Prospective Cohort Study to Monitor the Emergence of SARS-CoV-2 Spike Viral Variants in Immunocompromised Non-hospitalized Patients Exposed to Sotrovimab in Great Britain: LUNAR Study
Phase: PHASE4
Conditions: COVID-19
Sponsor: GlaxoSmithKline

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TITLE PAGE
Division: Pharma Research and Development 
Information Type: Epidemiology PASS Protocol 
Title: 
Prospective cohort study to monitor the emergence of SARS-
CoV-2 spike viral variants in immunocompromised non-
hospitalised patients exposed to sotrovimab in Great Britain: 
LUNAR study  
Compound 
Number: 
GSK4182136 
Development Phase 
IV 
Effective Date: 
24 January 2023 
 
Subject:  
SARS-CoV-2 infection 
Author(s):  
 
 
 
Indication Studied: Early treatment for SARS-CoV-2 infection 
 
Copyright 2022 the GlaxoSmithKline (GSK) group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited 
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PASS information *
Title 
Prospective cohort study to monitor the 
emergence of SARS-CoV-2 spike viral variants in 
immunocompromised non-hospitalised patients 
exposed to sotrovimab in Great Britain: LUNAR 
study 
Protocol version identifier 
Version 2 
Date of last version of 
protocol 
04 May 2022 
EU PAS (ENCEPP) register 
number 
EUPAS46386 
Active substance 
Sotrovimab [recommended INN] (also known as VIR-
7831 and GSK4182136) 
ATC code: J06BD05 
Medicinal product 
 XevudyTM 500 mg concentrate for solution for 
infusion 
Product reference 
 PLGB 19494/0301
Procedure number 
N/A 
Marketing 
authorisation holder(s) 
GlaxoSmithKline UK Limited 
980 Great West Road 
Brentford 
Middlesex 
TW8 9GS 
UK 
Joint Post Authorisation Safety 
Study PASS 
No 

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Research question and 
objectives 
Amongst immunocompromised non-hospitalised 
patients treated with sotrovimab as part of standard 
clinical care: 
 
Primary Objectives:  
1- Evaluate the proportion of patients eligible for 
sequence analysis that have any amino acid 
(AA) change from baseline in the epitope of 
sotrovimab binding in samples collected at 
Day 7, 14 and 28 (+/-2 days) 
2- Evaluate the proportion of patients eligible for
sequence analysis that have any AA change 
from baseline in the spike protein in samples 
collected at Day 7, 14 and 28 (+/-2 days) 
Secondary Objectives: 
1. Evaluate the proportion of patients eligible for 
sequence analysis with variants of concern 
(VOC) and under investigation (VUI) on the 
earliest possible sample including baseline  
2. Evaluate the proportion of patients with 
undetectable virus at Day 7, 14 and 28 (+/-2 
days) by reverse transcriptase polymerase 
chain reaction (RT-PCR) 
3. Evaluate the proportion of patients with key 
clinical outcomes (hospital admission, 
requirement for respiratory support, intensive 
care unit [ICU] admission and death) through 
Day 28 post sotrovimab administration 
4. Describe AA (detected at >5% allelic 
frequency) changes in the Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-
CoV-2) spike protein in samples collected at 
Day 7, 14 and 28 (+/-2 days) compared to 
baseline following sotrovimab administration 
for samples with viral loads above the 
threshold of the sequencing assay  
5. Describe AA changes in the consensus 
sequence (>50%) of SARS-CoV-2 spike 
protein in samples collected at Day 7, 14 and 
28 (+/-2 days) compared to baseline following 
sotrovimab administration for samples with 
viral loads below the threshold for detection of 
AA changes at >5% allelic frequency but with 
sufficient levels to generate consensus 
sequencing data 

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Country of study 
Great Britain 
Author 
, PhD, PharmD, MPH 
 
, 
Value 
Evidence 
and
Outcomes  
MARKETING AUTHORISATION HOLDER(S) *  
Marketing authorisation 
holder(s) 
GlaxoSmithKline UK Limited 
980 Great West Road 
Brentford 
Middlesex 
TW8 9GS 
UK 
MAH contact person 
 
 
 
 
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TABLE OF CONTENTS 
PAGE 
1. 
LIST OF ABBREVIATIONS ...................................................................................... 7 
2. 
RESPONSIBLE PARTIES ........................................................................................ 8 
3. 
ABSTRACT ............................................................................................................ 13 
4. 
AMENDMENTS AND UPDATES ............................................................................ 18 
5. 
MILESTONES ........................................................................................................ 22 
6. 
RATIONALE AND BACKGROUND ........................................................................ 22 
6.1. 
Background ................................................................................................ 22 
6.2. 
Rationale .................................................................................................... 24 
7. 
RESEARCH QUESTION AND OBJECTIVE(S) ...................................................... 24 
7.1. 
Primary Objectives ...................................................................................... 24 
7.2. 
Secondary Objectives ................................................................................. 25 
8. 
RESEARCH METHODS ......................................................................................... 25 
8.1. 
Study Design .............................................................................................. 25 
8.2. 
Study Population and Setting ...................................................................... 29 
8.2.1. 
Inclusion Criteria .......................................................................... 29 
8.2.2. 
Exclusion Criteria ......................................................................... 30 
8.3. 
Variables..................................................................................................... 30 
8.3.1. 
Exposure Definitions .................................................................... 30 
8.3.2. 
Outcome definitions ..................................................................... 30 
8.3.2.1. 
Primary Endpoint (Primary Objective) ......................... 30 
8.3.2.2. 
Secondary Endpoints ................................................. 31 
8.3.3. 
Confounders and Effect Modifiers ................................................ 31 
8.3.3.1. 
Patients Characteristics .............................................. 31 
8.4. 
Data Sources .............................................................................................. 33 
8.5. 
Study Size .................................................................................................. 33 
8.6. 
Data Management ...................................................................................... 35 
8.6.1. 
Timings of Assessment during Follow-up ..................................... 35 
8.7. 
Data analysis .............................................................................................. 36 
8.7.1. 
Essential Analysis ........................................................................ 36 
8.7.1.1. 
Primary Objective ....................................................... 36 
8.7.1.2. 
Secondary Objective .................................................. 37 
8.7.2. 
Exploratory Analysis .................................................................... 37 
8.7.3. 
General Considerations for Data Analyses .................................. 37 
8.7.4. 
Interim Analysis ........................................................................... 37 
8.8. 
Quality control and Quality Assurance ........................................................ 38 
8.8.1. 
Data Quality Assurance ............................................................... 38 
8.8.2. 
Access to Source Data/Documents.............................................. 38 
8.8.3. 
Archiving Study Documents ......................................................... 38 
8.8.4. 
Study Monitoring .......................................................................... 39 
8.8.5. 
Audits and Inspections ................................................................. 39 
8.9. 
Limitations of the Research Methods .......................................................... 39 
8.10. 
Study Closure/Uninterpretability of Results ................................................. 41 

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8.11. 
Other Aspects ............................................................................................. 41 
9. 
PROTECTION OF HUMAN SUBJECTS ................................................................ 42 
9.1. 
Ethical Approval and Subject Consent ........................................................ 42 
9.1.1. 
Regulatory and Ethical Considerations ........................................ 42 
9.1.2. 
Financial Disclosure ..................................................................... 42 
9.1.3. 
Informed Consent Process .......................................................... 42 
9.2. 
Participant Withdrawal ................................................................................ 43 
9.3. 
Subject Confidentiality ................................................................................ 43 
10. LEGAL BASIS FOR PROCESSING INDIVIDUAL HUMAN DATA .......................... 44 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS .......................................................................................................... 44 
11.1. 
Key Definitions ............................................................................................ 44 
11.2. 
Collection of adverse events/reactions ........................................................ 45 
11.3. 
Reporting of adverse events/reactions ........................................................ 45 
11.4. 
Safety collection and reporting study documentation .................................. 46 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS .............................................................................................................. 47 
13. REFERENCES ....................................................................................................... 48 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS ...................................................... 52 
 
 
 

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1.
LIST OF ABBREVIATIONS
AA 
Amino Acid 
ABPI 
Association of the British Pharmaceutical Industry 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019 
DMP 
Data Management Plan 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
GB 
Great Britain 
GISAID 
Global Initiative on Sharing All Influenza Data 
GSK 
GlaxoSmithKline 
HCP 
HealthCare Professional 
HSA 
Health Security Agency 
HSI 
Human Safety Information 
IC 
Immunocompromised 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
PASS 
Post Authorisation Safety Study 
PCR 
Polymerase Chain Reaction 
RT-PCR
Reverse Transcriptase Polymerase Chain Reaction
SAE(s)
Severe Adverse Event(s)
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SMP
Safety Management Plan
SOP
Standard Operating Procedure
UK
United Kingdom
UKHSA
United Kingdom Health Security Agency
VOC
Variant of Concern
VUI
Variant Under Investigation
WHO
World health Organization
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
XEVUDY 
 
None 
 

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2.
RESPONSIBLE PARTIES
Co-Principal Investigator: Professor Judith Breuer, University College London 
 
Co-Principal Investigator: Dr David Mark Lowe, University College London 
 
Qualified Person for Pharmacovigilance (QPPV): Heather Stein 
 
 
 
 
 

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SPONSOR SIGNATORY:
Title: 
Prospective cohort study to monitor the emergence of SARS-
CoV-2 spike viral variants in immunocompromised non-
hospitalised patients exposed to sotrovimab in Great Britain: 
LUNAR study 
Compound 
Number: 
 GSK4182136 
 
 
 
Myriam Drysdale 
Scientific Lead, Epidemiology, VEO, GSK 
 
Date 
 
Melissa Van Dyke 
Immunology Head, Epidemiology, VEO, GSK 
 
Date 
 
 
 
Heather Stein 
TA Head, Global Safety, GSK 
 
Date 
 
 
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SPONSOR INFORMATION PAGE
Study ID: 218407 
Sponsor Legal Registered Address and Sponsor Contact Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Sponsor Medical Monitor Contact Information: Medical Monitor Name and Contact 
Information will be provided separately 
Sponsor Serious Adverse Events (SAE) Contact Information:   Refer to Safety 
Management Plan (SMP)  
Regulatory Agency Identifying Number(s):  EudraCT number 2022-000754-29 

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
 
I confirm agreement to conduct the study in compliance with the protocol. 
 
I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described clinical study. 
 
I agree to ensure that all associates, colleagues, and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study. 
Investigator Name:  
_____________________________ 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 

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STUDY ADVISORY COMMITTEE
N/A 

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3.
ABSTRACT
Title  
Prospective cohort study to monitor the emergence of SARS-CoV-2 spike viral variants 
in immunocompromised non-hospitalised patients exposed to sotrovimab in Great 
Britain: LUNAR study  
 
Rationale and background  
Sotrovimab was granted a conditional marketing authorisation for the treatment of early 
coronavirus disease 2019 (COVID-19) infection in Great Britain (GB) on December 01, 
2021. Sotrovimab is an early treatment that will be prescribed to patients with severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who are at risk to 
progress to severe disease in non-hospitalised settings. There is a theoretical risk of 
monoclonal antibodies selecting for viral variants which could have the potential for 
increased transmissibility and/or reduced susceptibility to sotrovimab or to vaccine-
derived immunity. Immunocompromised (IC) patients, who are on a prioritised list to 
receive treatment should they become infected, present a particular risk for variants 
because of their potential for prolonged viral shedding, and thus, present a risk for the 
emergence of mutations and potential onward community transmission. 
This genomic surveillance study will aim to describe changes in the SARS-CoV-2 spike 
protein observed in IC patients receiving sotrovimab in sentinel sites at a national level to 
assess potential emergence of viral variants.  
Research question and objective(s) 
Amongst IC non-hospitalised patients treated with sotrovimab as part of standard clinical 
care: 
Primary Objectives:  
1. Evaluate the proportion of patients eligible for sequence analysis that have any 
amino acid (AA) change from baseline in the epitope of sotrovimab binding in 
samples collected at Day 7, 14 and 28 (+/-2 days) 
2. Evaluate the proportion of patients eligible for sequence analysis that have any 
AA change from baseline in the spike protein in samples collected at Day 7, 14 
and 28 (+/-2 days) 
 
Secondary Objectives: 
1. Evaluate the proportion of patients eligible for sequence analysis with variants of 
concern (VOC) and under investigation (VUI) on the earliest possible sample 
including baseline 
2. Evaluate the proportion of patients with undetectable virus at Day 7, 14 and 28 
(+/-2 days) by reverse transcriptase polymerase chain reaction (RT-PCR) 

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3. Evaluate the proportion of patients with key clinical outcomes (hospital 
admission, requirement for respiratory support, intensive care unit [ICU] 
admission and death) through Day 28 post sotrovimab administration 
4. Describe AA (detected at >5% allelic frequency) changes in SARS-CoV-2 spike 
protein in samples collected at Day 7, 14 and 28 (+/-2 days) compared to baseline 
following sotrovimab administration for samples with viral loads above the 
threshold of the sequencing assay 
5. Describe AA changes in the consensus sequence (>50%) of SARS-CoV-2 spike 
protein in samples collected at Day 7, 14 and 28 (+/-2 days) compared to baseline 
following sotrovimab administration for samples with viral loads below the 
threshold for detection of AA changes at >5% allelic frequency but with sufficient 
levels to generate consensus sequencing data 
 
Study design 
Prospective cohort study 
 
Non-hospitalised patients who are being treated with sotrovimab as part of 
standard of clinical care will be screened and enrolled if eligible (Day 0 = 
baseline). Informed consent, patient characteristics (demographic and clinical), 
and treatment history (related to COVID-19 and underlying diseases) will also be 
recorded at Day 0. 
 
Baseline nasal/oropharyngeal swab sample will be collected on site, as per 
protocol, under supervision after training and sent to the central analytical 
laboratory.  
 
Follow-up nasal/oropharyngeal swab samples (Day 7, 14 and 28 (+/-2 days)) will 
be collected by the patients using home test kits or by healthcare professionals 
(HCP) in case of hospitalisation, as per protocol, with samples sent to the central 
analytical laboratory. 
 
Sequencing analyses will be conducted on all SARS-CoV-2 positive 
nasal/oropharyngeal swab samples that meet the threshold criteria for the 
sequencing assay.  
Population, including the setting and study population 
Inclusion criteria:  
1. 
-year-old 
2. IC (as defined in the clinical commissioning policy [NHS England, 2022]) 
3. A positive PCR or antigen test for SARS-CoV-2 through clinical testing or 
routine screening undertaken as part of clinical management 
4. Prescribed treatment with sotrovimab as standard of clinical care  
5. Able to provide informed consent and willing to adhere to study-related 
procedures 
Exclusion criteria: 
1. Patients who require hospitalisation (related or not to COVID-19) at baseline 
2. Patients who initiated sotrovimab therapy in in-patient settings 
3. Patients unable to perform follow-up sample collection 

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4.
Blinded patients from other COVID-19 related trials
 
From the Clinical Commissioning Policy, the following groups will also be excluded 
from this study unless also eligible for sotrovimab under other Clinical Commissioning 
Policy IC criteria not listed below [NHS England, 2022]: 
  
5. Cohort of patients with rare neurological conditions 
6. 
 
7. In the cohort of patients with renal disease:: 
o Patients with chronic kidney stage (CKD) 4 or 5 (an eGFR less than 30 
ml/min/1.73m2) without immunosuppression (patients with renal 
disease cohort) 
8. In the cohort of patients with liver disease:  
o 
-Pugh class A who are not on immune 
suppressive therapy (compensated liver disease), class B or class C 
(decompensated liver disease) 
 
The decision to treat patients with sotrovimab will be made prior to and independently 
from the decision to enroll patients into the study 
. This is 
to ensure that sotrovimab is prescribed as per standard of clinical care. The patient will 
then be screened and enrolled in the study with informed consent and baseline sample 
collection taken prior to sotrovimab administration or if not possible, then either during 
sotrovimab infusion or as close as possible to the end of sotrovimab infusion (within 2 
hours of the end of the sotrovimab infusion). A patient who declines to be enrolled in the 
study will still receive sotrovimab when eligible for the treatment. 
Variables (for primary and secondary objectives) 
 
Exposure: Sotrovimab administration 
 
Primary endpoint: 
 
Proportion of patients eligible for sequence analysis that have any AA 
change from baseline in the epitope of sotrovimab binding in samples 
collected at Day 7, 14 and 28 (+/-2 days) (Primary Objective 1) 
 
Proportion of patients eligible for sequence analysis that have any AA 
change from baseline in the spike protein in samples collected at Day 7, 14 
and 28 (+/-2 days) (Primary Objective 2) 
 
Secondary endpoints: 
 
Proportion of patients eligible for sequence analysis with VOC and VUI 
on the earliest possible sample including baseline (Secondary Objective 
1)  
 
Proportion of patients with undetectable virus at Day 7, 14 and 28 (+/-2 
days) (Secondary Objective 2)  
 
Clinical outcomes at Day 7, 14 and 28 (+/-2 days) (Secondary Objective 
3): 
o Proportion of patients that are admitted to hospital for any cause 
and for COVID-19 reasons 
o Proportion of patients requiring new or increased oxygen support 

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o
Proportion of patients requiring invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO) 
o Proportion of all cause ICU admission 
o Proportion of all cause deaths and COVID-19 related deaths 
 
AA (detected at >5% allelic frequency) changes in the SARS-CoV-2 spike 
protein in samples collected at Day 7, 14 and 28 (+/-2 days) compared to 
baseline following sotrovimab administration for samples with viral loads 
above the threshold of the sequencing assay (Secondary Objective 4)  
 
AA changes in the SARS-CoV-2 spike consensus sequences from baseline 
in samples where viral load is insufficient for >5% allelic frequency 
analysis but sufficient to generate consensus level sequencing data 
(Secondary Objective 5) 
 
Covariables: 
Patient characteristics measured at baseline (demographics, number of days of COVID-
19 symptoms (if symptomatic) and number of days since initial COVID-19 positive test 
result at time of receiving treatment, co-morbidities including immunocompromising 
condition, treatment history including immunosuppressant treatment, previous SARS-
CoV-2 infections, COVID-19 vaccination status, serostatus if available, other treatment 
for COVID-19 including antivirals or other monoclonal antibodies). 
Data sources: 
After obtaining informed consent, inclusion/exclusion and baseline patient characteristics 
and treatment history data will be collected and documented. Any adverse event (AE) 
(serious and non-serious) observed during sotrovimab treatment (e.g., infusion-related 
reaction) and considered related to sotrovimab will be collected.  Completion of baseline 
nasal/oropharyngeal sample collection and dispensing of at home lab kits to the patient 
will be completed and documented prior to patient discharge. Any baseline patient 
characteristics or treatment history unable to be collected during the baseline visit can be 
collected retrospectively from the patient or 
s during the follow 
up period. Patients will receive a phone call at Day 7, 14 and 28 (+/- 2 days) to collect 
follow-up clinical outcomes and safety information (AEs) with a reminder for completion 
of at home nasal/oropharyngeal sample collection at the required timepoints. 
Participating sites may also contact patient  regular HCPs for clinical outcomes and 
safety information data as required. All baseline and follow-up data will be recorded in 
the electronic case report form (eCRF). 
Virology data will be reported following the central analytical laboratory analysis of 
baseline, day 7, 14 and day 28 (+/-2 days) nasal/oropharyngeal samples as detailed in the 
statistical analysis plan (SAP). 
Study size: 
As a sentinel surveillance study, the aim will be to set up approximately 10 sites that are 
geographically spread across all 3 GB countries and collect data from a target of 500 (up 
to 625) patients over the course of a year. Flexible enrolment caps per site and per month 
may be considered. The aim is to ensure continuous enrolment with appropriate 

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geographical representation over the 12-month study period to reflect the fast-evolving 
COVID-19 pandemic. In addition, the target sample size will be re-assessed after the first 
200-300 patients are enrolled in regard to progression towards achieving the primary 
objective, with the potential to decrease or increase the target number accordingly. 
Data analysis: 
Essential analyses 
 
Sequencing of samples on a regular basis (as detailed in the study laboratory 
manual) is required.  
o For patients eligible for sequencing analysis, proportion of patients with 
AA change from baseline in the epitope of sotrovimab (Primary Objective 
1) 
o For patients eligible for sequencing analysis, proportion of patients with 
AA change from baseline in the spike protein (Primary Objective 2) 
o For samples with viral load above the threshold for allelic frequency 
determination, AA changes in SARS-CoV-2 spike protein at >5% allelic 
frequency compared to baseline will be reported as described in the SAP 
(Secondary Objective 4) 
o For samples with viral load below the threshold for low (5%) allelic 
frequency analysis, but above the threshold for consensus sequence 
generation, AA changes in the SARS-CoV-2 spike protein consensus 
sequence from baseline will be reported as described in the SAP 
(Secondary Objective 5) 
 
For patients eligible for sequencing analysis, VOC, VUI and other lineages 
information as classified by UKHSA (United Kingdom Health Security Agency) 
and WHO (World Health Organization) will be identified from sequencing data 
(Secondary Objective 1) 
o This analysis will be done on the earliest possible sample and reported 
only once per patient as described in the SAP 
 
Comorbidities, clinical outcomes, patients with undetectable virus and safety 
events data will be described and reported with counts and proportions 
(Secondary Objective 2 and 3). 
Exploratory analyses 
1. Describe viral characteristics (e.g. viral load, VOC/VUI, AA changes) in patients 
who subsequently require hospital admission or die due to COVID-19 post 
sotrovimab treatment  
2. Establish whether changes in AA from baseline identified in the SARS-CoV-2 
spike protein are reported sequences in genomic databases (e.g. Global initiative 
on sharing all influenza data [GISAID]) 
 
Milestones: 
Actual Study Start: First Patient First Visit  21 June 2022 
Estimated Study End: Last Patient Last Visit  20 July 2023 

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4.
AMENDMENTS AND UPDATES
Amendme
nt or 
update no 
Date 
Section of 
study 
protocol 
Amendment or update 
Reason 
1 
03 May 
2022 
Abstract, 
Section 8.1 
Table 1 
Schedule of 
Activities, 
Section 
8.2.1 Study 
population 
and setting, 
Section 
8.6.1 
Timing of 
assessmen
t during 
follow-up  
The text in bold was added  
in the relevant sections. 
 nasal/oropharyngeal 
swab at baseline must be 
taken prior to the 
administration of 
sotrovimab or as close as 
possible to the end of 
 
The Ethics committee 
requested more time for 
patients to review and 
sign the ICF.  To avoid 
any delay in sotrovimab 
administration, it was 
agreed to collect the 
baseline 
nasal/oropharyngeal sw
ab just after sotrovimab 
infusion if it is not 
possible to collect 
before. By allowing for 
the baseline sample to 
be collected soon after 
infusion, the patient will 
have additional time to 
evaluate their 
participation whilst still 
enabling a viable 
sample to be collected. 
2  
03 May 
2022 
Abstract 
and Section 
5 
Milestones 
The text in bold was 
updated in the appropriate 
section:  
 
Estimated Study Start: 
First Patient First Visit  21 
June 2022 
 
Estimated Study End: Last 
Patient Last Visit  20 July 
2023 
 
Start of data collection: 
Estimated June 2022 
 
End data collection: 
Estimated July 2023 
 
Final report of study 
results: Estimated 
November 2023 
The study start has 
been delayed and new 
timelines are now 
proposed in the 
amendment 
 
 
 
 
 
 

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3 
20 
Januar
y 2023 
PASS 
information 
The ATC code for 
sotrovimab, J06BD05, was 
added 
Addition of ATC code 
4 
20 
Januar
y 2023 
PASS 
information 
Correction of a formatting 
error that truncated 
secondary objective 5 in 
the section Research 
question and objectives  
Correction following 
authority comment 
5 
20 
Januar
y 2023 
Abstract, 
Section 8.1 
Table 1 
Schedule of 
Activities, 
Section 
8.2.1 Study 
population 
and setting, 
Section 
8.6.1 
Timing of 
assessmen
t during 
follow-up 
The text in bold was added 
in the relevant sections: 
 nasal/oropharyngeal 
swab at baseline must be 
taken prior to the 
administration of 
sotrovimab or if not 
possible, then either 
during sotrovimab 
infusion or as close as 
possible to the end of 
sotrovimab infusion 
end of the sotrovimab 
infusion)  
 
Clarification of how long 
after the end of 
sotrovimab infusion the 
baseline swab can be 
taken 
 
 
6 
20 
Januar
y 2023 
Section 8.1 
Table 1 
Schedule of 
Activities,  
Section 
8.6.1 
Timing of 
assessmen
t during 
follow-up 
The text in bold was added 
in the relevant sections: 
Persistent positive results 
will be reported back to the 
sites upon site request 
(as described in the study 
reference manual).  
Preference of sites 
 
7 
20 
Januar
y 2023 
Section 5 
Milestones, 
Section 
8.7.4 
Interim 
Analysis  
An interim analysis 
assessing the primary and 
secondary objectives was 
added 
Health authority request 
8 
20 
Januar
y 2023 
Section 8.2 
Study 
Population 
and Setting 
Text in strikethrough was 
deleted: 
It will be conducted for a 
period of 12 months in 
approximately 10 sites 
selected following 
feasibility assessment from 
the list of COVID Medicine 
Delivery of COVID-19 
therapeutics to non-
hospitalised patients is 
expected to become 
part of routine NHS 
services from April 2023
(https://www.england.nh
s.uk/coronavirus/wp-

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Delivery Units (CMDUs 
[https://www.england.nhs.u
k/coronavirus/publication/c
ovid-medicine-delivery-
unit-directory/]) in GB, or 
until the enrollment of 500 
(up to 625) patients is met, 
or until sotrovimab is no 
longer used in GB, 
whichever comes first.  
content/uploads/sites/5
2/2022/12/C1677-
commissioning-
framework-covid-19-
therapeutics-for-non-
hospitalised-
patients.pdf) 
9 
20 
Januar
y 2023 
Abstract, 
Section 8.4 
Data 
sources, 
Section 
8.7.1.1 
Primary 
objective, 
Section 
8.7.1.2 
Secondary 
objective, 
Section 
8.7.3 
General 
considerati
ons for data 
analyses, 
Section 8.9 
Limitations 
of the 
research 
methods 
T
was replaced with 
  
The statistical analysis 
plan contains all details 
about what the study 
will report  
10 
20 
Januar
y 2023 
Abstract, 
Section 
8.7.2 
Exploratory 
Analyses 
The third exploratory 
analysis was removed: 3. 
Explore the feasibility of 
linkage with routinely 
collected samples (as per 
standard of clinical care) 
for spike protein monitoring 
in patients who remain 
SARS-CoV-2 positive 
beyond 28 days as part of 
a longer follow-up for this 
sub-population  
Exploratory analysis no 
longer relevant and not 
feasible 
11 
20 
Januar
y 2023 
Abstract, 
Section 8.1 
Study 
MHRA. 
Central Alert System CAS-
ViewAlert. Antivirals or 
Updated 
recommendations for 
antiviral treatment in 

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Design, 
Section 
8.2.1 
Inclusion 
criteria, 
Section 
8.2.2 
Exclusion 
criteria, 
Section 10 
References 
neutralising monoclonal 
antibodies (nMABs) for 
non-hospitalised patients 
with COVID-19 . 27 
January 2022. CAS-
ViewAlert (mhra.gov.uk)
was replaced with NHS 
England. Coronavirus » 
Interim Clinical 
Commissioning Policy: 
Treatments for non-
hospitalised patients with 
COVID-19. 28 November 
2022  
non-hospitalised 
patients with COVID-19 
12 
20 
Januar
y 2023 
Section 6.1 
Backgroun
d, Section 
10 
References 
The reference to the 
Summary of Product 
Characteristics for Xevudy 
(MHRA, 2021) was 
updated to 
GlaxoSmithKline UK, 2022 
Updated version of 
Summary of Product 
Characteristics 
13 
20 
Januar
y 2023 
Throughout 
protocol 
Minor corrections to 
punctuation have been 
made throughout the 
protocol 
Administrative changes 
 
 
 

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5.
MILESTONES
 
Milestone 
Planned date 
Start of data collection 
June 2022 
End of data collection 
Estimated July 2023 
Interim report of study results 
Q2 2023 
Registration in the EU PAS register 
March 2022 
Final report of study results 
Estimated November 2023 
 
6. 
RATIONALE AND BACKGROUND 
6.1. 
Background 
The novel beta-coronavirus SARS-CoV-2 (Coronavirus disease 2019 [COVID-19]) was 
first detected in December 2019, with initial reports of its emergence in Wuhan, China. 
Since this time, the virus, which can cause severe pneumonia in infected individuals, has 
spread throughout the world, causing unprecedented impacts on health, economy, and 
social security [Wu Z, 2020]. 
The spectrum of symptomatic COVID-19 ranges from mild disease without pneumonia 
to critical disease requiring hospitalisation with intensive care unit (ICU) care. As of 18 
February 2022, approximately 18.5 million cases (people who have had at least one 
positive COVID-19 test result) and approximately 181,424 COVID-19 deaths have been 
recorded in the United Kingdom (UK) [GOV.UK, 2022]. The risk of hospital admission 
for a person detected as a case of Omicron appears to be reduced compared to a case of 
Delta [UKHSA, 2022].  
COVID-19 vaccination remains the foundation for SARS-CoV-2 control, and vaccine 
effectiveness has reduced the magnitude of hospitalisations and deaths despite continued 
high viral circulation [Lopez Bernal J, 2021a; Lopez Bernal J, 2021b]. More than 48 
million people in the UK have received at least two doses of vaccine and about 38 million 
have received a booster/third dose [GOV.UK, 2022]. Nonetheless, vaccine 
immunogenicity and effectiveness are lower in certain high-risk groups such as those 
with immunocompromising conditions [Chodick, 2021; Embi, P. J, 2021].  
Sotrovimab (VIR-7831; GSK4182136) is a human neutralising anti-SARS-CoV-2 
antibody which contains a 2 AA Fc-
 
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 neutralise 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]. COMET-ICE, a randomised, double-blind, multi-centre, placebo-
controlled trial of sotrovimab for the early treatment of COVID-19 in non-hospitalised 
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among patients treated with sotrovimab compared with placebo [Gupta A, 2021]. This 
single pivotal study supported the Marketing Authorisation Application (MAA) in Great 
Britain (GB).  
The Medicines and Healthcare products Regulatory Agency (MHRA) granted a 
conditional marketing authorisation for sotrovimab for the treatment of people with mild 
to moderate COVID-19 who are at high risk of developing severe disease 
[GlaxoSmithKline UK, 2022]. The 
issued 
at the end of September 2021, showed that about 3.7 million individuals were included as 
being at highest risk for severe COVID-19, or about 6.5% of the population [NHS 
Digital, 2021; Office for National Statistics, 2021; Hippisley-Cox J, 2021]. 
Immunocompromised (IC) patients, a subset of the shielding list, are not only subject to 
increased risk of severe outcomes such as hospitalisation and mortality, but evidence also 
shows that this group are more likely to transmit the virus to their household contacts, 
leading to increased clusters of the virus. This population is also more likely to shed the 
virus for a longer duration, potentially increasing the risk of emergent variants [Lewis, 
2021; Aydillo, 2020; Niyonkuru, 2021].  
The impact of the recently detected Omicron variant on the effectiveness of vaccines and 
therapeutics is unknown pending further research, though very early findings suggest that 
the Omicron variant may have greater reinfection risk than Beta or Delta variants. In vitro 
studies of sotrovimab suggest that it retains antiviral activity against viral mutations in 
the spike proteins of Alpha, Beta, Gamma, Delta, Kappa, and Omicron BA.1 variants, 
whilst there is evidence of reduced antiviral activity of other currently authorised mAbs 
or vaccines [Torjesen, 2021; Pulliam, 2021; Cathcart, 2022]. In February 2022, GSK 
submitted preliminary in vitro data on the antiviral activity of sotrovimab against the 
BA.2 variant to the MHRA. These data are currently under assessment. GSK will provide 
all new relevant in vitro data on the variants of concern (VOC) and variants under 
investigation (VUI) of SARS-CoV-2 to the MHRA (UK). The protocol will not be 
updated for each new VOC or VUI, but GSK in vitro data will be published 
contemporaneously (e.g. in the Cathcart et al pre-print [Cathcart, 2022]). 
The epitope to which sotrovimab binds is comprised of 23 AAs. Amino acids comprising 
the epitope are highly conserved with >99.68% conservation among >5,500,000 spike 
sequences from SARS-CoV-2 deposited in the GISAID database as of 15 December 2021 
(https://www.gisaid.org). In vitro pseudotyped virus assessment shows that the epitope 
sequence polymorphisms P337H/K/L/R/T and E340A/K/G/Q/V confer reduced 
susceptibility to sotrovimab [Cathcart, 2022]. 
Sotrovimab is thus a potentially critical therapeutic in the fight against COVID-19, for 
which there remains a high unmet medical need despite the recent success of preventative 
measures such as vaccines. Challenges with access to vaccines, vaccine hesitancy, 
medical contraindications to vaccines, IC individuals who may not respond to a vaccine, 
and importantly, the potential emergence of variant viruses that escape vaccine-derived 
immunity, will all contribute to what is likely to be an unfortunately large and enduring 
number of COVID-19 cases in need of treatment.  

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IC individuals have been shown to be at higher risk of breakthrough infections and are at 
higher risk for hospitalisation and death despite high vaccine uptake [Di Fusco, 2021; 
Hippisley-Cox J, 2021]. The same immune deficiencies that may predispose patients to 
severe COVID-19 outcomes can also result in a failure to mount robust immunity to 
SARS-CoV-2 following vaccination, which is why it is likely that IC patients will highly 
benefit from sotrovimab administration [Kearns, P, 2021; Mahase, 2021; NHS England, 
2022; NICE, 2021].  
6.2. 
Rationale 
Since December 2020, a number of variants of SARS-CoV-2 have emerged globally, 
with a high level of uncertainty around their transmissibility, severity and potential for 
evading vaccine-induced immunity or developing resistance against antivirals and mAbs. 
SARS-CoV-2 variants can undergo mutations that alter the AAs in the spike protein of 
the virus [Harvey W.T, 2021]. In the UK, many of these variants have been detected and 
have since remained under surveillance by UKHSA through routine surveillance 
[UKHSA, 2021]. Variants may be designated as VOC or VUI, depending on the evidence 
at the time of their discovery.  
Sotrovimab is an early treatment that will be prescribed to SARS-CoV-2 patients at risk 
to progress to severe disease in non-hospitalised settings. There is a theoretical risk of 
monoclonal antibodies selecting for viral variants which could have the potential for 
increased transmissibility and/or reduced susceptibility to sotrovimab or to vaccine-
derived immunity. IC patients, who are on a prioritised list to receive treatment should 
they become infected, present a particular risk for variants because of their potential for 
prolonged viral shedding, and thus, present a risk for the emergence of mutations and 
potential onward community transmission.  
Thus, this genomic surveillance study will aim to describe changes in the SARS-CoV-2 
spike protein observed in IC patients receiving sotrovimab in sentinel sites at a national 
level to assess potential emergence of viral variants.  
7. 
RESEARCH QUESTION AND OBJECTIVE(S) 
Amongst IC non-hospitalised patients treated with sotrovimab as part of standard clinical 
care: 
7.1. 
Primary Objectives  
1. Evaluate the proportion of patients eligible for sequence analysis that have any 
AA change from baseline in the epitope of sotrovimab binding in samples 
collected at Day 7, 14 and 28 (+/-2 days) 
2. Evaluate the proportion of patients eligible for sequence analysis that have any 
AA change from baseline in the spike protein in samples collected at Day 7, 14 
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7.2. 
Secondary Objectives  
1. Evaluate the proportion of patients eligible for sequence analysis with VOC and 
VUI on the earliest possible sample including baseline  
2. Evaluate the proportion of patients with undetectable virus at Day 7, 14 and 28 
(+/-2 days) by RT-PCR 
3. Evaluate the proportion of patients with key clinical outcomes (hospital 
admission, requirement for respiratory support, ICU admission and death) through 
Day 28 post sotrovimab administration 
4. Describe AA (detected at >5% allelic frequency) changes in the SARS-CoV-2 
spike protein in samples collected at Day 7, 14 and 28 (+/-2 days) compared to 
baseline following sotrovimab administration for samples with viral loads above 
the threshold of the sequencing assay  
5. Describe AA changes in the consensus sequence (>50%) of SARS-CoV-2 spike 
protein in samples collected at Day 7, 14 and 28 (+/-2 days) compared to baseline 
following sotrovimab administration for samples with viral loads below the 
threshold for detection of AA changes at >5% allelic frequency but with sufficient 
levels to generate consensus sequencing data 
 
8. 
RESEARCH METHODS 
8.1. 
Study Design 
This study is a prospective cohort study (Figure 1). 
This study will enrol IC non-hospitalised patients 
-year-old infected with SARS-
CoV-2 and receiving sotrovimab treatment as per standard of clinical care for COVID-19 
in selected facilities. Patients who require hospitalisation for COVID-19 are currently not 
eligible to receive sotrovimab [NHS England, 2022] and will be excluded; there is other 
ongoing research that will evaluate this population if sotrovimab is administered to this 
patient population. Patients prescribed sotrovimab who were hospitalised for non-
COVID-19 reasons at baseline will also be excluded; this population being already 
eligible for other national genomic surveillance and requiring a different operational 
model. All participants that consent to be enrolled in the study will be followed up for up 
to 28 days post sotrovimab treatment. Patient and disease characteristics (e.g. 
demographics, number of days of COVID-19 symptoms (if symptomatic) and number of 
days since initial COVID-19 positive test result at time of receiving treatment, co-
morbidities including immunocompromising condition and risk factors for COVID-19 
progression, COVID-19 vaccination status, previous SARS-CoV-2 infection, serostatus if 
available) and treatment history (e.g. immunosuppressant treatment) will be collected at 
baseline (index date (D0), which corresponds to sotrovimab administration date). Other 
treatments for COVID-19 including antivirals or other monoclonal antibodies will be 
collected at baseline and follow-up if any. 
Nasal/oropharyngeal samples for virological analysis will be collected at baseline and at 
three follow-up time points (Day 7, 14 and 28 (+/-2 days)), as per protocol (see Table 1). 

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Patients will be asked to take a throat and nasal sample with the same swab at each 
follow-up time point.  
Collected nasal mid-turbinate swabs have demonstrated comparable sensitivity and good 
viral load correlation to clinician collected nasopharyngeal swabs (considered as the gold 
standard) for COVID-19 detection [Kojima, 2021; Alemany, 2021]. While the 
nasal/oropharyngeal sample will be collected on site at baseline under supervision after 
training (as detailed in the study reference manual), home test kits will be provided to the 
patients with clear explanations on the appropriate technique to collect the follow-up 
samples as well as instructions for return to the central analytical laboratory. The 
present on each of the home test kits 
(follow guidance in the study reference manual) and checked by study research staff, 
when these are provided to the patient to take home. Collection of the follow-up samples 
may also be performed by an HCP in case of hospitalisation. Home test kits are proposed 
to minimise 
in-person visits would require 
and to improve patient adherence to study-related procedures and follow up. All the 
samples will be sent to a central analytical laboratory for testing (i.e., viral load, and 
sequencing analyses amongst SARS-CoV-2 positive samples with sufficient viral load) 
(see Section 8.3.2).  
Select key clinical outcomes data (e.g. hospital admission, respiratory support, ICU 
admission and death) will be collected at Day 7, 14 and 28 (+/-2 days) and documented in 
the eCRF. Phone calls to the patients by the study research staff will be planned at these 
three follow-up time points with the aim to complete the eCRF and to remind the patients 
to collect their follow-up nasal/oropharyngeal sample.  

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Table 1 
Schedule of Activities 
 
Baseline  
(Day 0, 
sotrovimab 
index date) 
Follow Up 
Call 1 
(Day 7 ± 2)p 
Follow Up 
Call 2 
(Day 14 ± 2)p 
Follow Up 
Call 3 
(Day 28 ± 2)pq 
Pre-screeninga 
 
  
  
  
Confirmation of sotrovimab 
prescriptionb 
 
  
  
  
Informed Consent c 
 
  
  
  
Eligibility confirmationd 
 
  
  
  
Enrolmente 
 
  
  
  
Nasal nasal/oropharyngeal 
swab 
 f 
g 
g 
g 
Sotrovimab administrationh 
 
  
  
  
Demographyi 
 
  
  
  
Co-morbiditiesj 
 
  
  
  
Disease characterisationk 
 
  
  
  
Concomitant medicationsl 
 
 
 
 
Vaccination statusm 
 
 
 
 
Clinical Outcomesn 
  
 
 
 
 Adverse events related to 
sotrovimab treatmento 
 
 
 
 
a Pre-screening of potential patients is encouraged to make the eligibility and consent process as efficient as 
possible and reduce delay to sotrovimab administration. 
b Evidence that the decision to administer sotrovimab was taken prior to consenting the patient to join the 
 
c Informed consent must be taken prior to any study specific procedures being conducted with the patient.  
d Evidence that all inclusion and no exclusion criteria have been met m
medical records prior to enrolment.  
e Register patient in EDC (Electronic Data Capture) system. Assign subject identification number to patient 
and document on enrolment log and patient materials (ICF [Informed consent form], contact card) and 
sample collection kits.   
f The nasal/oropharyngeal swab at baseline must be taken prior to the administration of sotrovimab or if not 
possible, then either during sotrovimab infusion or as close as possible to the end of sotrovimab infusion 
(within 2 hours of the end of the sotrovimab infusion). Patients must be trained in the self-administration 
of nasal/oropharyngeal swabs at baseline to support sample collection at follow up timepoints. Three 
sample collection kits must be provided to the patient for at home sample collection at follow up 
timepoints, staff must ensure correct subject identification number is present on each kit.  

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g Nasal/oropharyngeal swabs at follow up timepoints will be self-administered by the patient or HCP in 
case of hospitalisation. Samples must be returned to the central analytical laboratory by post as soon as 
practically possible. Use of priority post boxes is encouraged to ensure samples reach the central analytical 
laboratory within the analysis window.  
h Sotrovimab administration is to be performed as per local standard of care and is not part of this study 
protocol.   
i Demographic data including age (year and range), sex, smoking status, ethnicity and BMI (range) to be 
 
j Refer to Section 8.3.3.1for list of relevant co-morbidities. Co-morbidities should be documented in the 
 
k Disease characterisation data including duration of COVID-19 symptoms (days), previous SARS-CoV-2 
records. 
l Concomitant medications, both related to and non-related to SARS-CoV-2 infection, must be collected at 
 
m COVID-19 vaccination status, including number of vaccinations, date (month) and brand, must be 
collected at baseline and during follow up calls 
 
n Clinical outcomes including hospital admission, respiratory support, ICU admission and death will be 
 
o Refer to Section 11.3 for details on safety events to be reported. 
p Patients who progress to severe disease and may require COVID-19 related hospitalisation should be 
actively contacted and followed-up where possible by site staff to obtain samples and follow up data as per 
protocol.  
q Patients with a persistent positive sample at the end of the 28 day follow up period will have their positive 
results reported back to the sites upon site request (as described in the study reference manual).  
Patients who progress to severe disease and may require COVID-19 related 
hospitalisation will be actively contacted and followed-up where possible by the study 
research staff from the site where sotrovimab was administered. They or HCPs involved 
hospitalised. 
Patients will be given a contact card and asked to notify the site if they cannot be 
contacted for the follow-up calls. To reduce loss to follow up of hospitalised patients, 
preference will be given to sites where it is likely that patients who require hospitalisation 
following enrolment will be readmitted to the study site. This will be assessed as part of 
site feasibility.  
Figure 1 
Study Design 

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8.2. 
Study Population and Setting 
This post approval study will aim to start as soon as possible since sotrovimab is now 
deployed in GB (England, Scotland, Wales). It will be conducted for a period of 12 
months in approximately 10 sites in GB, or until the enrollment of 500 (up to 625) 
patients is met, or until sotrovimab is no longer used in GB, whichever comes first. The 
aim will be to identify sites that are geographically spread across all three of the home 
nations. Preference will be given to sites where it is likely that patients who require 
hospitalisation following enrolment will be readmitted to the study site. Another key 
factor considered when selecting study sites will be the capacity to start the study 
quickly, from both a staffing and governance perspective. 
This study is intended to cover a fixed period of vulnerability when a limited number of 
drugs and vaccines are available to generate evidence to understand the risk of variant 
emergence. UKHSA may continue to monitor the evolving variants and their impact on 
COVID-19 therapeutic and vaccine effectiveness as part of their routine surveillance 
activity.  
8.2.1. 
Inclusion Criteria 
1. Adult patients aged 
 years  
2. IC (as defined in the clinical commissioning policy [NHS England, 2022]) 
3. A positive PCR or antigen test for SARS-CoV-2 through clinical testing or 
routine screening undertaken as part of clinical management 
4. Prescribed treatment with sotrovimab as standard of clinical care 
5. Able to provide informed consent and willing to adhere to study-related 
procedures 
The list of IC population eligible to receive sotrovimab will be derived from the IC 
cohorts outlined in the interim Clinical Commissioning Policy: neutralising monoclonal 
antibodies or antivirals for non-hospitalised patients with COVID-19. Patient cohorts 
considered at highest risk from COVID-19 and to be prioritised for treatment with 
nMABs [NHS England, 2022]. The list may include specific IC patients within the 
following cohorts: 
 Patients with a solid cancer 
 Patients with a haematological disease and stem cell transplant recipients 
 Patients with renal disease 
 Patients with liver disease 
 Patients with immune-mediated inflammatory disorders (IMID)  
 Immune deficiencies 
 HIV/AIDS  
 Solid organ transplant recipients 
Of note, the criteria for the IC cohorts are subject to change as they will follow the latest 
NHS guidance. The protocol will not be amended to accommodate updates to MHRA 
guidance, but the criteria will be updated accordingly in the study reference manual.  

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The decision to treat patients with sotrovimab will be made prior to and independently
from the decision of enrolling patients into this 
Informed consent form and baseline sample collection will be taken prior to sotrovimab 
administration or if not possible, then either during sotrovimab infusion or as close as 
possible to the end of sotrovimab infusion (within 2 hours of the end of the sotrovimab 
infusion). This study will therefore include patients who have received sotrovimab dosed 
as part of their standard clinical care 
8.2.2. 
Exclusion Criteria 
1. Patients who require hospitalisation (related or not to COVID-19) at baseline 
2. Patients who initiated sotrovimab therapy in inpatient settings 
3. Patients unable to perform nasal/oropharyngeal sample collection 
4. Blinded patients from other COVID-19 related trials 
 
From the Clinical Commissioning Policy, the following groups will also be excluded 
from this study unless also eligible for sotrovimab under other Clinical Commissioning 
Policy IC criteria not listed below [NHS England, 2022]: 
 
5. Cohort of patients with rare neurological conditions 
6. 
 
7. In the cohort of patients with renal disease: 
o Patients with chronic kidney stage (CKD) 4 or 5 (an eGFR less than 
30 ml/min/1.73m2) without immunosuppression (patients with renal disease 
cohort) 
8. In the cohort of patients with liver disease:  
o Patients with cirrhosis 
-Pugh class A who are not on immune 
suppressive therapy (compensated liver disease), 
-Pugh class B or C 
(decompensated liver disease) 
8.3. 
Variables 
8.3.1. 
Exposure Definitions 
Sotrovimab XevudyTM, dose and administration per standard of clinical care 
8.3.2. 
Outcome definitions 
8.3.2.1. 
Primary Endpoint (Primary Objective) 
1. Proportion of patients eligible for sequence analysis that have any AA change 
from baseline in the epitope of sotrovimab binding in samples collected at Day 7, 
14 and 28 (+/-2 days) (Primary Objective 1)  
2. Proportion of patients eligible for sequence analysis that have any AA change 
from baseline in the spike protein in samples collected at Day 7, 14 and 28 (+/-2 
days) (Primary Objective 2)  
 
 
Primary Endpoint (Primary Objective)

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Laboratory process
Samples will be dispatched by sites (baseline sample) and patients or HCPs if patients are 
hospitalised (follow-up samples) to a central analytical laboratory which will follow its 
own procedures for sequencing techniques.   
Sequence analysis of the SARS-CoV-2 spike gene will be attempted on swab samples 
from all participants eligible for sequence analysis. Viral load will also be measured for 
all samples. Changes in the spike protein that arise following treatment will be 
determined by comparing baseline and post-baseline sequencing data for a given patient. 
More detailed information will be available in the overarching study laboratory manual.  
8.3.2.2. 
Secondary Endpoints 
1. Proportion of patients eligible for sequence analysis with SARS CoV-2 VOC or 
VUI on the earliest possible sample (Secondary Objective 1)  
 Variant identification, pango lineage and AA changes in VOC and VUI in 
addition to their defining mutations will be reported 
2. Proportion of patients with undetectable virus at Day 7, 14 and 28 (+/-2 days) 
(Secondary Objective 2)  
3. Clinical outcomes through Day 28 post sotrovimab treatment (Secondary 
Objective 3):  
 Proportion of all cause hospital admissions and related to COVID-19 
 Proportion of patients requiring new or increased oxygen support 
(supplemental oxygen [not high flow], non-invasive ventilation or high-
flow, invasive mechanical ventilation or Extracorporeal membrane 
oxygenation [ECMO]) 
 Proportion of all cause ICU admissions 
 Proportion of all cause deaths and COVID-19 related deaths 
4. AA (detected at >5% allelic frequency) changes in the SARS-CoV-2 spike protein 
in samples collected at Day 7, 14 and 28 (+/-2 days) compared to baseline 
following sotrovimab administration for samples with viral loads above the 
threshold of the sequencing assay (Secondary Objective 4)  
5. AA changes in the SARS-CoV-2 spike consensus sequences from baseline in 
samples where viral load is insufficient for >5% allelic frequency analysis but 
sufficient to generate consensus level sequencing data (Secondary Objective 5)  
Of note, exploratory endpoints will be defined and pre-specified in the statistical analysis 
plan (SAP).  
8.3.3. 
Confounders and Effect Modifiers 
8.3.3.1. 
Patients Characteristics 
Demographic (at baseline) 
 Age (year) 
 Age range: 18-64; 65-74; 75-
 
 Sex 
Secondary Endpoints

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 Current smoking status (Yes = current smoker, No = ex-smoker, never smoker), 
 Ethnicity 
 Body mass index (BMI) (kg/m2): <18.5; 18.5-24.9; 25-29.9; 30-34.9; 35-39.9; 40 
Comorbidities (at baseline) see Section 8.4 for data source and collection 
 Immunocompromising condition 
o The specific conditions will be grouped by set of immunocompromising 
conditions for analytic purposes 
 
2) 
2) 
 Cardiovascular disease (including congenital heart disease) or hypertension 
 Cerebrovascular disease 
 Chronic obstructive pulmonary disease (COPD) 
 Asthma 
 Other chronic respiratory disease (moderate-to-severe), interstitial lung disease, cystic 
fibrosis and pulmonary hypertension 
 Chronic kidney disease and stage  
 Chronic liver disease 
 Diabetes mellitus (DM)  
 Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that 
confer medical complexity (for example, genetic or metabolic syndromes and severe 
congenital anomalies)  
 Pregnancy  
 Sickle cell disease  
 Having a medical-related technological dependence (e.g. tracheostomy, gastrostomy, 
or positive pressure ventilation [not related to COVID 19]) 
 Other 
Disease characteristic (at baseline) 
 Duration of COVID-19 symptoms (days) prior to receiving sotrovimab 
 Previous SARS-CoV-2 infection 
 Serostatus, if available, test used (i.e. assay manufacturer; test for antibodies to spike 
protein or test for nucleocapsid protein or other) and date 
Co-medication (data collected at baseline and follow-up time points) 
 Related to SARS-CoV-2 infection 
o Corticosteroids (inhaled, systemic) 
o Remdesivir 
o IL-6 inhibitors 
o Other mAbs (casirivimab and imdevimab, or other agents if licensed during 
the study period) 
o Antivirals (molnupiravir, nirmatrelvir and ritonavir, other) 
o Others following national guidance 
o Experimental drugs  
 

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 Non-related to SARS-CoV-2 infection (e.g. immunosuppressant treatment) 
COVID-19 vaccination status (data collected at baseline and follow-up time points) 
 Number of vaccinations, date (month) and brand of each vaccination  
8.4. 
Data Sources 
After obtaining informed consent, inclusion/exclusion and baseline patient characteristics 
and treatment history data will be collected and documented. Any initial AEs observed 
during sotrovimab treatment (e.g., infusion-related reaction), completion of baseline 
nasal/oropharyngeal sample and dispensing of at home lab kits to the patient will be 
completed and documented prior to patient discharge. Any baseline patient characteristics 
or treatment history unable to be collected during the baseline visit can be collected 
retrospectively directly 
up period. Patients will receive a phone call at Day 7, 14 and 28 (+/- 2 days) to collect 
follow-up clinical and safety outcomes information, any new or changes in co-
medications/ vaccination status, with a reminder for completion of at home 
nasal/oropharyngeal sample collection at the required timepoints. Participating sites may 
also contact patient
 HCPs for clinical and safety outcomes data as required. All 
baseline and follow-up data will be recorded in the eCRF. 
Virology (viral load and viral sequencing) data will be reported following the central 
analytical laboratory analysis of baseline, day 7, 14 and day 28 (+/-2 days) 
nasal/oropharyngeal samples as detailed in the SAP. 
(For patients progressing to severe COVID-19 and being hospitalised  see Section 8.1) 
8.5. 
Study Size 
The primary endpoints are the proportion of patients eligible for sequence analysis that 
have any AA change from baseline i) in the epitope of sotrovimab binding and ii) in the 
spike protein at Day 7, 14 and 28 (+/-2 days). The AA changes from baseline in the spike 
protein will be submitted to MHRA at the individual-patient level as part of ongoing 
surveillance reporting. Precision around the estimates of the primary endpoints will help 
to define the target sample size. No prior information about these precise endpoints is 
available, and the closest comparable available data are derived from the COMET-ICE 
clinical trial (i.e. conducted in immunocompetent patients with co-morbidities). 
Preliminary analyses of these sequencing data reported: 
- 
The percentage of sotrovimab treated patients that had treatment emergent AA 
changes detected in the epitope of sotrovimab binding at the consensus 
sequencing level was approximately 20% (when emergent changes were defined 
at 5% allelic frequency), and approximately 9% (when defined at 15% frequency) 
- 
The percentage of sotrovimab treated patients that had emergent AA changes 
more broadly across the spike protein was approximately 80% and 52% (defined 
at 5% and 15% allelic frequency respectively). 
A higher prevalence is expected in IC patients.  

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Precision calculations based on this information, and some additional values, are 
presented below (output from the software PASS (NCSS, LLC, Version 19.0.1). They 
show that, for example: 
 If 50% of patients with AA changes that meet the criteria for the variable of 
interest (i.e. the estimated percentage that gives the widest confidence interval 
(CI)) is observed, then a sample size of 500 patients will give reasonable precision 
around the estimate (95% CI 45.5%-54.5%). 
 If 9% of patients that meet the criteria is observed, a target sample size of 500 
patients will also yield reasonable precision around the estimate (95% CI 6.7%-
11.9%).  
Table 2 
Numerical Results for Two-Sided Confidence Intervals for One 
Proportion  Confidence Interval Formula: Score with Continuity 
Correction [Fleiss, 2003; Newcombe, 1998] 
Confidence 
Level 
Sample 
Size (N) 
Actual 
Width 
Proportion 
(P) 
Lower 
Limit 
Upper 
Limit 
0.950 
500 
0.041 
0.050 
0.033 
0.074 
0.950 
500 
0.052 
0.090 
0.067 
0.119 
0.950 
500 
0.055 
0.100 
0.076 
0.131 
0.950 
500 
0.078 
0.250 
0.213 
0.291 
0.950 
500 
0.089 
0.500 
0.455 
0.545 
0.950 
500 
0.089 
0.520 
0.475 
0.564 
0.950 
500 
0.072 
0.800 
0.762 
0.834 
0.950 
500 
0.065 
0.850 
0.815 
0.880 
 
Confidence level is the proportion of cIs (constructed with this same confidence level, sample size, 
etc.) that would contain the population proportion. 
 
N is the size of the sample draw from the population. 
 
Width is the distance from the lower limit to the upper limit. 
 
Actual width is the value of the width that is obtained from the procedure. 
 
Proportion (P) is the assumed sample proportion. 
 
Lower Limit is the lower limit of the CI. 
 
Upper Limit is the upper limit of the CI. 
Using an estimate of 20% of patients being lost to follow-up, the plan will be to increase 
recruitment up to 625 patients to meet the target sample size of 500. It is also anticipated 
that in some patients, the viral load in samples collected at days 7, 14, and 28 (+/-2 days) 
will be too low for determination of the variable of interest. While undetectable viral load 
is a goal for treatment, this would further reduce the number of patients contributing to 
the assessment of the primary endpoint. Nonetheless, there remains adequate precision if 

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there are fewer patients contributing to analyses at day 7, for example (e.g. if there were 
400 patients with a detectable viral load and 50% had AA changes that meet the criteria 
of interest, then the precision would be 95% CI 45.0-55.0%).  
As a sentinel surveillance study, the aim will be to collect 500 (and up to 625) patients 
over the course of a year across the GB to meet the target sample size. Flexible enrolment 
caps per site and per month may be considered. The aim is to ensure continuous 
enrolment with appropriate geographical representation over the 12-month study period, 
to reflect the fast evolving COVID-19 pandemic. In addition, the target sample size will 
be re-assessed after the first 200-300 patients are enrolled in regard to progression 
towards achieving the primary objective, with the potential to decrease or increase the 
target number accordingly. 
8.6. 
Data Management 
Data collection and data source is described in Section 8.4. 
 All participant data relating to the study will be recorded on eCRFs 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 eCRFs will be provided in 
eCRF completion guidelines. 
 The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process including systems used can be found in the study 
Data Management Plan (DMP) or equivalent contract research organisation (CRO) 
document. 
 The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organisations [CROs]). 
More granular level process for data management will be described in the overarching 
study DMP. 
8.6.1. 
Timings of Assessment during Follow-up 
Patients will be followed for 28 days from the time they received sotrovimab treatment 
(index date (D0)) in one of the clinical sites. Data and samples will be collected following 
the schedule below (see also Table 1):  
 Day 0 On-site screening: 
o Confirmation that decision to administer sotrovimab (per standard of clinical 
care) has been made by the treating HCP 
o Informed consent and enrolment 
o Baseline sample collection under supervision after training 
(nasal/oropharyngeal) prior to sotrovimab administration or if not possible, 
then either during sotrovimab infusion or as close as possible to the end of 
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Data collection of patient and disease characteristics (e.g. demographic, 
medications and comorbidities) when possible 
o Three sample collection kits must be provided to the patient for home 
collection at each follow up timepoints (D7, D14, D28 [+/-2days]), with 
subject identification present on each kit (as per guidance in the study 
reference manual).  
 Day 7 +/-2 days 
o Phone call: Data collection of clinical outcomes and any treatment related 
AEs reported by the patient, concomitant medications if any changes 
o Follow-up sample collection (nasal/oropharyngeal)  Home kit 
o Retrospective collection of baseline data with the patient or directly with 
patient HCP when not possible at Day 0 
 Day 14 +/-2 days  
o Phone call: Data collection of clinical outcomes and any treatment related 
AEs reported by the patient, concomitant medications if any changes 
o Follow-up sample collection (nasal/oropharyngeal)  Home kit 
o Retrospective collection of baseline data with the patient or directly with 
patient HCP when not possible at Day 0 
 Day 28 +/-2 days 
o Phone call: Data collection of clinical outcomes and any treatment related 
AEs reported by the patient, concomitant medications if any changes 
o Follow-up sample collection (nasal/oropharyngeal)  Home kit 
o Retrospective collection of baseline data with the patient or directly with 
patient HCP when not possible at Day 0 
For patients progressing to severe COVID-19 and being hospitalised  see Section 8.1. 
The follow-up of patients with a persistent positive sample at the end of the study period 
(i.e. Day 28) is described in Section 8.7.2 as an exploratory analysis. Persistent positive 
results will be reported back to the sites upon site request (as described in the study 
reference manual).  
8.7. 
Data analysis 
8.7.1. 
Essential Analysis 
This study is descriptive. Categorical variables will be described using counts, 
proportions and 95% CI and continuous variables will be described using measures of 
central tendency (e.g. mean, interquartile range, etc.) 
8.7.1.1. 
Primary Objective 
 
Sequencing of samples on a regular basis (as detailed in the study laboratory 
manual ) is required.  
 
The primary analysis of data will include:  
 
Proportion of patients eligible for sequence analysis that have any AA 
change from baseline in the epitope of sotrovimab binding 

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Proportion of patients eligible for sequence analysis that have any AA 
change from baseline in the spike protein  
 
More details on any sub-analyses performed by sub-groups will be described in 
the SAP. 
8.7.1.2. 
Secondary Objective 
 
VOC, VUI and other lineages information as classified by UKHSA and WHO 
will be identified from sequencing data for patients eligible for sequencing 
analysis (Secondary Objective 1) 
o This analysis will be done on the earliest possible sample and reported 
only once per patient as described in the SAP 
 
Comorbidities, clinical outcomes, patients with undetectable SARS-VoV-2 viral 
ribonucleic acid and safety events data will be described and reported with counts 
and proportions with a 95% CI (Secondary Objective 2 and 3). 
 
AA (detected at >5% allelic frequency) changes in the SARS-CoV-2 spike protein 
in samples collected at Day 7, 14 and 28 (+/-2 days) compared to baseline 
following sotrovimab administration for samples with viral loads above the 
threshold of the sequencing assay (Secondary Objective 4)  
 
 
 AA changes in the SARS-CoV-2 spike consensus sequences from baseline in 
samples where viral load is insufficient for >5% allelic frequency analysis but 
sufficient to generate consensus level sequencing data (Secondary Objective 5) 
 
8.7.2. 
Exploratory Analysis 
1. Describe viral characteristics (e.g. viral load, VOC/VUI, AA changes) in patients 
who subsequently require hospital admission or die due to COVID-19 post 
sotrovimab treatment  
2. Establish whether changes in AA from baseline identified in the SARS-CoV-2 
spike protein are reported sequences in the genomic databases (e.g. GISAID)  
 
8.7.3. 
General Considerations for Data Analyses   
More granularity for data analyses and reporting will be available in the overarching 
project SAP. 
 
8.7.4. 
Interim Analysis 
An interim analysis is planned to be conducted to support regulatory health authority post 
authorisation commitments. The analysis aims to assess the primary and secondary 
objectives and is due in Q2 2023. For details about the analysis refer to the SAP. 

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8.8. 
Quality control and Quality Assurance 
To ensure compliance with all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit. See Section 8.8.5 for more details regarding the audit 
process.  
8.8.1. 
Data Quality Assurance 
Syneos Health and GSK are responsible for following standard operating procedures 
(SOPs) to ensure data quality and integrity, including archiving of statistical programs, 
appropriate documentation of data cleaning and validity for created variables, and 
description of available data. All sites will be trained by the Site Management Associate 
(SMA) on the protocol, study logistics, and the EDC system.  
Veeva Vault CDMS (Clinical Data Management System) will be the EDC system used to 
manage data collection during this study; it is a software tool designed to ensure quality 
assurance and facilitate data capture during clinical studies. All participant data relating 
to the study will be recorded on electronic CRF unless transmitted to the sponsor or 
designee electronically (e.g., laboratory data). The investigator is responsible for ensuring 
prospective data is entered in a timely manner and verifying that data are accurate and 
correct by physically or electronically signing the eCRF. Guidance on completion of 
CRFs will be provided in the eCRF Guidelines. 
On-line logic checks will be built into the EDC system as much as possible, so that 
missing or illogical data are not submitted. In the event that inconsistent data persist, 
queries may be issued electronically to the clinical study site and answered electronically 
by the study site personnel. 
8.8.2. 
Access to Source Data/Documents 
The Investigator will allow Sponsor representatives, contract designees, authorised 
regulatory authority inspectors, and Independent Ethics Committee (IEC) to have direct 
access to all documents pertaining to the study. 
8.8.3. 
Archiving Study Documents 
Essential clinical documents will be maintained to demonstrate the validity of the study 
and the integrity of the data collected. All study materials will be returned to the Sponsor 
after the study has been completed. 
Master files should be established at the beginning of the study, maintained for the 
duration of the study and retained according to the appropriate regulations. According to 
International Council on Harmonisation (ICH) guidelines, essential documents should be 
retained for a minimum of 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
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8.8.4.
Study Monitoring
Subject data will be monitored using a risk-based approach, with remote monitoring 
being preferred to reduce burden on sites. The monitoring strategy will be documented in 
the study Site Management (monitoring) Plan and will include flexibility in approach to 
account for COVID-19 restrictions that may change during the study.  
8.8.5. 
Audits and Inspections 
Responsible IEC/Competent Authority and/or the 
group, or its designee, may request access to all source documents, case report forms, and 
other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times 
for these activities. 
8.9. 
Limitations of the Research Methods 
Strengths of the proposed study include its prospective design, which provides clear 
temporal information, and use of advanced laboratory methods to describe AA changes in 
viral genetic sequence in an IC population that is at risk for both poor clinical outcomes 
and the development of novel substitutions, deletions or insertions in the spike protein of 
SARS-CoV-2 virus. 
There are several limitations to the interpretation of the results of this study, summarised 
below: 
Design 
This surveillance study will aim to monitor the emergence of changes in spike protein 
over time following the administration of sotrovimab. The aim will be to monitor the 
changes in the entire spike protein, but some substitutions, deletions or insertions of 
concern may occur outside of the spike. All changes that are identified in the SARS-
CoV-2 spike protein will be recorded and reported per the SAP. 
Selection bias 
Since patients who are hospitalised for non-COVID-19 reasons or who are unable to 
collect nasal/oropharyngeal swabs will be excluded, there is a possibility of selection bias 
in recruiting a somewhat healthier population. However, it is expected that the impact on 
the primary outcome will be minimal. Immunosuppressed status, regardless of 
hospitalisation status, should be the main factor impacting the AA changes in the spike 
protein. Since the study will enrol a range of highly IC patients, selection bias should be 
minimal. 
Testing procedures 
The baseline sample will be a nasal/oropharyngeal swab collected on site and supervised 
by a HCP, while pragmatic, patient-focused solutions will ask study participants to 

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collect their follow up samples at 7-, 14- and 28-days using home test kits. Study staff 
will not be able to verify whether samples are collected and handled properly, which may 
impact the sensitivity of subsequent sequencing testing of patient samples. However, this 
collection approach was weighed against asking COVID-19 positive, IC people having to 
seek testing outside their residence. Self-collected nasal/oropharyngeal swabs have 
demonstrated comparable sensitivity and good viral load correlation to clinician collected 
nasopharyngeal swabs (considered as the gold standard) for SARS-CoV-2 detection 
[Kojima, 2021; Alemany, 2021]. The patients will also be trained to increase chances of 
getting the appropriate samples. Finally, nasopharyngeal swabs generally should not be 
done in patients with significant thrombocytopenia or bleeding disorders, which some of 
this IC population would likely have. 
Distribution of virus across the respiratory tract may vary between patients. Therefore, an 
infected patient may have detectable virus in sputum but not in nasal/oropharyngeal 
swabs. This limitation and the potential for false negative results when using 
nasal/oropharyngeal swabs are acknowledged. Regular re-assessments of the sample 
collection strategy to ensure the appropriate capture of the primary outcome will be 
planned. 
Loss to follow up 
Although the duration of follow up is relatively short (28 day +/- 2 days) all data will be 
collected remotely, and samples will be provided by post and relies on patient compliance 
with protocol procedures. It is expected that there may be challenges obtaining follow up 
information and samples from enrolled patients. Clinical sites will proactively contact 
patients on at least 3 occasions over a period of 4 days (+/- 2 days from expected date) in 
order to reduce loss to follow-up. Reasons for loss-to-follow-up will be recorded in the 
eCRF if available. Attempts will also be made by the study staff to contact or follow-up 
patients if they are admitted to the hospital. 
 
In evaluating clinical outcomes and safety events at later time points, it is possible that 
loss to follow up will be differential, with patients experiencing adverse clinical 
outcomes or safety events either more or less likely to maintain contact with study staff.  
In the presence of differential loss to follow up, the data from participants who remain 
under observation would be biased for related outcomes. Substantial baseline 
characteristic data on patients should be available to quantitatively evaluate whether there 
are significant differences between patients lost to follow-up and patients with complete 
follow-up.  
Geographical coverage 
The geographical coverage will be limited to the sentinel sites that agree to participate in 
this study. The identification of viral variants in the IC patients may not be generalisable 
to all parts of GB. 
Duration of follow-up 

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Concerns about the development of novel viral variants resulting from infections in 
immunosuppressed patients are based in part on the tendency of these patients to develop 
prolonged infections.  The proposed design may not be able to detect the development of 
these variants if they develop later in the course of a prolonged infection (>28 days), or if 
they fail to rise above the threshold of detection for the sequencing assay. The feasibility 
of linkage with routinely collected samples (as per standard of clinical care) for spike 
protein monitoring in patients who remain SARS-CoV-2 positive beyond Day 28 will be 
explored (see Section 8.7.2).  
Role of Sotrovimab 
Immunosuppressed populations are of particular concern for the development of novel 
variants because of their tendency to develop prolonged infections, which can expose 
SARS-CoV-
 (or therapeutic antibodies or donor-derived 
antibodies in normal human immunoglobulin products) without viral clearance and create 
selective pressure for viral mutations allowing for immune evasion. This patient 
population is of public health interest for sentinel surveillance in the detection of variants 
of interest and concern, and the proposed study will contribute valuable information to 
the effort being undertaken by UKHSA.  However, the lack of an untreated comparator 
group in the proposed study design means that it will not allow for any meaningful 
inference into the association between treatment with sotrovimab and the development of 
novel viral mutations. Genomic databases (e.g. GISAID) will be used to contextualise the 
changes in AA from baseline that are identified in the SARS-CoV-2 spike protein in this 
study. 
8.10. 
Study Closure/Uninterpretability of Results 
Information Bias 
Relying on investigators to fill out the assessment forms might induce the presence of 
missing data, which can result in bias. Entry of prospectively collected data into eCRFs 
will minimise missing or incorrect data by having automated queries. Clear instructions 
and engagement with the study staff with appropriate training will minimise the amount 
of missing data. 
Rules about how missing data will be handled will be included in the SAP.  
Patients Lost to Follow-up or without Follow-up Data 
See Section 8.9 
8.11. 
Other Aspects 
Not Applicable 

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9.
PROTECTION OF HUMAN SUBJECTS
9.1. 
Ethical Approval and Subject Consent 
9.1.1. 
Regulatory and Ethical Considerations  
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki (version 2008) and applicable legal and regulatory requirements 
and related guidances, especially Directive 2001/83/EC, Regulation (EC) No 726/2004 
(REG) and Commission Implementing Regulation (EU) No 520/2012 (IR) as detailed in 
Good Pharmacovigilance Practices (GVP) Modules V, VI and VIII.  
It is the responsibility of GSK and the Investigators to have prospective approval of the 
study protocol, protocol amendments, and other relevant documents (e.g., ICFs), if 
applicable, from the IEC/Competent Authorities. Any necessary extensions or renewals 
of IEC approval must be obtained for changes to the study such as amendments to the 
protocol, the ICF, or other study documentation. 
The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IEC 
 Notifying the IEC of SAE or other significant safety findings as required by IEC 
procedures 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines (if applicable), the IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations 
9.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
9.1.3. 
Informed Consent Process  
Informed consent will be obtained from all patients before enrolment into the study. Each 
investigator will ensure that each patient who needs to provide informed consent is given 
full and adequate oral and written information about the nature and purpose of the study. 
The patient will be given the opportunity to ask questions and allowed time to consider 
the information provided. All parties will ensure protection of participant personal data 
and will not include names on any sponsor forms, reports, publications, or in any other 
disclosures, except where required by the local laws and regulations.  

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The signed and dated informed consent must be obtained before any study procedures 
including sample collection or data entry into the eCRF. The investigator must store the 
original, signed ICF. A copy of the signed ICF must be given to the patient. If the patient 
decides not to participate, the reason will be collected in the eCRF. The option of using e-
Consent will be explored and the process by which consent is collected will be updated as 
needed and provided to sites via other means. 
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 authorised 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. 
GS
and other information to carry out this study; understand the results of this study; learn 
more about sotrovimab or about the study disease; 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. 
9.2. 
Participant Withdrawal 
Participation in this study is voluntary and patients may withdraw from the study at any 
time without prejudice. If the patient withdraws or is withdrawn, the reason will be 
collected in the eCRF. The ICF will explain that in case of withdrawal, all study data 
collected before withdrawal will be kept in the study database. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. If a 
participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
The process of managing subject samples collected but not analysed at the time of 
withdrawal will be managed following the process as described in the study reference 
manual. The Sponsor reserves the right, at any time, to discontinue enrolment of 
additional patients into the study, at any site; or to discontinue the study, for medical or 
administrative reasons. 
9.3. 
Subject Confidentiality 
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation in the UK. The participant must be informed that his/her personal study-
related data will be used by the sponsor 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. 

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The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IEC members, and by inspectors from regulatory authorities. 
10. 
LEGAL BASIS FOR PROCESSING INDIVIDUAL HUMAN 
DATA 
Study Use means the use of IHD is as stated in the original study protocol and/or aligned 
with the informed consent form to answer the study objectives and satisfy regulatory 
requirements and learn more about the product studied and the disease/condition studied. 
This includes bringing the product to market or maintaining market access which 
includes working with government agencies, insurers or health care payers and aiding 
ficacy, safety, or effectiveness of the product. 
11. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
11.1. 
Key Definitions 
This study adopts the following ICH definitions: 
Adverse event: Any untoward medical occurrence in a patient, or clinical investigation 
subject, administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. 
 An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding) symptom or disease (new or exacerbated) temporally 
associated with the use of a Medicinal Product including those used in combination 
with a medical device.  For a marketed Medicinal Product, this can also include 
failure to produce expected benefits (i.e. lack of efficacy, with or without an AE), and 
AEs associated with circumstances of Overdose whether accidental or intentional, 
Medication Errors, Abuse or effects of drug withdrawal, or Misuse or those related to 
a deficiency occurring with a medical device or combination product.  
Adverse Drug Reaction (ADR): A response to a medicinal product which is noxious 
and unintended. Response in this context means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a 
medicinal product and an occurrence is suspected. 
Serious adverse event: any untoward medical occurrence that at any dose that 1) results 
in death, 2) is life threatening, 3) requires inpatient hospitalisation or prolongs existing 
hospitalization, 4) results in persistent or significant disability/incapacity or 5) is a 
congenital anomaly. 
Spontaneous events:  
 Those AEs observed related to the GSK product under evaluation but exempted from 
collection, if justified, are reported as spontaneous events.  

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 Those AEs observed related to any other GSK product (not under evaluation)are 
reported as spontaneous events.  
 If any ADRs are observed related to drug product(s) not related to the Sponsor 
(GSK), the Investigator should report the ADRs to the appropriate marketing 
authorisation application of the product(s) or Health Authority per local regulations. 
More detailed definitions of AE types are provided in the SMP. 
The Investigator or Sponsor must provide a causality assessment regarding the 
relationship of any AE to the medicinal product. 
Further details of the causality assessment can be provided in the protocol or the reader 
can be referred to the SMP. 
11.2. 
Collection of adverse events/reactions 
Adverse events (serious and non-serious) will be collected following the administration 
of sotrovimab if considered related to sotrovimab. Events should only be collected if they 
are 
Safety data will 
be collected by the study research HCP on site at baseline and by phone at Day 7, 14 and 
28 (+/-2 days). Only safety events related to sotrovimab will be collected. The study 
population is likely to have many comorbidities and AEs may be symptoms of their 
underlying diseases. 
As they are not related to study objectives, spontaneously captured AEs related to other 
GSK products, or non-GSK products, are not systematically collected, but are reported 
(see adverse event reporting in Section 11.3 below).  
11.3. 
Reporting of adverse events/reactions 
All AEs (serious and non-serious) systematically collected and considered causally 
related to sotrovimab will be entered into the CRF, as well as pregnancy exposures, and 
should be reported to the GSK Case Management Group. These will be classified as 
individual case safety reports (ICSRs). Reporting process and timelines are provided in 
the SMP. 
AEs related to any other GSK product, will be classified as spontaneous reports and 
reported to the Safety department as such. 
HCPs (and any study vendor) can report these spontaneous adverse reactions to GSK via 
the following web link:  
https://www.gsk.com/en-gb/contact-us/report-a-possible-side-effect/  
Adverse reactions related to non-GSK product, will also be classified as spontaneous 
reports. Healthcare professionals (and any study vendor) will be informed of the 
possibility to report these spontaneous adverse reactions to the marketing authorisation 
holder of the suspected medicinal product (studied or not) OR to the concerned 
competent authority via the national spontaneous reporting system.  

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It is the responsibility of the Sponsor of the product in question rather than the 
Investigator to report these spontaneous ADRs to the Regulatory Authorities according to 
applicable regulations.   
11.4. 
Safety collection and reporting study documentation 
A Safety Management Plan (SMP) will be developed for the study and will provide 
detailed information on the study specific pharmacovigilance processes and procedures.  
 
This plan will include the following elements to ensure a comprehensive approach to 
safety event collection and reporting:  
 
Supplier pharmacovigilance training 
 
Investigator and site staff pharmacovigilance training  
 
Safety-specific roles 
 
AEs collection, pregnancy exposures and reporting processes 
 
Health safety information (HSI) collection processes 
 
Causality assessment 
 
HSI Reporting processes 
 
HSI reporting tools/forms Frequency of data review 
 
Reviewing and reporting results  
 
Interim reports 
 
PVP oversight process 
 
Provision of final study report 

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
GSK and/or a designated party will prepare safety and other summary reports, as required 
by the appropriate regulatory authority. In addition, these data may be summarised 
periodically for presentation at professional conferences and sessions, as appropriate. 
GSK is responsible for presentations and/or publications. For studies that are fully or 
partially conducted by investigators who are not employees of the GSK group of 
companies, GSK and the investigator should agree in advance a publication policy 
allowing the principal investigator to independently prepare publications based on the 
study results irrespective of data ownership. GSK should be entitled to view the results 
and interpretations included in the manuscript and provide comments prior to submission 
of the manuscript for publication. Results from this study will be submitted for 
publication in international peer-reviewed journals and will be disseminated 
appropriately to inform MHRA and other regulatory agencies, public health guidance and 
risk assessment, as well as to relevant expert clinical groups. Any public reporting will 
contain aggregate data and will avoid any risk of deductive disclosure. 

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13.
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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Contact details of all Investigators participating in the study will be kept in stand-alone 
documents.