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.

  
CLINICAL STUDY PROTOCOL  
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  
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 Title: Intramuscular VIR-7831 (sotrovimab) for mild/moderate COVID-19  
Study Phase: Phase III  
 
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 2021 Vir Biotechnology, Inc. and the GlaxoSmithKline group of companies. All 
rights reserved. Unauthorized copying or use of this information is prohibited. 
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INVESTIGATOR SIGNATURE PAGE 
 
VIR BIOTECHNOLOGY, INC 
499 ILLINOIS STREET SUITE 500 
SAN FRANCISCO, CA 94158 
 
STUDY ACKNOWLEDGMENT 
 
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, Protocol Amendment 4, 27 May 2022 
 
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 
 
 
 
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Table 1: 
Protocol Document History 
Document 
Date 
Amendment 4 
27 May 2022 
Amendment 3 
04 October 2021 
Amendment 2 
29 June 2021 
Amendment 1 
05 May 2021 
Original Protocol 
12 February 2021 
Table 2: 
Protocol Amendment 4 Summary of Changes 
Section # and 
Name 
Description of Change 
Brief Rationale 
Page 1/Protocol 
Title 
Updated to reflect the addition 
of safety substudy to the title 
Reference to safety substudy is 
needed in title 
Section 1.1 
Synopsis, Overall 
Design 
Updated with reference to 
safety substudy 
For clarity, details of safety substudy 
are described in substudy rather than 
in Section 1.1 of the original protocol 
 
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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY .................................................................. 9 
1.1. 
Synopsis .............................................................................................. 9 
1.2. 
Study Schema ................................................................................... 14 
1.3. 
Schedule of Activities ....................................................................... 15 
2. 
INTRODUCTION ............................................................................ 17 
2.1. 
Study Rationale ................................................................................. 17 
2.2. 
Background ....................................................................................... 18 
2.3. 
Benefit/Risk Assessment .................................................................. 21 
2.3.1. 
Risk Assessment ............................................................................... 22 
2.3.2. 
Benefit Assessment ........................................................................... 29 
2.3.3. 
Overall Benefit: Risk Conclusion ..................................................... 29 
3. 
OBJECTIVES AND ENDPOINTS .................................................. 30 
4. 
STUDY DESIGN ............................................................................. 33 
4.1. 
Overall Design .................................................................................. 33 
4.2. 
Scientific Rationale for Study Design .............................................. 34 
4.3. 
Justification for Dose ........................................................................ 36 
4.3.1. 
Sotrovimab ........................................................................................ 36 
4.4. 
End of Study Definition .................................................................... 37 
5. 
STUDY POPULATION ................................................................... 38 
5.1. 
Inclusion Criteria .............................................................................. 38 
5.1.1. 
Age and Risk Factors ........................................................................ 38 
5.1.2. 
Type of Participant and Disease Characteristics .............................. 38 
5.1.3. 
Sex and Contraceptive/Barrier Requirements .................................. 39 
5.1.4. 
Informed Consent ............................................................................. 39 
5.2. 
Exclusion Criteria ............................................................................. 40 
5.2.1. 
Medical Conditions ........................................................................... 40 
5.2.2. 
Prior/Concurrent Clinical Study Experience .................................... 40 
5.2.3. 
Other Exclusions ............................................................................... 40 
5.3. 
Lifestyle Considerations ................................................................... 40 
5.4. 
Pre-Screening .................................................................................... 41 
5.5. 
Screen Failures .................................................................................. 41 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
 .......................................................................................................... 42 
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6.1. 
Study Intervention(s) Administered ................................................. 42 
6.2. 
Preparation/Handling/Storage/Accountability .................................. 43 
6.3. 
Randomization .................................................................................. 43 
6.4. 
Study Intervention Compliance ........................................................ 44 
6.5. 
Dose Modification ............................................................................ 44 
6.6. 
Continued Access to Study Intervention after the End of the Study 44 
6.7. 
Treatment of Overdose ..................................................................... 44 
6.8. 
Concomitant Therapy ....................................................................... 45 
6.8.1. 
Medication Not Permitted During the Study .................................... 45 
6.8.2. 
Permitted Concomitant Medication .................................................. 45 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ............. 46 
7.1. 
Discontinuation of Study Intervention.............................................. 46 
7.1.1. 
Temporary Discontinuation .............................................................. 46 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................. 46 
7.3. 
Lost to Follow Up ............................................................................. 47 
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................ 48 
8.1. 
Screening Period ............................................................................... 48 
8.1.1. 
Medical History ................................................................................ 48 
8.1.2. 
SARS-CoV-2 Diagnostic Testing ..................................................... 49 
8.1.3. 
Secondary Contact Information ........................................................ 49 
8.2. 
Efficacy Assessments ....................................................................... 49 
8.2.1. 
Hospitalization and Death Data Collection ...................................... 49 
8.2.2. 
SARS-CoV-2 Serology Analysis ...................................................... 49 
8.2.3. 
Phone Call for Subsequent COVID-19 Illness ................................. 50 
8.2.4. 
Long COVID Assessment ................................................................ 50 
8.3. 
Safety Assessments ........................................................................... 50 
8.3.1. 
Physical Examinations ...................................................................... 50 
8.3.2. 
Vital Signs ........................................................................................ 50 
8.3.3. 
Electrocardiograms ........................................................................... 51 
8.3.4. 
Local Tolerability Assessment ......................................................... 51 
8.3.5. 
Virologic Measures ........................................................................... 51 
8.3.6. 
Resistance Analyses .......................................................................... 51 
8.3.7. 
Clinical Safety Laboratory Assessments .......................................... 52 
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8.3.8. 
Pregnancy Testing ............................................................................ 53 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ............................................................................... 53 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information
 .......................................................................................................... 54 
8.4.2. 
Assessment of Severity ..................................................................... 54 
8.4.3. 
Method of Detecting AEs and SAEs ................................................ 54 
8.4.4. 
Follow-up of AEs and SAEs ............................................................. 54 
8.4.5. 
Regulatory Reporting Requirements for SAEs ................................. 55 
8.4.6. 
Pregnancy ......................................................................................... 55 
8.4.7. 
Cardiovascular and Death Events ..................................................... 56 
8.4.8. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................. 56 
8.4.9. 
Adverse Events of Special Interest ................................................... 56 
8.4.9.1. 
Systemic Reactions and Hypersensitivity Reactions ........................ 57 
8.4.9.2. 
Local infusion/injection site reactions (LI/ISR) ............................... 57 
8.4.9.3. 
Immunogenicity ................................................................................ 57 
8.4.9.4. 
Antibody Dependent Enhancement .................................................. 57 
8.5. 
Pharmacokinetics .............................................................................. 58 
8.6. 
Immunogenicity Assessments .......................................................... 58 
9. 
STATISTICAL CONSIDERATIONS ............................................. 60 
9.1. 
Statistical Hypotheses ....................................................................... 60 
9.2. 
Sample Size Determination .............................................................. 60 
9.3. 
Analysis Sets ..................................................................................... 61 
9.4. 
Statistical Analyses ........................................................................... 62 
9.4.1. 
General Considerations ..................................................................... 62 
9.4.2. 
Primary Endpoint(s) .......................................................................... 63 
9.4.3. 
Secondary Endpoint(s) ...................................................................... 64 
9.4.4. 
Exploratory Endpoint(s) ................................................................... 64 
9.4.5. 
Safety Analysis ................................................................................. 64 
9.4.6. 
Other Analysis .................................................................................. 64 
9.5. 
Interim Analysis ................................................................................ 64 
9.6. 
Multiple Comparisons and Multiplicity............................................ 65 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ........................................................................ 66 
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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .................................................................................. 66 
10.1.1. 
Regulatory and Ethical Considerations ............................................ 66 
10.1.2. 
Financial Disclosure ......................................................................... 66 
10.1.3. 
Informed Consent Process ................................................................ 67 
10.1.4. 
Data Protection ................................................................................. 67 
10.1.5. 
Committees Structure ....................................................................... 67 
10.1.6. 
Dissemination of Clinical Study Data .............................................. 68 
10.1.7. 
Data Quality Assurance .................................................................... 69 
10.1.8. 
Source Documents ............................................................................ 70 
10.1.9. 
Study and Site Start and Closure ...................................................... 70 
10.1.10. 
Publication Policy ............................................................................. 71 
10.2. 
Appendix 2: Clinical Laboratory Tests ............................................. 72 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ........................... 74 
10.3.1. 
Definition of AE ............................................................................... 74 
10.3.2. 
Definition of SAE ............................................................................. 75 
10.3.3. 
Definition of Cardiovascular Events ................................................ 76 
10.3.4. 
Recording and Follow-Up of AE and SAE ...................................... 77 
10.3.5. 
Reporting of SAEs ............................................................................ 78 
10.3.6. 
Expedited Reporting to Health Authorities, Investigators and Ethics 
Committees ....................................................................................... 79 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ............................ 80 
10.4.1. 
Definitions: ....................................................................................... 80 
10.4.2. 
Contraception Guidance: .................................................................. 82 
10.5. 
Appendix 5: Local Tolerability Assessment1 ................................... 83 
10.6. 
Appendix 6: Long COVID Questionnaire ........................................ 84 
11. 
REFERENCES ................................................................................. 87 
 
LIST OF TABLES  
Table 1: 
Sotrovimab PK Parameters Following a 500 mg IV Dose: COMET-
ICE Lead-in Phase ............................................................................ 21 
Table 3: 
Overview of Study Intervention ....................................................... 42 
Table 4: 
Protocol-Required Safety Laboratory Tests ..................................... 73 
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LIST OF FIGURES  
Figure 1: 
Mean (+ standard deviation [SD]) Sotrovimab Serum 
Concentration-Time Plots (Linear and Semi-log): COMET-ICE 
Lead-In Phase ................................................................................... 20 
 
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1. 
PROTOCOL SUMMARY  
1.1. 
Synopsis  
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. 
Rationale:  
There is an urgent medical need for therapeutics for the treatment of Severe Acute 
Respiratory Syndrome coronavirus-2 (SARS-CoV-2) infection, the cause of coronavirus 
disease 2019 (COVID-19). Early treatment of mild and moderate disease in outpatients 
could prevent the more severe sequelae of COVID-19 requiring hospitalization, such as 
respiratory failure, thromboembolic disease leading to pulmonary embolism and stroke, 
arrhythmias, and shock. Furthermore, a potent treatment given early in disease could 
ameliorate the severity and duration of COVID-19 and potentially reduce transmission. 
The ability to administer such a treatment easily in community settings is desirable.  
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 improve 
bioavailability in the respiratory mucosa (Hope 2019) and increase half-life (Ko 2014). 
Furthermore, Vir has formulated this monoclonal antibody for both intravenous (IV) and 
intramuscular (IM) administration. 
As of June 2021, there are three anti-SARS-CoV-2 monoclonal antibody treatments that 
are authorized under Emergency Use Authorization (EUA) from the FDA for the early 
treatment of COVID-19: bamlanivimab/etesevimab (Eli Lilly 2021b), 
casirivimab/imdevimab (Regeneron 2021), and sotrovimab (FDA 2021). These mAb 
treatments are administered intravenously which has limited their availability as hospitals 
and clinics generally provide infusions in dedicated facilities usually reserved for 
chemotherapy or other biologics (Goldstein 2020). There is a need to develop a more 
convenient method of administration so patients can have easier access to 
anti-SARS-CoV-2 antibody treatments. Sotrovimab, administered intravenously, is 
currently being 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 patients 
(VIR-7831-5001; GSK study 214367; COMET-ICE). The COMET-ICE study uses the 
first generation formulation of sotrovimab (Gen1) which can only be given intravenously. 
The second generation formulation (Gen2) of sotrovimab can be administered 
intravenously or intramuscularly. 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 patients which demonstrated an 85% (p=0.002) reduction in hospitalization or death 
in patients receiving sotrovimab compared to placebo (Vir 2021). 
This current study aims to assess the efficacy, safety, and tolerability of intramuscular 
(IM) sotrovimab versus intravenous (IV) sotrovimab when given to high-risk patients for 
the treatment of mild/moderate COVID-19. This study will evaluate the clinical efficacy 
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of two dose levels of IM sotrovimab compared with IV sotrovimab in preventing 
progression of COVID-19 by utilizing a non-inferiority (NI) design.  
Gen2 sotrovimab material is also currently being studied to evaluate safety, tolerability, 
and pharmacokinetics in patients with mild to moderate COVID-19 
[GSK216912 (VIR-7831-5006), also known as COMET-PEAK]. In COMET-PEAK, 
Part A is comparing the safety and pharmacokinetics of Gen1 and Gen2 sotrovimab when 
administered intravenously. Part B of COMET-PEAK will also compare the virologic 
activity of intravenous versus intramuscular administration of sotrovimab in patients with 
mild to moderate COVID-19 at low-risk of disease progression. Intramuscular injection 
of sotrovimab will also be evaluated in a planned study of prophylaxis against COVID-19 
[GSK214368 (VIR-7831-5003), also known as COMET-STAR].  
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Objectives and Endpoints:  
Objectives  
Endpoints 
Primary 
 
Evaluate the efficacy of two dose levels of 
intramuscular sotrovimab versus 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 
Secondary  
 
Safety 
Describe the safety and tolerability of 
intramuscular and intravenous sotrovimab 
 
• 
Occurrence of adverse events (AEs) 
• 
Occurrence of serious adverse events (SAEs)  
• 
Occurrence of adverse events of special 
interest (AESI) 
• 
Occurrence of disease related events (DRE) 
Assess the immunogenicity of sotrovimab 
Incidence and titers (if applicable) of serum anti-
drug antibody (ADA) to sotrovimab 
Efficacy 
Evaluate the efficacy of two dose levels of 
intramuscular versus intravenous sotrovimab on 
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 
• 
Hospitalization for acute management of 
illness for any duration and for any cause 
OR 
• 
Death 
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Objectives  
Endpoints 
Evaluate the efficacy of two dose levels of 
intramuscular versus intravenous sotrovimab in 
preventing COVID-19 respiratory disease 
progression  
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  
Compare the virologic activity of sotrovimab 
given IM (two dose levels) or IV in reducing 
SARS-CoV-2 viral load  
• 
Mean area under the curve of SARS-CoV-2 
viral load in nasal secretions as measured by 
qRT-PCR from Day 1 to Day 8 (AUCD1-8) 
• 
Change from baseline in viral load by qRT-
PCR at Day 8 
• 
Proportion of participants with a persistently 
high SARS-CoV-2 viral load at Day 8 by 
qRT-PCR 
Pharmacokinetics 
Assess the pharmacokinetics (PK) of sotrovimab 
in serum following IV and IM (two dose levels) 
administration 
 
IV and IM sotrovimab pharmacokinetics (PK) in 
serum 
Exploratory  
 
Describe the effect of two doses levels of 
intramuscular versus intravenous sotrovimab on 
incidence and duration of time on total hospital 
length of stay (LOS), incidence and duration of 
time on a ventilator, and ICU length of stay  
• 
Incidence of hospitalization through Day 29 
• 
Total hospital LOS  
• 
Proportion of participants requiring ICU stay 
or mechanical ventilation through Day 29 
• 
Total ICU LOS 
Monitor SARS-CoV-2 resistant mutants against 
sotrovimab 
• 
SARS-CoV-2 resistance mutants to 
sotrovimab at baseline 
• 
Emergence of viral resistance mutants to mAb 
by SARS-CoV-2  
Compare the virologic activity of sotrovimab 
given IM (two dose levels) or IV in reducing 
SARS-CoV-2 viral load 
• 
Change from baseline in viral load in nasal 
secretions by qRT-PCR during follow-up 
period at Day 5, 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 
• 
Mean area under the curve of SARS-CoV-2 
viral load as measured by qRT-PCR from Day 
1 to Day 5 (AUCD1-5) and Day 1 to 11 
(AUCD1-11) 
Compare the effect of different sample collection 
methods in SARS-CoV-2 viral load (e.g. 
nasopharyngeal swab, saliva) 
• 
SARS-CoV-2 viral load measured by qRT-
PCR 
Evaluate the effect of sotrovimab on the 
development of SARS-CoV-2 antibodies 
• 
SARS-CoV-2 anti-N antibody at Day 1 and 
Day 29 
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Objectives  
Endpoints 
Describe the effect of sotrovimab on Long 
COVID symptoms 
• 
Incidence and severity of Long COVID 
symptoms at W12, W24 and W36 
 
Overall Design:  
This study is a Phase 3 randomized, multi-center, open label, non-inferiority study of 
intramuscular (IM) versus intravenous (IV) administration of sotrovimab, a monoclonal 
antibody (mAb) against SARS-CoV-2 for the treatment of mild/moderate COVID-19 in 
participants aged 12 years old and older at high risk of disease progression. The study 
will randomize 1:1:1 to receive a single dose IV infusion of sotrovimab or a single IM 
injection of sotrovimab at one of two dose levels.  
Participants with early, mild/moderate COVID-19 who are not on supplemental oxygen 
and at risk for disease progression will receive an IV infusion or IM injection of 
sotrovimab. The IV sotrovimab dose will be 500 mg and will be infused over 15 minutes. 
The IM sotrovimab dose will be either 250 mg or 500 mg given at a single timepoint. The 
250 mg IM dose will be given either as a single 250 mg (4ml) injection in the 
dorsogluteal muscle or as two 2 ml injections in each deltoid muscle. The 500 mg IM 
dose will be administered as two 4 ml injections in each dorsogluteal muscle.  
After IV infusion or IM injection, participants will be monitored for 30 minutes with vital 
signs assessments performed every 15 minutes. Injection site reaction assessments, for 
IM arms only, will be performed at 15 and 30 minutes after injection. All participants 
will be actively monitored on an outpatient basis with frequent collection of 
nasopharyngeal swabs for virology and blood draws for PK sampling, as well as weekly 
in-clinic evaluations at Weeks 1, 2, 3, and 4 as detailed in the Schedule of Activities. 
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. 
COMET-TAIL will now include a safety substudy, which will examine the safety and 
tolerability of single ascending dose sotrovimab, for which a complete protocol, 
including study design, is outlined in the Safety Substudy Clinical Study Protocol 
document. 
Number of Participants:  
Approximately 1020 participants were to be enrolled and randomized 1:1:1 to receive a 
single 500 mg IV infusion of sotrovimab, a single 500 mg IM injection of sotrovimab, or 
a single 250 mg IM injection of sotrovimab. An interim analysis (IA) was originally 
planned for an independent data monitoring committee (IDMC) to evaluate each dose 
level of IM sotrovimab versus IV sotrovimab for safety, futility and efficacy when 
approximately 50% of participants enrolled and reached Day 29. During the conduct of 
the study, the joint safety review team (JSRT) noted a discrepancy in the rate of 
progression to hospitalization occurring in the 250 mg IM arm compared with the 500 mg 
IM and IV arms, and an ad hoc interim dataset was escalated to the IDMC for review. As 
a result of this review, enrollment into the 250 mg IM arm was discontinued and the 
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study design was changed to a 2-arm study with 1:1 randomization up to ~340 
participants/arm into the remaining 2 arms of 500 mg IM and 500 mg IV. 
Intervention Groups and Duration:  
Screening assessments will be performed within 48 hours prior to randomization. 
Screening can occur on the same day as randomization. Eligible participants will be 
treated with a single IM or IV dose of sotrovimab on Day 1 and followed for up to 
36 weeks.  
Participants will be stratified based on: 
1. Age: 12-17 years old, 18-64 years old, and ≥65 years old  
2. COVID-19 Vaccination History: receipt of any COVID-19 vaccine  
3. Region of the world due to potential differences in standard of care for 
COVID-19 management and different circulating SARS-CoV-2 variants.  
Saliva SARS-CoV-2 qRT-PCR substudy  
To evaluate the comparability of SARS-CoV-2 quantitative RT-PCR when performed on 
saliva versus nasopharyngeal (NP) swabs, an optional sub-study may be performed. Up to 
200 subjects will have paired saliva and NP collected at 4 timepoints during the study 
(D1, D8, D15, D22). 
1.2. 
Study Schema  
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1.3. 
Schedule of Activities  
Table 1: 
Schedule of Activities 
Study Stage 
Screening Dosing 
Follow-up Period 
Study Visit Week 
 
 
W1 
W2 
W3 
W4 
W8 j 
W12 
W16 j 
W20 
W24 
(EWk) 
W28 j 
W32 j 
W36 j 
(EOS/EWk)
Study Visit Day ± Visit 
Window 
D -2 to -1 
D1 
D3 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 
 
 
 
 
 
 
 
 
Local tolerability assessment  
 
Xb 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight & height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (including O2 
saturation) 
X 
Xc 
 
 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
Local safety lab assessments 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessments 
 
Xe 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
SARS-CoV-2 diagnostic test i 
(point-of-care or local 
laboratory test) 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Electrocardiogram 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for 
virology 
 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Saliva sample for virology  
(optional substudy) 
 
Xe 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
Blood sample for PK analysis 
 
Xg 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
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Study Stage 
Screening Dosing 
Follow-up Period 
Study Visit Week 
 
 
W1 
W2 
W3 
W4 
W8 j 
W12 
W16 j 
W20 
W24 
(EWk) 
W28 j 
W32 j 
W36 j 
(EOS/EWk)
Study Visit Day ± Visit 
Window 
D -2 to -1 
D1 
D3 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 
Blood sample for anti-drug 
antibody 
 
Xe 
 
 
 
 
 
 
X 
 
X 
 
X 
Xk 
 
 
 
Blood sample for anti-N 
SARS-CoV-2 antibody 
 
Xe 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Long COVID assessment 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Phone call or clinic visit for 
subsequent COVID19 illness 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review/record AE/SAE  
 
Xh 
Concomitant medications 
 
X 
a Complete physical examination should be performed on Day 1; all other visits should be symptom-directed physical examinations. 
b Local tolerability assessments should be performed at 15 mins (± 5 mins) and 30 minutes (± 5 mins) after injection (only for participants who received IM 
injection).  
c Vital signs on Day 1 should be recorded prior to dose administration and at 15 mins (± 5 mins) and 30 mins (± 5 mins) after injection or infusion.  
d All local lab assessments may be performed or not as determined necessary by the investigator or required by local regulations.  
e On Day 1, sample collection will occur pre-dose. 
f Electrocardiogram at screening only for participants with a history of cardiovascular disease or diabetes 
g On Day 1, PK sample will be collected pre-dose. 
h Adverse events will be assessed up to Week 12 post dose. Serious adverse events (SAEs) will be assessed up to Week 36. 
i Participants may be tested at screening if symptom onset ≤ 7 days, but dosing (D1 visit) must also occur ≤ 7 days of symptom onset. 
j Week 8,Week 16, Week 28, Week 32 and Week 36 are planned as site phone calls to participants only. 
k 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.  
  
 
 
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2. 
INTRODUCTION  
2.1. 
Study Rationale  
This study is a Phase 3 randomized, multi-center, open label study of intramuscular (IM) 
versus intravenous (IV) administration of sotrovimab, a monoclonal antibody (mAb) 
against SARS-CoV-2 for the prevention of progression of mild/moderate COVID19 in 
participants 12 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). Adolescents, aged 12-17 years of age, at high-risk for COVID-19 
progression include those with obesity (BMI ≥85th percentile for age/gender), chronic 
kidney disease, sickle-cell disease, congenital heart disease, neurodevelopmental 
disorders, medically-related technology dependence such as tracheostomy, 
ventilator-support, or a gastrostomy tube, or 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; 
Shekerdemian 2021) The study will include outpatients 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 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 is currently being studied in a Phase 3 placebo-controlled trial evaluating the 
efficacy of sotrovimab in preventing progression of COVID-19 in high-risk patients 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 patients which demonstrated an 85% (p=0.002) reduction in 
hospitalization or death in patients receiving sotrovimab compared to placebo. 
Sotrovimab was well-tolerated with no safety signals detected. (Vir 2021) In addition, 
recently both the NIH COVID-19 Treatment Guidelines and the Infectious Diseases 
Society of America have both recommended monoclonal antibody therapy treatment for 
high-risk individuals with mild/moderate COVID-19. (NIH 2021) 
In light of positive data from COMET-ICE demonstrating overwhelming clinical efficacy 
of sotrovimab in preventing COVID-19 disease progression 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.  
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Give the urgent unmet medical need and the ethical considerations of a 
placebo-controlled design in the setting of already demonstrated clinical efficacy, the 
design for this current trial is a non-inferiority study comparing the clinical efficacy of 
two dose levels of IM sotrovimab versus IV sotrovimab using a clinical endpoint of 
progression of COVID-19 as defined by hospitalisation >24 hours or death by Day 29. 
The primary endpoint to assess efficacy of treatment is progression of mild/moderate 
COVID-19 defined by hospitalization >24 hours for acute management of illness or death 
due to any cause within 29 days of randomization. The transition from outpatient status 
without hypoxemia to hospitalization for acute care or death is a clinically significant 
metric. A 29-day period to assess the primary endpoint is appropriate as the median time 
for COVID-19 related hospital admission has been reported to be 7-11 days and the 
median time to clinical deterioration, 9-12 days (Huang 2020; Zhou 2020). Key 
secondary endpoints include evaluations of safety and tolerability for IM administration 
of sotrovimab, pharmacokinetics and comparability of anti-viral activity of IM versus IV 
sotrovimab  
The study was planned to first evaluate non-inferiority of 500 mg of sotrovimab given IM 
versus 500mg of sotrovimab given IV. If non-inferiority was demonstrated, an additional 
non-inferiority evaluation was to be performed of 250mg IM of sotrovimab versus 500mg 
IV of sotrovimab. 
 
An ad hoc meeting of the IDMC was called on on 11-August-2021. The IDMC concurred 
that recruitment to the sotrovimab 250 mg IM arm be permanently discontinued. The 
enrollment for sotrovimab 250 mg IM arm was terminated afterwards. Therefore the 
non-inferiority evaluation of 250mg IM of sotrovimab versus 500mg IV of sotrovimab 
will not be performed (See Section 9.1). 
 
2.2. 
Background  
A novel betacoronavirus was first reported in December 2019 causing severe pneumonia 
in Wuhan, China. Since that time, SARS-CoV-2 has spread throughout the world leading 
to over 145 million confirmed cases and over 3 million deaths as of April 24, 2021 
(COVID-19 dashboard, Johns Hopkins).  
There is an urgent need for effective treatment throughout the course of illness. Emerging 
data suggest that morbidity and mortality associated with COVID-19 exceeds that of 
influenza and risk factors for progression to severe disease and mortality, include lifestyle 
and demographic factors, and the presence of pre-existing comorbidities. (Gold 2020; 
Jordan 2020; Weiss 2020; Zheng 2020) Reported case fatality rates vary markedly by 
country, with current estimates of overall rates ranging from 1.8% to 3.4% and mortality 
rates exceeding 25% for some populations. (Bialek 2020 Ferguson 2020) Based on 
current experience in China, the UK, and Italy, experts have estimated that approximately 
30% of those who are hospitalized will require critical care and that 50% of those in 
critical care will die. In addition, an age-dependent proportion of those that do not require 
critical care will also die (Ferguson 2020). Mortality rates are likely to be impacted by 
access to appropriate care as intensive care unit (ICU) beds and critical care capacity 
becomes overwhelmed.  
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Not only is there a high unmet need for treatment of those with severe disease but also for 
therapies designed to prevent the progression of disease in those with early infection. 
Currently available data suggest that SARS-CoV-2 is associated with a relatively long 
incubation period, with mean incubation period from exposure to symptomatic disease of 
approximately 5 days with the 95% percentile of the distribution at 12.5 days (Li 2020). 
In a study of two cohorts of adult inpatients with COVID-19, the median time to 
progression to severe disease (ICU admission/development of ARDS) from 
onset-of-symptoms was 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 
(Wölfel 2020; Zou 2020). Notably, although viral nucleic acid was detected well after 
symptom resolution in participants with mild infection, shedding of infectious virus in 
sputum was limited to the first week of symptoms (Wölfel 2020).  
There are currently three investigational monoclonal antibody products against 
SARS-CoV-2 that have emergency use authorization (EUA) for the treatment of mild to 
moderate COVID-19. Casirivimab/imdevimab was granted an EUA on November 21, 
2020 for the treatment of mild to moderate COVID-19 in high-risk patients. 
Bamlanivimab (LY-CoV555) was granted an EUA on November 9th, 2020 for the 
treatment of patients 12 years old and older who are at high risk of progressing to severe 
COVID-19 and/or hospitalization. However, given the high levels of resistance that has 
developed in SARS-CoV-2 to monotherapy with bamlanivimab, the FDA revoked the 
EUA for bamlanimivab on April 16, 2021 (FDA 2021). 
 Therefore, bamlanivimab is 
only recommended for treatment in combination with etesevimab, which was granted an 
EUA on February 9, 2021. These mAb products showed a decline in SARS-CoV-2 
respiratory viral load with administration and early data suggests that administration can 
prevent progression to severe disease in these patients (Chen 2020; Eli Lilly 2021; 
Weinreich 2021). Sotrovimab was granted an EUA on May 26, 2021 (FDA 2021) 
Vir Biotechnology, Inc. (Vir) has developed a fully human neutralizing 
anti-SARS-CoV-2 antibody, sotrovimab (VIR-7831; GSK4182136), which contains a 
2 amino acid Fc-modification (“LS”) that is designed to improve bioavailability in the 
respiratory mucosa and increase half-life. Sotrovimab binds to a conserved epitope on the 
SARS-CoV and SARS-CoV-2 spike protein outside the receptor-binding motif and has 
been shown to neutralize pseudovirus and live virus in several independent laboratories 
(Pinto 2020). This unique binding site may retain activity against emerging SARS-CoV-2 
variants that may be resistant to other mAbs (Wang 2021). The epitope to which 
sotrovimab binds is comprised of 23 amino acids. Amino acids comprising the epitope 
are highly conserved with >99.89% conservation among >1,000,000 currently available 
sequences of SARS-CoV-2 (https://www.gisaid.org). In vitro pseudotyped virus 
assessment shows that the epitope sequence polymorphisms P337H/L/R/T and 
E340A/K/G confer reduced susceptibility to sotrovimab. The presence of the highly 
prevalent D614G variant, either alone or in combination, did not alter neutralization of 
sotrovimab. Pseudotyped virus in vitro assessments indicate that sotrovimab retains 
activity against the UK (B.1.1.7: H69-, V70-, Y144‑, N501Y, A570D, D614G, P681H, 
T716I, S982A, D1118H), South Africa (B.1.351: L18F, D80A, D215G, R246I, K417N, 
E484K, N501Y, D614G, A701V), Brazil (P.1: D138Y, D614G, E484K, H655Y, K417T, 
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L18F, N501Y, P26S, R190S, T1027I, T20N, V1176F) and California (CAL.20C: 
D614G, L452R, S13I, W152C) variant spike proteins. (Cathcart 2021; MacCallum 2021) 
Thus, it is expected that sotrovimab will retain activity against most SARS-CoV-2 strains 
even when given as monotherapy. 
In the Phase 3 placebo-controlled trial evaluating the efficacy of sotrovimab in preventing 
progression of COVID-19 in high-risk patients with mild/moderate COVID-19 
(VIR-7831-50001; COMET-ICE), serum PK from the Lead-in phase is available to date. 
There were 10 participants in the sotrovimab arm of the Lead-in Phase of this study. One 
participant discontinued early due to withdrawal of consent following infusion with 
sotrovimab. The mean maximum observed concentration (Cmax) of 500 mg sotrovimab 
was 219 µg/mL following a 1 hour IV infusion. The mean serum level on Day 29 is 
37.2 µg/mL. The mean clearance (CL) and volume of distribution at steady state (Vss) 
were 125 mL/day and 8.1 L, respectively. The median half-life was 48.8 days. The mean 
PK profile and parameters are presented in Figure 1 and Table 3 respecitvely.  
Mean (+ standard deviation [SD]) Sotrovimab Serum Concentration-Time Plots (Linear 
and Semi-log): COMET-ICE Lead-In Phase 
Figure 1: 
Mean (+ standard deviation [SD]) Sotrovimab Serum 
Concentration-Time Plots (Linear and Semi-log): COMET-ICE 
Lead-In Phase 
 
Note: Lower limit of quantification (LLQ)=0.1 µg/mL. Excludes anomalous concentrations identified as 
sampling errors by the clinical pharmacologist. 
Data is based on 1-hour infusion time. 
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Table 3: 
Sotrovimab PK Parameters Following a 500 mg IV Dose: COMET-
ICE Lead-in Phase 
Parameter 
Dose 
500 mg 
(N = 9a) 
Cmax, µg/mL 
219 (45.5) 
Tmax, day 
0.04 (0.04, 0.05) 
Clast, µg/mL 
5.41 (37.2) 
Tlast, day 
161 (160, 167) 
AUCD1-29, day*µg/mL 
1529 (9.6) 
AUClast, day*µg/mL 
3714 (14.5) 
AUC % Extrapolated 
9.4 (37.9) 
AUCinf, day*µg/mL 
4116 (16.9) 
CL (mL/day) 
125 (17.9) 
Vz, L 
8.76 (15.7) 
Vss, L 
8.1 (11.1) 
t1/2, day 
48.8 (37.8, 59.4) 
Abbreviations: AUC = area under the curve; AUClast = area under the serum concentration-time curve 
from time zero to time of last measurable concentration; AUC % Extrapolated = area under the plasma 
concentration-time curve extrapolated from time to infinity as a percentage of total AUC; AUCD1-29 = 
area under the serum concentration-time curve from Day 1 to Day 29; AUCinf = area under the serum 
concentration-time curve from time zero to infinity; Clast = last measurable serum concentration; Cmax = 
maximum observed concentration; CL = clearance; t1/2 = terminal elimination half life; tmax = time to 
reach Cmax; tlast = time of the last quantifiable concentration; Vss = volume of distribution at steady 
state; Vz = apparent volume of distribution during terminal phase. 
Note: Parameters are reported as mean (%CV) except for Tmax, Tlast, and t1/2, which are presented as 
median (min, max).  
Data is based on 1-hour infusion time. 
a N=8 for AUCD1-29 as participant 10016 was missing all PK samples prior to Study Day 5. 
Partial sparse serum PK through study Day 29 from 363 participants in the COMET-ICE 
Expansion phase is available to date. The mean serum concentration of sotrovimab on 
study Day 29 is 25.8 μg/mL. 
Furthermore, sotrovimab has recently been formulated to allow for either intravenous or 
intramuscular administration. Administration via intramuscular dosing could allow 
greater access to mAb treatment without the requirement of dedicated infusion centers, as 
is often required for intravenous administration. IM administration of sotrovimab will be 
compared to IV administration in this study. 
2.3. 
Benefit/Risk Assessment  
Information about the reasonably expected adverse events of sotrovimab may be found in 
the Investigator’s Brochure. 
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2.3.1. 
Risk Assessment  
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention: Sotrovimab 
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 24 Weeks (estimated 5 half-lives) to 
assess for the potential of immunogenicity 
(measurement of ADA) as well as if ADA is 
potentially causally associated with specific safety 
concerns and/or impact efficacy. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Antibody Dependent Enhancement (ADE) 
due to sub-neutralizing levels of 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 
patients, run a more severe course in the 
setting of limited antibodies generated by 
prior infection.  
The potential for enhanced disease in this 
setting is due to increased uptake of virus by 
FcR-expressing cells, such as macrophages, 
and increased viral replication in these cells. 
Recent data shows that SARS-CoV-2 does not 
replicate efficiently in macrophages 
[Hui 2020], suggesting minimal to no risk of 
ADE via this mechanism.  
 
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: 
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. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
ADE due to enhanced disease pathology from 
viral antigen-antibody related immune 
complex deposition or complement activation 
and immune cell recruitment in target organs 
There is the possibility that a large amount of 
antibody that binds, but does not neutralize, 
virus in the presence of a high viral load could 
result in immune complex deposition and 
complement activation in tissue sites of high 
viral replication, such as the lungs, vascular 
endothelia, renal or cardiovascular tissue 
[Hamming 2004], leading to tissue 
damage/immune complex disease 
This is hypothesized to have contributed to 
inflammation and airway obstruction 
observed in the small airways of infants who 
received a formalin-inactivated (FI) 
respiratory syncytial virus (RSV) vaccine 
[Polack 2002] and in a few cases of fatal 
H1N1 influenza infection [Wu 2010] 
The potential for enhanced disease in this 
setting may be due to low affinity or cross-
reactive antibodies with poor or no 
neutralizing activity. 
Triggering of cytokine release by antibody-
virus-FcR interactions although usually 
highly beneficial due to their direct antiviral 
effects and immune cell recruitment to control 
viral spread in tissues, also has the potential to 
enhance pathologic changes initiated by the 
viral infection. 
Observational data from 20,000 COVID-19 
patients treated with convalescent plasma, 
although not placebo controlled, is suggestive 
that even polyclonal mixtures of neutralizing 
and non-neutralizing antibodies can be safely 
administered [Joyner 2020] 
Monitoring: 
• 
In this study, periodic review of clinical 
signs and symptoms of COVID-19, 
clinical chemistry, adverse events, end-
organ disease and histopathological 
diagnoses (as available per routine care) 
will be performed by the Joint Safety 
Review Team to identify potential cases 
of immune complex disease. 
• 
Assessments of the overall duration and 
severity of COVID-19 will be performed 
by the JSRT to assess for unusually 
severe disease in mAb-treated 
participants. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Sotrovimab shows potent binding in vitro as 
well as neutralization of pseudovirus and live 
virus thus this risk is deemed to be low. 
 
As of 10 March 2021, based on data from 583 
randomized patients, the COMET-ICE study 
enrollment has been stopped due to evidence 
of clinical efficacy based on the 
recommendation of IDMC. Since then, up to a 
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 in hospitalized 
patients with COVID-19 symptoms which 
was terminated due to futility did not reveal 
any safety concerns overall and no ADE. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Systemic reactions including hypersensitivity 
reactions (SR/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. 
As of 24 April 2021, approximately 
1417 participants have been randomized to 
either the IV infusion of sotrovimab Gen1 
(500 mg dose) or placebo in two ongoing 
clinical studies: 1057 participants in a study 
evaluating sotrovimab for the treatment of 
non-hospitalized individuals (COMET ICE 
Study) with mild to moderate COVID-19, and 
approximately 360 participants in a study 
evaluating sotrovimab for the treatment of 
individuals hospitalized with COVID-19 
(ACTIV 3-TICO Study). 
Based on the assessment of the data, the 
majority of the SR/HSR in the COMET ICE 
study have been grade 1 or 2. In the 
hospitalized study (ACTIV-3 TICO), severe 
or life-threatening allergic reactions have been 
infrequently reported during infusion of 
sotrovimab. There has been a single report of 
anaphylactic reaction during the IV infusion 
of sotrovimab.The infusion was stopped and 
treatment with medications including 
epinephrine was provided which led to 
resolution of the event. 
Participant selection: Participants will be 
excluded if they have a history of hypersensitivity 
to other monoclonal antibodies or any of the 
excipients present in the investigational product. 
Monitoring:  
• 
Guidelines for monitoring relevant adverse 
events encompassing hypersensitivity, 
angioedema and anaphylaxis as well as for the 
management of acute anaphylactic shock and 
minor allergic episodes will be in place at 
investigational sites. 
• 
Joint Safety Review Team reviews will be 
conducted at regular intervals to determine if 
a significant safety signal of severe 
hypersensitivity reaction is identified.  
• 
Systemic reactions including HSRs are 
categorized as AESIs 
Mitigation:  
Investigators will be provided with general 
guidance on management of hypersensitivity 
reactions and such reactions will be managed 
appropriately per local guidelines/medical 
judgment. Pre-medications will be permitted at 
the investigator’s discretion and will be 
appropriately documented. 
Vital signs will be monitored prior to dose 
administration and at 15 mins and 30 mins after 
infusions/injections. 
• 
Investigators will be instructed to discontinue 
IV infusions or injections for participants who 
develop Grade 3 or higher systemic reactions. 
If a participant experiences a Grade 2 SR, 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
investigators will be instructed to pause the 
infusion/injection. The infusion/injection may 
subsequently resume at a slower pace of 
infusion, at the investigator’s discretion, 
and/or after symptomatic treatment (e.g., anti-
histamines, IV fluids). IV infusion and IM 
injection will be administered in the clinic 
with staff trained in emergency care & 
resuscitation procedures & emergency care kit 
on hand during treatment & post therapy 
observation periods. 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Local Infusion/Injection Site Reactions 
Intramuscular injections may be associated 
with local reactions (e.g. swelling, induration, 
pain). 
• A GLP injection site reaction study in 
minipigs demonstrated tolerability after 
intramuscular injection 
• A similar fully human IgG1 monoclonal 
antibody specific to influenza A (VIR-
2482) has been studied in a recent Phase 1 
trial. Intramuscular injection of this IgG1 
was well-tolerated with minimal injection 
site reactions (Sager 2020) 
• Intramuscular dosing of sotrovimab is 
being evaluated in Part B of the COMET-
PEAK study (VIR-7831-5006; 
GSK216912). This study (COMET-TAIL) 
will not begin until the JSRT from 
COMET-PEAK has determined there are 
no significant local tolerability issues from 
the Lead-in portion of COMET-PEAK, 
Part B (N=20 sotrovimab IM recipients) 
Monitoring: 
• 
Local infusion/injection site Reactions will be 
monitored closely in the Lead-in phase of Part 
B of the 
COMET-PEAK GSK216912/VIR-7831-5006 
(N=10 in the Gen2 sotrovimab IV arm; N=10 
in the Gen 2 sotrovimab IM arm) for 2 hours. 
Local tolerability data will be assessed by the 
JSRT. Enrollment into this study will not 
begin until JSRT review of the Lead-in phase 
of COMET-PEAK, Part B. 
• 
Vital signs will be monitored prior to dose 
administration and at 15 mins and 30 mins 
after injection/infusion.  
• 
Local infusion/Injection site reactions are 
categorized as AESIs 
• 
Monitor for Local infusion/injection site 
reactions throughout study. 
Mitigation: 
Local infusion/injection site reactions will be 
managed appropriately per local 
guidelines/medical judgment. 
 
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2.3.2. 
Benefit Assessment  
There is biologic 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 patients 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. 
In addition, 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 patients 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) 
The study population to be enrolled in this study has a high unmet medical need and is 
similar to the study population from COMET-ICE. Sotrovimab administered 
intramuscularly may or may not improve the time to clinical response or overall clinical 
outcome versus IV sotrovimab in an individual participant with mild or moderate 
COVID-19 who participates in this study. However, there is potential benefit from their 
participation in this study resulting from their data allowing evaluation of IM sotrovimab 
as a potential treatment for COVID-19.  
2.3.3. 
Overall Benefit: Risk Conclusion  
The overall benefit-risk assessment takes into account 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 patients has been demonstrated. 
In addition, based on data from ~ 1200 non hospitalized and hospitalized subjects who 
have received IV infusion of sotrovimab, there have been no significant safety concerns 
observed. 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. 
Based on the high 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. 
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3. 
OBJECTIVES AND ENDPOINTS  
Objectives  
Endpoints 
Primary 
 
Evaluate the efficacy of two dose levels of 
intramuscular sotrovimab versus 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 
Secondary  
 
Safety 
Describe the safety and tolerability of 
intramuscular and intravenous sotrovimab 
 
• 
Occurrence of adverse events (AEs) 
• 
Occurrence of serious adverse events (SAEs)  
• 
Occurrence of adverse events of special 
interest (AESI) 
• 
Occurrence of disease related events (DRE) 
Assess the immunogenicity of sotrovimab 
Incidence and titers (if applicable) of serum anti-
drug antibody (ADA) to sotrovimab 
Efficacy 
Evaluate the efficacy of two dose levels of 
intramuscular versus intravenous sotrovimab on 
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 
• 
Hospitalization for acute management of 
illness for any duration and for any cause 
OR 
• 
Death 
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Objectives  
Endpoints 
Evaluate the efficacy of two dose levels of 
intramuscular versus intravenous sotrovimab in 
preventing COVID-19 respiratory disease 
progression  
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  
Compare the virologic activity of sotrovimab 
given IM (two dose levels) or IV in reducing 
SARS-CoV-2 viral load  
• 
Mean area under the curve of SARS-CoV-2 
viral load in nasal secretions as measured by 
qRT-PCR from Day 1 to Day 8 (AUCD1-8) 
• 
Change from baseline in viral load by qRT-
PCR at Day 8 
• 
Proportion of participants with a persistently 
high SARS-CoV-2 viral load at Day 8 by 
qRT-PCR 
Pharmacokinetics 
Assess the pharmacokinetics (PK) of sotrovimab 
in serum following IV and IM (two dose levels) 
administration 
 
IV and IM sotrovimab pharmacokinetics (PK) in 
serum 
Exploratory  
 
Describe the effect of two doses levels of 
intramuscular versus intravenous sotrovimab on 
incidence and duration of time on total hospital 
length of stay (LOS), incidence and duration of 
time on a ventilator, and ICU length of stay  
• 
Incidence of hospitalization through Day 29 
• 
Total hospital LOS  
• 
Proportion of participants requiring ICU stay 
or mechanical ventilation through Day 29 
• 
Total ICU LOS 
Monitor SARS-CoV-2 resistant mutants against 
sotrovimab 
• 
SARS-CoV-2 resistance mutants to 
sotrovimab at baseline 
• 
Emergence of viral resistance mutants to mAb 
by SARS-CoV-2  
Compare the virologic activity of sotrovimab 
given IM (two dose levels) or IV in reducing 
SARS-CoV-2 viral load 
• 
Change from baseline in viral load in nasal 
secretions by qRT-PCR during follow-up 
period at Day 5, 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 
• 
Mean area under the curve of SARS-CoV-2 
viral load as measured by qRT-PCR from Day 
1 to Day 5 (AUCD1-5) and Day 1 to 11 
(AUCD1-11) 
Compare the effect of different sample collection 
methods in SARS-CoV-2 viral load (e.g. 
nasopharyngeal swab, saliva) 
• 
SARS-CoV-2 viral load measured by qRT-
PCR 
Evaluate the effect of sotrovimab on the 
development of SARS-CoV-2 antibodies 
• 
SARS-CoV-2 anti-N antibody at Day 1 and 
Day 29 
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Objectives  
Endpoints 
Describe the effect of sotrovimab on Long 
COVID symptoms 
• 
Incidence and severity of Long COVID 
symptoms at W12, W24 and W36 
 
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4. 
STUDY DESIGN  
4.1. 
Overall Design  
This study is a Phase 3 randomized, multi-center, open label, non-inferiority study of 
intramuscular (IM) versus intravenous (IV) administration of sotrovimab, a monoclonal 
antibody (mAb) against SARS-CoV-2 for the treatment of mild/moderate COVID-19 in 
participants aged 12 years and older at high risk of disease progression. The study will 
randomize participants 1:1:1 to receive a single dose IV infusion of sotrovimab or a 
single IM injection of sotrovimab at one of two dose levels.  
Participants with early, mild/moderate COVID-19 who are not on supplementary oxygen 
and at risk for disease progression will receive an IV infusion or IM injection of 
sotrovimab. The IV sotrovimab dose will be 500 mg and will be infused over 15 minutes. 
The IM sotrovimab dose will be either 250 mg or 500 mg given at a single timepoint. The 
250 mg IM dose will be given either as a single 250 mg (4ml) injection in the 
dorsogluteal muscle or as two 2ml injections in each deltoid muscle. The 500 mg IM dose 
will be administered as two 4ml injections in each dorsogluteal muscle. 
After IV infusion or IM injection, participants will be monitored for 30 minutes with vital 
signs assessments performed every 15 minutes. Injection site reaction, for IM arms only, 
will be evaluated at 15 and 30 minutes after dosing.  
All participants will be actively monitored on an outpatient basis with frequent collection 
of nasopharyngeal swabs for virology and blood draws for PK sampling, as well as 
weekly in-clinic evaluations at Weeks 1, 2, 3, and 4 as detailed in the Schedule of 
Activities. 
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 1020 participants were to be enrolled and randomized 1:1:1 to receive a 
single 500 mg IV infusion of sotrovimab, a single 500 mg IM injection of sotrovimab, or 
a single 250 mg IM injection of sotrovimab. 
Study Oversight and Rationale for Change in Study Design in Amendment 3  
An interim analysis (IA) was originally planned for an IDMC to evaluate each dose level 
of IM sotrovimab versus IV sotrovimab for safety, futility and efficacy when 
approximately 50% of participants enrolled and reached Day 29. As described in Section 
10.5.1, a Joint Safety Review Team was also in place to review in-stream safety data for 
identification of any safety concerns. During the conduct of the study, the JSRT noted a 
discrepancy in the rate of progression to hospitalization occurring in the 250 mg IM arm 
compared with the 500 mg IM and IV arms, and an ad hoc interim dataset was escalated 
to the IDMC for review. As a result of this review, enrollment into the 250 mg IM arm 
was discontinued at N=195, and the study design was changed to a 2-arm study with 
randomization 1:1 into the remaining 2 arms of 500 mg IM and 500 mg IV. The formal 
planned interim analysis was also eliminated as described in Section 9.5. 
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Intervention Groups and Duration:  
Screening assessments will be performed within 48 hours prior to randomization. 
Screening can occur on the same day as randomization. Eligible participants will be 
treated with a single IM or IV dose of sotrovimab on Day 1 and followed for up to 
36 weeks.  
Participants will be stratified based on: 
1. Age: 12-17 years old, 18-64 years old, and ≥65 years old  
2. COVID-19 Vaccination History: receipt of any COVID-19 vaccine  
3. Region of the world due to potential differences in standard of care for 
COVID-19 management and different circulating SARS-CoV-2 variants.  
Saliva SARS-CoV-2 qRT-PCR substudy  
To evaluate the comparability of SARS-CoV-2 quantitative RT-PCR when performed on 
saliva versus nasopharyngeal (NP) swabs, an optional sub-study may be performed. Up to 
200 subjects will have paired saliva and NP collected at 4 timepoints during the study 
(D1, D8, D15, D22). 
4.2. 
Scientific Rationale for Study Design  
This study is a Phase 3 randomized, multi-center, open label, non-inferiority study of 
intramuscular (IM) versus intravenous (IV) administration of sotrovimab, a monoclonal 
antibody (mAb) against SARS-CoV-2 for the prevention of progression of mild/moderate 
COVID19 in participants 12 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) Adolescents, aged 12-17 years of age, at high-risk for 
COVID-19 progression include those with obesity (BMI ≥85th percentile for 
age/gender), sickle-cell disease, congenital heart disease, neurodevelopmental disorders, 
medically-related technology dependence such as tracheostomy, ventilator-support, or a 
gastrostomy tube, or 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; Shekerdemian 2020) The study will 
include outpatients infected with SARS-CoV-2, the virus that causes COVID-19, as 
confirmed by local laboratory tests and/or point of care tests. 
Although children appear to have more mild disease when infected with SARS-CoV-2 
and only 0.1%-1.9% of COVID-19 cases result in hospitalization (AAP 2021), a number 
of risk factors have been identified that are associated with increased risk of severe 
disease. These include children with complex medical history due to genetic, neurologic, 
or metabolic conditions or with congenital heart disease. Children with obesity, 
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sickle-cell disease, and chronic lung disease may also be at higher risk of hospitalization. 
Of note, approximately one-third of hospitalized children are admitted to the intensive 
care unit. (CDC 2021). Given the potential for severe disease in high-risk children, there 
is a significant unmet need for a medication that could prevent COVID-19 progression. 
Since hospitalization rates are somewhat lower in children, the adolescent population in 
this study will be limited to <10% of the total population.  
Sotrovimab is currently being studied in a Phase 3 placebo-controlled trial evaluating the 
efficacy of sotrovimab in preventing progression of COVID-19 in high-risk patients 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 patients which demonstrated an 85% (p=0.002) reduction in 
hospitalization or death in patients receiving sotrovimab compared to placebo (Vir 2021). 
Sotrovimab was well-tolerated with no safety signals detected. In addition, recently both 
the NIH COVID-19 Treatment Guidelines and the Infectious Diseases Society of 
America have both recommended monoclonal antibody therapy treatment for high-risk 
individuals with mild/moderate COVID-19 (NIH 2021). 
In light of recent positive data from COMET-ICE demonstrating overwhelming clinical 
efficacy of sotrovimab in preventing COVID-19 disease progression 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.  
Given the urgent unmet medical need and the ethical considerations of a 
placebo-controlled design in the setting of already demonstrated clinical efficacy, the 
design for this current trial is a non-inferiority study comparing the clinical efficacy of IV 
sotrovimab and two dose levels of IM sotrovimab. The primary endpoint to assess 
efficacy of treatment is progression of mild/moderate COVID-19 defined by 
hospitalization >24 hours for acute management of illness or death due to any cause 
within 29 days of randomization. A 3.5% non-inferiority margin on the risk difference 
scale will be used. These criteria were selected based on feedback from the FDA after 
taking into consideration multiple monoclonal antibody programs and their efficacy in 
preventing progression of COVID-19 in high-risk individuals. The study will first 
evaluate non-inferiority between 500 mg of sotrovimab given IM versus 500mg of 
sotrovimab given IV. If non-inferiority is demonstrated, an additional non-inferiority 
evaluation will be performed between 250 mg IM of sotrovimab and 500 mg IV of 
sotrovimab. 
The transition from outpatient status without hypoxemia to hospitalization for acute care 
or death is a clinically significant metric. A 29-day period to assess the primary endpoint 
is appropriate as the median time for COVID-19 related hospital admission in patients 
who are hospitalised has been reported to be 7-11 days and the median time to clinical 
deterioration, 9-12 days (Huang 2020; Zhou 2020). Key secondary endpoints include 
evaluations of safety and tolerability for IM administration of sotrovimab, comparability 
of anti-viral activity of IV versus IM sotrovimab, and pharmacokinetics.  
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4.3. 
Justification for Dose  
4.3.1. 
Sotrovimab  
The single 500 mg IV dose of sotrovimab to be evaluated was selected based on 
extensive nonclinical data and expected human PK extrapolated from cynomolgus 
monkeys. This IV dose is currently being evaluated in ongoing clinical trials 
COMET-ICE (NCT04545060), ACTIV-3-TICO (NCT04501978) and BLAZE-4 
(NCT04634409), with approximately 700 patients dosed to date. 
The 250 and 500 mg IM doses were selected based on in vitro neutralization data, in vitro 
resistance data, and simulated IM PK based on preliminary IV PK from the 500 mg dose 
being evaluated in ongoing clinical studies (COMET-ICE, ACTIV-3-TICO, BLAZE-4). 
Sotrovimab neutralized SARS-CoV-2 live virus with an average EC90 value 
of 186.3 ng/mL (range: 125.8 – 329.5 ng/mL) (PC-7831-0105). In resistance analyses, 
no viral breakthrough was observed through 10 passages at fixed concentrations of 
antibody, indicating the potential for sotrovimab to have a high barrier to resistance 
(PC-7831-0109). Using an increasing concentration selection method to force resistance 
emergence, E340A was identified as a monoclonal antibody-resistant mutant (MARM) 
conferring a >100-fold reduction in susceptibility to sotrovimab. Notably, E340 is 99.9% 
conserved among available SARS-CoV-2 sequences. Due to the binary nature of the 
resistance selection results, a specific inhibitory quotient (IQ) was not informed by the 
resistance profiling.  
Based on preliminary IV PK data from the Lead-in phase of an ongoing clinical study 
evaluating sotrovimab in the early treatment of COVID-19 (COMET-
ICE; NCT04545060), the mean serum concentration of sotrovimab following a single 
500 mg IV dose is 37.3µg/mL (N=9). Based on the PK data available to date, >20% of 
the AUC is being extrapolated so final CL, V, AUC and t1/2 have not been determined; 
however a preliminary estimate of the median half-life of sotrovimab is approximately 
47 days. 
IM doses of 250 and 500 mg were selected to ensure that sotrovimab concentrations in 
lung are maintained at or above levels anticipated to be neutralizing for the duration of 
the treatment window. Based on the EC90 (0.33 μg/mL) from the highest end of the 
EC90 range (PC-7831-0105), and accounting for the lung:serum ratio for IgG (assumed 
conservative value of 0.25; reported range 0.25-0.68 for whole lung and interstitial fluid, 
respectively; Baxter 1994, Covel1 1986, Datta-Mannan 2019, Lobo 2004), and assuming 
70% bioavailability following intramuscular administration, IM doses of 250 and 500 mg 
are expected to maintain serum levels at or above 5x and 10x lung tissue adjusted 
EC90 from 1 day post-dose through the Day 29 primary endpoint, respectively.  
Prior clinical experience with a 500 mg IV dose of sotrovimab has been gained in the 
setting of the early treatment of COVID-19 (COMET-ICE; NCT04545060). Available 
preliminary blinded safety data from this study has demonstrated an acceptable safety 
profile in individuals actively infected with SARS-CoV-2. An interim analysis of data 
from 583 high-risk patients demonstrated an 85% (p=0.002) reduction in hospitalization 
or death in patients receiving sotrovimab compared to placebo. (Vir 2021) 
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Dosing in Adolescents  
The recommended doses in patients aged 12 years and above are the same as adults. 
Assuming conventional allometric scaling of exposure with bodyweight, and data from 
the National Examination Nutritional Health Survey (NHANES) on weight for age 
distribution), the expected overlap in exposure with adults is at least 60%, although the 
lightest adolescents may have exposures marginally above adults. Any risk of 
under-dosing adolescents is small. The sponsor therefore proposes the same dosing 
recommendation for adolescents as adults. 
4.4. 
End of Study Definition  
A participant is considered to have completed the study if he/she has completed the 
Week 36 visit. The end of the study is defined as the date of the last contact of the last 
participant in the study. 
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5. 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
5.1.1. 
Age and Risk Factors  
1. Participant must be aged 12 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 12-17 years old: diabetes, obesity (BMI ≥85th percentile for age/gender 
based on CDC growth charts), chronic kidney disease (e.g. eGFR <60), 
sickle-cell disease, congenital heart disease, neurodevelopmental disorders, 
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 
NOTE: Participants age 12-17 years old should not exceed 10% of the total 
study population 
 
b. 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  
1. 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 
2. Oxygen saturation ≥94% on room air 
AND 
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3. 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 
4. 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  
1. No gender restrictions 
2. Female participants must meet and agree to abide by the following contraceptive 
criteria. Contraception use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and one of the following conditions applies: 
a. Is a woman of non-childbearing potential (WONCBP) as defined in 
Section 10.4. 
OR 
b. Is a WOCBP and using a contraceptive method that is highly effective, with a 
failure rate of <1%, as described in Section 10.4 of the protocol during the 
study intervention period and for up to 36 weeks after the last dose of study 
intervention. The investigator should evaluate potential for contraceptive 
method failure (e.g., noncompliance, recently initiated) in relationship to the 
first dose of study intervention. 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) before the first dose of study intervention. See 
Section 8.3.8 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  
1. 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. 
2. 
OR 
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3. If participants are not capable of giving written informed consent, alternative 
consent procedures will be followed as described in Section 10.1.3. 
4. Participants <18 years old will be required to sign an assent form in addition to a 
parent or guardian signing the informed consent. 
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 in the next 24 hours 
2. Symptoms consistent with severe COVID-19 as defined by shortness of breath at 
rest or respiratory distress or requiring supplemental oxygen  
3. Participants who, in the 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. Immunocompetent individuals who are fully vaccinated against SARS-CoV-2. A 
person is considered fully vaccinated if at least 14 days have passed since 
receiving the final dose in a COVID-19 vaccine series. 
8. Receipt of convalescent plasma from a recovered COVID-19 patient or 
anti-SARS-CoV-2 mAb within the last 3 months. 
9. Participants who, in the judgment of the investigator, will be unlikely or unable to 
comply with the requirements of the protocol through Day 29 
10. (France Only) Adult patient protected by the law (under legal guardianship, 
curatorship or judicial protection or incapable of giving consent personally as 
defined by Articles L. 1121-5 to L.1121-8, L.1122-1-2 and L. 1122-2 of the 
French public health code) 
5.3. 
Lifestyle Considerations  
Lifestyle considerations are not applicable to this study. 
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5.4. 
Pre-Screening  
Sites may have the option to pre-screen patients to participate in the clinical study. Sites 
may pre-screen and administer a SARS-CoV-2 test to patients 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. 
5.5. 
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. 
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6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study Intervention(s) Administered  
Overview of study interventions is provided in Table 3. Detailed instructions for the 
administration of study drug will be provided in a separate pharmacy manual. 
Table 4: 
Overview of Study Intervention 
Arm Name 
Sotrovimab IV 
500mg 
Sotrovimab IM 
500mg 
Sotrovimab IM 
250mg 
Intervention 
Name 
VIR-7831 
VIR-7831 
VIR-7831 
Type  
Biologic 
Biologic 
Biologic 
Dose Formulation Solution in single-use 
vial  
Solution in single-use 
vial  
Solution in single-use 
vial  
Unit Dose 
Strength(s) 
500 mg/vial (62.5 
mg/mL) 
500 mg/vial (62.5 
mg/mL) 
500 mg/vial (62.5 
mg/mL) 
Dosage Level(s) 
500 mg once  
500 mg once  
250 mg once  
Route of 
Administration 
IV infusion 
IM injection  
IM injection 
IMP and NIMP 
IMP 
IMP 
IMP 
Sourcing 
VIR-7831 will be 
provided centrally by 
the Sponsor.  
VIR-7831 will be 
provided centrally by 
the Sponsor.  
VIR-7831 will be 
provided centrally by 
the Sponsor.  
Dosing 
instructions 
See Pharmacy Manual 
See Pharmacy 
Manual 
See Pharmacy 
Manual 
Special 
instructions 
Gently mix VIR-7831 
prior to withdrawing 
from vial 
Gently mix VIR-7831 
prior to withdrawing 
from vial 
Gently mix VIR-
7831 prior to 
withdrawing from 
vial 
Packaging and 
Labelling 
Study intervention will 
be provided in a single-
use vial in an 
individual carton and 
labelled as required per 
country requirement. 
Study intervention 
will be provided in a 
single-use vial in an 
individual carton and 
labelled as required 
per country 
requirement. 
Study intervention 
will be provided in a 
single-use vial in an 
individual carton and 
labelled as required 
per country 
requirement. 
Current/Former 
Name(s) or 
Alias(es) 
VIR-7831, 
GSK4182136 
VIR-7831, 
GSK4182136 
VIR-7831, 
GSK4182136 
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6.2. 
Preparation/Handling/Storage/Accountability  
Instructions for the preparation of study drug will be provided in a separate pharmacy 
manual. 
1. The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the pharmacy manual.  
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, medical monitor and/or Sponsor 
study contact. 
6.3. 
Randomization  
All participants will be centrally randomized using an Interactive Web Response System 
(IWRS). Before the study is initiated, the log in information and directions for the IWRS 
will be provided to each site. 
Participants will be randomized in a 1:1:1 ratio to receive sotrovimab 500 mg IV, 
sotrovimab 500 mg IM, or sotrovimab 250 mg IM. 
Participants will be stratified based on: 
1. Age: 12-17 years old, 18-64 years old, and ≥65 years old  
2. COVID-19 Vaccination History: receipt of any COVID-19 vaccine  
3. Region of the world due to potential differences in standard of care for 
COVID-19 management and different circulating SARS-CoV-2 variants.  
 
Following the discontinuation of sotrovimab 250 mg IM arm (See Section 9.1), no 
participants were enrolled and randomized into this arm. The remaining participants were 
randomized in a 1:1 ratio to receive sotrovimab 500 mg IV or sotrovimab 500 mg IM. 
 
 
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6.4. 
Study Intervention Compliance  
Participants will receive sotrovimab either by IM or 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  
There are two potential doses in this study and dose modifications are not applicable. See 
Section 7.1 for instructions to discontinue study treatment for safety reasons. 
6.6. 
Continued Access to Study Intervention after the End of the 
Study  
COVID-19 is an acute illness and participants are not expected to need continued access 
to 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: 
4. Contact the medical monitor immediately. 
5. Closely monitor the participant for AE/SAE and laboratory abnormalities. 
6. Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF. 
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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: 
7. reason for use 
8. dates of administration including start and end dates 
9. dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Fully vaccinated immunocompetent patients are not eligible for the study. However, 
partially vaccinated participants are allowed to be enrolled and randomised. A person is 
considered fully vaccinated if at least 14 days have passed since receiving the final dose 
in a COVID-19 vaccine series. The specific COVID-19 vaccine received should be 
recorded along with the date of the vaccine.  
6.8.1. 
Medication Not Permitted During the Study  
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. 
Receipt of any SARS-CoV-2 vaccine is not permitted within 90 days after dosing per 
CDC guidelines 
(https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html).  
6.8.2. 
Permitted Concomitant Medication  
All medication that the participant is receiving as local, established standard of care for 
acute COVID-19 is permitted. 
Any concerns regarding the acceptability of potential treatments should be discussed with 
the medical monitor(s). 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1. 
Discontinuation of Study Intervention  
A participant will be permanently discontinued from completion of drug injection if they 
experience life-threatening, injection-related reaction including severe allergic or 
hypersensitivity reactions, severe cytokine release syndrome, or Grade 4 injection site 
reaction (Section 10.4). 
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 after the first 
injection, investigators will be instructed to pause prior to the second injection. A 
subsequent injection may be administered at the investigator’s discretion, and/or after 
symptomatic treatment (e.g. anti-histamines, IV fluids). 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
• A participant may withdraw from the study at any time at his/her own request, at the 
request of their LAR (legally authorized representative) or may be withdrawn at any 
time at the discretion of the investigator for safety, behavioral, or compliance reasons. 
This is expected to be uncommon. 
• At the time of withdrawal from the study, if possible, an early withdrawal (EW) visit 
should be conducted, as shown in the Schedule of Activities (Section 1.3). 
Participants may be contacted by phone. See Schedule of Activities for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• If the participant withdraws consent or the LAR requests that the participant is 
withdrawn for disclosure of future information, the sponsor/designee may retain and 
continue to use any data collected before such a withdrawal of consent. 
• If the participant withdraws from the study, he/she or the LAR may request 
destruction of any samples taken and not tested, and the investigator must document 
this in the site study records. 
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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 schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• If participants cannot be reached after 3 telephone calls at least 24 hours apart, their 
listed secondary contact person(s) or health care provider will be contacted. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are described in 
Section 10.1.9.  
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8. 
STUDY ASSESSMENTS AND PROCEDURES  
This section lists the parameters of each planned study assessment. 
• Study procedures and their timing are summarized in Section 1.3 (Schedule of 
Activities).  
• Select follow-up visits as noted in the Schedule of Activities are planned to be phone 
call from site to participants. Follow-up visits may be performed at the clinic or as a 
home visit.  
• Protocol waivers or exemptions are not allowed.  
• Immediate safety concerns should be discussed with the medical monitor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 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. 
• 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. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• 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 
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condition(s) is currently ongoing will be collected for all participants and should be 
updated prior to dosing.  
8.1.2. 
SARS-CoV-2 Diagnostic Testing  
Documentation of laboratory-confirmed SARS-CoV-2 infection via a validated 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 2021).  
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. 
SARS-CoV-2 Serology Analysis  
In order to evaluate the effect of sotrovimab treatment on seroconversion and the 
development of host anti-SARS-CoV-2 antibodies, blood for testing of anti-N 
SARS-CoV-2 antibodies will be collected at baseline and at Week 4. Since sotrovimab 
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may interfere with anti-spike SARS-CoV-2 tests, antibodies directed against the 
nucleocapsid protein will be measured. 
8.2.3. 
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. This phone call will 
assess whether the participant was diagnosed again with COVID-19 and whether this 
illness resulted in any healthcare encounters. Any medications given as a result of this 
illness will also be recorded. 
8.2.4. 
Long COVID Assessment  
After first being infected with SARS-CoV-2, some people experience a wide range of 
symptoms, e.g., fatigue, difficulty thinking or concentrating, cough, depression, etc., that 
can last weeks or months, known as Long COVID or Post-Acute Sequelae of 
SARS-CoV-2 infection (CDC 2021; NIH 2021). To monitor for development of Long 
COVID, participants will be asked a series of questions during the Week 12, Week 24 
and Week 36/EOS visit to evaluate a range of symptoms in the past 30 days. These 
questions will assess whether or not the participant has experienced persistent symptoms 
related to their COVID-19 diagnosis, types of symptoms, and severity of symptoms. The 
questions can be asked and completed via phone call or during the in-clinic visit (See 
Section 10.6). 
8.3. 
Safety Assessments  
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.3.1. 
Physical Examinations  
A complete physical examination will be performed on Day 1. For all other visits the 
physical examination will be symptom-directed as outlined in the Schedule of Activities. 
• A complete physical examination will include, at a minimum, assessments of 
the Skin, Cardiovascular, Respiratory, and Abdominal systems.  
• Height and weight will also be measured and recorded at Screening. Body mass index 
(BMI) will be calculated from these measurements.  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.3.2. 
Vital Signs  
On Day 1, vital signs should be recorded prior to dose administration and at 15 mins and 
30 mins after injection or infusion.  
• Vital sign measurements will include blood pressure, pulse rate, temperature 
(oral preferred), respiratory rate, and oxygen saturation. 
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• 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. 
Local Tolerability Assessment  
A local tolerability assessment will be performed for participants who received an IM 
injection of sotrovimab per the Schedule of Activities. Injection site(s) should be 
monitored for pain, tenderness, redness, and swelling. A local tolerability assessment tool 
is provided in (Section 10.5). This is not applicable for IV sotrovimab recipients. 
The injection site(s) will be marked and mapped for later observation and should be 
documented. The tolerability assessment will be performed at approximately 15 minutes 
and 30 minutes following study drug administration and at Days 3, 5, and 8 per the 
Schedule of Activities (Section 1.3).  
At the discretion of the investigator, unscheduled visits are permitted as needed for 
follow up of any unresolved local tolerability symptoms.  
8.3.5. 
Virologic Measures  
Samples for virological analysis will be collected in accordance with the laboratory 
manual and Schedule of Activities (Section 1.3).  
• Nasopharyngeal swabs will be collected for SARS-CoV-2 RT-PCR 
• Saliva will also be collected in an optional substudy for SARS-CoV-2 RT-PCR 
• Samples may also be used for resistance surveillance analysis 
• Day 1 samples may be used to evaluate for other respiratory infections 
8.3.6. 
Resistance Analyses  
In order to monitor for resistance, resistance surveillance will be conducted for all 
participants who are randomized and dosed. Deep sequencing analysis of the 
SARS-CoV-2 spike gene will be attempted to identify substitutions in the mAb epitope or 
substitutions outside the epitope that arise during treatment. NP samples from baseline 
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and the last evaluable post-baseline visit at Day 8 or later will be subjected to deep 
sequencing 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 for 2 consecutive visits, or 
viral load becomes quantifiable for 2 consecutive visits after having been below the limit 
of quantification. For identified substitutions that qualify for phenotypic analysis, in vitro 
phenotypic analysis of the antiviral activity of sotrovimab using a SARS-CoV-2 spike 
pseudovirus system will be attempted and analyzed for reduced susceptibility to 
sotrovimab. 
8.3.7. 
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) 
− The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
− Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
− All laboratory tests with values considered 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. 
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8.3.8. 
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. 
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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 procedure, invasive tests or 
change in existing therapy) will be recorded from the time participant 
consents to participate in the study.  
• Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions not as AEs. 
• All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Section 10.3. The 
investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of it being available. 
• Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor or designee. 
8.4.2. 
Assessment of Severity  
Standard toxicity grading according to the DAIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events, version 2.1 (July 2017) will be used to grade all AEs.  
8.4.3. 
Method of Detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
8.4.4. 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AEs of special 
interest (as defined in Section 8.4.8), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Section 10.3. 
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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 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. 
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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 10.3, 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. 
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 in the study protocol as relevant known 
toxicities of other therapeutic mAbs or as a result of signals observed from previous 
studies in the nonclinical programs of sotrovimab that will be monitored by the Sponsor 
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either during or at the end of the study. These will be updated during the course of the 
study based on accumulating safety data. 
AESI include: 
• Systemic Infusion and Injection-related reactions including hypersensitivity 
reactions occurring on same day as infusions 
• Local infusion/injection site reactions 
• Immunogenicity related adverse drug reactions 
• Adverse events potentially related to antibody dependent enhancement of disease 
8.4.9.1. 
Systemic Reactions and Hypersensitivity Reactions  
Please refer to local or institutional guidelines for monitoring relevant adverse events 
encompassing hypersensitivity, angioedema, anaphylaxis, acute anaphylactic shock and 
minor allergic episodes. Pre-medications will be permitted at the investigator’s discretion 
and will be appropriately documented. 
8.4.9.2. 
Local infusion/injection site reactions (LI/ISR)  
Injections may be associated with local reactions (e.g. swelling, induration, pain). Local 
tolerability assessment is discussed in Section 8.3.3. 
8.4.9.3. 
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.  
8.4.9.4. 
Antibody Dependent Enhancement  
Antibody-dependent enhancement (ADE) of disease theoretically can occur via one of 
three previously described mechanisms: 
6. By facilitating viral entry into host cells and enhancing viral replication in these 
cells;  
7. By increasing viral fusion with target host cells, enhancing viral replication in 
these cells. 
8. 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 
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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 patients with 
COVID-19 symptoms, which was terminated due to futility, 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. 
• 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 
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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). 
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9. 
STATISTICAL CONSIDERATIONS  
9.1. 
Statistical Hypotheses  
The primary objective of this study is to evaluate the efficacy of IM sotrovimab versus IV 
sotrovimab in preventing the progression of mild/moderate COVID-19. 
The primary endpoint is progression of COVID-19 through Day 29 as defined by 
hospitalization > 24 hours for acute management of illness OR death.  
Denoting the proportions of participants with progression of COVID-19 by Day 29 in the 
sotrovimab 500 mg IM arm, sotrovimab 250 mg IM arm and sotrovimab 500 mg IV arm 
as PIM500, PIM250 and PIV500, respectively, then the null (H0) and alternative (HA) 
hypotheses are as follows using a non-inferiority margin of 3.5% (per feedback from the 
FDA, as mentioned in Section 4.2) on the risk difference scale: 
1) Sotrovimab 500 mg IM vs sotrovimab 500 mg IV:  
H0: PIM500 – PIV500 ≥ 3.5%. HA: PIM500 – PIV500 < 3.5% 
2) Sotrovimab 250 mg IM vs sotrovimab 500 mg IV:  
H0: PIM250 – PIV500 ≥ 3.5%. HA: PIM250 – PIV500 < 3.5% 
  
The above two hypotheses will be tested according to the hierarchical testing principal, 
with more details described in Section 9.6. 
An ad hoc meeting of the IDMC was called on on 11-August-2021. The IDMC concurred 
that recruitment to the sotrovimab 250 mg IM arm be permanently discontinued. The 
enrollment for sotrovimab 250 mg IM arm was terminated afterwards. Therefore 
hypothesis 2) will not be tested. (See Section 9.5 and Section 9.6). 
9.2. 
Sample Size Determination  
Sotrovimab IM participants and sotrovimab IV participants were planned to be enrolled 
and randomized in a 1:1:1 ratio to receive a single dose IV infusion of sotrovimab or a 
single IM injection of sotrovimab at one of two dose levels, in an open-label manner. 
Approximately 1020 (340 per arm) participants were planned to be randomly assigned to 
study intervention. This sample size would provide approximately 90% power to 
demonstrate that IM injection of sotrovimab is non-inferior to IV infusion of sotrovimab 
in terms of the proportion of participants with progression of COVID-19 through Day 29 
with a one-sided 2.5% type I error rate, assuming COVID-19 progression rates of 2% in 
the sotrovimab IM and IV arms and 3.5% non-inferiority margin on the risk difference 
scale.  
Following the discontinuation of sotrovimab 250 mg IM arm (See Section 9.1), no more 
participants were enrolled and randomized into this arm. The remaining participants were 
randomized in a 1:1 ratio to receive sotrovimab 500mg IV or sotrovimab 500 mg IM. 
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Sample Size/Power Sensitivity  
The table below shows the study power for showing non-inferiority for different true 
progression rates on the sotrovimab IV arm and when the progression rate in sotrovimab 
IM arm (either sotrovimab 500 mg IM or sotrovimab 250 mg IM) is equal to or higher 
than that on IV, given a sample size of N=340 per arm. 
 
 
Progression rate in sotrovimab IV arm 
Progression rate in sotrovimab IM 
arm minus progression rate in 
sotrovimab IV arm 
1.0% 
1.5% 
2.0% 
0%  
99% 
95% 
90% 
+0.1% 
98% 
94% 
87% 
+0.2% 
97% 
91% 
85% 
+0.3% 
95% 
90% 
82% 
9.3. 
Analysis Sets  
For the purposes of analysis, the following mainanalysis sets are defined: 
Participant Analysis Set 
Description 
Intent-to-Treat (ITT) 
All participants who were randomized. Participants who were 
randomized under protocol amendment Version 1 and were 
immunocompetent and fully vaccinated will be excluded from 
ITT population. Participants will be analyzed according to the 
route of administration and dose level they were randomized to: 
sotrovimab IM (500 mg), sotrovimab IM (250 mg) or 
sotrovimab IV (500 mg).  
Safety 
All participants who are randomized and exposed to study 
intervention. Participants will be analyzed according to the 
route of administration and dose level they actually received: 
sotrovimab IM (500 mg), sotrovimab IM (250 mg) or 
sotrovimab IV (500 mg). 
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) 
Virology 
All participants who were randomized and with a lab confirmed 
quantifiable nasopharyngeal swab at Day 1. Participants who 
were randomized under protocol amendment Version 1 and 
were immunocompetent and fully vaccinated will be excluded 
from the Virology analysis set. Participants will be analysed 
according to the route of administration and dose level they 
were randomized to: sotrovimab IM (500mg), sotrovimab IM 
(250 mg) or sotrovimab IV (500mg). This will be the primary 
analysis set for virology. 
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9.4. 
Statistical Analyses  
The statistical analysis plan will be finalized prior to first subject first visit (FSFV) and it 
will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
Any change to the data analysis methods described in the protocol will require an 
amendment only if it changes a principal feature of the protocol. Any other change to the 
data analysis methods described in the protocol and the justification for making the 
change will be described in the statistical analysis plan. Additional exploratory analyses 
of the data will be conducted as deemed appropriate. 
9.4.1. 
General Considerations  
In the case of a difference between the stratification assigned at the time of randomization 
and the data collected in the eCRF, the analyses will be performed based on the data 
collected in the eCRF, not the stratum assigned at randomization.  
Two-sided 95% confidence intervals will be used unless otherwise specified. 
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9.4.2. 
Primary Endpoint(s)  
Primary Estimand 
The primary efficacy endpoint will primarily be assessed using an estimand that uses a 
hypothetical strategy to deal with the main intercurrent events as detailed below.  
Target Participant 
Population 
All participants in the ITT population based on sotrovimab 500 mg IV 
and 500 mg IM arms, excluding participants who did not meet key 
inclusion/exclusion criteria. Key inclusion/exclusion criteria used to 
define the primary analysis population will be defined in the statistical 
analysis plan. 
Primary Endpoint 
Progression of COVID-19 through Day 29 as defined by hospitalization 
> 24 hours for acute management of illness or death 
Intercurrent 
events 
The anticipated intercurrent events are: 
• 
Not receiving randomized treatment (e.g. treatment 
misallocation) or an alternative study treatment 
• 
Discontinuation of study intervention as described in Section 7.1 
• 
Use of medication not permitted during the study as listed in 
Section 6.8.1 up to Day 29 
All intercurrent events will be handled using a hypothetical strategy, i.e. 
assuming the intercurrent event had not occurred. Further details for the 
intercurrent events will be provided in the statistical analysis plan. 
Summary 
measure 
Absolute difference in the proportion of participants meeting the 
primary endpoint 
Analysis Method 
The proportion of participants meeting the primary endpoint will be 
compared between treatments using a generalized linear model (GLM) 
with identity link, adjusted for treatment group (sotrovimab 500 mg IV 
and 500mg IM), COVID-19 vaccination history (yes/no), age 
(12-18 years old, 19 to 64 years old, ≥65 years old), region and gender 
(female vs. male). If the model does not converge then some covariate(s) 
may be combined or removed. Further details will be provided in the 
statistical analysis plan.  
Handling of 
missing data and 
intercurrent 
events leading to 
exclusion of data 
Data observed in the period following an intercurrent event will be 
excluded from the analysis. Data from this period will be assumed 
“missing at random” (MAR). 
For participants that withdraw from the study and do not meet the 
primary endpoint at the time of withdrawal, data in the post-withdrawal 
period will also be assumed MAR. 
Further details will be provided in the statistical analysis plan. 
Supplementary Estimands  
A supplementary estimand will be conducted in the ITT population by handling all 
intercurrent events with a treatment policy strategy (i.e. regardless of the intercurrent 
events occurring), with all the other attributes being the same as in the primary estimand. 
To estimate this estimand, all data collected in the population of interest up to Day 29 
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will be included in the analysis. Missing data due to participant withdrawal from study 
will be handled in the same manner as the primary estimand. 
Other sensitivity/supplementary estimands for the primary efficacy endpoint analysis will 
be considered if deemed needed. Further details will be provided in the statistical analysis 
plan. 
9.4.3. 
Secondary Endpoint(s)  
Full details of all analysis methods for the secondary endpoints will be provided in the 
statistical analysis plan. 
9.4.4. 
Exploratory Endpoint(s)  
Full details of all analysis methods for the exploratory endpoints will be provided in the 
statistical analysis plan. 
9.4.5. 
Safety Analysis  
For safety data, no formal hypotheses will be tested. Occurrence of AEs, 
non-COVID-19 -related AEs, SAEs, non-COVID 19 related SAEs, and AESIs, including 
laboratory tests and vital signs will be displayed in the form of listings, frequencies, 
summary statistics, graphs, and statistical analyses where appropriate. Interpretation will 
be aided by clinical expertise. 
As noted in Section 8.4, since it will not be possible to delineate in a single participant 
whether the hospitalization is directly related to COVID-19 complications or could be 
related to sotrovimab causing more severe disease due to ADE, all hospitalizations 
regardless of cause will be included in the primary endpoint and will also be counted as 
serious adverse events. To inform on the number and nature of non-COVID-19 adverse 
events and serious adverse events, additional safety analyses will be performed in which 
select, pre-specified terms consistent with known progression of COVID-19 disease will 
be excluded. Details of these and all analyses, including example outputs, will be 
documented in the statistical analysis plan. 
9.4.6. 
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  
The Joint Safety Review Team (JSRT) comprising individuals from Vir and GSK will 
review safety data at regular intervals throughout the conduct of the study. Details of the 
JSRT process is recorded in relevant SRT documents. 
A single interim analysis (IA) was initially planned to be performed for evaluation of 
safety, efficacy and futility when approximately 50% of participants are enrolled and 
reach Day 29. The IA data was to be evaluated by an IDMC. However, prior to the time 
of the planned analysis, the JSRT noted a discrepancy in the rate of progression to 
hospitalization occurring in the 250mg IM arm compared with the 500mg IM and IV 
arms. Upon review of the cumulative data, the JSRT made the decision to pause 
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enrollment into the 250mg IM arm on 04-August-2021 and escalated the issue to the 
IDMC. An ad hoc meeting of the IDMC was called on 11-August-2021 and based upon 
their review of the data, the IDMC concurred that enrollment in the 250mg IM arm 
should be discontinued. As this ad hoc IDMC meeting occurred prior to the timepoint 
when the formal interim analysis would have occurred and concluded with discontinuing 
one arm of the study combined with an unexpected rapid increase in the rate of 
enrollment, it was not feasible to conduct the formal interim analysis. 
9.6. 
Multiple Comparisons and Multiplicity  
The full details of the multiplicity strategy of this study will be provided in the in the 
statistical analysis plan.  
There were 2 hypotheses for the primary endpoint: 
(1) non-inferiority of sotrovimab 500 mg IM versus sotrovimab 500 mg IV  
(2) non-inferiority of sotrovimab 250 mg IM versus sotrovimab 500 mg IV  
Hypotheses (1) and (2) will be tested using the primary estimand according to the 
hierarchical testing principal as follows: 
• If the null hypothesis for (1) is rejected, i.e., the upper bound of the two-sided 
95% confidence interval for the risk difference between sotrovimab 500 mg 
IM and sotrovimab 500 mg IV is less than the pre-specified 3.5% non-
inferiority margin, then hypothesis for (2) will be tested.  
• If the null hypothesis for (1) is not rejected, then hypothesis for (2) will not 
be tested.  
Below is the summary of possible hypothesis testing results regarding non-inferiorities of 
(1) and (2): 
Which Null Hypothesis is Rejected  
Non-inferiority Declared For 
Hypotheses (1) and (2)  
sotrovimab 500 mg IM vs. sotrovimab 500 mg 
IV  
and 
sotrovimab 250 mg IM vs. sotrovimab 500 mg 
IV  
Hypothesis (1) but Not (2)  
Only sotrovimab 500 mg IM vs. sotrovimab 500 
mg IV  
Hypothesis (1) is NOT rejecteda      
None  
a Null hypothesis for (2) won’t be tested in this case 
As described in Section 9.5, the sotrovimab 250 mg IM arm was discontinued. Therefore, 
only hypothesis (1) above in Section 9.6 will be tested. 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
− Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU Clinical Trials 
Directive 2001/20/EC or Regulation (EU) No. 536/2014 (if applicable), and all 
other applicable local regulations 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor or designee with sufficient, 
accurate financial information as requested to allow the sponsor/designee to submit 
complete and accurate financial certification or disclosure statements to the appropriate 
regulatory authorities. Investigators and sub-investigators are responsible for providing 
information on financial interests during the course of the study and for 1 year after 
completion of the study. 
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10.1.3. 
Informed Consent Process  
• The investigator or his/her representative will explain the nature of the study 
to the participant or their legally authorized representative and answer all 
questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A signed copy of the ICF(s) must be provided to the participant or their legally 
authorized representative.  
Vir (alone or working with others) may use the participant’s coded study data and 
samples and other information to carry out this study; understand the results of this study; 
learn more about 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 
patients; 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. 
10.1.5. 
Committees Structure  
Independent Data Monitoring Committee (IDMC)  
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An IDMC will perform an interim analysis to make recommendations to Vir/GSK as 
detailed in the IDMC Charter. Details regarding the IDMC process, structure and 
function will be available in the IDMC charter, which is available upon request.  
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. The JSRT will monitor injection site 
reaction data in both of the sotrovimab IM arms to assess local tolerability issues.  
10.1.6. 
Dissemination of Clinical Study Data  
• Where required by applicable regulatory requirements, an investigator 
signatory will be identified for the approval of the clinical study report. The 
investigator will be provided reasonable access to statistical tables, figures, 
and relevant reports and will have the opportunity to review the complete 
study results at a sponsor site or other mutually-agreeable location. 
• Sponsor or designee will also provide all investigators who participated in the study 
with a summary of the study results and will tell the investigators what treatment their 
study participants received. The investigator(s) is/are encouraged to share the 
summary results with the study participants, as appropriate. 
• Under the framework of the SHARE initiative, the sponsor intends to make 
anonymized participant-level data from this trial available to external researchers for 
scientific analyses or to conduct research that can help advance medical science or 
improve patient care. This helps ensure the data provided by trial participants are used 
to maximum effect in the creation of knowledge and understanding. Requests for 
access may be made through www.clinicalstudydatarequest.com. 
• Sponsor or its designee will provide the investigator with the randomization codes for 
their site only after completion of the full statistical analysis. 
• The procedures and timing for public disclosure of the protocol and results summary 
and for development of a manuscript for publication for this study will be in 
accordance with GSK Policy. 
• A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
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10.1.7. 
Data Quality Assurance  
• All participant data relating to the study will be recorded on printed or 
electronic CRFs unless transmitted to the sponsor or designee electronically 
(e.g., laboratory data). The investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the 
CRF.  
• Guidance on completion of CRFs will be provided in the data entry guidelines. 
• Quality Tolerance limits (QTLs) will be pre-defined in the Integrated Quality Risk 
Management Plan to identify systematic issues that can impact participant safety 
and/or reliability of study results. These pre-defined parameters will be monitored 
during and at the end of the study, and all deviations from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Monitoring details describing strategy including definition of study critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are provided 
in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the 
sponsor.  
• As hospitalization and mortality are both primary study endpoints and serious adverse 
events, instream data cleaning including updating and reconciliation of hospitalization 
events between the safety dataset and efficacy dataset will be performed throughout 
the study duration and any changes or updates to the SAEs of hospitalization or 
mortality will be reflected in the efficacy dataset. 
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10.1.8. 
Source Documents  
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at 
the investigator’s site. 
• Data reported on the printed CRFs or entered in the electronic eCRFs that are 
transcribed from source documents must be consistent with the source documents or 
the discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
• Definition of what constitutes source data and its origin can be found in [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 documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
10.1.9. 
Study and Site Start and Closure  
First Act of Recruitment  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study/Site Termination  
Vir reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of Vir. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
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For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment of participants (evaluated after a reasonable amount of 
time) by the investigator 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or suspension, 
as specified by the applicable regulatory requirements. The investigator shall 
promptly inform the participant(s) and should assure appropriate participant therapy 
and/or follow-up 
10.1.10. 
Publication Policy  
• The results of this study may be published or presented at scientific meetings. 
If this is foreseen, the investigator agrees to submit all manuscripts or 
abstracts to the sponsor before submission. This allows the sponsor to protect 
proprietary information and to provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in Table 5 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. 
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Table 5: 
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  
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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting  
10.3.1. 
Definition of AE  
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to the 
study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a study intervention. 
 
Definition of Unsolicited and Solicited AE 
• 
An unsolicited adverse event is an adverse event that was not solicited using a 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 injection site 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. 
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Events Meeting the AE Definition 
• 
Clinically significant changes in laboratory assessments. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
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. 
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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 
 
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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. 
• 
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 
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Assessment of Causality 
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. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
pharmacovigilance to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor with a copy of any post-mortem findings 
including histopathology.  
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to the sponsor or designee within 24 
hours of receipt of the information. 
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 
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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.  
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Page 80 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions:  
Woman of Childbearing Potential (WOCBP)  
Women in the following categories are considered WOCBP (fertile): 
9. Following menarche 
10. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
− A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.  
− Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
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Woman of Nonchildbearing Potential (WONCBP)  
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following (for 
the purpose of this study): 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
2. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
• Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
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10.4.2. 
Contraception Guidance:  
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)  
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should 
be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.) 
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation 
o oral 
o intravaginal 
o transdermal 
o 
injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
o oral 
o 
injectable 
• Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant. 
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10.5. 
Appendix 5: Local Tolerability Assessment1  
• 
Study Visit Day: ____________  
• 
Timepoint: ____________  
• 
Time Performed: ____________ 
• 
Injection Location (check ONE): 
☐LEFT DORSOGLUTEAL 
 
☐RIGHT DORSOGLUTEAL 
☐LEFT DELTOID  
 
 
☐RIGHT DELTOID  
Local 
Reaction to 
Injectable 
Product 
Absent 
(Grade 0) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain  
☐ Absent 
☐ Does 
not 
interfere 
with 
activity 
☐ Repeated 
use of non-
narcotic pain 
reliever > 24 hr 
or interferes 
with activity 
☐ Any use of 
narcotic pain 
reliever or 
prevents 
daily activity 
☐ ED visit or 
hospitalisation 
Tenderness 
☐ Absent 
☐ Mild 
discomfort 
to touch 
☐ Discomfort 
with movement 
☐ Significant 
discomfort at 
rest 
☐ ED visit or 
hospitalisation 
Erythema/ 
Redness 
(Length) 
cm 
☐ Absent 
☐ 2.5 to 
5.0 cm 
________ 
cm 
☐ 5.1 to 10.0 
cm 
________ cm 
☐ > 10.0 cm 
________ cm 
☐ Necrosis or 
exfoliative 
dermatitis 
Induration/ 
Swelling  
☐ Absent 
☐ 2.5 to 
5.0 cm 
and does 
not 
interfere 
with 
activity 
________ 
cm 
☐ 5.1 to 10.0 
cm or interferes 
with daily 
activity 
________ cm 
☐ > 10.0 cm 
or prevents 
daily activity 
________ cm 
☐ Necrosis 
 
____________________________________ 
First Initial & Surname (print)  
 
____________________________ _______/_______/_______ 
Signature  Date 
1 Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials 2007, FDA 
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10.6. 
Appendix 6: Long COVID Questionnaire  
In the past 30 days, has the subject experienced any of the following long COVID symptoms? 
Yes/No 
1. 
Did the subject have 
a fever? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
2. 
Did the subject have 
a cough? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
3 
Did the subject have 
a sore throat? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
4 
Did the subject have 
muscle aches 
(myalgia)? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
5 
Did the subject have 
joint 
pain 
(arthralgia)? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
6 
Did the subject have 
fatigue? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
7 
Did the subject have 
malaise? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
8 
Did the subject have 
shortness of breath? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
9 
Did the subject have 
a headache? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
10 
Did the subject have 
vomiting? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
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In the past 30 days, has the subject experienced any of the following long COVID symptoms? 
Yes/No 
11 
Did the subject have 
nausea? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
12 
Did the subject 
have diarrhea? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; 
mild/moderate/severe) 
13 
Did the subject have 
loss of smell? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; 
mild/moderate/severe). 
14 
Did the subject have 
loss of taste? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
15 
Did the subject have 
chills? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
16 
Did the subject have 
a skin rash? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
17 
Did the subject have 
difficulty thinking 
or concentrating/ 
brain fog? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
18 
Does the subject 
have chest pain? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
19 
Does the subject 
have palpitations? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
20 
Does the subject 
have trouble 
sleeping? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
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In the past 30 days, has the subject experienced any of the following long COVID symptoms? 
Yes/No 
21 
Does the subject 
have hair loss? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
22 
Has the subject 
experienced 
depression? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
23 
Has the subject 
experienced 
anxiety? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; 
mild/moderate/severe) 
24 
Does the subject 
have impaired 
mobility? 
Yes/No 
If Yes, 
  
What was the grade or severity of the 
symptom? (Grade 1/2/3; mild/moderate/severe) 
25 
Does the subject 
have other 
symptoms? 
Yes/No 
If Yes, specify 
  
[enter free text]  
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11. 
REFERENCES  
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