Occurrence of adverse events (AEs) through 
Day 8 
• 
Occurrence of serious adverse events (SAEs) 
through Day 8 
• 
Occurrence of adverse events of special 
interest (AESIs) through Day 8 
• 
Occurrence of disease related events (DREs) 
through Day 8 
Secondary  
 
Safety 
Describe the safety and tolerability up through 
Week 36 of high dose ascending intravenous 
sotrovimab  
• 
Occurrence of adverse events (AEs) through 
Week 12 
• 
Occurrence of serious adverse events (SAEs) 
through Week 36 (end of study) 
• 
Occurrence of adverse events of special 
interest (AESIs) through Week 12 
• 
Occurrence of disease related events (DREs) 
through Week 12 
Safety 
Assess the immunogenicity up through Week 24 
of high dose ascending intravenous sotrovimab  
Incidence and titers (if applicable) of serum anti-
drug antibody (ADA) and neutralizing antibody 
(if applicable) to sotrovimab through Week 24 
Pharmacokinetics 
Assess the pharmacokinetics (PK) up to Week 24 
of high dose ascending sotrovimab in serum 
following IV administration 
 
IV sotrovimab pharmacokinetics (PK) in serum 
through Week 24 
Exploratory  
 
Efficacy 
Evaluate the efficacy up through Day 29 of high 
dose ascending intravenous sotrovimab in 
preventing the progression of mild/moderate 
COVID-19  
Progression of COVID-19 through Day 29 as 
defined by: 
• 
Hospitalization > 24 hours for acute 
management of illness due to any cause 
OR 
• 
Death 
Efficacy 
Evaluate the efficacy up through Day 29 of high 
dose ascending intravenous sotrovimab in 
preventing the progression of mild/moderate 
COVID-19  
Progression of COVID-19 through Day 29 as 
defined by: 
• 
Visit to a hospital emergency room for 
management of illness  
OR 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 11 
Objectives  
Endpoints 
• 
Hospitalization for acute management of 
illness for any duration and for any cause 
OR 
• 
Death 
Efficacy 
Evaluate the efficacy up through Day 29 of high 
dose ascending intravenous sotrovimab in 
preventing the progression of COVID-19 
respiratory disease  
Development of severe and/or critical respiratory 
COVID-19 as manifested by requirement for 
respiratory support (including oxygen) at Day 8, 
Day 15, Day 22, and Day 29  
Efficacy 
Describe the effect of high dose ascending 
intravenous sotrovimab on the incidence of ICU 
stay and mechanical ventilation use through 
Day 29  
Incidence of participants requiring ICU stay or 
mechanical ventilation through Day 29 
Resistant Mutants 
Monitor SARS-CoV-2 resistant mutants against 
sotrovimab through Day 29 
• 
SARS-CoV-2 resistance mutants to 
sotrovimab at baseline 
• 
Emergence of viral resistance mutants to mAb 
by SARS-CoV-2  
Virologic Activity 
Evaluate the virologic activity of high dose 
ascending intravenous sotrovimab in reducing 
SARS-CoV-2 viral load through Day 29 
• 
Change from baseline in viral load in nasal 
secretions by qRT-PCR during the follow-up 
period at Day 5, Day 8, Day 11, Day 15, 
Day 22, and Day 29 
• 
Undetectable SARS-CoV-2 in nasal 
secretions by qRT-PCR at Day 3, Day 5, 
Day 8, Day 11, Day 15, Day 22, and Day 29 
• 
Proportion of participants with a persistently 
high SARS-CoV-2 viral load at Day 8 by 
qRT-PCR 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 12 
Overall Design:  
The safety substudy is designed as a multi-center, open label substudy of high dose intravenous 
sotrovimab in participants with early, mild/moderate COVID-19 who are not on supplemental 
oxygen and are at risk for disease progression.  Participants will receive an IV infusion of 
sotrovimab at different doses and infusion times (2000 mg infused over 60 minutes [planned], 
30 minutes [optional] and 15 minutes [optional]) and up to 3000 mg (infused over 90 minutes 
[optional]) depending on which cohort the participant is enrolled in.  
A total of up to 500 participants will be enrolled in this substudy and the cohorts will occur as 
outlined in the study schema (Section 1.2). 
• Cohort A: Approximately 200 participants will be enrolled in Cohort A and receive 
2000 mg of sotrovimab infused over 60 minutes.  
o 30 participants will be enrolled in a safety lead in, and relevant safety data 
through Day 8 will be reviewed by the Joint Safety Review Team (JSRT). Note, 
there will be no pause in Cohort A while the safety lead in data is reviewed. 
o 170 additional participants will then be enrolled to complete Cohort A. 
Enrollment will pause and a review of relevant safety data through Day 8 for 
these remaining participants in Cohort A will be performed by the JSRT. Looking 
at the totality of the data for 200 participants, the JSRT will make a safety 
assessment and a decision to open Cohorts B1 and/or C will be made.  
• Optional Cohort B1: If a decision to proceed to cohort B1 is made, approximately 
50 participants will receive 2000 mg of sotrovimab infused over 30 minutes. The JSRT 
will then pause and review the relevant safety data through Day 8 from Cohort B1. 
Following the JSRT’s safety assessment, a decision to open Cohort B2 will be made. 
• Optional Cohort B2: If a decision to proceed to Cohort B2 is made, approximately 50 
participants will be enrolled, and they will each receive 2000 mg of sotrovimab infused 
over 15 minutes. Review of relevant safety data through Day 8 will then be performed by 
the JSRT. 
• Optional Cohort C: If a decision to proceed to Cohort C is made, approximately 
200 participants will be enrolled in Cohort C, and they will each receive up to 3000 mg of 
sotrovimab, infused over 90 minutes. Note that this cohort may occur immediately after 
Cohort A. 
o 30 participants will be enrolled in a safety lead in, and relevant safety data 
through Day 8 will be reviewed by the JSRT. Note, there will be a pause in 
enrollment while relevant safety data through day 8 from the safety lead in group 
is reviewed. 
o 170 additional participants will then be enrolled into this cohort. The JSRT will 
then meet to review safety data through Day 8 from this complete cohort.   
o If a lower dose than 2000 mg is selected for this cohort, there will be no safety 
lead-in for Cohort C and the infusion and monitoring times will be determined 
following safety review by the JSRT based on available safety data.  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 13 
Cohorts B1, B2 and C will all be considered optional cohorts and can be opened following 
completion of the Cohort A safety assessment by the JSRT (B1 and C; B2 following JSRT safety 
assessment of B1).  
After IV infusion, participants in the safety lead in Cohort A, and potentially Cohort C if a dose 
higher than 2000 mg is administered, will be monitored for 2 hours with vital signs assessments 
performed at 15 minutes, 30 minutes, 45 minutes, 1 hour and 2 hours. Participants in the 
remainder of Cohort A (and potentially Cohort C), Cohorts B1 and B2 will be monitored for up 
to 1 hour. As detailed in the Schedule of Activities, participants will be actively monitored on an 
outpatient basis with frequent collection of safety information through weekly in-clinic 
evaluations at Weeks 1, 2, 3, and 4, nasopharyngeal swabs for virology, and blood draws for PK 
sampling. Starting at Week 8, participants will be monitored monthly via phone call or in-clinic 
evaluation to assess for the incidence and severity of subsequent COVID-19 illness, if any, for a 
total of 36 weeks from dosing. 
Number of Participants:  
Approximately 200 participants (up to 500 with the optional cohorts) will be enrolled into this 
safety substudy.  
In Cohort A of the safety substudy, 200 participants will be enrolled to receive a single 2000 mg 
IV infusion of sotrovimab over 60 minutes. Optional Cohorts B1 and B2 (in which participants 
will receive 2000 mg IV infusion of sotrovimab over 30 minutes and 15 minutes, respectively) 
will each enroll 50 participants. 
Optional Cohort C (in which participants will receive up to 3000 mg IV infusion of sotrovimab 
over 90 minutes) will enroll 200 participants.  
Intervention Groups and Duration:  
Screening assessments in the safety substudy will be performed within 48 hours prior to 
randomization. There is no required minimum amount of time from screening to randomization 
provided that all eligibility criteria are met/confirmed. 
Eligible participants will be treated with a single IV dose of 2000 or up to 3000 mg sotrovimab 
on Day 1 (depending on which cohort the participant is in) and followed for up to 36 weeks.  
This is an open label study and all participants enrolled will receive sotrovimab treatment. 
Should multiple optional cohorts (i.e., Cohort B1 and Cohort C) be enrolling at the same time, 
participants will be randomly assigned to a cohort using a pre-defined schema. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 14 
1.2. 
Study Schema  
  
 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 15 
1.3. 
Schedule of Activities  
Study Stage 
Screening Dosing 
Follow-up Period 
Study Visit Week 
 
 
W1 
W2 
W3 
W4 
W8 i  W12 W16 i  W20 
W24 
(EWj) W28 i  W32 i  
W36 i  
(EOS/E
W) 
Study Visit Day ± Visit Window 
D -2 to 1 
D1 
D
3 
D5±
1 
D8±
1 
D11±
1 
D15±
1 
D22±
1 
D29±2 D57±
4 
D85±
7 
D113±
7 
D141±
7 
D169±
7 
D197±7 D224±
7 
D252±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria including baseline 
COVID-19 symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
Xa 
Xa 
Xa 
 
Xa 
 
Xa 
Xa 
Xa 
 
 
 
 
 
 
 
 
Body weight & height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (including O2 saturation) 
X 
Xb 
 
 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
Local safety lab assessments 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessments 
 
Xd 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
SARS-CoV-2 diagnostic test h 
(point-of-care or local laboratory test) 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Electrocardiogram 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administrationk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for virology 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Blood sample for PK analysis 
 
Xf 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
Blood sample for anti-drug antibody 
 
Xd 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
Phone call for subsequent COVID19 illnessm  
 
X 
 
X 
 
 
X 
X 
X 
Clinic visit for subsequent COVID19 illnessm 
 
 
X 
 
X 
X 
 
 
 
Review/record AE/SAE  
 
Xg 
Concomitant medications 
 
X 
a  Complete physical examination should be performed on Day 1; all other visits should be symptom-directed physical examinations. 
b For lead-ins in Cohorts A and C, vital signs on Day 1 should be recorded prior to dose administration and at 15 mins (± 5 mins) and 30 mins (± 5 mins), 45 min (± 5 min), 1 hour 
(± 5 mins), and 2 hours (± 5 mins) post dosing. For all other participants (outside of those included in the lead-ins in Cohorts A and C), vital signs should be recorded at 15 mins 
(± 5 mins), 30 mins (± 5 mins), 45 min (± 5 min) and 1 hour (± 5 mins) post dosing 
c All local lab assessments may be performed or not as determined necessary by the investigator or required by local regulations.  
d On Day 1, sample collection will occur pre-dose. 
e Electrocardiogram at screening only for participants with a history of cardiovascular disease or diabetes 
f On Day 1, PK sample will be collected pre-dose and at the end of infusion 
g Adverse events will be assessed up to Week 12 post dose. Serious adverse events (SAEs) will be assessed up to Week 36. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 16 
h Participants may be tested at screening if symptom onset ≤ 7 days, but dosing (D1 visit) must also occur ≤ 7 days of symptom onset. 
i Week 8, Week 16, Week 28, Week 32 and Week 36 are planned as site phone calls to participants only. 
j If subject withdraws early from the study prior to Week 24, then the W24 visit assessments will be performed as the EW visit. If subject withdraws early from the study after 
Week 24, the W36 visit assessments will be performed as the EW visit. 
k Cohort A 2000 mg to be infused over 60 minutes, Cohort B1 2000 mg to be infused over 30 minutes, Cohort B2 2000 mg to be infused over 15 minutes, Cohort C (up to 3000 
mg to be infused over 90 minutes if 3000 mg is selected) 
l Note, randomization may only apply if enrolling Cohorts B1 (2000 mg IV over 30 minutes) and Cohort C (up to 3000 mg IV over 90 minutes if 3000 mg is selected) 
simultaneously 
m Clinic visits should be planned only when study samples need to be collected 
 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 17 
2. 
INTRODUCTION  
2.1. 
Study Rationale  
In this amendment, the safety substudy is designed as a phase 3, multi-center, open label study of 
intravenous (IV) administration of sotrovimab, a monoclonal antibody (mAb) against 
SARS-CoV-2 for the prevention of progression of mild/moderate COVID-19 in participants 
18 years old and older at high risk of disease progression. High-risk adults include participants 
≥55 years old regardless of co-morbidities and individuals age 18 or older with comorbidities 
associated with worse outcomes in adults, including diabetes, obesity (BMI≥30), chronic kidney 
disease, congestive heart failure, chronic lung diseases (i.e. chronic obstructive pulmonary 
disease, moderate to severe asthma requiring steroids, interstitial lung disease, cystic fibrosis, 
and pulmonary hypertension), immunosuppressive disease or immunosuppressive medications, 
or chronic liver disease (CDC 2021). The study will include participants infected with 
SARS-CoV-2, the virus that causes COVID-19, as confirmed by local laboratory tests and/or 
point of care tests.  
Enrollment in the study will be performed at study site, based on hospital local practice. If a 
patient agrees to participate and qualifies, his/her primary doctor will be informed as per local 
regulation of his/her study participation by the study doctor. 
Sotrovimab has been studied in a Phase 3 placebo-controlled trial evaluating the efficacy of 
sotrovimab in preventing progression of COVID-19 in high-risk participants with mild/moderate 
COVID-19 (VIR-7831-50001; COMET-ICE). On 10 Mar 2021, the independent data monitoring 
committee for COMET-ICE recommended that the study be stopped for enrollment due to 
evidence of clinical efficacy. This was based on an interim analysis of data from 583 participants 
which demonstrated an 85% (p=0.002) reduction in hospitalization or death in participants 
receiving sotrovimab compared to placebo. Sotrovimab was well-tolerated with no safety signals 
detected. (Vir 2021)  
The COMET-TAIL study was then designed to assess the efficacy, safety, and tolerability of 
intramuscular (IM) sotrovimab versus intravenous (IV) sotrovimab when given to high-risk 
participants for the treatment of mild/moderate COVID-19. This study evaluated the clinical 
efficacy of two dose levels of IM sotrovimab compared with IV sotrovimab in preventing 
progression of COVID-19 by utilizing a non-inferiority (NI) design. Enrollment was completed 
on 19-AUG-2021 and the day 29 analysis indicated the following: in the IM administration 
(500mg) arm of the trial, there was a 2.7% rate of progression to hospitalization for more than 
24 hours or death through Day 29 of the trial, compared to 1.3% in the IV administration arm 
(also 500 mg). The adjusted difference between the IM and IV arms of the trial was 1.11% with a 
95% confidence interval (CI) of -1.24% to 3.45%. The upper bound of the 95% CI was within 
the predetermined 3.5% non-inferiority margin set for the trial’s primary endpoint in consultation 
with the US Food and Drug Administration (FDA). 
Since then, several factors have contributed to the need for evaluation of different doses of 
sotrovimab. First, the development of the Omicron variant and its sublineages has caused the 
landscape to evolve substantially as described in the COVID-19 treatment guidelines from the 
NIH (COVID-19 Treatment Guidelines Panel 2022). 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 18 
In the safety substudy, the aim will be to evaluate the safety and tolerability of sotrovimab across 
a single ascending dose level and over different infusion times when given for the treatment of 
mild/moderate COVID-19 to participants at high risk of disease progression. The existing non-
clinical and clinical safety data support evaluation of sotrovimab across the range of doses in this 
sub study. The study will monitor for serious adverse events through Week 36. Additional 
information regarding data analysis is included in the statistical sections of this protocol and 
further details will be included in the statistical analysis plan (SAP). 
2.2. 
Background  
In December 2019, SARS-CoV-2, a novel betacoronavirus, was first reported to cause severe 
pneumonia in Wuhan, China and subsequently had a rapid spread around the world. As of May 
2022, over 521 million cases of COVID-19 and over 6.3 million associated deaths have been 
reported globally, and over 82 million cases including over 999,000 deaths have been reported in 
the US (JHU 2022).  
Sotrovimab is being developed for the prevention and treatment of COVID-19. Sotrovimab is a 
human IgG1κ mAb derived from the parental mAb S309, a mAb directed against the spike 
protein of SARS-CoV-1 that potently cross-neutralizes SARS-CoV-2, the causative agent of 
COVID-19 (Pinto 2020). Sotrovimab has an Fc modification (“LS”) that is designed to improve 
bioavailability in the respiratory mucosa and increase half-life. Sotrovimab binds with high 
affinity to the receptor binding domain of the SARS-CoV-2 spike protein. Sotrovimab retains 
neutralization activity in vitro against variants of concern and interest of the SARS-CoV-2 virus 
as defined by the World Health Organization, including, but not limited to, B.1.1.7 (Alpha, UK 
origin), B.1.351 (Beta, South Africa origin), P.1 (Gamma, Brazil origin), B.1.427/B.1.429 
(Epsilon, California origin) B.1.526 (Iota, New York origin), B.1.617.1 (Kappa, India origin), 
B.1.617.2 (Delta, India origin), AY.1 (Delta Plus, India origin), AY.2 (Delta Plus, India origin), 
C.37 (Lambda, Peru origin), B.1.621 (Mu, Colombia origin), B.1.1.529/BA.1 (Omicron, South 
Africa origin), and B.1.1.529/BA.1.1 (Omicron, South Africa origin) (Cathcart 2022) variant 
spike proteins with fold-changes in half maximal effective concentration (EC50) values of less 
than 5-fold as compared to wild-type spike. In vitro neutralization experiments indicate that 
sotrovimab neutralizes authentic Omicron BA.2 virus with a 15.7-fold change in EC50 value 
relative to wild-type (Cathcart 2022).  Sotrovimab neutralized authentic Omicron BA.2 virus 
with a geometric mean EC90 value of 9476.3 ng/mL (range: 6796.8 to 14760.0 ng/mL; 35.1-fold 
change in EC90 value relative to wild-type) (PC-7831-0155). 
Sotrovimab has been demonstrated to reduce hospitalization and/or death by 79% in non-
hospitalized participants with mild to moderate COVID-19 who are at risk of progressing to 
severe disease when administered intravenously (IV) within 7 days of infection in a Phase 3 
early treatment study COMET-ICE (Study VIR-7831-5001/GSK Study 214367) 
(Sotrovimab 2022). PK parameters are available from 9 participants in the Lead-in Phase of 
COMET-ICE. The geometric mean Cmax of 500 mg sotrovimab is 246 µg/mL (%CVb 39.4) 
following a 1-hr IV infusion. The estimated steady state volume of distribution is 7 L (%CVb 
11.6) indicating limited distribution outside the vascular space.  Sotrovimab has a geometric 
mean clearance of 90.3 mL/day (%CVb 25.2) and a median (min, max) half-life of 
56.5 (42.4, 77.3) days. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 19 
2.2.1. 
 Clinical Experience with Sotrovimab   
As of 18 August 2021, a total of 1843 participants have received sotrovimab (500 mg dose) 
administered IV or intramuscularly in the Vir/GSK-sponsored clinical studies. Sotrovimab has 
been well tolerated when administered both intravenously and intramuscularly with no serious 
safety concerns identified to date. A summary of serious adverse event (SAE) and other safety 
data are included for these studies in the sotrovimab Investigator’s Brochure. 
Sotrovimab received Emergency Use Authorization in the US based on the results from 
COMET-ICE, a seamless FIH/Phase 2/3 study assessing the safety and efficacy of a single 
500 mg IV dose of sotrovimab for the early treatment of COVID-19 in non-hospitalized 
participants at high risk for progression and subsequent hospitalization. Based on the results from 
COMET-ICE, temporary Authorizations have also been granted for sotrovimab in several 
countries, including Canada (Interim Order), Singapore (Pandemic Special Access), United Arab 
Emirates, Bahrain, Kuwait, Oman, Qatar, Thailand, and Brazil; provisional/conditional 
marketing approval has been granted in Australia, Saudi Arabia, United Kingdom, Japan and 
Switzerland; and full marketing approval has been granted in the European Union. 
Other ongoing Vir/GSK-sponsored studies include a Phase 2 COMET-PEAK safety, PK, and 
virology study in early treatment (VIR-7831-5006/GSK Study 216912; NCT04779879), a Phase 
3 COMET-TAIL study of intramuscular injection for early treatment (VIR-7831-5008), a Phase 
2 study COMET-PACE study in pediatric participants for early treatment (VIR-7831-5005), and 
a Phase 1 pharmacokinetic (PK) study with healthy Japanese participants (VIR-7831-5009/GSK 
Study 217653; NCT04988152). In addition, Vir/GSK supported clinical studies (ACTIV-3-TICO 
[VIR-7831-5004, GSK Study 215149], BLAZE-4 [VIR-7831-5007, 217079]) are evaluating 
sotrovimab as a single agent or in combination. A summary of SAE and other safety data are 
included for these studies in the sotrovimab Investigator’s Brochure (IB).  
Sotrovimab at 1000 mg IV is also being evaluated in the UK-based RECOVERY platform trial, 
where hospitalized participants with confirmed COVID-19 are randomized to receive different 
candidate therapies. The RECOVERY Trial Independent Data Monitoring Committee’s 
04 March 2022 review of safety and efficacy data, inclusive of 568 participants that received 1 g 
IV sotrovimab, suggested no reason to modify the protocol.  
To date, partial Gen 2 IV PK is available from BLAZE-4 (NCT04634409), COMET-PEAK 
(NCT04779879) and the Japan PK Study (NCT04988152).  
2.3. 
Benefit/Risk Assessment  
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 20 
2.3.1. 
Risk Assessment  
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention: Sotrovimab 
Infusion reactions 
including 
hypersensitivity 
reactions (HSR) 
While sotrovimab is a fully human IgG, Systemic reactions 
(SR), including hypersensitivity reactions, are a potential 
general risk associated with the mAb class of therapeutics. 
 
Given the totality of pre-clinical and clinical data to date it is the 
Sponsor’s position that a up to 3000 mg dose may be safely used 
in individuals with mild to moderate COVID-19. 
 
There was no evidence of systemic infusion reactions in 
toxicology studies were conducted with sotrovimab in monkeys.  
 
Available safety data from the clinical development program 
comes from evaluation of a 500 mg dose of sotrovimab 
administered by IV infusion, a 500 mg and a 250 mg dose 
administered by IM injection for early treatment of COVID-19, 
and a 1000 mg dose currently being evaluated in an ongoing 
clinical study in hospitalized participants with severe 
COVID-19. Safety data from the clinical program to date have 
demonstrated a low rate of adverse events at the time of Day 29 
analysis, particularly SAE and Grade 3-4 AEs. The 
COMET-ICE (Phase 2/3) and COMET-TAIL (Phase 3) studies 
demonstrated infrequent Grade 3 and 4 AEs and SAEs in the 
treatment groups.  
 
COMET-TAIL did not demonstrate a pattern of incrementing 
safety findings associated with increasing dose or exposure as it 
compared 250 mg IM to 500 mg IM and 500 mg IV dosing. 
Participant selection:  
Participants will be excluded if they have a history of 
hypersensitivity to any of the excipients present in the 
investigational product. 
 
Monitoring: 
• 
During the Lead-In phase, participants will be 
monitored regularly at 15 minutes, 30 minutes, 45 
minutes, 1 hour, and 2 hours post-administration 
of study treatment (including vital signs, see the 
SoA in Section 1.3). Post-infusion monitoring 
time will only be reduced to 1 hour for additional 
participants enrolled after the lead in phase is 
complete. 
• 
A Joint Safety Review Team (JSRT) review will 
be conducted at regular intervals, inclusive of 
active monitoring of lead-in data.  
o JSRT will review safety data before 
completing full cohort enrollment (after 
lead in phases), before any dose escalation 
(to review safety of the dose just prior to 
it) and before any decreases in infusion 
times (to review safety of the infusion 
time just prior to it) 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
 
Amendment 4 
Vir Biotechnology, Inc. 
Page 21 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 
In the COMET-ICE study in participants with mild/moderate 
COVID-19 at high risk of progression, IRRs that occurred 
within 24 hours post infusion (pyrexia, chills, dizziness, 
dyspnea, pruritus, rash, and other infusion-related reaction) were 
reported in 6 (1%) of participants in the sotrovimab arm and 
6 (1%) of participants in the placebo arm. All IRRs were 
nonserious, and Grade 1 or 2 severity and none led to treatment 
pausing or discontinuation. In the sotrovimab arm, all of the 
cases of IRRs were considered resolved and in the placebo arm, 
one participant had an event considered not resolved at the time 
of data cut-off. In COMET-ICE, all HSRs observed in the study 
were nonserious, of Grade 1 (mild) or Grade 2 (moderate) 
severity and reported in 2% of participants who received 
sotrovimab and in <1% who received placebo (9 participants 
treated with sotrovimab; 5 participants treated with placebo). 
None of the reactions in either arm led to pausing or 
discontinuation of the infusions. All events across both 
treatment groups were reported as resolved or resolving at the 
time of data cut-off.  
 
No anaphylaxis events were reported in the COMET-ICE study 
in participants with mild to moderate COVID-19 not requiring 
hospitalization at study entry.  
 
No anaphylaxis or serious hypersensitivity reactions were 
reported in the COMET-TAIL study in participants with mild to 
moderate COVID-19 not requiring hospitalization at study entry. 
 
 
 
• 
Investigational product will be administered in the 
clinic with staff trained in emergency care and 
resuscitation procedures with emergency care kit 
on hand during the study intervention 
administration and post-therapy observation 
periods.  
• 
Investigators will be instructed to discontinue IV 
infusions for participants who develop Grade 3 or 
higher infusion reactions. 
• 
If a participant experiences a Grade 2 IRR, 
investigators will be instructed to pause the 
infusion. The infusion may subsequently resume 
at a slower pace, at the investigator’s discretion, 
and/or after symptomatic treatment (eg, 
antihistamines, IV fluids). 
• 
Infusion-related reactions including HSRs will be 
categorized as AESIs (as has been done in the past 
for other studies). 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 22 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
A potentially life-threatening allergic reaction (anaphylaxis) was 
observed in 1 adult participant who received sotrovimab in the 
study of individuals hospitalized with COVID-19 (the 
ACTIV-3-TICO study). The anaphylaxis was considered by the 
investigator to be related to study intervention. The participant 
was treated for the allergic reaction and recovered. 
Additional cases of anaphylaxis after dosing have been reported 
from post-marketing pharmacovigilance. 
 
The RECOVERY trial is a pragmatic platform clinical trial 
evaluating different treatments in hospitalized participants with 
serious COVID-19 and is currently ongoing in the UK. Given 
the pragmatic nature of the trial, limited safety data are collected 
during the course of the study with the focus being on SAEs that 
are believed to be related (with reasonable possibility) to the 
study treatment. RECOVERY is not a GSK/Vir sponsored trial, 
and therefore Vir does not currently have direct access to the 
blinded safety data from this study. However, a trial DMC letter 
dated 11 May 2022 noted that recruitment is ongoing and as of 
2 May 2022, 996 participants had been randomized 1:1 
(sotrovimab: standard of care). This trial DMC letter (dated 
11 May 2022) also confirmed that review of safety data on 
996 patients (1:1 sotrovimab: standard of care) was completed 
and  that the trial may continue with no changes in conduct 
[DMC Report 2022]. The RECOVERY team has confirmed that 
up to the 21 March 2022 there has been only 1 related SAE 
reported. This was a case of suspected allergic reaction treated 
with adrenaline. The participant apparently improved within 2 
hours without further complication and was discharged 5 days 
later. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 23 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Enhanced risk of 
systemic reactions 
including 
hypersensitivity 
reactions (SR/HSR) 
due to higher dose 
levels 
See “Infusion reactions including hypersensitivity reactions 
(HSR)” 
 
It is possible that the risk of infusion reactions may be enhanced 
due to increase doses used, however as noted in the dose 
justification: the no-observed-adverse-effect-level for VIR-7831 
was established when VIR-7831 was administered via IV 
infusion at 500 mg/kg (the highest dose tested) once a week for 
2 weeks in cynomolgus monkeys (TX-7831-0102). Based on a 
preliminary population PK model for sotrovimab, the predicted 
AUCinf following a 2000 mg IV dose is 21,400 µg*day/mL and 
predicted Cmax is 636 µg/mL. Based on the proposed 2000 mg 
IV dose, the margins based on nonclinical Cmax and AUC 
margins of 21- and 10x, respectively, support the proposed 
clinical dose of 2 g IV. The AUCinf following a 3 g IV dose is 
32,100 µg*day/mL and predicted Cmax is 954 µg/mL. Based on 
the proposed 3000 mg IV dose, the margins based on nonclinical 
Cmax and AUC margins of 14- and 7x, supporting the proposed 
doses up to 3000 mg. 
See Mitigation Strategy for "Infusion reactions 
including hypersensitivity reactions (HSR)” 
Enhanced risk of 
systemic reactions 
including 
hypersensitivity 
reactions (SR/HSR) 
due to decreased 
infusion times 
See “Infusion reactions including hypersensitivity reactions 
(HSR)”  
It is possible that decreased infusion times in Cohort B1 (30-
minute infusion time of 2000 mg) and B2 (15-minute infusion 
time of 2000 mg) may enhance the possibility of a systemic 
reaction including hypersensitivity reactions (SR/HSR) 
See Mitigation Strategy for "Infusion reactions 
including hypersensitivity reactions (HSR)” 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 24 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Immunogenicity 
While sotrovimab is a fully human IgG, the development of 
anti-drug antibodies (ADA) that have the potential to impact 
safety and/or efficacy are a potential general risk associated with 
the mAb class of therapeutics. 
Monitoring: 
This study will include participant follow-up for a 
period of 36 weeks to assess for the potential of 
immunogenicity (measurement of ADA) as well as if 
ADA is potentially causally associated with specific 
safety concerns and/or impact efficacy. 
Antibody 
Dependent 
Enhancement 
(ADE) due to sub-
neutralizing levels 
of sotrovimab 
enhancing fusion or 
leading to FcR 
mediated increased 
viral uptake and 
replication with 
virus production 
This is a concern related to the potential for participants with 
sub-neutralizing mAb levels to experience a higher incidence of 
infection and/or more severe disease compared to participants 
with no circulating mAb and/or established protective immunity 
to SARS-CoV-2.  
ADE associated with Dengue virus 1-4 serotype infections is 
one of the most widely cited examples in which reinfection with 
a different serotype can, in a minority of participants, run a more 
severe course in the setting of limited antibodies generated by 
prior infection.  
The potential for enhanced disease in this setting is due to 
increased uptake of virus by FcR-expressing cells, such as 
macrophages, and increased viral replication in these cells. 
Recent data shows that SARS-CoV-2 does not replicate 
efficiently in macrophages [Hui 2020], suggesting minimal to no 
risk of ADE via this mechanism.  
As of 10 March 2021, the COMET ICE study enrollment has 
been stopped based profound efficacy on the recommendation of 
IDMC. The total of 1057 participants have been randomized to 
either the IV infusion of sotrovimab Gen1 (500 mg dose) or 
placebo. Based on the Joint SRT review of blinded data, there 
has been no confirmed events of ADE. 
Monitoring: 
There is a safety lead in of 30 subjects for the initial 
2000 mg and 3000 mg cohorts (Cohorts A and C) to 
aid in early detection of ADE.  
We recognize that ADE may not present until later 
time points, thus 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 
sotrovimab levels.  
Assessments for unusually severe disease in mAb-
treated participants will be performed by the JSRT to 
assess for unusually severe disease in mAb-treated 
participants. Re-infection will be assessed as new 
SAEs related to COVID-19 infection during follow up 
period. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 25 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
ADE due to 
enhanced disease 
pathology from 
viral antigen-
antibody related 
immune complex 
deposition or 
complement 
activation and 
immune cell 
recruitment in 
target organs 
There is the possibility that a large amount of antibody that 
binds, but does not neutralize, virus in the presence of a high 
viral load could result in immune complex deposition and 
complement activation in tissue sites of high viral replication, 
such as the lungs, vascular endothelia, renal or cardiovascular 
tissue [Hamming 2004], leading to tissue damage/immune 
complex disease 
This is hypothesized to have contributed to inflammation and 
airway obstruction observed in the small airways of infants who 
received a formalin-inactivated (FI) respiratory syncytial virus 
(RSV) vaccine [Polack 2002] and in a few cases of fatal H1N1 
influenza infection [Wu 2010] 
The potential for enhanced disease in this setting may be due to 
low affinity or cross-reactive antibodies with poor or no 
neutralizing activity. 
Triggering of cytokine release by antibody-virus-FcγR 
interactions although usually highly beneficial due to their direct 
antiviral effects and immune cell recruitment to control viral 
spread in tissues, also has the potential to enhance pathologic 
changes initiated by the viral infection. 
Observational data from 20,000 COVID-19 participants 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] 
Sotrovimab shows potent binding in vitro as well as 
neutralization of pseudovirus and live virus thus this risk is 
deemed to be low. 
In clinical studies to as of May 2022 there has been no evidence 
of ADE associated with sotrovimab. 
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 sotrovimab 
levels.  
Periodic review of clinical signs and symptoms of 
COVID-19, clinical chemistry, AEs, end-organ 
disease and histopathological diagnoses will be 
performed by the JSRT to identify potential cases of 
immune complex disease.  
Assessments for unusually severe disease in mAb-
treated participants will be performed by the JSRT. 
Re-infection will be assessed as new SAEs related to 
COVID-19 infection during follow-up period. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 26 
2.3.2. 
Benefit Assessment:  
There is a biological rationale which supports the use of sotrovimab, an antiviral mAb in the 
early treatment of COVID-19 to prevent progression. Sotrovimab has been demonstrated in vitro 
to be a highly potent fully human IgG neutralizing SARS-CoV-2 antibody which has the 
potential to be an effective therapeutic in mild to critically ill participants with COVID-19. 
Sotrovimab does not bind to normal human tissues in a tissue cross-reactivity study and there 
were no adverse findings after 2 weeks in the 2-week repeat dose monkey toxicity study. The 
no -observed -adverse -effect-level (NOAEL) in the monkey study was 500 mg/kg, the highest 
dose tested. 
Intravenous sotrovimab has been shown in a Phase 3 study (COMET-ICE) to be highly effective 
at preventing progression of mild/moderate COVID-19 when administered to participants who 
are at high-risk for severe disease. Furthermore, other anti-SARS-CoV-2 mAbs (bamlanivimab 
+/- etesevimab, casirivimab/imdevimab) have preliminarily been shown to decrease respiratory 
viral load and prevent progression to hospitalization or severe disease. (Chen 2020; Eli Lilly 
2021; Weinreich 2021) 
Available data suggest that SARS-CoV-2 infection is associated with variable incubation period, 
dependent on factors such as the infecting variant, patient risk group and vaccination status. 
Studies conducted from the first phase of the pandemic in 2020 describe the median incubation 
period as greater than five days [Lauer 2020]. Further studies looking at the Delta variant 
estimate this period to be four days [Grant 2022]. Whilst epidemiological studies on the Omicron 
variant are still ongoing, early research suggests the median incubation period for this variant is 
approximately three days [Brandal 2021; Helmsdal 2021; Jansen 2021]. The median time to 
progression to severe disease (ICU admission/development of acute respiratory distress 
syndrome) from onset of symptoms has been estimated to be 12 days (range 8 to 15 days) with a 
median duration from onset to death or discharge of 21 days (range 17 to 25 days) [Zhou 2020]. 
In addition, viral loads are highest early in the course of disease and tend to fall once severe 
sequelae have ensued, although remain detectable by RT-PCR well into the course of disease 
[Zhou, 2020; Wölfel, 2020]. The average duration of SARS-CoV-2 RNA shedding is estimated 
at 17·0 days in upper respiratory tract, 14·6 days in lower respiratory tract, 17·2 days in stool, 
and 16·6 days in serum samples [Cevik, 2021]. Notably, although viral nucleic acid can be 
detected well after symptom resolution in individuals with mild infection, shedding of infectious 
virus in sputum appears to be limited to the first week of symptoms [Wölfel, 2020]. 
These data suggest that early intervention with a potently neutralizing antibody prior to the onset 
of severe sequelae of disease may effectively prevent disease progression and hasten the 
resolution of disease.  This study is warranted given that COVID-19 is considered a serious 
disease or condition - defined as a disease or condition associated with morbidity that has 
substantial impact on day-to-day functioning, and that may lead to more severe complications. 
Throughout the pandemic, the SARS-CoV-2 virus has continued to mutate, resulting in new 
variants. Some of these variants emerge and disappear while others persist. Because new variants 
will continue to emerge, this substudy is designed to collect clinical safety data at higher dose(s) 
of sotrovimab. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 27 
2.3.3. 
Overall Benefit: Risk Conclusion  
The overall benefit-risk assessment considers the potential benefit of sotrovimab treatment 
through the potential ability to suppress viral replication and clear infected cells. The benefit in 
preventing the progression of mild to moderate non-hospitalized COVID 19 in high-risk 
participants has been demonstrated. 
In addition, based on data from ~ 1200 non hospitalized and hospitalized subjects who have 
received IV infusion of sotrovimab in clinical studies performed by the sponsor, there have been 
no significant safety concerns observed as of 19-FEB-2022. Although there is a theoretical risk 
of ADE with anti-SARS-CoV2 mAbs in the presence of infection, no evidence of ADE with 
SARS-CoV-2 has been observed in the available literature to date. 
In this safety substudy, participants will be closely monitored by medical monitoring and 
frequent JSRTs during this study.  Safety will be monitored as described and decreases in 
infusion time will not be pursued unless it is agreed that there are no safety signals seen in 
previous cohorts. 
The higher doses of sotrovimab tested in this study introduce the theoretical possibility of 
increased infusion related reactions and adverse events; however, the strong non-clinical profile 
with wide margins, and the robust safety profile of sotrovimab 500 mg across multiple clinical 
studies and 1000 mg in the RECOVERY study (without evidence of safety signals) suggest that 
higher doses will be beneficial to the population at need, with minimal risk.  
Based on the unmet medical need and considering the measures taken to minimize risk to 
participants taking part in this study, the potential risks identified in association with sotrovimab 
are justified by the anticipated benefits that may be afforded to participants with mild to 
moderate COVID-19. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 28 
3. 
OBJECTIVES AND ENDPOINTS  
Objectives  
Endpoints 
Primary 
 
Safety 
Describe the safety and tolerability up through 
Day 8 of high dose ascending intravenous 
sotrovimab  
 
• 
Occurrence of adverse events (AEs) through 
Day 8 
• 
Occurrence of serious adverse events (SAEs) 
through Day 8 
• 
Occurrence of adverse events of special 
interest (AESIs) through Day 8 
• 
Occurrence of disease related events (DREs) 
through Day 8 
Secondary  
 
Safety 
Describe the safety and tolerability up through 
Week 36 of high dose ascending intravenous 
sotrovimab  
• 
Occurrence of adverse events (AEs) through 
Week 12 
• 
Occurrence of serious adverse events (SAEs) 
through Week 36 (end of study) 
• 
Occurrence of adverse events of special 
interest (AESIs) through Week 12 
• 
Occurrence of disease related events (DREs) 
through Week 12 
Safety 
Assess the immunogenicity up through Week 24 
of high dose ascending intravenous sotrovimab  
Incidence and titers (if applicable) of serum anti-
drug antibody (ADA) and neutralizing antibody 
(if applicable) to sotrovimab through Week 24 
Pharmacokinetics 
Assess the pharmacokinetics (PK) up to Week 24 
of high dose ascending sotrovimab in serum 
following IV administration 
 
IV sotrovimab pharmacokinetics (PK) in serum 
through Week 24 
Exploratory  
 
Efficacy 
Evaluate the efficacy up through Day 29 of high 
dose ascending intravenous sotrovimab in 
preventing the progression of mild/moderate 
COVID-19  
Progression of COVID-19 through Day 29 as 
defined by: 
• 
Hospitalization > 24 hours for acute 
management of illness due to any cause 
OR 
• 
Death 
Efficacy 
Evaluate the efficacy up through Day 29 of high 
dose ascending intravenous sotrovimab in 
preventing the progression of mild/moderate 
COVID-19  
Progression of COVID-19 through Day 29 as 
defined by: 
• 
Visit to a hospital emergency room for 
management of illness  
OR 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 29 
Objectives  
Endpoints 
• 
Hospitalization for acute management of 
illness for any duration and for any cause 
OR 
• 
Death 
Efficacy 
Evaluate the efficacy up through Day 29 of high 
dose ascending intravenous sotrovimab in 
preventing the progression of COVID-19 
respiratory disease  
Development of severe and/or critical respiratory 
COVID-19 as manifested by requirement for 
respiratory support (including oxygen) at Day 8, 
Day 15, Day 22, and Day 29  
Efficacy 
Describe the effect of high dose ascending 
intravenous sotrovimab on the incidence of ICU 
stay and mechanical ventilation use through 
Day 29  
Incidence of participants requiring ICU stay or 
mechanical ventilation through Day 29 
Resistant Mutants 
Monitor SARS-CoV-2 resistant mutants against 
sotrovimab through Day 29 
• 
SARS-CoV-2 resistance mutants to 
sotrovimab at baseline 
• 
Emergence of viral resistance mutants to mAb 
by SARS-CoV-2  
Virologic Activity 
Evaluate the virologic activity of high dose 
ascending intravenous sotrovimab in reducing 
SARS-CoV-2 viral load through Day 29 
• 
Change from baseline in viral load in nasal 
secretions by qRT-PCR during the follow-up 
period at Day 5, Day 8, Day 11, Day 15, 
Day 22, and Day 29 
• 
Undetectable SARS-CoV-2 in nasal 
secretions by qRT-PCR at Day 3, Day 5, 
Day 8, Day 11, Day 15, Day 22, and Day 29 
• 
Proportion of participants with a persistently 
high SARS-CoV-2 viral load at Day 8 by 
qRT-PCR 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 30 
4. 
STUDY DESIGN  
4.1. 
Overall Design  
The safety substudy is designed as a multi-center, open label substudy of high dose intravenous 
sotrovimab in participants with early, mild/moderate COVID-19 who are not on supplemental 
oxygen and are at risk for disease progression.  Participants will receive an IV infusion of 
sotrovimab at different doses and infusion times (2000 mg infused over 60 minutes [planned], 
30 minutes [optional] and 15 minutes [optional]) and up to 3000 mg (infused over 90 minutes 
[optional]) depending on which cohort the participant is enrolled in.  
A total of up to 500 participants will be enrolled in this substudy and the cohorts will occur as 
outlined in the study schema (Section 1.2). 
• Cohort A: Approximately 200 participants will be enrolled in Cohort A and receive 
2000 mg of sotrovimab infused over 60 minutes.  
o 30 participants will be enrolled in a safety lead in, and relevant safety data 
through Day 8 will be reviewed by the Joint Safety Review Team (JSRT). Note, 
there will be no pause in Cohort A while the safety lead in data is reviewed. 
o 170 additional participants will then be enrolled to complete Cohort A. 
Enrollment will pause and a review of relevant safety data through Day 8 for 
these remaining participants in Cohort A will be performed by the JSRT. Looking 
at the totality of the data for 200 participants, the JSRT will make a safety 
assessment and a decision to open Cohorts B1 and/or C will be made.  
• Optional Cohort B1: If a decision to proceed to Cohort B1 is made, approximately 
50 participants will receive 2000 mg of sotrovimab infused over 30 minutes. The JSRT 
will then pause and review the relevant safety data through Day 8 from Cohort B1. 
Following the JSRT’s safety assessment, a decision to open Cohort B2 will be made. 
• Optional Cohort B2: If a decision to proceed to Cohort B2 is made, approximately 50 
participants will be enrolled, and they will each receive 2000 mg of sotrovimab infused 
over 15 minutes. Review of relevant safety data through Day 8 will then be performed by 
the JSRT. 
• Optional Cohort C: If a decision to proceed to Cohort C is made, approximately 
200 participants will be enrolled in Cohort C, and they will each receive up to 3000 mg of 
sotrovimab, infused over 90 minutes. Note that this cohort may occur immediately after 
Cohort A. 
o 30 participants will be enrolled in a safety lead in, and relevant safety data 
through Day 8 will be reviewed by the JSRT. Note, there will be a pause in 
enrollment while relevant safety data through day 8 from the safety lead in group 
is reviewed. 
o 170 additional participants will then be enrolled into this cohort. The JSRT will 
then meet to review safety data through Day 8 from this complete cohort.   
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 31 
o If a lower dose than 2000 mg is selected for this cohort, there will be no safety 
lead-in for Cohort C and the infusion and monitoring times will be determined 
following safety review by the JSRT based on available safety data.  
Cohorts B1, B2 and C will all be considered optional cohorts and can be opened following 
completion of the Cohort A safety assessment by the JSRT (B1 and C; B2 following JSRT safety 
assessment of B1).  
After IV infusion, participants in the safety lead in Cohort A, and potentially Cohort C if a dose 
higher than 2000 mg is administered, will be monitored for 2 hours with vital signs assessments 
performed at 15 minutes, 30 minutes, 45 minutes, 1 hour and 2 hours. Participants in the 
remainder of Cohort A (and potentially Cohort C), Cohorts B1 and B2 will be monitored for up 
to 1 hour. As detailed in the Schedule of Activities, participants will be actively monitored on an 
outpatient basis with frequent collection of safety information through weekly in-clinic 
evaluations at Weeks 1, 2, 3, and 4, nasopharyngeal swabs for virology, and blood draws for PK 
sampling. Starting at Week 8, participants will be monitored monthly via phone call or in-clinic 
evaluation to assess for the incidence and severity of subsequent COVID-19 illness, if any, for a 
total of 36 weeks from dosing. 
Number of Participants:  
Approximately 200 participants (up to 500 with the optional cohorts) will be enrolled into this 
safety substudy.  
In Cohort A of the safety substudy, 200 participants will be enrolled to receive a single 2000 mg 
IV infusion of sotrovimab over 60 minutes. Optional Cohorts B1 and B2 (in which participants 
will receive 2000 mg IV infusion of sotrovimab over 30 minutes and 15 minutes, respectively) 
will each enroll 50 participants. 
Optional Cohort C (in which participants will receive up to 3000 mg IV infusion of sotrovimab 
over 90 minutes) will enroll 200 participants.  
Intervention Groups and Duration:  
Screening assessments in the safety substudy will be performed within 48 hours prior to 
randomization. There is no required minimum amount of time from screening to randomization 
provided that all eligibility criteria are met/confirmed. 
Eligible participants will be treated with a single IV dose of 2000 or up to 3000 mg sotrovimab 
on Day 1 (depending on which cohort the participant is in) and followed for up to 36 weeks.  
This is an open label study and all participants enrolled will receive sotrovimab treatment. 
Should multiple optional cohorts (i.e., Cohort B1 and Cohort C) be enrolling at the same time, 
participants will be randomly assigned to a cohort using a pre-defined schema. 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 32 
4.2. 
Scientific Rationale for Study Design  
This study is a multi-center, open label study of high dose IV sotrovimab, a monoclonal antibody 
(mAb) against SARS-CoV-2 for the prevention of progression of mild/moderate COVID-19 in 
participants 18 years old and older at high risk of medical complications from COVID-19. 
High-risk adults include participants ≥55 years old regardless of co-morbidities and individuals 
age 18 or older with comorbidities associated with worse outcomes in adults, including diabetes, 
obesity (BMI ≥30), chronic kidney disease, congestive heart failure, chronic lung diseases (i.e. 
chronic obstructive pulmonary disease, moderate to severe asthma requiring steroids, interstitial 
lung disease, cystic fibrosis, and pulmonary hypertension), sickle cell disease, 
neurodevelopmental disorders, immunosuppressive disease or receiving immunosuppressive 
medications, or chronic liver disease (CDC 2021). The study will include participants infected 
with SARS-CoV-2, the virus that causes COVID-19, as confirmed by local laboratory tests 
and/or point of care tests. 
Sotrovimab has been studied in a Phase 3 placebo-controlled trial evaluating the efficacy of 
sotrovimab in preventing progression of COVID-19 in high-risk participants with mild/moderate 
COVID-19 (VIR-7831-5001; COMET-ICE). On 10 Mar 2021, the independent data monitoring 
committee for COMET-ICE recommended that the study be stopped for enrollment due to 
evidence of clinical efficacy. This was based on an interim analysis of data from 583 participants 
which demonstrated an 85% (p=0.002) reduction in hospitalization or death in participants 
receiving sotrovimab compared to placebo (Vir 2021). Sotrovimab was well-tolerated with no 
safety signals detected.  
The COMET-TAIL study was then designed to assess the efficacy, safety, and tolerability of 
intramuscular (IM) sotrovimab versus intravenous (IV) sotrovimab when given to high-risk 
participants for the treatment of mild/moderate COVID-19. This study evaluated the clinical 
efficacy of two dose levels of IM sotrovimab compared with IV sotrovimab in preventing 
progression of COVID-19 by utilizing a non-inferiority (NI) design. Enrollment was completed 
on 19-AUG-2021 and the day 29 analysis indicated the following: in the IM administration 
(500mg) arm of the trial, there was a 2.7% rate of progression to hospitalization for more than 
24 hours or death through Day 29 of the trial, compared to 1.3% in the IV administration arm 
(also 500 mg). The adjusted difference between the IM and IV arms of the trial was 1.11% with a 
95% confidence interval (CI) of -1.24% to 3.45%. The upper bound of the 95% CI was within 
the predetermined 3.5% non-inferiority margin set for the trial’s primary endpoint in consultation 
with the US Food and Drug Administration (FDA). 
Since COMET-ICE and COMET-TAIL, several factors have contributed to the need for 
evaluation of different doses of sotrovimab. First, the development of the omicron variant has 
caused the landscape to evolve substantially as described in the COVID-19 treatment guidelines 
from the NIH (COVID-19 Treatment Guidelines Panel 2022). Understanding the safety and 
tolerability of sotrovimab across a broader dose range will provide the data should a higher dose 
of sotrovimab be required to treat a variant that is less susceptible to sotrovimab in the future. 
Additionally, evaluation of sotrovimab across a range of doses will allow for additional clinical 
pharmacology evaluation of population PK parameters, including variability across different 
patient populations (vulnerable and pediatric populations). Adolescent and pediatric subjects will 
not be included in this study due to insufficient PK data in adult subjects at this time. Of note, the 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 33 
COMET-PACE study in the pediatric population is currently ongoing to evaluate sotrovimab in 
this vulnerable population. 
Thus, this study will now consist of two parts, the original protocol, and the safety substudy. In 
the safety substudy, the aim will be to evaluate the safety and tolerability of sotrovimab across a 
single ascending dose level and at different infusion times when given to high-risk participants 
for the treatment of mild/moderate COVID-19. The existing non-clinical and clinical safety data 
support evaluation of sotrovimab across a range of doses in this sub study. 
Given the positive data from COMET-ICE and COMET-TAIL demonstrating clinical efficacy of 
sotrovimab in preventing COVID-19 disease progression, in addition to the existence of oral 
antivirals, and the changes in treatment guidelines noted above, enrollment to placebo is not 
ethically favorable for participants who are at risk of disease progression as it would 
unnecessarily subject participants to potential morbidity and mortality despite the availability of 
an otherwise favorable intervention. Thus, this study is designed as an open-label study with no 
formal inferential testing.  
The primary endpoint is the occurrence of adverse events (AEs), serious adverse events (SAEs), 
occurrence of adverse events of special interest (AESIs) and occurrence of disease related events 
(DREs) through Day 8. Secondary endpoints include evaluations of safety and tolerability (AEs, 
AESIs and DREs through Week 12, and SAEs through Week 36), immunogenicity (incidence of 
ADA and neutralizing antibody), and assessment of PK. 
The safety lead ins and pauses for JSRT review after completion of each cohort will allow for a 
closer safety analysis as the dose ascends during this study. 
4.3. 
Justification for Dose  
4.3.1. 
Sotrovimab  
The IV doses (2000 mg or up to 3000 mg) selected for this substudy were chosen to establish 
safety and tolerability across a broad range to allow for flexible dosing options for future 
variants. 
Based on clinical pharmacology modeling, a 2000 mg IV dose of sotrovimab is expected to 
maintain serum concentrations ≥120 µg/mL in 90% of participants for 28 days post-dose.  These 
concentrations are ≥111 fold above WT tissue adjusted EC90 (assuming a lung: serum ratio of 
0.25, measured value for sotrovimab) or ≥45 x taEC90 (assuming lung: serum ratio of 0.10). 
Therefore, sotrovimab levels are expected to remain sufficiently above EC90 to provide adequate 
protection against variants such as BA.2 that confer moderate fold shifts in in vitro neutralization 
potency (BA.2 leads to 35-fold change in EC90; geomean of Wisconsin and BEI isolates 
combined).  A single dose of up to 3000 mg IV dose of sotrovimab would provide additional 
flexibility in the case that future variants with major shifts (>50) in EC90 arise.  A single dose of 
up to 3000 mg IV dose is expected to maintain serum concentrations ≥180 µg/mL in 90% of 
participants for 28 days post-dose.  These concentrations are ≥167 fold above WT tissue adjusted 
EC90 (assuming a lung: serum ratio of 0.25, measured value for sotrovimab) or >67 x taEC90 
(assuming lung: serum ratio of 0.10).  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 34 
The no-observed-adverse-effect-level for VIR-7831 was established when VIR-7831 was 
administered via IV infusion at 500 mg/kg (the highest dose tested) once a week for 2 weeks in 
cynomolgus monkeys (TX-7831-0102). Based on a preliminary population PK model for 
sotrovimab, the predicted AUCinf following a 2000 mg IV dose is 21,400 µg*day/mL and 
predicted Cmax is 636 µg/mL. Based on the proposed 2000 mg IV dose, the margins based on 
nonclinical Cmax and AUC margins of 21- and 10x, respectively, support the proposed clinical 
dose of 2 g IV. The AUCinf following a 3 g IV dose is 32,100 µg*day/mL and predicted Cmax is 
954 µg/mL. Based on the proposed 3000 mg IV dose, the margins based on nonclinical Cmax and 
AUC margins of 14- and 7x, supporting the proposed doses up to 3000 mg. 
4.4. 
End of Study Definition  
A participant is considered to have completed the sub-study if he/she has completed the Week 36 
visit. The end of the sub-study is defined as the date of the last contact of the last participant in 
the study. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 35 
5. 
STUDY POPULATION:  
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
5.1.1. 
Age and Risk Factors  
1. Participant must be aged 18 years or older at time of consent AND at high risk of 
progression of COVID-19 based on the presence of one or more of the following risk 
factors:  
a. For 18-54 years old: diabetes (requiring medication), obesity (BMI ≥ 30), chronic 
kidney disease (i.e., eGFR <60 by MDRD), congenital heart disease, congestive heart 
failure (NYHA class II or more), chronic lung diseases (i.e. chronic obstructive 
pulmonary disease, moderate to severe asthma requiring steroids, interstitial lung 
disease, cystic fibrosis, and pulmonary hypertension), sickle cell disease, 
neurodevelopmental disorders, immunosuppressive disease or receiving 
immunosuppressive medications, or chronic liver disease 
OR 
2. Participant ≥ 55 years old, irrespective of co-morbidities  
a. NOTE: Target approximately 20% of participants of the study population ≥ 65 years 
old 
5.1.2. 
Type of Participant and Disease Characteristics  
3. Participants who have a positive SARS-CoV-2 test result within 7 days of randomization 
(by any validated diagnostic test e.g., RT-PCR, antigen-based testing on any specimen 
type) 
AND 
4. Oxygen saturation ≥94% on room air 
AND 
5. Have symptoms of COVID-19 defined by one or more of the following: fever, chills, 
cough, sore throat, malaise, headache, joint or muscle pain, change in smell or taste, 
vomiting, diarrhea, shortness of breath on exertion 
AND 
6. Participant to be dosed less than or equal to 7 days from onset of symptoms to dosing day 
(D1) 
5.1.3. 
Sex and Contraceptive/Barrier Requirements  
7. No gender restrictions 
8. 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. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Page 36 
 
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 
Appendix 4: Contraceptive and Barrier Guidance Section 10.4. 
OR 
b. Is a WOCBP and using a contraceptive method that is effective or highly effective, 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 8.3.7 Pregnancy Testing of the protocol. 
− If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive. 
− Additional requirements for pregnancy testing during and after study intervention are 
located in Section 1.3 of the protocol. 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy 
5.1.4. 
Informed Consent  
9. Capable of giving signed informed consent as described in Section 10.1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
OR 
10. If participants are not capable of giving written informed consent, alternative consent 
procedures will be followed as described in Section 10.1.3. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. 
Medical Conditions  
1. Currently hospitalized or judged by the investigator as likely to require 
hospitalization for the treatment of COVID-19 in the next 24 hours 
2. Symptoms consistent with severe COVID-19 as defined by new onset shortness of 
breath at rest or respiratory distress, or requiring hospitalization for continuous 
supplemental oxygen  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 37 
3. Participants who, in the judgment of the investigator are likely to die in the next 
7 days. 
4. Known hypersensitivity to any constituent present in the investigational product 
5.2.2. 
Prior/Concurrent Clinical Study Experience  
5. 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  
6. Enrollment in any trial of an investigational drug, vaccine or device study for 
SARS-CoV-2/COVID-19 within 90 days prior to Day 1 or within 5 half-lives of the 
investigational compound, whichever is longer 
5.2.3. 
Other Exclusions  
7. Receipt of convalescent plasma from a recovered COVID-19 patient or 
anti-SARS-CoV-2 mAb within the last 3 months. 
8. Participants who, in the judgment of the investigator, will be unlikely or unable to 
comply with the requirements of the protocol 
5.3. 
Pre-Screening  
Sites may have the option to pre-screen participants to participate in the clinical study. Sites may 
pre-screen and administer a SARS-CoV-2 test to participants who meet the Age and Risk Factor 
in Section 5.1.1, and display symptoms of COVID. Pre-screening is optional and not required by 
any site. 
5.4. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
any protocol deviations and any serious adverse events (SAEs). 
Re-screening may be performed as long as the participant is able to be dosed within 7 days after 
the onset of COVID-19 symptoms. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 38 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
6.1. 
Study Intervention(s) Administered  
Overview of study interventions is provided in Table 3. Detailed instructions for the 
administration of study drug will be provided in a separate pharmacy manual. 
Table 1: 
Overview of Study Intervention 
Arm Name 
Sotrovimab IV 
Intervention Name 
VIR-7831 
Type  
Biologic 
Dose Formulation 
Solution in single-use vial  
Unit Dose Strength(s) 
500 mg/vial (62.5 mg/mL) 
Dosage Level(s) 
2000 mg once or up to 3000 mg once  
Route of Administration 
IV infusion 
IMP and NIMP 
IMP 
Sourcing 
VIR-7831 will be provided centrally by the Sponsor.  
Dosing instructions 
See Pharmacy Manual 
Special instructions 
Gently mix VIR-7831 prior to withdrawing from vial 
Packaging and Labelling 
Study intervention will be provided in a single-use vial and labelled as 
required per country requirement. 
Current/Former Name(s) 
or Alias(es) 
VIR-7831, GSK4182136 
6.2. 
Preparation/Handling/Storage/Accountability  
Instructions for the preparation of study drug will be provided in a separate pharmacy manual. 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study interventions 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study intervention 
are provided in the pharmacy manual.  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 39 
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. 
Randomization  
This is an open label study and all participants enrolled will receive sotrovimab treatment. 
Should multiple optional cohorts (i.e., Cohort B1 and Cohort C) be enrolling at the same time, 
participants will be randomly assigned to a cohort using a predefined schema.  
6.4. 
Study Intervention Compliance  
Participants will receive sotrovimab IV directly from the investigator or designee, under medical 
supervision. The date and start and stop times of the dose administered will be recorded in the 
source documents. The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention. 
6.5. 
Dose Modification  
Dose modifications are not applicable. See Section 7.1 for instructions to discontinue study 
treatment for safety reasons. 
6.6. 
Continued Access to Study Intervention after the End of the Study  
COVID-19 is an acute illness and participants are not expected to need continued access to 
sotrovimab after the end of the study. 
6.7. 
Treatment of Overdose  
No specific treatment is recommended for an overdose. The treatment physician may provide 
supportive measures depending on the symptoms.  
In the event of an overdose, the treating physician should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdosing in the 
CRF. 
6.8. 
Concomitant Therapy  
Any medication or vaccine (including over the counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest that the 
participant is receiving at the time of enrollment or receives during the study must be recorded 
along with: 
1. Reason for use 
2. Dates of administration including start and end dates 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 40 
3. 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  
1. Receipt of convalescent plasma from a recovered COVID-19 patient or anti-SARS-CoV-
2 mAb is not permitted during the study unless these are given as local standard of care if 
a participant is hospitalized. 
2. Receipt of antivirals against COVID-19, including Paxlovid, molnupiravir, remdesivir, or 
passive antibody therapies are not permitted for the duration of the study unless these are 
given as local standard of care. 
3. Receipt of investigational treatments is not permitted for the duration of the study. 
4. Vaccination against COVID-19 will not be allowed 1 week prior to dosing and 8 days 
after dosing. 
6.8.2. 
Permitted Concomitant Medication  
All medication that the participant is receiving as local, established standard of care for acute 
COVID-19 is permitted. 
Any concerns regarding the acceptability of potential treatments should be discussed with the 
medical monitor(s). 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 41 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1. 
Discontinuation of Study Intervention  
A participant will be permanently discontinued from completion of drug infusion if they 
experience a life-threatening, infusion-related reaction including severe allergic or 
hypersensitivity reactions, severe cytokine release syndrome. 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for follow-up assessments. See the Schedule of Activities in Section 1.3 for 
data to be collected at the time of discontinuation of study intervention and follow-up and for any 
further evaluations that need to be completed. 
7.1.1. 
Temporary Discontinuation  
If a participant experiences a mild allergic or hypersensitivity reaction, the investigators will be 
instructed to pause the infusion. The infusion may be restarted at the investigator’s discretion, 
and/or after symptomatic treatment (e.g., antihistamines, IV fluids). 
7.2. 
Participant Discontinuation/Withdrawal from Study  
• A participant may withdraw from the study at any time at his/her own request, at the request 
of their LAR (legally authorized representative) or may be withdrawn at any time at the 
discretion of the investigator for safety, behavioral, or compliance reasons. This is expected 
to be uncommon. 
• At the time of withdrawal from the study, if possible, an early withdrawal (EW) visit should 
be conducted, as shown in the Schedule of Activities (Section 1.3). Participants may be 
contacted by phone. See Schedule of Activities for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
• If the participant withdraws consent or the LAR requests that the participant is withdrawn for 
disclosure of future information, the sponsor/designee may retain and continue to use any 
data collected before such a withdrawal of consent. 
• If the participant withdraws from the study, he/she or the LAR may request destruction of 
any samples taken and not tested, and the investigator must document this in the site study 
records. 
7.3. 
Lost to Follow Up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 42 
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.  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 43 
8. 
STUDY ASSESSMENTS AND PROCEDURES  
This section lists the parameters of each planned study assessment. 
1. Study procedures and their timing are summarized in Section 1.3 (Schedule of 
Activities).  
2. Select follow-up visits as noted in the Schedule of Activities are planned to be phone 
calls from site to participants. Follow-up visits may be performed at the clinic or as a 
home visit.  
3. Protocol waivers or exemptions are not allowed.  
4. 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. 
5. Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
6. 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. Re-screening may be performed as long as the participant 
is able to be dosed within 7 days after the onset of COVID-19 symptoms. 
7. Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count and COVID-19 testing) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified criteria 
and was performed within the time frame defined in the Schedule of Activities. 
8. Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
9. Clinical Research Associates will review the participants’ records to verify that 
prioritized 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 records. 
8.1. 
Screening Period  
Informed consent must be obtained before conducting any study procedures. Screening will be 
performed within 48 hours prior to randomization and include the assessments outlined in the 
Schedule of Activities (Section 1.3).  
Screening visit and Day 1 visit may occur on the same day. 
8.1.1. 
Medical History  
Relevant medical history within the last three years, as determined by the Investigator, should be 
reported. Details regarding illnesses and allergies, date(s) of onset, and whether condition(s) is 
currently ongoing will be collected for all participants and should be updated prior to dosing.  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 44 
8.1.2. 
SARS-CoV-2 Diagnostic Testing  
Documentation of laboratory-confirmed SARS-CoV-2 infection via a validated molecular 
diagnostic test or antigen test 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 diagnostic test 
that has received an Emergency Use Authorization from the FDA (FDA 2022).  
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 
from dosing.  
8.1.3. 
Secondary Contact Information  
In order to minimize the potential for missing data related to the primary endpoint of mortality or 
need for hospitalization, sites should collect participant contact information for two secondary 
contacts (e.g., caregiver, family member, friend). The site may also request health care provider 
contact information and medical care facilities the participant is likely to go to if they get sick.  
Contact information for secondary contacts or health care provider will not be recorded in any 
eCRF. Contact information should be reviewed and updated at each clinic visit, home visit, and 
during site phone calls.  
8.2. 
Efficacy Assessments  
8.2.1. 
Hospitalization and Death Data Collection  
A hospitalization event and the clinical care that is received during a hospitalization as well as 
death are components of primary, secondary, and exploratory endpoints. Data from the 
hospitalization and/or death should be captured in the electronic data capture (EDC) system 
including but not limited to: 
1. Serious Adverse Event (SAE) form 
2. Dates that the participant is hospitalized and discharged 
3. Dates that the participant is admitted to an intensive care unit 
4. Details on the amount of and type of supplemental oxygen and/or ventilatory support that 
the participant received 
5. Date, time, and cause of death 
8.2.2. 
Phone Call for Subsequent COVID-19 Illness  
To monitor participants for subsequent COVID-19 illness after Day 29, participants will be 
called at Week 8, Week 16, Week 28, Week 32, and Week 36 (as they don’t have to come in for 
a clinic visit on these days). This phone call will assess whether the participant was diagnosed 
again with COVID-19 and whether this illness resulted in any healthcare encounters. Any 
medications given because of this illness will also be recorded. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 45 
8.3. 
Safety Assessments  
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.3.1. 
Physical Examinations  
A complete physical examination will be performed on Day 1. For all other visits the physical 
examination will be symptom-directed as outlined in the Schedule of Activities. 
• A complete physical examination will include, at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, and Abdominal systems.  
• Height and weight will also be measured and recorded at Screening. Body mass index (BMI) 
will be calculated from these measurements.  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.3.2. 
Vital Signs  
On Day 1, vital signs should be recorded prior to dose administration and at 15 mins, 30 mins, 
45 mins, 1 hour and 2 hours after infusion for participants who are part of the lead in, and for 15 
mins, 30 mins, 45 mins and 1 hour after infusion for participants who are not part of the lead in.  
• Vital sign measurements will include blood pressure, pulse rate, temperature (oral preferred), 
respiratory rate, and oxygen saturation. 
• Blood pressure and pulse measurements will be assessed while participant is semi-supine or 
sitting with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (e.g., television, cell phones). 
8.3.3. 
Electrocardiograms  
At Screening, a single 12-lead ECG is required ONLY for participants with past medical history 
of a cardiovascular condition such as an arrhythmia, coronary artery disease, congestive heart 
failure, valvular disease, OR diabetes mellitus.  
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.  
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. 
8.3.4. 
Virologic Measures  
Samples for virological analysis will be collected in accordance with the laboratory manual and 
Schedule of Activities (Section 1.3).  
• Nasopharyngeal swabs will be collected for SARS-CoV-2 RT-PCR 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 46 
• Samples may also be used for resistance surveillance analysis 
• Day 1 samples may be used to evaluate for other respiratory infections 
8.3.5. 
Resistance Analyses  
To monitor for viral resistance, resistance surveillance will be conducted for all participants who 
are randomized and dosed. Next-generation sequencing (NGS) analysis of the SARS-CoV-2 
spike gene will be attempted to identify substitutions in the mAb epitope or substitutions outside 
of the epitope that arise during treatment. NP samples from baseline and the last evaluable post-
baseline visit at Day 5 or later will be subjected to NGS analysis, including participants who do 
not experience a decline in viral load or who experience virologic rebound. Virologic rebound 
will be defined as participants who experience an increase of >1 log10 copies/mL in viral load, or 
viral load becomes quantifiable after having been below the limit of quantification. For identified 
substitutions that qualify for phenotypic analysis, in vitro phenotypic analysis of the antiviral 
activity of sotrovimab using a SARS-CoV-2 spike pseudotyped virus system will be attempted 
and analyzed for reduced susceptibility to sotrovimab. 
8.3.6. 
Clinical Safety Laboratory Assessments  
• See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) for the timing and frequency.  
• Laboratory assessments at Screening visit will be performed locally at the clinical site 
as determined necessary by the investigator or as required by local regulations. 
• All protocol-required laboratory test performed locally and/or centrally, as defined in 
Section 10.2, must be conducted in accordance with the laboratory manual and 
Schedule of Activities (Section 1.3) 
o 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.  
o 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. 
o All laboratory tests with values considered by the investigator to be clinically 
significantly abnormal during participation in the study should be repeated until 
the values return to normal or baseline or are no longer considered significantly 
abnormal by the investigator or medical monitor.  
▪ If clinically significant values do not return to normal/baseline within a 
period of time judged reasonable by the investigator, the etiology should 
be identified, and the sponsor notified. 
• If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE), then the results 
must be recorded. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 47 
8.3.7. 
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 Early Withdrawal visit. If serum 
pregnancy test is required, it will be performed locally. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participant’s participation in the study. 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting  
The definitions of adverse events (AE) or serious adverse events (SAEs) can be found in 
Section 10.3. 
The definitions of unsolicited and solicited adverse events can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
Hospitalization or death are typically considered SAEs and they are included in the primary 
endpoint. However, if a hospitalization or adverse event is related to expected progression, signs, 
or symptoms of COVID-19 (as detailed in Section 8.4.8) or if hospitalization is due to elective 
treatment of a pre-existing condition that did not worsen from baseline as noted in Section 10.3 it 
will not be considered as an SAE. These events will be collected and reported as SAEs only if 
the event is more severe than expected for the participant’s current clinical status and medical 
history or if the investigator feels that it is related to study drug. These will be collected and 
reported as SAEs as delineated in Section 8.4.1 below. Since it will not be possible to delineate 
in a single participant whether the hospitalization is directly related to COVID-19 complications 
or could be related to sotrovimab causing more severe disease due to ADE, all hospitalizations 
for management of acute illness, regardless of cause, will be included in the primary endpoint.  
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue the study (see Section 7). As noted in Section 8.2.1 data on 
hospitalization or death should additionally be recorded in the eCRF for all relevant sections. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information  
• All AEs will be collected from dose administration through Week 12 post-dose. SAEs 
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 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 48 
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. 
8.4.2. 
Assessment of Severity  
Standard toxicity grading according to the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, version 2.1 (July 2017) will be used to grade all AEs.  
8.4.3. 
Method of Detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence.  
8.4.4. 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and non-serious AEs of special interest (as defined in 
Section 8.4.8), will be followed until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is given in Section 10.3. 
8.4.5. 
Regulatory Reporting Requirements for SAEs  
PPD and GlaxoSmithKline (GSK) are acting on behalf of Vir for the purposes of global safety 
reporting for this study as outlined in the PPD/Vir Safety Medical Management Plan and 
Expedited Safety Reporting Documents. 
• Prompt notification by the investigator to PPD 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.  
• The sponsor or designee has a legal responsibility to notify both the local regulatory 
authorities and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor or designee will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional Review 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 49 
Boards (IRB)/Independent Ethics Committees (IEC), and investigators. Details for 
notification of expedited and periodic safety reporting can be found in the Expedited and 
Periodic Safety Reporting Plan (ESRP). 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) as outlined in the ESRP will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and GSK policy and 
forwarded to investigators as necessary. 
8.4.6. 
Pregnancy  
• Details of all pregnancies in female participants will be collected after the start of study 
intervention and until Week 36. 
• 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. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant will be followed to determine the outcome of the pregnancy and for up to 1 
year after birth. The investigator will collect follow-up information on the participant and the 
neonate/child, and the information will be forwarded to the sponsor or designee. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor or designee as described in 
Section 8.4.1. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
8.4.7. 
Cardiovascular and Death Events  
Specific Cardiovascular (CV) and Death sections of the CRF will be required to be completed 
for all deaths and cardiovascular events detailed in Section 8.4, whether these events are 
considered SAEs or not. These sections include questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms. 
The CV information should be recorded in the specific cardiovascular section of the CRF within 
one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is reported. 
Initial and follow-up reports regarding death must be completed within one week of when the 
death is reported. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 50 
8.4.8. 
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, or resulting 
in hospitalization as noted in Section 8.4, should not be reported as an AE or SAE.  
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 
considered as expected progression, signs, or symptoms of COVID-19:  
• hypoxemia due to COVID-19 requiring supplemental oxygen 
• 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). 
8.4.9. 
Adverse Events of Special Interest  
Adverse events of special interest are defined as relevant known toxicities of other therapeutic 
mAbs or are defined from signals observed in previous studies in the nonclinical or clinical 
sotrovimab programs, that the sponsor will monitor throughout the study. AESIs may be updated 
during the study based on accumulating safety data. 
Adverse events of special interest include: 
• Infusion-related reactions including hypersensitivity reactions within 24 hours after infusion 
• Hypersensitivity reactions occurring at any time post dose 
• Immunogenicity related AEs 
• Adverse events potentially related to ADE of disease. Antibody-dependent enhancement 
theoretically can occur via 1 of 3 previously described mechanisms described in 
Section 8.4.9.3. 
8.4.9.1. 
Systemic Reactions and Hypersensitivity Reactions  
Please refer to local or institutional guidelines for monitoring relevant adverse events 
encompassing infusion related reactions including hypersensitivity, angioedema, anaphylaxis, 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 51 
acute anaphylactic shock and minor allergic episodes. Premedications will be permitted at the 
investigator’s discretion and will be appropriately documented. 
8.4.9.2. 
Immunogenicity  
Unwanted immunogenicity is an immune response by an organism against a therapeutic protein. 
This reaction leads to production of anti-drug-antibodies (ADA) which may inactivate the 
therapeutic effects of the treatment and, in rare cases, induce adverse events. This study will 
include participant follow-up for a period of 5 half-lives to assess for the development of ADA 
and potential impacts on safety, PK and/or efficacy.  
8.4.9.3. 
Antibody Dependent Enhancement  
Antibody-dependent enhancement (ADE) of disease theoretically can occur via one of three 
previously described mechanisms: 
1. By facilitating viral entry into host cells and enhancing viral replication in these cells  
2. By increasing viral fusion with target host cells, enhancing viral replication in these cells 
3. By enhancing disease pathology from viral antigen-antibody related immune complex 
deposition or complement activation and immune cell recruitment in target organs  
The first two mechanisms are hypothesized to occur at sub-neutralizing antibody concentrations 
(Arvin 2020). This study will include participant follow-up for a period of 5 half-lives to assess 
for the potential of enhanced disease in the context of waning sotrovimab levels, which may 
manifest as an increased incidence of re-infection or increased severity of re-infections after 
recovery from initial illness. The third mechanism is hypothesized to occur at high levels of 
antigen (i.e., viral load) and antibody potentially leading to immune complex deposition and 
complement activation in tissue sites of high viral replication. This may manifest as acute 
deterioration temporally associated with sotrovimab dosing or as increased severity or duration 
of illness in sotrovimab-treated participants vs. placebo-treated participants.  
As of 10 March 2021, enrollment into the COMET ICE study, evaluating sotrovimab for the 
treatment of non-hospitalized individuals with mild to moderate COVID-19, has been stopped 
based on the recommendation of IDMC. The total of 1057 participants have been randomized to 
either the IV infusion of sotrovimab Gen1 (500 mg dose) or placebo. Based on the Joint SRT 
review of blinded data, there has been no confirmed events of ADE. The ACTIV-3 TICO study 
of sotrovimab treatment in hospitalized participants with COVID-19 symptoms, which was 
terminated due to futility, did not reveal any safety concerns overall and no ADE. The COMET 
TAIL study did not reveal any safety concerns overall and no ADE. 
As described in Section 2.3.1, AEs potentially related to ADE of the disease will be reviewed by 
the JSRT to see if there are unusually severe manifestations of COVID-19 in treated individuals. 
8.5. 
Pharmacokinetics  
Blood samples for serum PK will be collected as detailed in the Schedule of Activities 
(Section 1.3). Instructions for the collection and handling of biological samples will be provided 
by the sponsor or designee in the laboratory manual. 
• The actual date and time (24-hour clock time) of each sample will be recorded. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 52 
• Samples collected for analyses of sotrovimab serum concentration may also be used 
to evaluate safety or efficacy aspects related to concerns arising during or after the 
study. 
• At visits during which whole blood samples are collected to obtain serum endpoints 
other than PK for sotrovimab, one sample of sufficient volume can be used. 
Serum concentrations may be combined with data from other studies evaluating sotrovimab for 
the purpose of population PK model development. Pharmacokinetic analyses may be conducted 
to explore exposure-response relationships between PK parameters and selected antiviral 
variables. These analyses may include graphical plots, tabular summaries, and various linear 
and/or nonlinear analyses. Details of the PK analyses will be provided in the analysis plan. 
8.6. 
Immunogenicity Assessments  
Antibodies to sotrovimab 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 sotrovimab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to sotrovimab and/or further characterize the immunogenicity of sotrovimab. 
The detection and characterization of antibodies to sotrovimab 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 sotrovimab 
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.  
Samples will be collected in accordance with the laboratory manual and Schedule of Activities 
(Section 1.3). 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 53 
9. 
STATISTICAL CONSIDERATIONS  
9.1. 
Statistical Hypotheses  
The primary objective of the study is to describe the safety and tolerability of high dose 
ascending intravenous sotrovimab administered over different infusion times. No formal 
statistical hypothesis testing is planned. 
9.2. 
Sample Size Determination  
A sample size of approximately 200, and up to 500 participants (with 300 participants designed 
to be included through optional cohorts as determined by the Joint Safety Review team (JSRT)) 
was selected to assess the safety profile of an increased dose of sotrovimab robustly and 
efficiently. Adverse events with a frequency of  l% and < 10% are considered common/frequent 
as per the 2nd edition of the CIOMS Working Groups III and IV (CIOMS 1999). 
The first cohort, Cohort A, will include approximately 200 participants dosed at 2000 mg IV 
with an infusion time of 60 minutes. With 200 participants, there is a 90% chance of observing at 
least one particular adverse event of interest, if the true incidence rate of that adverse event is not 
below 1.14%. Of note, in COMET-ICE, the infusion related reaction (IRR) rate was 1.14%. 
Cohort B1 is optional and can occur after Cohort A if there are no significant safety signals or 
concerns found in Cohort A. It would include approximately 50 participants dosed at 2000 mg 
with an infusion time of 30 minutes. With 50 participants, there is a 90% chance of observing at 
least one particular adverse event of interest, if the true incidence rate of that adverse event is not 
below 4.5%. 
Cohort B2 is optional and can occur after Cohort B1 if there are no significant safety signals or 
concerns found in Cohort A or B1. It would include approximately 50 participants dosed at 2000 
mg with an infusion time of 15 minutes. With 50 participants, there is a 90% chance of observing 
at least one particular adverse event of interest, if the true incidence rate of that adverse event is 
not below 4.5%. 
Cohort C is optional and can occur after Cohort A if there are no significant safety signals or 
concerns found in Cohort A. It would include approximately 200 participants dosed at up to 3000 
mg IV with an infusion time of 90 minutes (if 3000 mg IV is selected). With 200 participants, 
there is a 90% chance of observing at least one particular adverse event of interest, if the true 
incidence rate of that adverse event is not below 1.14%. 
Cohorts B1, B2 and C will all be considered optional cohorts and will be opened following 
completion of Cohort A following assessment by the JSRT. 
The precision of event rate estimation is shown in the table below, as indicated by the width of 
95% confidence intervals. More specifically, the total number of 500 participants reflects the 
precisions when summarizing over all cohorts, and the total number of 300 participants reflects 
the precisions when summarizing over all 2000 mg cohorts. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 54 
Table 2: 
Precision of Estimated Event Rate 
Total Number of Participants 
Number of Participants 
with a Particular Event 
Event Rate 
95% Confidence 
Interval 
500 (overall study size, including Cohorts A, 
B1, B2, and C)  
3 
0.5% 
(0.12%, 1.74%) 
 
5 
1.0% 
(0.33%, 2.32%) 
 
10 
2.0% 
(0.96%, 3.65%) 
 
25 
5.0% 
(3.26%, 7.29%) 
 
50 
10.0% 
(7.51%, 12.97%) 
 
250 
50.0% 
(45.53%, 54.47%) 
300 (combined number of participants dosed 
at 2000 mg, includes Cohorts A, B1 and B2) 
2 
0.5% 
(0.08%, 2.39%) 
 
3 
1.0% 
(0.21%, 2.89%) 
 
6 
2.0% 
(0.74%, 4.30%) 
 
15 
5.0% 
(2.83%, 8.11%) 
 
30 
10.0% 
(6.85%, 13.97%) 
 
150 
50.0% 
(44.20%, 55.80%) 
200 (individual study size for Cohorts A or C) 
1 
0.5% 
(0.01%, 2.75%) 
 
2 
1.0% 
(0.12%, 3.57%) 
 
4 
2.0% 
(0.55%, 5.04%) 
 
10 
5.0% 
(2.42%, 9.00%) 
 
20 
10.0% 
(6.22%, 15.02%) 
 
100 
50.0% 
(42.87%, 57.13%) 
50 (individual study size for cohorts B1 or B2) 
0 
0.5% 
(0.00%, 7.11%) 
 
1 
1.0% 
(0.05%, 10.65%) 
 
1 
2.0% 
(0.05%, 10.65%) 
 
3 
5.0% 
(1.25%, 16.55%) 
 
5 
10.0% 
(3.33%, 21.81%) 
 
25 
50.0% 
(35.53%, 64.47%) 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 55 
9.3. 
Analysis Sets  
For the purposes of analysis, the following main analysis sets are defined: 
Participant Analysis Set 
Description 
Safety 
All participants who were enrolled and exposed to study intervention. 
Participants will be summarized according to actual dose and 
infusion time received during the study.  
Intent-to-Treat (ITT) 
All participants who were randomized and exposed to study 
intervention.  Participants will be summarized according to the dose 
they were assigned to. 
Pharmacokinetic 
All participants in the Safety analysis set who had at least 1 non-
missing PK assessment (post-dose non-quantifiable [NQ] values will 
be considered as non-missing values). Participants will be 
summarized according to treatment which they received. 
Virology 
All participants who were enrolled and with a lab confirmed 
quantifiable nasopharyngeal swab at Day 1. Participants will be 
summarized according to actual dose received during the study. This 
will be the primary analysis set for virology. 
 
9.4. 
Statistical Analyses  
 The statistical analysis plan will be finalized prior to formal reporting of Cohort A for the sub-
study and it will include a more detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the safety endpoints. All 
statistical analyses will be descriptive. The details of the descriptive summary statistics will be 
outlined in the statistical analysis plan. 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the statistical analysis plan. Additional exploratory analyses of the data will be conducted as 
deemed appropriate.  
9.4.1. 
Primary Endpoints  
The primary objective of the safety substudy is to describe the safety and tolerability through 
Day 8 of high dose ascending intravenous sotrovimab. Summaries of AEs, SAEs, AESI, 
COVID-related AEs through Day 8 will be presented by MedDRA SOC and PT using frequency 
counts and percentages (i.e., number and percentage of subjects with an event). When 
summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE will be counted once.  
In addition, a listing containing individual subject level AE data for all deaths and other serious 
and significant AEs will be provided separately. All AEs, including pre- and post-treatment AEs, 
will be presented in individual subject data listings.  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 56 
9.4.2. 
Secondary Endpoint(s)  
Details of the analyses for the secondary endpoints will be provided in the statistical analysis 
plan. 
9.4.3. 
Exploratory Endpoint(s)  
Details of the analyses for the exploratory endpoints will be provided in the statistical analysis 
plan. 
9.4.4. 
Other Safety Analysis  
Number and percentage of subjects with AEs, SAEs, COVID-19 related AEs and COVID-19 
related SAEs, and AESIs beyond Day 8, including laboratory tests and vital signs will be 
displayed in the form of listings, frequencies, summary statistics, and graphs where appropriate. 
Interpretation will be aided by clinical expertise. 
To inform on the number and nature of non-COVID-19 adverse events and serious adverse 
events, additional safety analyses will be performed in which select, pre-specified terms 
consistent with known progression of COVID-19 disease will be excluded. Details of these and 
all analyses, including example outputs, will be documented in the statistical analysis plan. 
9.4.5. 
Other Analysis  
Full details of all analysis methods of immunogenicity and population pharmacokinetics will be 
provided in the statistical analysis plan. 
9.5. 
Interim Analysis  
No interim analyses are planned. Note that the JSRT will review the safety and tolerability data 
from each cohort when all subjects in a cohort have completed Day 8. The details of the safety 
data review through Day 8 will be outlined in the statistical analysis plan.  
9.6. 
Multiple Comparisons and Multiplicity  
No statistical testing will be conducted in the safety substudy. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 57 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC 
− Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, EU Clinical Trials Directive 2001/20/EC or 
Regulation (EU) No. 536/2014 (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor or designee with sufficient, accurate 
financial information as requested to allow the sponsor/designee to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators and sub-investigators are responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Page 58 
10.1.3. 
Informed Consent Process  
• The investigator or his/her representative will explain the nature of the study to the 
participant or their legally authorized representative and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A signed copy of the ICF(s) must be provided to the participant or their legally authorized 
representative.  
Vir (alone or working with others) may use the participant’s coded study data and samples and 
other information to carry out this study; understand the results of this study; learn more about 
sotrovimab or about the study disease; fulfill legal and regulatory obligations, including 
reporting safety information about sotrovimab, this study, and the results of this study to 
regulatory authorities; provide information about the safety and use of sotrovimab to 
investigators and institutions that plan to administer sotrovimab to participants; publish the 
results of these research efforts; work with government agencies or insurers to have sotrovimab 
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. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 59 
10.1.5. 
Joint Safety Review Team  
A Joint Safety Review Team (JSRT) comprised of team members from clinical research, 
pharmacovigilance and statistics from Vir and GSK will meet at regular intervals throughout the 
conduct of the study for review of instream safety data for identification of safety concerns. If a 
potential safety issue is identified, the JSRT may escalate this to an ad hoc IDMC meeting for 
further evaluation.  
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 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. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 60 
• Quality Tolerance limits (QTLs) will be pre-defined in the Integrated Quality Risk 
Management Plan to identify systematic issues that can impact participant safety and/or 
reliability of study results. These pre-defined parameters will be monitored during and at the 
end of the study, and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Monitoring details describing strategy including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as Risk Management and 
Mitigation Strategies and Analytical Risk-Based Monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 25 years from the issue of the final Clinical Study Report 
(CSR)/equivalent summary unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.  
• As hospitalization and mortality are both primary study endpoints and serious adverse events, 
instream data cleaning including updating and reconciliation of hospitalization events 
between the safety dataset and efficacy dataset will be performed throughout the study 
duration and any changes or updates to the SAEs of hospitalization or mortality will be 
reflected in the efficacy dataset. 
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 [Investigator Source 
Data Agreement]. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 61 
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  
10.1.9.1. First Act of Recruitment  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
10.1.9.2. 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 
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. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 62 
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in Table 3 will be performed by the central laboratory and/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. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 63 
Table 3: 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
 
WBC count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum Glutamic-
Oxaloacetic 
Transaminase (SGOT) 
Total and direct 
bilirubin 
 
Creatinine 1 
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 Repeat within 1 week if above the normal range  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 64 
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 Participant Diary 
and that is communicated 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 such as infusion reactions and systemic events for which the 
participant is specifically questioned.  
 
Events Meeting the AE Definition 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfill the definition of an AE or SAE. 
• 
Clinically significant changes in laboratory assessments. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 65 
 
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. 
• 
Elective treatment of a pre-existing condition that did not worsen from baseline.  
• 
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. 
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 AE. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 66 
An SAE is defined as any serious adverse event that, at any dose: 
d. 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. 
 
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 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 67 
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 
sponsor in lieu of completion of the required form. 
• 
There may be instances when copies of medical records for certain cases are requested by 
pharmacovigilance staff. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before submission. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
Assessment of Intensity 
• 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should 
not be confused with an SAE. Severe is a category utilized for rating the intensity of an event; and 
both AE and SAE can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
The investigator is obligated to assess the relationship between study intervention and each occurrence 
of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 68 
Assessment of Causality 
• 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
10.3.5. 
Reporting of SAEs  
SAE Reporting via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAEs will be the electronic data collection (EDC) tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool to 
report the event within 24 hours. Details to be provided in the Study Specific SAE Reporting 
Guidelines. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
The investigator or medically-qualified sub-investigator must show evidence within the eCRF 
(e.g., check review box, signature, etc.) of review and verification of the relationship of each SAE 
to IP/study participation (causality) within 24 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 will be included in the Study Specific SAE Reporting Guidelines 
 
10.3.6. 
Expedited Reporting to Health Authorities, Investigators and Ethics Committees  
Expedited Reporting 
The Sponsor or their third-party delegates will promptly evaluate all serious adverse events and non-
serious adverse events to identify and expeditiously communicate new safety findings to investigators, 
IRBs, ECs, and health authorities based on applicable legislation as per the Expedited and Periodic 
Safety Reporting Plan. 
 
To determine reporting requirements for single adverse event cases, the Sponsor or their third-party 
delegate will assess the expectedness of these events using the sotrovimab Investigator’s Brochure.  
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 69 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
10.4.1.1. Woman of Nonchildbearing Potential (WONCBP)  
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this study): 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, 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 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 (> 40 IU/L or mIU/mL) is required.  
• Females on HRT and whose menopausal status is in doubt and in whom highly effective 
methods are contraception are required 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. 
10.4.1.2. Woman of Childbearing Potential (WOCBP)  
Women in the following categories are considered WOCBP (fertile): 
3. Following menarche 
4. From the time of menarche until becoming postmenopausal or premenopausal with 
permanent infertility (see above) 
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 (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 70 
10.4.2. 
Contraception Guidance  
Contraceptivesa Allowed During the Study Include: 
Highly Effective Methodsb 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 ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)b 
• 
Bilateral tubal occlusion, bilateral tubal ligation, or bilateral salpingectomy 
• 
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 Methodsb 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 ovulationc 
− 
oral 
− 
intravaginal 
− 
transdermal 
− 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
− 
oral 
− 
injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant. 
Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥ 1% per year when used 
consistently and correctly 
• 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode 
of action 
• 
Male or female condom with or without spermicidee 
• 
Cervical cap, diaphragm, or sponge with spermicide 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 71 
Contraceptivesa Allowed During the Study Include: 
• 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods)c 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly. 
c Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical 
Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
d Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence (calendar, 
sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method (LAM) are not acceptable methods of contraception.  
e Male condom and female condom should not be used together (due to risk of failure from friction). 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 72 
11. 
REFERENCES  
AAP. Children and COVID-19: State-Level Data Report. https://services.aap.org/en/pages/2019-
novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report/. Accessed 
May 5, 2021. 
Ali SO, Takas T, Nyborg A, Shoemaker K, Kallewaard NL, Chiong R, Dubovsky F, Mallory 
RM. Evaluation of MEDI8852, an Anti-Influenza A Monoclonal Antibody, in Treating Acute 
Uncomplicated Influenza. Antimicrob Agents Chemother. 2018 Oct 24;62(11). pii: e00694-18. 
doi: 10.1128/AAC.00694-18. Print 2018 Nov. PubMed PMID: 30150460; PubMed Central 
PMCID: PMC6201130. 
Arvin AM, Fink K, Schmid MA, Cathcart A, Spreadfico R, Havenar-Daughton C, Lanzavecchia 
A, Corti D, Virgin HW. A perspective on potential antibody-dependent enhancement of SARS-
CoV-2. Nature. https://doi.org/10.1038/s41586-020-2538-8 (2020). 
Baxter LT, Zhu H, MackensenDG, Jain RK. Physiologically based pharmacokinetic model for 
specific and nonspecific monoclonal antibodies and fragments in normal tissues and human 
tumor xenografts in nude mice. Cancer Res. 1994 Mar 15; 54(6): 1517–1528. 
Bialek S, Boundy E, Bowen V, Chow N, Cohn A, Dowling N, Ellington S, Gierke R, Hall A, 
MacNeil J, Patel P, Peacock G, Pilishvili T, Razzaghi H, Reed N, Ritchey M, Sauber-Schatz E. 
Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United 
States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep 2020;69:343-346. DOI: 
http://dx.doi.org/10.15585/mmwr.mm6912e2. 
Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: 
practical considerations and management strategy for intensivists. Intensive Care Med. 2020 
Apr;46(4):579-582. doi: 10.1007/s00134-020-05967-x. Epub 2020 Feb 26. PubMed PMID: 
32103284; PubMed Central PMCID: PMC7079839. 
Brandal, L., MacDonald, E., Veneti, L., Ravlo, T., Lange, H., Naseer, U., Feruglio, S., Bragstad, 
K., Hungnes, O., Ødeskaug, L., Hagen, F., Hanch-Hansen, K., Lind, A., Watle, S., Taxt, A., 
Johansen, M., Vold, L., Aavitsland, P., Nygård, K. and Madslien, E., 2021. Outbreak caused by 
the SARS-CoV-2 Omicron variant in Norway, November to December 2021. Eurosurveillance, 
26(50). 
Cathcart A, Havenar-Daughton C, Lempp F, Ma D, Schmid M, Agostini M, Gaurino, B, Di iulio, 
J, Rosen L, Tucker H, Dillen J, Subramanian S, Sloan B, Bianchi S, Pinto D, Saliba C, Culap K, 
Qojcechowskyj J, Noack J, Zhou J, Kaiser H, Lee S, Farhat N, Chase A, Montiel-Ruiz M, 
Dellota Jr E, Park A, Spreafico R, Sahakyan A, Lauron E, Czudnochowski N, Cameroni E, 
Ledoux S, Kawaoka Y, Werts A, Colas C, Soriaga L, Telenti A, Purcell L, Seungmin H, Snell G, 
Virgin H, Corti D, Hebner C. The dual function monoclonal antibodies VIR-7831 and VIR-7832 
demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv. April 1 2022. 
doi: https://doi.org/10.1101/2021.03.09.434607 
CDC. Information for Pediatric Healthcare Providers. https://www.cdc.gov/coronavirus/2019-
ncov/hcp/pediatric-hcp.html. Accessed 2 April, 2021 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 73 
CDC. Underlying Medical Conditions Associated with High Risk for Severe COVID-19: 
Information for Healthcare Providers. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-
care/underlyingconditions.html. Accessed 5 May 2021 
CDC. Hospitalization Rates and Characteristics of Children Aged <18 Years Hospitalized with 
Laboratory-Confirmed COVID-19 — COVID-NET, 14 States, March 1–July 25, 2020. 
https://www.cdc.gov/mmwr/volumes/69/wr/mm6932e3.htm?s_cid=mm6932e3_w. Accessed 5 
May 2021 
CDC. Post-COVID Conditions. https://www.cdc.gov/coronavirus/2019-ncov/long-term-
effects/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F201
9-ncov%2Flong-term-effects.html. Accessed 04 Oct 2021 
Cevik, M., Tate, M., Lloyd, O., Maraolo, A., Schafers, J. and Ho, A. SARS-CoV-2, SARS-CoV, 
and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic 
review and meta-analysis. The Lancet Microbe. 2021; 2(1): e13-e22.  
Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, Huhn G, Cardona J, Mocherla B, 
Stosor V, Shawa I, Adams AC, Van Naarden J, Custer KL, Shen L, Durante M, Oakley G, 
Schade AE, Sabo J, Patel DR, Klekotka P, Skovronsky DM; BLAZE-1 Investigators. SARS-
CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. 2021 
Jan 21;384(3):229-237. doi: 10.1056/NEJMoa2029849. Epub 2020 Oct 28. PMID: 33113295; 
PMCID: PMC7646625. 
Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, Ma K, Xu D, Yu H, Wang H, Wang T, Guo 
W, Chen J, Ding C, Zhang X, Huang J, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical 
characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 
2020 Mar 26;368:m1091. doi: 10.1136/bmj.m1091. Erratum in: BMJ. 2020 Mar 31;368:m1295. 
PMID: 32217556; PMCID: PMC7190011. 
Council for International Organizations of Medical Sciences (CIOMS). Report of CIOMS 
Working Groups III and V. 1999. https://cioms.ch/wp-content/uploads/2018/03/Guidelines-for-
Preparing-Core-Clinical-Safety-Info-Drugs-Report-of-CIOMS-Working-Group-III-and-V.pdf. 
Accessed 20-MAY-2022 
Covell DG, Barbet J, Holton OD, Black CD, Parker RJ, Weinstein JN. Pharmacokinetics of 
monoclonal immunoglobulin G1, F(ab')2, and Fab' in mice. Cancer Res.1986 Aug;46(8):3969-
78. 
Datta-Mannan A. Mechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal 
Antibodies and Peptides. Drug Metab Dispos. 2019 Oct;47(10):1100-1110. 
Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. Projecting human 
pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? MAbs. 
2011 Jan-Feb;3(1):61-6. doi: 10.4161/mabs.3.1.13799. Epub 2011 Jan 1. PMID: 20962582; 
PMCID: PMC3038012. 
DMC report, RECOVERY trial. 2022, https://www.recoverytrial.net/files/2022_03_04- 
recovery-dmc-report.pdf. Accessed on March 2022. 
Eli Lilly, bamlanivimab EUA Letter of Authorization 090, 09 February 2021, accessed 11 
February 2021 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 74 
Eli Lilly, Bamlanivimab and Etesevimab EUA Letter of Authorization 094, 09 February 2021, 
Accessed 11 Feburary 2021 
FDA (Food and Drug Administration). FDA news release. 2021 May 26. Accessed 2021 Jun 04. 
https://www.fda.gov/news-events/press-announcements/coronavirus-COVID-19-update-
fdaauthorizes-additional-monoclonal-antibody-treatment-COVID-19. 
FDA. Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 
Pandemic (updated 14 May 2020). https://www.fda.gov/media/136238/download, 2020. 
FDA. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for 
Monoclonal Antibody Bamlanivimab. https://www.fda.gov/news-events/press-
announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-
monoclonal-antibody-bamlanivimab. Accessed May 5, 2021 
FDA. In Vitro Diagnostics EUAs (Updated 14 April 2022). https://www.fda.gov/medical-
devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-
devices/vitro-diagnostics-euas, accessed 11 February 2021 
Ferguson N, Laydon D, Nedjati Gilani G, Imai N, Ainslie K, Baguelin M, Bhatia S, Boonyasiri 
A, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Dorigatti I, Fu H, Gaythorpe K, Green 
W, Hamlet A, Hinsley W, Okell L, Van Elsland S, Thompson H, Verity R, Volz E, Wang H, 
Wang Y, Walker P, Winskill P, Whittaker C, Donnelly C, Riley S, Ghani A. Impact of non-
pharmaceutical interventions (NPIs) to reduce COVID- 19 mortality and healthcare demand. 
Imperial College COVID-19 Response Team, 16 March 2020. doi: 
https://doi.org/10.25561/77482. 
Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients 
hospitalized with laboratory-confirmed coronavirus disease 2019 - COVID-NET, 14 states, 
March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-464. 
https://www.cdc.gov/mmwr/volumes/69/wr/mm6915e3.htm 
Gold JAW, Wong KK, Szablewski CM, Patel PR, Rossow J, da Silva J, Natarajan P, Morris SB, 
Fanfair RN, Rogers-Brown J, Bruce BB, Browning SD, Hernandez-Romieu AC, Furukawa NW, 
Kang M, Evans ME, Oosmanally N, Tobin-D'Angelo M, Drenzek C, Murphy DJ, Hollberg J, 
Blum JM, Jansen R, Wright DW, Sewell WM 3rd, Owens JD, Lefkove B, Brown FW, Burton 
DC, Uyeki TM, Bialek SR, Jackson BR. Characteristics and Clinical Outcomes of Adult Patients 
Hospitalized with COVID-19 - Georgia, March 2020. MMWR Morb Mortal Wkly Rep. 2020 
May 8;69(18):545-550. doi: 10.15585/mmwr.mm6918e1. PMID: 32379729; PMCID: 
PMC7737948. 
Goldstein RH, Walensky RP. The Challenges Ahead With Monoclonal Antibodies: From 
Authorization to Access. JAMA. 2020 Dec 1;324(21):2151-2152. doi: 
10.1001/jama.2020.21872. PMID: 33175110. 
Grant, R., Charmet, T., Schaeffer, L., Galmiche, S., Madec, Y., Von Platen, C., Chény, O., 
Omar, F., David, C., Rogoff, A., Paireau, J., Cauchemez, S., Carrat, F., Septfons, A., Levy-
Bruhl, D., Mailles, A. and Fontanet, A., 2022. Impact of SARS-CoV-2 Delta variant on 
incubation, transmission settings and vaccine effectiveness: Results from a nationwide case-
control study in France. The Lancet Regional Health - Europe, 13, p.100278. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 75 
Guan WJ, Ni ZY, Hu Y, et al. Characteristics of coronavirus disease 2019 in China. N Engl J 
Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2002032 
Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of 
ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS 
pathogenesis. J Pathol. 2004 Jun;203(2):631-7. doi: 10.1002/path.1570. PMID: 15141377; 
PMCID: PMC7167720. 
Helmsdal, G., Hansen, O., Møller, L., Christiansen, D., Petersen, M. and Kristiansen, M., 2021. 
Omicron outbreak at a private gathering in the Faroe Islands, infecting 21 of 33 triple-vaccinated 
healthcare workers. 
Hershberger E, Sloan S, Narayan K, Hay CA, Smith P, Engler F, Jeeninga R, Smits S, Trevejo J, 
Shriver Z, Oldach D. Safety and efficacy of monoclonal antibody VIS410 in adults with 
uncomplicated influenza A infection: Results from a randomized, double-blind, phase-2, 
placebo-controlled study. EBioMedicine. 2019 Feb; 40:574-582. doi: 
10.1016/j.ebiom.2018.12.051. Epub 2019 Jan 9. PubMed PMID: 30638863; PubMed Central 
PMCID: PMC6412085. 
Hope T. Multiscale imaging of therapeutic antibody distribution and localization. Presented at: 
2019 HIV & HBV Cure Forum; Jul 20-21; Mexico City, Mexico. Accessed 2020 Apr 14. 
https://www.iasociety.org/Web/WebContent/File/HIV_Cure_Forum_2019/Session5/FT5-
2Hope.pdf. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, 
Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang 
R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-
6736(20)30183-5. Epub 2020 Jan 24. Erratum in: Lancet. 2020 Jan 30; PMID: 31986264; 
PMCID: PMC7159299. 
Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV 
epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus 
outbreak in Wuhan, China. Int J Infect Dis. 2020; 91:264-266. doi: 10.1016/j.ijid.2020.01.009. 
Hui KPY, Cheung MC, Perera RAPM, Ng KC, Bui CHT, Ho JCW, Ng MMT, Kuok DIT, Shih 
KC, Tsao SW, Poon LLM, Peiris M, Nicholls JM, Chan MCW. Tropism, replication 
competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory 
tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet. 2020 May 07; 
https://doi.org/10.1016/S2213-2600(20)30193-4. 
Hwang IK, Shih WJ, DeCani JS, Statistics In Medicine. Dec 1990 (Volume9, Issue 12, 1439-
1445) Group sequential designs using a family of type I error probability spending functions. 
Jansen, L., Tegomoh, B., Lange, K., Showalter, K., Figliomeni, J., Abdalhamid, B., Iwen, P., 
Fauver, J., Buss, B. and Donahue, M., 2021. Investigation of a SARS-CoV-2 B.1.1.529 
(Omicron) Variant Cluster — Nebraska, November–December 2021. MMWR. Morbidity and 
Mortality Weekly Report, 70(5152), pp.1782-1784. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 76 
JHU (Johns Hopkins University) Coronavirus COVID-19 Global Cases by the Center for 
Systems Science and Engineering website: 
https://www.arcgis.com/apps/dashboards/bda7594740fd40299423467b48e9ecf6. Accessed 06 
Jan 2022. 
Jordan RE, Adab P, Cheng KK. Covid-19: risk factors for severe disease and death. BMJ. 2020 
Mar 26;368:m1198. doi: 10.1136/bmj.m1198. PMID: 32217618. 
Joyner MJ, Bruno KA, Klassen SA, Kunze KL, et al. Safety Update: COVID-19 Convalescent 
Plasma in 20,000 Hospitalized Patients. Mayo Clin Proc. 2020; 95. 
https://mayoclinicproceedings.org/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_ft95_6
_8.pdf. 
Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein 
FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H Thromb Res. 2020; PMID 
32291094 Clinical characteristics of 113 deceased patients with coronavirus disease 2019: 
retrospective study. 
Ko S-Y, Pegu A, Rudicell RS, Yang Z-Y, Joyce MG, Chen X, Wang K, Bao S, Kraemer TD, 
Rath T, Zeng M, Schmidt SD, Todd J-P, Penzak SR, Saunders KO, Nason MC, Haase AT, Rao 
SS, Blumberg RS, Mascola JR, Nabel GJ. 2014. Enhanced neonatal Fc receptor function 
improves protection against primate SHIV infection. Nature. 2014 Oct 30; 514(7524):642-5. doi: 
10.1038/nature13612. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983; 
70:659-63. 
Lauer, S., Grantz, K., Bi, Q., Jones, F., Zheng, Q., Meredith, H., Azman, A., Reich, N. and 
Lessler, J., 2020. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From 
Publicly Reported Confirmed Cases: Estimation and Application. Annals of Internal Medicine, 
172(9), pp.577-582. 
Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing 
X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, 
Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, 
Ma Z, Zhang Y, Shi G, Lam TTY, Wu JT, Gao GF, CowlingBJ, Yang B, Leung GM, Feng Z. 
Early Transmission Dynamics in Wuhan, China, ofNovel Coronavirus-Infected Pneumonia. N 
Engl J Med. 2020 Mar 26;382(13):1199-1207. doi: 10.1056/NEJMoa2001316. Epub 2020 Jan 
29. PubMed PMID: 31995857. 
Lim JJ, Derby MA, Zhang Y, Deng R, Larouche R, Anderson M, Maia M, Carrier S, Pelletier I, 
Girard J, Kulkarni P, Newton E, Tavel JA. A Phase 1, Randomized, Double-Blind, Placebo-
Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and 
Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy 
Volunteers. Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00279-17. doi: 
10.1128/AAC.00279-17. PMID: 28559255; PMCID: PMC5527589. 
Liu Y, Yan LM, Wan L, Xiang TX, Le A, Liu JM, Peiris M, Poon LLM, Zhang W.. Viral 
dynamics in mild and severe cases of COVID-19. Lancet Infect Dis 2020;doi: 10.1016/S1473-
3099(20)30232-2.  
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 77 
Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J 
Pharm Sci. 2004 Nov;93(11):2645-68. 
McCallum M, De Marco A, Lempp F, Tortorici M, Pinto D, Walls A, Beltramello M, Chen A, 
Liu Z, Zatta F, Zepeda S, di Iulio S, Bowen J, Montiel-Ruiz M, Zhou J, Rosen L, Bianchi S, 
Guarino B, Fregni C, Abdelnabi R, Foo S, Rothlauf P, Bloyet L, Benigni F, Cameroni E, Neyts J, 
Riva A, Snell G, Telenti A, Whelan S, Virgin H, Corti D, Pizzuto M, Veesler D. N-terminal 
domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Biorxiv. 2021 Jan 14. 
doi: https://doi.org/10.1101/2021.01.14.426475 
NICE. COVID-19 rapid guideline: critical care in adults (NG159). 
https://www.nice.org.uk/guidance/ng159, 2020 
NIH. COVID-19 Treatment Guidelines https://www.covid19treatmentguidelines.nih.gov/ 
Accessed 2022 May 
NIH. NIH launches new initiative to study “Long COVID”. https://www.nih.gov/about-nih/who-
we-are/nih-director/statements/nih-launches-new-initiative-study-long-covid. Accessed 04 Oct 
2021 
Pablo N Perez-Guzman, Anna Daunt, Sujit Mukherjee et al. Clinical characteristics and 
predictors of outcomes of hospitalised patients with COVID-19 in a London NHS Trust: a 
retrospective cohort study (2020), doi: https://doi.org/10.25561/78613 
Petrilli et al, medrxiv N=1999 (hosp) OpenSAFELY (NHS data) N=5683 Deaths REF: COVID-
19 dashboard, Johns Hopkins https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html 
Pinto D, Park Y, Beltramello M et al. Cross-neutralization of SARS-CoV-2 by a human 
monoclonal SARS-CoV antibody. Nature. Published online May 18, 2020. 
https://doi.org/10.1038/s41586-020-2349-y 
Polack FP, Teng MN, Collins PL, Prince GA, Exner M, Regele H, Lirman DD, Rabold R, 
Hoffman SJ, Karp CL, Kleeberger SR, Wills-Karp M, Karron RA. A role for immune complexes 
in enhanced respiratory syncytial virus disease. J Exp Med. 2002 Sep 16;196(6):859-65. doi: 
10.1084/jem.20020781. PMID: 12235218; PMCID: PMC2194058. 
Poon A, Powers JH 3rd, Leidy NK, Yu R, Memoli MJ. Using the Influenza Patient-reported 
Outcome (FLU-PRO) Diary to Evaluate Symptoms of Influenza Viral Infection in a Healthy 
Human Challenge Model. BMC Infect Dis. 2018 Jul 28;18(1):353. doi: 10.1186/s12879-018-
3220-8. 
Powers JH, Bacci ED, Leidy NK, Poon JL, Stringer S, Memoli MJ, et al. Performance of the 
inFLUenza Patient-Reported Outcome (FLU-PRO) Diary in Patients with Influenza-Like Illness 
(ILI). PLoS One. 2018 Mar 22;13(3):e0194180. doi: 10.1371/journal.pone.0194180. eCollection 
2018. 
Powers JH, Bacci ED, Guerrero ML, Leidy NK, Stringer S, Kim K, Memoli MJ, et al. 
Reliability, Validity, and Responsiveness of InFLUenza Patient-Reported Outcome (FLU-
PRO©) Scores in Influenza-Positive Patients. Value Health. 2018 Feb;21(2):210-218. doi: 
10.1016/j.jval.2017.04.014. Epub 2017 Jun 7. 
Regeneron, casirivimab and imdevimab EUA Letter of Authorization, Accessed 11 February 
2021 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 78 
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and 
Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. 
JAMA. Published online April 22, 2020. doi:10.1001/jama.2020.6775. 
Sager J, D. Hong, A. Bonavia, L. Connolly, D. Cebrik, M. Fanget, E. Mogalian, P. Griffin. 
Preliminary safety and pharmacokinetic profile of VIR-2482: a monoclonal antibody for the 
prevention of influenza A illness. IDWeek Chasing the Sun Poster. Accessed 11 February 2021  
Shekerdemian LS, Mahmood NR, Wolfe KK, Riggs BJ, Ross CE, McKiernan CA, Heidemann 
SM, Kleinman LC, Sen AI, Hall MW, Priestley MA, McGuire JK, Boukas K, Sharron MP, 
Burns JP; International COVID-19 PICU Collaborative. Characteristics and Outcomes of 
Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian 
Pediatric Intensive Care Units. JAMA Pediatr. 2020 Sep 1;174(9):868-873. doi: 
10.1001/jamapediatrics.2020.1948. PMID: 32392288; PMCID: PMC7489842. 
Sotrovimab Fact Sheet. 
https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Sotrovimab/pd
f/SOTROVIMAB-EUA.PDF#nameddest=HCPFS. Accessed Mar 7, 2022. 
Vir. Press Release. Vir Biotechnology and GSK Announce VIR-7831 Reduces Hospitalization 
and Risk of Death in Early Treatment of Adults with COVID-19. Issued 2021 March 21.  
Wang P, Liu L, Iketani S, Luo Y, Guo Y, Wang M, Yu J, Zhang B, Kwong PD, Graham BS, 
Mascola JR, Chang JY, Yin MT, Sobieszczyk M, Kyratsous CA, Shapiro L, Sheng Z, Nair MS, 
Huang Y, Ho DD. Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to 
Antibody Neutralization. bioRxiv [Preprint]. 2021 Jan 26:2021.01.25.428137. doi: 
10.1101/2021.01.25.428137. PMID: 33532778; PMCID: PMC7852271. 
Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Musser BJ, Soo Y, Rofail 
D, Im J, Perry C, Pan C, Hosain R, Mahmood A, Davis JD, Turner KC, Hooper AT, Hamilton 
JD, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Kohli A, Sachdeva Y, Graber X, 
Kowal B, DiCioccio T, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD; Trial 
Investigators. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N 
Engl J Med. 2021 Jan 21;384(3):238-251. doi: 10.1056/NEJMoa2035002. Epub 2020 Dec 17. 
PMID: 33332778; PMCID: PMC7781102. 
Weiss P, Murdoch DR. Clinical course and mortality risk of severe COVID-19. Lancet. 2020 
Mar 28;395(10229):1014-1015. doi: 10.1016/S0140-6736(20)30633-4. Epub 2020 Mar 17. 
PMID: 32197108; PMCID: PMC7138151. 
WHO. World Health Organization Incidence of thrombotic complications in critically ill ICU 
patients with COVID-19. https://www.who.int/health-topics/coronavirus#tab=tab_3 (Carolina 
WHO checklist reference) 2021. Accessed 11 February 2021 
Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with 
COVID-2019. Nature. 2020 Apr 01. https://doi.org/10.1038/s41586-020-2196-x 
Wu JT, Ma ES, Lee CK, Chu DK, Ho PL, Shen AL, Ho A, Hung IF, Riley S, Ho LM, Lin CK, 
Tsang T, Lo SV, Lau YL, Leung GM, Cowling BJ, Malik Peiris JS. The infection attack rate and 
severity of 2009 pandemic H1N1 influenza in Hong Kong. Clin Infect Dis. 2010 Nov 
15;51(10):1184-91. doi: 10.1086/656740. PMID: 20964521; PMCID: PMC3034199. 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

VIR-7831 
VIR-7831-5008 (GSK Study 217114) 
Vir Biotechnology, Inc. 
Amendment 4 
Vir Biotechnology, Inc. 
Confidential 
Page 79 
Yang H, et al. O0814 Phase IIb study evaluating the efficacy and safety of anti-influenza A 
monoclonal antibody, CT-P27, in subjects with acute uncomplicated Influenza A Infection. 29th 
European Congress of Clinical Microbiology and Infectious Diseases. Amsterdam, Netherlands. 
2019 Apr 13-16. Poster presentation. 
Yu J, Powers JH 3rd, Vallo D, Falloon J. Evaluation of Efficacy Endpoints for a Phase IIb Study 
of a Respiratory Syncytial Virus Vaccine in Older Adults Using Patient-Reported Outcomes with 
Laboratory Confirmation. Value Health. 2020 Feb;23(2):227-235. doi: 
10.1016/j.jval.2019.09.2747. Epub 2019 Nov 21. 
Zheng S, Fan J, Yu F, Feng B, Lou B, Zou Q, Xie G, Lin S, Wang R, Yang X, Chen W, Wang 
Q, Zhang D, Liu Y, Gong R, Ma Z, Lu S, Xiao Y, Gu Y, Zhang J, Yao H, Xu K, Lu X, Wei G, 
Zhou J, Fang Q, Cai H, Qiu Y, Sheng J, Chen Y, Liang T. Viral load dynamics and disease 
severity in participants infected with SARS-CoV-2 in Zhejiang province, China, January-March 
2020: retrospective cohort study. BMJ. 2020 Apr 21;369:m1443. doi: 10.1136/bmj.m1443. 
PMID: 32317267; PMCID: PMC7190077. 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li 
H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of 
adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 
Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. 
Erratum in: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038. 
PubMed PMID: 32171076. 
Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, Yu J, Kang M, Song Y, Xia J, Guo Q, 
Song T, He J, Yen HL, Peiris M, Wu J. SARS-CoV-2 Viral Load in Upper Respiratory 
Specimens of Infected Participants. N Engl J Med. 2020 Mar 19;382(12):1177-1179. doi: 
10.1056/NEJMc2001737. Epub 2020 Feb 19. PubMed PMID: 32074444. 
 
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD

Signature Page for VV-CLIN-001188 v5.0
Signature Page for VV-CLIN-001188 v5.0
Approval Task
01 Jun 2022   Protocol Amendment Amendment #4/ Substudy PART B  | VV-TMF-6829167 | 1.0
Approved
PPD
PPD