Conditions: COVID-19
Keywords: SARS CoV-2 LUNAR Coronavirus disease 2019 (COVID-19) Pandemic Sotrovimab Monoclonal antibody Immunocompromised (IC)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 217
Healthy volunteers: no

Brief summary:
Sotrovimab binds to a conserved epitope on the severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 spike protein outside the receptor-binding motif and has been shown to reduce the risk of hospitalization and/or death when administered as early treatment in non-hospitalized patients that are at risk for progression to severe disease. Immunocompromised (IC) patients are prioritized to receive early treatment for COVID-19 as they are at high risk of disease progression, and because of their potential for prolonged viral shedding and the resulting increased risk of emergent viral 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 participants receiving sotrovimab as standard of clinical care in sentinel sites at a national level to assess potential emergence of viral variants.

Detailed description:

Arms:
arm 1: Immunocompromised non-hospitalized participants will receive sotrovimab as standard of clinical care for COVID-19 in sentinel sites

Interventions: intervention 1: Sotrovimab
Intervention descriptions: intervention 1: Sotrovimab dose and administration per standard of clinical care

Protocol document:
Prot_000.pdf: 
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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 
PPD


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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 
patients, demonstrated 79% reduction in disease progression to hospitalisation or death 


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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 
and 28 (+/-2 days) 


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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 
sotrovimab infusion (within 2 hours of the end of the sotrovimab infusion). 


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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 
development of the study treatment. 


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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.
REFERENCES
Alemany, A., Millat-Martinez, P., Ouchi, D., Corbacho-Monné, M., Bordoy, A. E., 
Esteban, C., ... et al.. (2021). Self-collected mid-nasal swabs and saliva specimens, 
compared with nasopharyngeal swabs, for SARS-CoV-2 detection in mild COVID-19 
patients. Journal of Infection. 
Aydillo, T., Gonzalez-Reiche, A. S., Aslam, S., van de Guchte, A., Khan, Z., Obla et al. 
(2020). Shedding of viable SARS-CoV-2 after immunosuppressive therapy for 
cancer. New England journal of medicine, 383(26), 2586-2588. 
Cathcart, A. L., Havenar-Daughton, C., Lempp, F. A., Ma, D., Schmid, M., Agostini et 
al. (2022). The dual function monoclonal antibodies VIR-7831 and VIR-7832 
demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv. Updated 
18 February 2022. 
https://urldefense.com/v3/__https://www.biorxiv.org/content/10.1101/2021.03.09.434607
v11__;!!AoaiBx6H!nWLodTlcgzyrNFhdkTeeggUVExPJzTPo9PSLv7X71XQRqXuaiJka
L1XP8NXHikBi$ Last accessed 18 February 2022. 
Chodick, G., Tene, L., Rotem, R. S., Patalon, T., Gazit, S., Ben-Tov et al. (2021). The 
effectiveness of the TWO-DOSE BNT162b2 vaccine: analysis of real-world 
data. Clinical Infectious Diseases. 
Di Fusco, M., Moran, M. M., Cane, A., Curcio, D., Khan, F., Malhotra et al. J. L. (2021). 
Evaluation of COVID-19 vaccine breakthrough infections among immunocompromised 
patients fully vaccinated with BNT162b2. Journal of Medical Economics, 24(1), 1248-
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GlaxoSmithKline UK. Xevudy 500 mg concentrate for solution for infusion. Summary of 
Product Characteristics. May 2022. 
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Embi, P. J., Levy, M. E., Naleway, A. L., Patel, P., Gaglani, M., Natarajan et al. (2021). 
Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-
19 Associated Hospitalizations Among Immunocompromised Adults
Nine States, 
January September 2021. Morbidity and Mortality Weekly Report, 70(44), 1553. 
Fleiss, J. L., Levin, B., Paik, M.C. 2003. Statistical Methods for Rates and Proportions. 
Third Edition. John Wiley & Sons. New York. 
GOV.UK. UK. Summary | Coronavirus (COVID-19) in the UK. 
https://coronavirus.data.gov.uk/ 18 February 2022. Last accessed 18 February 2022.  
Gupta A, Gonzalez-Rojas Y, Juarez E. Effect of the Neutralizing SARS-CoV-2 Antibody 
Sotrovimab in Preventing Progression of COVID-19: A Randomized Clinical Trial. 2021. 
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Harvey W.T, Carabelli A.M, Jackson B et al. SARS-CoV-2 variants, spike mutations 
and immune escape. Nature Reviews Microbiology volume 19, pages 409 424 (2021) 
Hippisley-Cox J, Coupland C.A.C, Nisha Mehta N. et al. Risk prediction of covid-19 
related death and hospital admission in adults after covid-19 vaccination: national 
prospective cohort study BMJ 2021; 374 
Kearns, P., Siebert, S., Gaskell, C., Kirkham, A., Pirrie, S., Bowden et al. (2021). 
Examining the immunological effects of COVID-19 vaccination in patients with 
conditions potentially leading to diminished immune response capacity the OCTAVE 
trial. 
Kojima Self-Collected Oral Fluid and Nasal Swabs Demonstrate Comparable Sensitivity 
to Clinician Collected Nasopharyngeal Swabs for Coronavirus Disease 2019 Detection. 
Clin Infect Dis. 2021 Nov 2;73(9):e3106-e3109.  
Levin AT, Hanage WP, Owusu-Boaitey N, et al. Assessing the age specificity of 
infection fatality rates for COVID-19: systematic review, meta-analysis, and public 
policy implications. Eur J Epidemiol. 2020. Dec;35(12):1123-1138.  
Lewis, N. M., Chu, V. T., Ye, D., Conners, E. E., Gharpure, R., Laws et al.  (2021). 
Household transmission of severe acute respiratory syndrome coronavirus-2 in the United 
States. Clinical Infectious Diseases, 73(7), 1805-1813. 
Lopez Bernal J, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) 
Variant. N Engl J Med. 2021b. NEJMoa2108891. Published online 2021 Jul 21. 
doi: 10.1056/NEJMoa2108891 
Lopez Bernal J, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca 
vaccines on covid-19 related symptoms, hospital admissions, and mortality in older 
adults in England: test negative case-control study. BMJ 2021a. 373: n1088. Published 
online 2021 May 13. doi: 10.1136/bmj.n1088 
Mahase E. Covid-19: UK approves monoclonal antibody sotrovimab for over 12s at high 
risk BMJ 2021; 375 :n2990 doi:10.1136/bmj.n2990 
Newcombe, R. G. 1998. 'Two-Sided Confidence Intervals for the Single Proportion: 
Comparison of Seven Methods.'Statistics in Medicine, 17, pp. 857-872. 
NHS Digital. Coronavirus Shielded Patient List open data set, England 
(https://digital.nhs.uk/dashboards/shielded-patient-list-open-data-set). Last accessed 3 
December 2021. 
NHS England. Coronavirus » Interim Clinical Commissioning Policy: Treatments for 
non-hospitalised patients with COVID-19. 28 November 2022. 
https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2022/11/C1710-
interim-clinical-commissioning-policy-treatments-for-non-hospitalised-patients-with-
covid-19-nov-22.pdf. Last accessed 14 December 2022. 


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NICE Guidelines: COVID-19 rapid guideline: managing COVID-19. Last updated: 01 
December 2021.  https://www.nice.org.uk/guidance/NG191 (last accessed 13 December 
2021). 
Niyonkuru M, Rune Micha Pedersen R.M., Assing K. et al. Prolonged viral shedding of 
SARS-CoV-2 in two immunocompromised patients, a case report. BMC Infectious 
Disease 2021 21:743 (2021) 
Office for National Statistics. Population estimates for the UK, England and Wales, 
Scotland and Northern Ireland: mid-2020 
(https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/popul
ationestimates/bulletins/annualmidyearpopulationestimates/mid2020#the-uk-population-
at-mid-2020). Last accessed 3 December 2021 
Pinto D, Park Y-J, Beltramello M, et al. Cross-neutralization of SARS-CoV-2 by a 
human monoclonal SARS-CoV antibody. Nature 2020;583:290-295. 
Planas, D., Veyer, D., Baidaliuk, A., Staropoli, I., Guivel-Benhassine, F., Rajah et al.  
(2021). Reduced sensitivity of SARS-CoV-2 variant Delta to antibody 
neutralization. Nature, 596(7871), 276-280. 
Pulliam, J. R., van Schalkwyk, C., Govender, N., von Gottberg, A., Cohen, C., Groome et 
al.  (2021). SARS-CoV-2 reinfection trends in South Africa: analysis of routine 
surveillance data. medRxiv. 
Reis, B. Y., Barda, N., Leshchinsky, M., Kepten, E., Hernán, M. A., Lipsitch et al.  
(2021). Effectiveness of BNT162b2 vaccine against delta variant in adolescents. New 
England Journal of Medicine. 
Sheikh, A., Robertson, C., & Taylor, B. (2021). BNT162b2 and ChAdOx1 nCoV-19 
vaccine effectiveness against death from the delta variant. New England Journal of 
Medicine. 
Torjesen I. Covid-19: Omicron may be more transmissible than other variants and partly 
resistant to existing vaccines, scientists 
fear BMJ 2021; 375 :n2943 doi:10.1136/bmj.n2943 
UK Health Security Agency (UKHSA). Interim protocol: Genomic surveillance of 
patients with COVID-19 who are treated with neutralising monoclonal antibody or 
immunosuppressed. 2021. Genomic surveillance of patients with COVID-19 
(publishing.service.gov.uk). Last accessed 13 December 2021. 
UK Health Security Agency (UKHSA). SARS-CoV-2 variants of concern and variants 
under investigation in England Technical briefing 33. 11 February 2022. 
(https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment
_data/file/1054357/Technical-Briefing-36-11February2022_v2.pdf). Last accessed 18 
February 2022 


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Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and 
B.1.1.7. Nature 2021;593:130-135. 
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus 
Disease 2019 (COVID-
From the Chinese Center for Disease Control and Prevention. JAMA. 2020. 
Feb;323(13):1239-1242.  


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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. 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  218407
Official Title of Study: Prospective cohort study to monitor the emergence 
of SARSCoV-2 spike viral variants in immunocompromised nonhospitalised 
patients exposed to sotrovimab in Great Britain: LUNAR study
Date of Document: 18-July-2023 (the latest date has been redacted as PI on 
page 3)


 
 
 
 
 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 1 of 43 
Statistical Analysis Plan for Real World Research Studies 
 
Sponsor Name: GlaxoSmithKline (GSK) 
 
Protocol Number: 218407 
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 
 
Protocol Version and Date: 
Version 01, 04-May-2022 
 
Syneos Health Project Code: 7035538 
 
Authors: 
, Sr Biostatistician 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to GlaxoSmithKline. Acceptance of 
this document constitutes agreement by the recipient that no information contained herein will be 
published or disclosed without prior written authorization from an official of GlaxoSmithKline. However, 
this document may be disclosed to appropriate Institutional Review Board (IRB) and Ethics Committees 
(ECs) or duly authorized representatives of a national regulatory authority under the condition that they 
are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 
PPD


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 2 of 43 
1. Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owners 
Revision Summary 
1.0 
12-Jan-2023 
Initial Release Version (Interim Analysis) 
2.0 
14-Jul-2023 
Updates for Final Analysis 
 
PPD


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 3 of 43 
I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
, Senior Biostatistician 
Name, Title
Lead Biostatistician 
 
Signature 
 
Date (DD-Mmm-YYYY) 
, Mgr, statistical 
Programmer 
Name, Title 
Lead Statistical Programmer 
 
Signature
 
Date (DD-Mmm-YYYY) 
Name, Title 
Senior Reviewing Biostatistician 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 4 of 43 
GlaxoSmithKline Approval 
, Lead Biostatistician 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
 
 
 
 
, Virology Lead 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
, Clinical Science Lead 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
, Scientific Lead, 
Epidemiology 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
, Study Delivery Lead
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 5 of 43 
2. Table of Contents 
1. 
Revision History ................................................................................................................. 2 
Approvals .................................................................................................................................. 3 
1. 
Glossary of Abbreviations ................................................................................................... 7 
2. 
Purpose .............................................................................................................................. 9 
2.1 
Responsibilities ................................................................................................... 9 
2.2 
Timings of Analyses ............................................................................................ 9 
3. 
Study Objectives .............................................................................................................. 10 
4. 
Study Details/Design ........................................................................................................ 11 
4.1 
Brief Description .................................................................................................11 
4.2 
Study Design .......................................................................................................11 
4.3 
Participant Selection ..........................................................................................12 
4.3.1 
Inclusion Criteria ................................................................................................12 
4.3.2 
Exclusion Criteria ...............................................................................................12 
4.4 
Determination of Sample Size ............................................................................12 
4.5 
Treatment Assignment and Blinding .................................................................12 
4.6 
Administration of Study Medication ..................................................................12 
4.7 
Study Procedures and Flowchart ......................................................................13 
5. 
SARS-CoV-2 Genomic Analysis Results Workflow ........................................................... 15 
6. 
Endpoints ......................................................................................................................... 17 
7. 
Analysis Sets .................................................................................................................... 18 
7.1 
Screened Set .......................................................................................................18 
7.2 
Safety Set ............................................................................................................18 
7.3 
Virology Set .........................................................................................................18 
7.4 
Safety Completers Set ........................................................................................19 
8. 
General Aspects for Statistical Analysis ........................................................................... 19 
8.1 
General Methods .................................................................................................19 
8.2 
Key Definitions ....................................................................................................20 
8.3 
Missing Data........................................................................................................20 
8.3.1 
Missing Adverse Events (AE) and Medication Dates .......................................21 
8.4 
Visit Windows .....................................................................................................23 
8.5 
Pooling of Centers ..............................................................................................23 


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 6 of 43 
8.6
Subgroups...........................................................................................................23
9. 
Demographic, Other Baseline Characteristics and Medication ......................................... 24 
9.1 
Subject Disposition and Withdrawals ...............................................................24 
9.2 
Protocol Deviations ............................................................................................24 
9.3 
Demographic and Baseline Characteristics......................................................24 
9.4 
Medical History and Concomitant Diseases .....................................................24 
9.5 
Prior and Concomitant Medication ....................................................................25 
10. 
Efficacy ............................................................................................................................ 25 
10.1 
Primary Efficacy Endpoint and Analysis ...........................................................25 
10.2 
Secondary Efficacy Endpoint and Analysis ......................................................26 
11. 
Safety ............................................................................................................................... 28 
11.1 
Adverse Events ...................................................................................................28 
11.2 
Vital Signs ...........................................................................................................29 
12. 
Programming Considerations ........................................................................................... 29 
12.1 
General Considerations .....................................................................................29 
12.2 
Table, Figures, and Listing Format ....................................................................29 
12.2.1 
General ................................................................................................................ 29 
12.2.2 
Headers ................................................................................................................ 30 
12.2.3 
Display Titles ........................................................................................................ 30 
12.2.4 
Column Headers .................................................................................................. 31 
12.2.5 
Body of the Data Display ..................................................................................... 31 
12.2.6 
Footnotes ............................................................................................................. 33 
13. 
Quality Control ................................................................................................................. 33 
14. 
Index of Tables ................................................................................................................. 35 
15. 
Index of Figures................................................................................................................ 40 
16. 
Index of Listings ............................................................................................................... 41 
17. 
Shells ............................................................................................................................... 43 
17.1 
Table Shells .........................................................................................................43 
17.2 
Figure Shells .......................................................................................................43 
18. 
Appendices ...................................................................................................................... 43 


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 7 of 43 
1. 
Glossary of Abbreviations 
Abbreviation 
Description 
AA 
Amino Acid 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
CI 
Confidence Interval 
CMDU 
COVID-19 Medicine Delivery Units 
COVID-19 
Coronavirus Disease 2019 
DIA 
Data Import Agreement 
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 
has 
Health Security Agency 
his 
Human Safety Information 
IC 
Immunocompromised 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
QC 
Quality Control 
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 


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 8 of 43 
TFL 
Tables Figures Listings 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SFTP 
Secure File Transfer Protocol 
SOP 
Standard Operating Procedure 
SYNH 
Syneos Health 
TEAE 
Treatment Emergent Adverse Events 
UCL 
University College of London 
UK 
United Kingdom 
UKHSA 
United Kingdom Health Security Agency 
VOC 
Variant of Concern 
VUI 
Variant Under Investigation 
WHO 
World health Organization 
EOS 
End of Study 
EAP 
External Alliance Portal 


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 9 of 43 
2. 
Purpose 
The purpose of this statistical analysis plan (SAP) is to document the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used to ensure they are 
complete and appropriate to allow valid conclusions regarding the study objectives. 
This genomic surveillance study will aim to describe changes in the Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) spike protein observed in Immunocompromised (IC) patients receiving 
sotrovimab in sentinel sites at a national level to assess potential emergence of viral variants in Great 
Britain (GB). 
2.1 Responsibilities 
Syneos Health (SYNH) will perform the statistical analyses and is responsible for the production and 
quality control of all tables, figures and listings. 
2.2 Timings of Analyses 
As part of this genomic surveillance study, an interim and final analysis to United Kingdom (UK) 
Medicines and Healthcare products Regulatory Agency (MHRA) has been committed by GlaxoSmithKline 
(GSK). Interim analysis was performed half-way in to the recruitment period (i.e., 6 months over the whole 
recruitment period of 1 year) and the final analysis will be conducted after all participants complete the 
final study visit or terminate early from the study. 
  Tables, Figures and Listings pertaining to Interim and Final analysis can be found (See Section 14, 15, 
16). 
 
 
 


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 10 of 43 
3. 
Study Objectives 
 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 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 
 Exploratory Objectives 
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]) 
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. 
 
 
 


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 11 of 43 
4. 
Study Details/Design 
4.1 Brief Description 
Sotrovimab was granted a conditional marketing authorisation for the treatment of early coronavirus 
disease 2019 (COVID-19) infection in 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. 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. 
4.2 Study Design 
This is a phase IV, prospective cohort study amongst IC non-hospitalised patients treated with sotrovimab 
as part of standard clinical care to monitor the emergence of SARS-CoV-2 spike viral variants. 
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) 
Figure 1 
 
 
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. 


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 12 of 43 
Sequencing analyses will be conducted on all SARS-CoV-2 positive nasal/oropharyngeal swab 
samples that meet the threshold criteria for the sequencing assay. 
 
4.3 Participant Selection 
4.3.1 Inclusion Criteria 
The inclusion criteria for are defined in the protocol section 8.2.1. 
4.3.2 Exclusion Criteria 
The exclusion criteria are defined in the protocol section 8.2.2. 
4.4 Determination of Sample Size 
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 whole of GB to meet the target sample size. Flexible enrolment caps 
per site and per month will 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. 
 
For Further details please refer protocol section 8.5. 
 
4.5 Treatment Assignment and Blinding 
Not Applicable. 
 
4.6 Administration of Study Medication 
Sotrovimab Xevudy TM, dose and administration per standard of clinical care. 
 
 
 


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4.7 Study Procedures and Flowchart 
Table 1: 
 


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5. 
SARS-CoV-2 Genomic Analysis Results Workflow 
Figure 
2
 
University College of London (UCL) Central Analytical Laboratory: 
SARS-CoV-2 Genomic analysis will be performed by the assigned central analytical laboratory, University 
College of London (UCL), receiving all study patients nasal/oropharyngeal swab samples as described in 
the Study Lab Manual. Figure 2 shows genomic and viral load data movement between UCL, Syneos 
Health, and GSK. UCL generates the raw sequencing FASTA/FASTQ and related files which would then 
be uploaded to UK HSA/CLIMB database by UCL as part of MHRA requirements in-stream. UCL also 
takes the responsibility to upload the raw sequencing files to GSK via sFTP in near real-time which GSK 
will be using for bioinformatic analysis of amino acid substitutions in spike protein. UCL uses its 
bioinformatic pipeline to create a Pharmacology File (PF) having only viral variant calling VOC/VUI 
information based on the whole genome sequence and sends it to Syneos Health for analysis and MHRA 
reporting. 
 
GlaxoSmithKline (GSK) 
GSK receives the raw sequencing files from UCL and create its own bioinformatic pipeline to create 
another Pharmacology File consisting of amino acid substitutions in spike protein and sends it to Syneos 
Health for statistical analysis and MHRA reporting. The interim and final reports would be shared with 
MHRA directly by GSK. 


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Syneos Health (SYNH) 
Syneos Health receives Pharmacology Files (PF) from both UCL and GSK and will perform study 
management, clinical data management and statistical analysis for MHRA interim and final analysis. 
 
UCL will share PF (VOC/VUI based on the whole genome sequence) and viral load data in excel (.csv) 
format using dedicated SFTP according to agreed Data Import Agreement (DIA) with SYNH. Likewise, GSK 
will share the bioinformatic analysis of amino acid substitutions in spike protein file under excel (.csv) format 
using dedicated SFTP according to agreed Data Import Agreement (DIA) with SYNH. The data transfer 
from GSK and UCL to SYNH would be in cumulative fashion, and all reporting would also be cumulative 
each time. The data will be stored at SYNH server (M: Drive).  
 
SYNH would merge the sequencing data (PF) coming from GSK with UCL (VOC/VUI based on the whole 
genome sequence 
AA 
derived for analyses (i.e., Interim and Final).  
Viral load data will be received from UCL and SYNH takes responsibility for conversion of copies/mL into 
log10 copies/mL for analysis.  
 
All the raw data (FASTA/ FASTQ/BAM/VCF files) will be directly uploaded to GSK
FTP in near-real time 
by UCL and SYNH will not be involved in this process. 


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6. 
Endpoints 
Primary Endpoints 
1. Proportion of patients eligible for sequence analysis that have any Amino Acid 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 Amino Acid change from 
baseline in the spike protein in samples collected at Day 7, 14 and 28 (+/-2 days)  
(Primary Objective 2) 
 Secondary Endpoints 
3. Proportion of patients eligible for sequence analysis with SARS CoV-2 VOC or VUI on the earliest 
possible sample (Secondary Objective 1)  
mutations will be reported 
4. Proportion of patients with undetectable virus at Day 7, 14 and 28 (+/-2 days)  
(Secondary Objective 2) 
5. 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 
6. 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) 
7. 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)  
Exploratory Endpoints 
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. 


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The following separate tables will be presented to support the above viral characteristics 
endpoint: 
 
Please refer Table 1.26 for analysis on VOC/VUI for hospitalized patients. 
 
Summary of viral load results by clinical outcomes (Please refer Table 1.49 of TLF 
shells). 
 
Summary of proportion of subjects with undetectable viral load by clinical outcomes. 
(Please refer Table 1.50 of TLF shells). 
 
Summary of proportion of amino acid substitutions at baseline and post-baseline in 
spike protein - consensus sequence (allelic frequency >50%) in patients with clinical 
outcomes. (Please refer Table 1.51 of TLF shells). 
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). 
We will explore the feasibility of extracting the virology data from the GISAID database for the final report
and cross-refer to output Table 1.11. 
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. 
Feasibility was assessed during the interim analyses with UKHSA and the linkage was not an option. 
Therefore, it will not be part of Final Analysis. 
 
 
 
7. 
Analysis Sets 
7.1 
Screened Set 
The Screened Set will include all patients who were screened at Visit Day 0 (i.e. gave informed 
consent). This set will be used for the listing and summarization of subject disposition. 
7.2 
Safety Set 
The Safety Set (SS) will include all participants who were enrolled and exposed to study 
intervention. 
7.3 
Virology Set 
The Virology Set (VS) will include all participants who were enrolled and exposed to study 
intervention with a positive PCR test by GOSH qPCR having Viral load above lower limit of 
detection (i.e., viral load >= LLOD) as threshold at baseline. 
 


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7.4 
Safety Completers Set  
The Safety Completers Set (SCS) will include all participants who were enrolled, exposed to 
study intervention (Sotrovimab) and who have been followed for 30 days (i.e., enrolled prior to 
01Jan2023) or withdrew from the study early. This population will be used for outputs relating to 
Clinical Outcomes for the planned Interim Analysis only. 
 
8. 
General Aspects for Statistical Analysis  
8.1 
General Methods 
 
All participants entered into the database will be included in participant data listings. 
 
 
Quantitative (continuous) data including absolute values and changes from baseline, where 
appropriate, will be summarized with number of observations (n), mean, standard deviation (SD), 
median, interquartile range (IQR), minimum and maximum. 
 
 
For the summary statistics of all continuous variables unless otherwise specified, minimum and 
maximum will be presented to the same number of decimal places as the raw data. Mean, 
median, Q1, Q3, and IQR will be presented to one more decimal places than the raw data, and 
SD will be presented to two more decimal places than the raw data. 
 
 
Qualitative (categorical) data will be summarized using number of observations (n), and frequency 
and percentages of patients. Unless stated otherwise, the calculation of percentages will be based 
on the total number of patients with non-missing data. For some of the endpoints, 95% CI of 
proportion will also be displayed.   
 
 
All statistical analyses will be conducted using SAS® for Windows® Version 9.4 or higher. 
 
 


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8.2 
Key Definitions 
 
End of Study (EOS)  
The EOS is defined as the date the last participant completes the last visit as shown in the Schedule of 
Activities in Section 4.8. 
 
Study day 
Event date can be adverse events, labs, or any other assessments during the study. 
sotrovimab, study day = event date  date of first dose of 
sotrovimab + 1. 
If the event date < date of first dose of sotrovimab, study day = event date  date of first dose of 
sotrovimab. 
 
Baseline Value 
Baseline value will be defined as the last non-missing value recorded prior to sotrovimab administration or 
as close as possible to the end of sotrovimab infusion. 
Retrospective collection of baseline data with the patient or directly with patient HCP will be conducted 
when not possible at Day 0. In all cases baseline is defined to be Day 0. 
 
Change from Baseline (CFB) 
CFB = Post-baseline value  Value at baseline 
Treatment Emergent  
Treatment emergent amino acid substitutions include subjects where baseline and post-baseline records 
exist.  
Treatment emergence for consensus will include baseline records of allelic frequency >5% and post-
baseline >50% as thresholds, whereas treatment emergence for minority will include baseline records of 
allelic frequency >5% and post-baseline >5% as thresholds. 
 
Consensus sequence is defined as allelic frequency >50% and minority species with allelic frequency 
>5%. 
 
Lower Limit of Detection (LLOD) 
LLOD of the assay is defined as 453 copies/mL (equivalent to Ct=38). 
 
Lower Limit of Quantification (LLOQ) 
LLOQ of the assay is defined as 1570 copies/mL (equivalent to Ct=36.18). 
 
Viral load Negatives 
The threshold to declare a viral load negative is the LLOD.  
 
 
8.3 
Missing Data 
For participants who are withdrawn from the study prior to the end of the study, all data collected up to the 
point of discontinuation will be used for analysis. 
 
Imputation will be performed on post-baseline viral loads depending on the viral load results as below:  


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Viral loads that are missing or less than the LLOD (453) will be imputed as 0.5*LLOD = 0.5*453=226.5 
copies/ml = 2.36 log10c/ml. 
Viral loads that are above the LLOD but lower than the LLOQ (1570) will be imputed as LLOQ  
0.5*(LLOQ-LLOD) = 1011.5 copies/ml = 3.00 log10c/ml. 
 
 
Possible VL results 
LLOD 
LLOQ 
Reported in the 
listings as: 
Imputation for analysis: 
Missing (as Ct>45) 
453 
1570 
NEG 
Half LLOD = 226.5 copies/ml = 
2.36 log10c/ml 
<LLOD, e.g. 400 
453 
1570 
NEG 
Half LLOD = 226.5 copies/ml = 
2.36 log10c/m 
Between LLOD and 
LLOQ, e.g. 1000 
453 
1570 
<1570  
LLOQ  0.5*(LLOQ-LLOD) = 
1011.5 copies/ml = 3.00 log10c/ml 
>LLOQ, e.g 2000 
453 
1570 
Numeric result 
None  use numeric result 
  
 
 
For calculating age, birth date will be imputed as follows: 
 
 
Completely missing dates of birth will remain as missing, with no imputation applied. Consequently, the 
age of the subject will not be calculated and will remain missing. 
     
8.3.1 Missing Adverse Events (AE) and Medication Dates 
Incomplete/missing AE/ Concomitant medication start and end dates are not expected, in case of 
incomplete/missing AE/Concomitant medication start and end dates, imputation will be performed as 
stated below.      
 
Adverse Events 
 
Partial dates for AE recorded in the CRF will be imputed using the 
following conventions: 
 
Missing start 
day 
 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = 1st of month. 
 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and 
year of study treatment start date then 
 
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date= 1st of month. 
 
Else set start date = study treatment start 
date. 


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o
Else set start date = 1st of month.
Missing start 
day and month 
 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = January 1. 
 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment 
start date then 
 
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date = January 1. 
 
Else set start date = study treatment start 
date.       
o 
Else set start date = January 1. 
Missing stop 
day  
Last day of the month will be used. 
Missing stop 
day and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
 
 
Completely missing start or end dates will remain missing, with no 
imputation applied.  
Concomitant 
Medications/Medical 
History 
 
Partial dates for any concomitant medications recorded in the CRF will 
be imputed using the following convention:  
Missing start day  If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 1st 
of month.  
Else if study intervention start date is not missing:  
 
If month and year of start date = month 
and year of study intervention start date, then  
 If stop date contains a full date and stop 
date is earlier than study intervention start 
date, then set start date= 1st of month.  
 Else set start date = study intervention 
start date.  
Else set start date = 1st of month.  
Missing start day 
and month  
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 
January 1.  
Else if study intervention start date is not missing:  
 
If year of start date = year of study 
intervention start date, then  
 If stop date contains a full date and stop 
date is earlier than study intervention start 
date, then set start date = January 1.  
 Else set start date = study. intervention 
  
Else set start date = January 1.  
Missing end day  A '28/29/30/31' will be used for the day (dependent on 
the month and year).   
Missing end day 
and month  
A '31' will be used for the day and 'Dec' will be used for 
the month.  


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Completely 
missing start/end 
date  
No imputation
 
 
 
 
 
8.4 
Visit Windows 
Analysis will be based on nominal visit, excluding all the unscheduled visits. Unscheduled assessments 
will be listed but will not be included in the summarization. 
 
8.5 
Pooling of Centers 
Not Applicable since no adjustment for center or by center analyses are planned. 
8.6 
Subgroups 
Not Applicable. 
 
 


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9. 
Demographic, Other Baseline Characteristics and Medication 
9.1 
Subject Disposition and Withdrawals 
Subject disposition will be summarized for all subjects in the Screened Set. The summary table will show 
the number of subjects screened, the number of screen failures and reason for screen failures, and who 
discontinued the study prematurely along with the primary reasons for discontinuation. 
Reasons for discontinuation of study will also be listed, including the time in days before discontinuation 
from study.  
Eligibility criteria, and informed consent information will be listed for all subjects in the Safety Set. 
Screening failures (including screen failure date and primary reason for failure) will be listed separately. 
 
9.2 
Protocol Deviations 
Non-
of protocol deviations and categorization into Not Important / Important will be performed in the Data 
Review Meeting (DRM) prior to database lock.  
All protocol deviations related to study inclusion or exclusion criteria, conduct of the trial, patient 
management, dosing, and sampling procedures or patient assessment will be listed. The list of protocol 
deviations will be reviewed by the Sponsor, the principal investigator and the study statistician, and 
finalized before database lock during the DRM. All protocol deviations (Not important and Important) 
observed during the conduct of the study will be listed. Important protocol deviations (patients with at 
least one important PD overall and split by PD category) will be summarized for safety population. 
 
9.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including age, age group, sex, race, ethnicity, body mass 
index (BMI), current smoking status will be summarized for safety population using standard descriptive 
statistics. Further separate summary tables including demographic and baseline characteristics for 
subjects who did not clear the virus at D28 (viral load above LLOD at D28) and for subjects with 
sequence data available will also be presented. 
 
In addition, duration of COVID-19 symptoms (days) prior to receiving sotrovimab, previous SARS-CoV-2 
infection, Serostatus, if available the test used for serology, COVID-19 Disease History, Number of days 
since initial COVID-19 positive test result, Test used for COVID-19 testing, number of previous COVID-19 
infections, COVID-19 Vaccination status, Product name of COVID-19 vaccine, number of doses of 
vaccine will also be summarized using standard descriptive statistics. 
 
All demography data will be listed.  
9.4 
Medical History and Concomitant Diseases 
Medical history, as recorded at screening/baseline and concomitant diseases, will be summarized 
separately for the safety population presenting the number and percentages of subjects within each CRF 
pre-defined classified conditions. Concomitant diseases are all events which are ongoing at first intake of 
study medication. A separate summary of medical conditions and comorbidities for subjects who did not 
clear the virus at D28 (viral load above LLOD at D28) and subjects with sequence data available will also 
be presented. 
 


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9.5 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded by the Anatomical Therapeutic Chemical (ATC) 
classification system according to the World Health Organization Drug Dictionary (WHO-DD). Medications 
will be classified as concomitant or prior and summarized by ATC class (level 2, therapeutic subgroup) 
and preferred drug name for all subjects in the safety population.  
Prior medication is defined as any medication taken before the date of the first dose of study treatment. 
Concomitant medication is defined as any medication taken on or after the date of the first dose of study 
treatment.  
Concomitant medication will be recorded, including the medication name, daily dose, unit, regimen, 
administration route, reason for administration (text field) and medication start and end dates or ongoing. 
All prior and concomitant medications will be listed, with a flag identifying prior medications, for all 
subjects in the Safety population. 
The summary tables will show the frequency and percentage of subjects in each group with at least one 
usage of medication on the sub-class level within each ATC class sorted alphabetically. 
 
10. Efficacy 
Treatment Emergent Amino acid Substitutions/Amino acid Change from Baseline is defined as any amino 
acid substitutions detected at post-baseline visits compared to baseline sequence. 
10.1 
Primary Efficacy Endpoint and Analysis  
Primary efficacy analyses will be conducted for the safety populations.  
The primary endpoints in this study are  
 
Proportion of patients eligible for sequence analysis that have any AA change from baseline in 
the epitope of sotrovimab binding. 
The proportion of subjects with epitope amnio acid change from baseline will be summarized showing the 
counts and percentages of patients in each epitope substitution change by post-baseline visits (Day 7, 14 
and 28 (+/-2 days)) and overall and will be presented separately for Minority species (>5% allelic 
frequency) as well as consensus sequence (>50% allelic frequency). 
 
Proportion of patients with epitope substitution change by VOC/VUI for Consensus Sequence (Allelic 
frequency >50%) and for Minority species (>5% allelic frequency) was also presented by visit for interim 
analysis reporting, but will not be included in the final analysis. 
 
 
Proportion of patients eligible for sequence analysis that have any AA change from baseline in 
the spike. 
The proportion of subjects with spike amnio acid change from baseline will be summarized showing the 
counts and percentages of patients in each spike substitution change by post-baseline visits (Day 7, 14 
and 28 (+/-2 days))  and overall and will be presented separately for Minority species (>5% allelic 
frequency) as well as consensus sequence (>50% allelic frequency). 
 


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10.2 
Secondary Efficacy Endpoint and Analysis 
Secondary efficacy analyses will be conducted for the safety populations, unless otherwise stated.  
The secondary endpoints in this study are: 
 
Proportion of patients eligible for sequence analysis with SARS CoV-2 VOC/VUI on the earliest 
possible sample. 
The proportion of patients with VOC/VUI will be summarized showing the counts and percentages of 
patients by each variants based on WHO classification and Pango sub-lineage for the earliest possible 
VOC/VUI sample including baseline. A data listing including WHO label and Pango sub-lineage will be 
provided. 
 
Proportion of patients with undetectable virus (i.e. viral load < LLOD) 
 Summary of proportion of patients with undetectable virus would be based on safety population and 
summarized by Day 7, 14 and 28 (+/-2 days).  
 
Clinical outcomes through Day 28 post-sotrovimab treatment: 
The following clinical outcomes will be summarized by count and percentage of patients and its 95% CI 
by VOC/VUI, Non-VOC/VUI, and Overall: 
 
Proportion of patient with all-cause hospital admissions 
 
Proportion of patient with COVID-19 related hospital admissions. 
 
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 patient with all-cause ICU admissions. 
 
Proportion of patient with COVID-19 related ICU admissions. 
 
Proportion of patient who died through Day 28. 
 
Proportion of patient who died through Day 28 due to COVID-19. 
In addition, the clinical outcomes would also be summarized by VOC/VUI variants and also by Medical 
Condition/Comorbidity.     
The above outputs for Clinical outcomes will be based on the Safety Completers Population for the 
Interim Analysis and safety population for Final Analysis. 
 
Data listings on clinical outcomes separately for hospital admission, ICU admission, oxygen support, 
death will be listed.   


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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 
 
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 
For the above endpoints, Baseline and post-baseline (Day 7, 14 and 28 (+/-2 days)) AA 
substitutions will be summarized by showing the counts and percentages of patients in spike and 
epitope substitutions separately for Minority species (>5% allelic frequency) as well as consensus 
sequence (>50% allelic frequency).  
 
Treatment emergent AA substitutions in spike as well as epitope for minority species and 
consensus sequence would be listed separately. 
 
A similar baseline and post-baseline AA substitutions summary were presented by VOC/VUI 
variants for the interim but will not be included in the final analysis.. 
 
Data listings will be provided for all the baseline and post-baseline AA substitutions in spike as 
well as epitope for minority species and consensus sequence separately. 
 
 
Viral load  
 Absolute and change from baseline viral load summaries will be based on Safety and Virology 
population respectively on log10 copies/mL.   
An overall summary of viral load (log10 copies/mL) with actual values and change from baseline 
values of viral load as well as by Day 0, Day 7, 14 and 28 (+/-2 days) using descriptive statistics 
will be displayed and presented graphically over time. 
In addition, viral load (log10 copies/mL) with actual values and change from baseline values will 
also be summarized by VOC/VUI variants, and for Epitope Substitutions by Residue and 
presented graphically over time.  Also, individual subject profile plots of viral load by VOC/VUI will 
be graphically presented based on viral load imputed values. 
.A summary of viral load (log10 copies/mL) with actual values using descriptive statistics will be 
presented for the subset of subjects who had missing viral load at Baseline, and separately for 
the subset of subjects who had a viral load available at Baseline. 
Listings will be provided for all viral load data as well as a separate listing including only epitope 
substitution. 
 
 
 
 


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Viral Rebound 
A subject has experienced a virologic rebound when following conditions are met:  
If subject is in the  safety population and: 
o 
Viral load increases >1 log10 copies/mL at any point in time following any 
previous sample. 
 OR 
o 
Viral load becomes quantifiable after having been below the limit of quantification (LLOQ) or 
limit of detection (LLOD).  
A table will be summarized with number of subjects who met viral rebound and will also list out their viral 
load information. 
 
 
11. Safety 
All safety analyses will be conducted using the safety population.  
In this study, only events considered related to sotrovimab are collected and referred to adverse drug 
reactions (ADRs). Therefore, any reference to AE in subsequent sections indicates ADR, unless 
otherwise stated. 
Safety will be assessed on the basis of reporting and analyzing of AE .  
Only descriptive statistics will be produced.  
11.1 
Adverse Events 
All subjects in the safety population will be included in the AE summaries. Adverse events will be 
summarized by the system organ class (SOC) and preferred term (PT) based on the MedDRA dictionary 
version 25.0.  
Treatment emergent adverse events are defined as adverse events that occurred or worsened on or after 
the first dose of the study treatment.   The summary tables will include the number of subjects and the 
number of events. Percentages will be based on the number of subjects. For summaries by SOC and PT, 
a subject will be counted once at the SOC level and once at each PT within the SOC level.  
For summaries by SOC, PT, and maximum severity, a subject will be counted once at the highest severity 
level for which the event occurred at the SOC level and the highest severity level for each unique PT 
within that SOC level. Therefore, subjects may only contribute once to each PT and once to each SOC 
level. The summaries presenting frequency of AEs by SOC and PT will be ordered in the descending 
frequency of SOC and then, within a SOC in descending frequency of PT. 
. 
In addition, summary tables for AESIs of hypersensitivity reactions and anaphylactic reactions using 
MedDRA Hypersensitivity SMQ Code 20000214 BROAD Search and Anaphylactic reaction SMQ Code 
20000021 Narrow Search plus the Algorithmic PT search defined in MedDRA will also be generated. 
 
The following tables will be provided: 


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An overall summary of the number and percentage of subjects reporting TEAEs, serious TEAEs, 
Severe TEAEs, TEAEs leading to TEAEs leading to Study Discontinuation and TEAEs resulting 
in death. 
 
TEAEs by system organ class (SOC) and preferred term (PT) 
 
TEAEs by system organ class, preferred term and maximum severity 
 
Serious TEAEs by System Organ Class and Preferred Term 
 
TEAES leading to Withdrawal from Study by System Organ Class and Preferred Term 
 
Fatal treatment-emergent serious adverse events by System Organ Class and Preferred Term 
 
AESIs of hypersensitivity reaction  
 
AESIs of anaphylactic reaction 
 
TEAEs will be summarized and listed accordingly.   Additional listings will be provided for serious adverse 
events (SAEs; defined in Section 11 of the Protocol), fatal SAEs. 
 
11.2 
Vital Signs 
No vital signs parameters were collected. 
 
 
12. Programming Considerations 
12.1 
General Considerations 
 
A separate SAS program will be created for each output. 
 
Each output will be stored in a separate file 
 
Output files will be delivered in Word format (RTF) and portable document format pdf 
12.2 
Table, Figures, and Listing Format 
 
12.2.1 
General 
 
All TFLs will be produced in landscape format on A4 paper size, unless otherwise specified  
  All TFLs will be produced using the Courier New font, size 8 which is the smallest acceptable point 
size for the Regulatory Authorities 
 The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides 
 Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities 
 Legends will be used for all figures with more than one variable, group, or item displayed 
 TFLs will be in black and white (no color), unless otherwise specified 


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Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below) 
 Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
employed on a case-by-case basis 
 Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate 
 The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Efficacy 
2.1 to 2.n 
2.1 to 2.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Section 
Listings 
ICH Listings 
1 to x 
Other Listings 
y to z 
  
12.2.2 
Headers 
All output will have the following header at the top left of each page: 
 GlaxoSmithKline, Protocol 218407 
 All output will have Page n of N at the top or bottom right corner of each page. TFLs are internally 
paginated in relation to the total length (i.e., the page number will appear sequentially as page n of 
N, where N is the total number of pages in the table) 
 The date the output was generated will appear along with the program name as a footer on each 
page 
12.2.3 
Display Titles 
 Each TFL will be identified by the designation and a numeral. (i.e., Listing 1.1). A decimal system 
(x.y and x.y.z) are used to identify TFLs with related contents. The title will be centered. The title 
and table designation will be single spaced. A solid line spanning the margins will separate the 
display titles from the Column headers. There will be one blank line between the last title and the 
solid line 
Protocol: 218407                                                                                                               Page x of y 
          Population: Safety 
 
 
 
 
 
        Data as of (DDMMMYYYY)                          
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 


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12.2.4 
Column Headers 
 Column headings will be displayed immediately below the solid line described above in initial 
upper-case characters 
 In the case of effectiveness tables, the variable (or characteristic) column will be on the far left 
followed by the treatment group columns and total column (if applicable). P-values may be 
presented under the total column or in separate p-value column (if applicable). Within-treatment 
comparisons may have p-values presented in a row beneath the summary statistics for that 
treatment 
 For numeric variables, include unit  in column or row heading when appropriate 
 Analysis set sizes will be presented in the column heading as (N=xx) (or in the row headings, if 
subjects in the analysis set 
12.2.5 
Body of the Data Display 
12.2.5.1 General Conventions 
Data in columns of a table or listing are formatted as follows: 
 Alphanumeric values will be left-justified 
 Whole numbers (e.g., counts) will be right-justified; and 
 Numbers containing fractional portions will be decimal aligned 
12.2.5.2 
Table Conventions 
 Units will be included where available 
 For categorical parameters, all categories will be presented in the table, even if n=0 for all 
treatment groups in a given category. For example, the frequency distribution for symptom severity 
would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
 An Unknown or Missing category will be added to each parameter for which information is not 
available for 1 or more subjects  


Statistical Analysis Plan (SAP)
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Unless otherwise specified, the estimated mean and median for a set of values will be printed out 
to 1 more significant digit than the original values, and standard deviations will be printed out to 2 
more significant digits than the original values. The minimum and maximum will report the same 
significant digits as the original values. For example, systolic blood pressure will be presented as 
follows: 
N 
 XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
 Percentage values will be printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise noted, for all percentages, the 
number of subjects in the analysis set for the treatment group who have an observation will be the 
denominator. Percentages after zero counts will not be displayed and percentages equating to 
100% will be presented as 100%, without decimal places  
 Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data will be presented by the body system, treatment class, or SOC with the 
highest occurrence in decreasing order, assuming all terms are coded. Within the body system, 
drug class and SOC, medical history (by preferred term), drugs (by ATC1 code), and adverse 
events (by preferred term) will be displayed in decreasing order. If incidence for more than 1 term is 
identical, they will then be sorted alphabetically. Missing descriptive statistics which cannot be 
estimated will be reported as -  
 The percentage of subjects will normally be calculated as a proportion of the number of subjects 
assessed for the analysis set presented. However, careful consideration is required in many 
instances due to the complicated nature of selecting the denominator, usually the appropriate 
number of subjects exposed. Details will be described in footnotes or programming notes, as 
necessary 
 For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, a footnote or programming note will be added describing whether the 
subject is included in the summary statistics for all relevant categories or just 1 category as well as 
the selection criteria 
 Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by (cont)  at the top of each subsequent page. The 
overall summary statistics for the subheading should only be output on the first relevant page 
12.2.5.3 
Listing Conventions 
 Listings will be sorted for presentation in order of subject number, visit/collection day, and 
visit/collection time 
 Missing data will be represented on subject listings as either a hyphen ( - ) with a corresponding 
footnote ( - = unknown or not evaluated ), or as N/A , with the footnote N/A = not applicable , 
whichever is appropriate 


Statistical Analysis Plan (SAP)
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Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
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Dates will be printed in SAS DATE9.format ( DDMMMYYYY : e.g: 01JUL2000). Missing portions of 
dates will be represented on subject listings as dashes (--JUL2000). Dates that are missing 
because they are not applicable for the subject will be output as N/A , unless otherwise specified 
 All observed time values will be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study 
 Units will be included where available 
12.2.5.4 
Figure Conventions 
 Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis 
12.2.6 Footnotes 
 A solid line spanning the margins will separate the body of the data display from the footnotes  
 All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display 
 Footnotes will always begin with Note:  if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote will start on a new line, where possible 
 Subject specific footnotes are avoided, where possible 
 Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page  
 The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, the date the program was run, and the listing source 
 
 Sources and/or cross-references in footnotes will use the keyword prefix (in singular form) for each 
reference and will be separated by a comma when multiple cross references are displayed 
Example 
Listing source: Listing 16.2.4.1.1, Listing 16.2.4.1.2, Listing 16.2.4.2.1 
13. Quality Control 
SAS programs are developed to produce output such as analysis datasets, summary tables, figures, and 
data listings, or statistical analyses. An overview of the development of programs is detailed in 
Developing Statistical Programs SOP (3907). 
The Developing Statistical Programs SOP (3907), Conducting the Transfer of Biostatistical Deliverables 
SOP  (3908) and the SAS Programming and Validation Plan (3906A) describe the quality control 
procedures that are performed for all SAS programs and output. Quality control is defined as the 
operational techniques and activities undertaken to verify that the SAS programs produce the output by 
checking for their logic, efficiency and commenting and by review of the produced output. 


Statistical Analysis Plan (SAP)
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This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
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Page 34 of 43 
 
 


Statistical Analysis Plan (SAP)
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Page 35 of 43 
 
14. Index of Tables 
List of Interim and Final Reports
PopulationAnalysis
Tables
Table 1.1 
Subject Disposition 
Screened  Interim, 
Final 
Table 1.2 
Summary of Subject Demographic and Baseline Characteristics Safety   
Interim, 
Final 
 
Table 1.3 
Summary of Proportion of Amino Acid Substitutions in the Spike 
protein for Any Substitutions  Consensus Sequence (Allelic 
frequency >50%) 
Safety    
Interim, 
Final 
Table 1.4 
Summary of Proportion of Amino Acid Substitutions in Epitope 
for Any Substitutions  Consensus Sequence (Allelic frequency 
>50%) 
Safety    
Interim, 
Final 
Table 1.5 
Summary of Proportion of Amino Acid Substitutions in the Spike 
protein for Any Substitutions  Minority species (Allelic 
frequency >5%) 
Safety   
Interim, 
Final 
Table 1.6 
Summary of Proportion of Amino Acid Substitutions in Epitope 
for Any Substitutions  Minority species (Allelic frequency >5%) Safety   
Interim, 
Final 
Table 1.7 
Summary of Proportion of Amino Acid Substitutions at Baseline 
and Post-Baseline in Spike protein  Consensus Sequence 
(Allelic frequency >50%) 
Safety   
Interim, 
Final 
Table 1.8 
Summary of Proportion of Amino Acid Substitutions at Baseline
and Post-Baseline in Epitope  Consensus Sequence (Allelic 
frequency >50%) 
Safety   
Interim, 
Final 
Table 1.9 
Summary of Proportion of Amino Acid Substitutions at Baseline 
and Post-Baseline in Spike protein  Minority species (Allelic 
frequency >5%) 
Safety   
Interim, 
Final 


Statistical Analysis Plan (SAP)
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This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
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Table 1.10 
Summary of Proportion of Amino Acid Substitutions at Baseline 
and Post-Baseline in Epitope  Minority species (Allelic 
frequency >5%) 
Safety   
Interim, 
Final 
Table 1.11 
Summary of Proportion of Treatment-emergent Amino Acid 
Substitutions in the Spike Protein for Any Substitutions  
Consensus Sequence (Allelic frequency >50%) 
Safety   
Interim, 
Final 
Table 1.12 
Summary of Proportion of Treatment-emergent Amino Acid 
Substitutions in the Epitope for Any Substitutions  Consensus 
Sequence (Allelic frequency >50%) 
Safety   
Interim, 
Final 
Table 1.13 
Summary of Proportion of Treatment-emergent Amino Acid 
Substitutions in the Spike Protein for Any Substitutions  
Minority species (Allelic frequency >5%) 
Safety   
Interim, 
Final 
Table 1.14 
Summary of Proportion of Treatment-emergent Amino Acid 
Substitutions in the Epitope for Any Substitutions  Minority 
species (Allelic frequency >5%) 
Safety   
Interim, 
Final 
Table 1.15 
Summary of Proportion of Subjects with a Variant of 
Concern/Under Investigation (VOC/VUI)  
Safety   
Interim, 
Final 
Table 1.161 
Summary of Absolute Viral Load (log 10 copies/mL) as 
measured by qRT-PCR from Nasal/oropharyngeal swabs 
Safety   
Interim, 
Final 
Table 1.162 
Summary of Absolute Viral Load (log 10 copies/mL) as 
measured by qRT-PCR from Nasal/oropharyngeal swabs for 
Subjects with missing Baseline Viral Load 
Safety   
 
Interim, 
Final 
Table 1.163 
Summary of Absolute Viral Load (log 10 copies/mL) as 
measured by qRT-PCR from Nasal/oropharyngeal swabs for 
Subjects with Baseline Viral Load 
Safety   
 
Interim, 
Final 
Table 1.164 
Summary of Change from Baseline in Viral Load (log 10 
copies/mL) as measured by qRT-PCR from Nasal/oropharyngeal 
swabs 
Virology   
 
Interim, 
Final 


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Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
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Table 1.171 
Summary of Absolute Viral Load (log 10 copies/mL) as 
measured by qRT-PCR from Nasal/oropharyngeal swabs by 
Variant of Concern (VOC)/ Variant Under Investigation (VUI)     
Safety   
 
Interim, 
Final 
Table 1.172 
Summary of Change from Baseline in Viral Load (log 10 
copies/mL) as measured by qRT-PCR from Nasal/oropharyngeal 
swabs by Variant of Concern (VOC)/ Variant Under Investigation 
(VUI) 
Virology   Interim, 
Final 
Table 1.18 
Proportion of subjects with undetectable viral load as measured 
by qRT-PCR from Nasal/oropharyngeal swab through Day 28 
Safety   
Interim, 
Final 
Table 1.19 
Summary of Proportion of Epitope substitutions at Baseline, 
Post-Baseline by VOC/VUI - Consensus Sequence (Allelic 
frequency >50%) 
Safety   
Interim
Table 1.20 
Summary of Proportion of Treatment Emergent Epitope 
substitutions by VOC/VUI - Consensus Sequence (Allelic 
frequency >50%) 
Safety   
Interim
Table 1.21 
Summary of Proportion of Epitope substitutions at Baseline, 
Post-Baseline by VOC/VUI - Minority species (Allelic frequency 
>5%)  
Safety   
Interim
Table 1.22 
Summary of Proportion of Treatment Emergent Epitope 
substitutions by VOC/VUI - Minority species (Allelic frequency 
>5%) 
Safety   
Interim 
Table 1.231 
Summary of Absolute in Viral Load (log 10 copies/mL) as 
measured by qRT-PCR from Nasal/oropharyngeal swabs for 
Epitope Substitutions by Residue 
Safety   
 
Interim, 
Final 
Table 1.232 
Summary of Change from Baseline in Viral Load (log 10 
copies/mL) by Baseline, Post-Baseline Epitope substitution (>=3 
subjects) 
Virology    
Interim, 
Final 
Table 1.241 
Summary of Absolute in Viral Load (log 10 copies/mL) by 
Treatment-Emergent Epitope substitution (>=3 subjects) 
Safety   
 


Statistical Analysis Plan (SAP)
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Interim, 
Final 
Table 1.242 
Summary of Change from Baseline in Viral Load (log 10 
copies/mL) by Treatment-Emergent Epitope substitution (>=3 
subjects) 
Virology  
Interim, 
Final 
Table 1.25 
Summary of Clinical Outcomes 
Completer 
(IA) 
Safety (FA) 
Interim,
 Final 
Table 1.26 
Summary of Clinical Outcomes by VOC/VUI 
Completer 
(IA) 
Safety (FA) 
Interim,
 Final 
Table 1.27 
Proportion of Subjects requiring Hospitalization Admission by 
Demographics/Medical Condition/Comorbidity 
Completer 
(IA) 
Safety (FA) 
Interim,
 Final 
Table 1.28 
Proportion of Subjects requiring ICU Admission by 
Demographics/Medical Condition/Comorbidity 
Completer 
(IA) 
Safety (FA) 
Interim,
 Final 
Table 1.29 
Proportion of Subjects requiring Respiratory Support by 
Demographics/Medical Condition/Comorbidity 
Completer 
(IA) 
Safety (FA) 
Interim,  
Final 
Table 1.30 
Proportion of Subjects who died by Demographics/Medical 
Condition/Comorbidity 
Completer 
(IA) 
Safety  
Interim, 
Final  
Table 1.31 
Overall Summary of Treatment-Emergent Adverse Events 
Safety   
Interim, 
Final 
Table 1.32 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
Safety   
Interim, 
Final 


Statistical Analysis Plan (SAP)
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Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
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Table 1.33 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity 
Safety   
Interim, 
Final 
Table 1.34 
Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
Safety   
Interim, 
Final 
Table 1.35 
Treatment-Emergent Adverse Events leading to Withdrawal 
from Study by System Organ Class and Preferred Term 
Safety   
Interim, 
Final 
Table 1.36 
Treatment-Emergent Fatal Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety   
Interim, 
Final 
Table 1.37 
Summary of Hypersensitivity Adverse Reactions by Preferred 
Term 
Safety   
Interim, 
Final 
Table 1.38 
Summary of Anaphylactic Adverse Reactions by Preferred Term Safety   
Interim, 
Final 
Additional Tables for Final Analysis
Table 1.39
Summary of Important Protocol Deviations
Safety
Final
Table 1.40 
Summary of Medical History 
(Immunocompromising/comorbidity) 
Safety 
Final
Table 1.41
Summary of Concomitant Medications
Safety
Final
Table 1.42 
Summary of Subject who did not clear the COVID-19 virus at 
D28 by Demographics Medical Condition/Comorbidity 
Safety 
Final
Table 1.43 
Summary of Sequenced subjects by Demographics/Medical 
Condition/Comorbidity across visits 
Safety 
Final
Table 1.44
Cumulative Proportion of Participants Meeting Viral Rebound
Safety
Final
Table 1.45 
Summary of Proportion of Subjects with Amino Acid 
Substitutions in the Spike protein for Any Substitutions  
Consensus Sequence (Allelic frequency >50%) 
Safety 
Final
Table 1.46 
Summary of Proportion of Subjects with Amino Acid 
Substitutions in the Spike protein for Any Substitutions  
Minority species (Allelic frequency >5%) 
Safety 
Final


Statistical Analysis Plan (SAP)
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Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
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Filing requirements: TMF 
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Table 1.47 
Summary of Proportion of Subjects with Treatment-emergent 
Amino Acid Substitutions in the Spike protein for Any 
Substitutions  Consensus Sequence (Allelic frequency >50%) 
Safety 
Final
Table 1.48 
Summary of Proportion of Subjects with Treatment-emergent 
Amino Acid Substitutions in the Spike protein for Any 
Substitutions  Minority species (Allelic frequency >5%) 
Safety 
Final
Table 1.49 
Summary of Absolute Viral Load (log 10 copies/mL) as 
measured by qRT-PCR from Nasal/oropharyngeal swabs in 
subjects with clinical outcomes 
Safety 
Final
Table 1.50 
Proportion of subjects with undetectable viral load as measured 
by qRT-PCR from Nasal/oropharyngeal swab through Day 28 in 
subjects with clinical outcomes 
Safety 
Final
Table 1.51 
Summary of Proportion of Amino Acid Substitutions at Baseline 
and Post-Baseline in Spike protein - Consensus Sequence (Allelic 
frequency >50%) in subjects with clinical outcomes 
Safety 
Final
 
 
15. Index of Figures 
Figures 
List of Interim and Final Reports 
PopulationAnalysis 
1.1 
Mean Change from Baseline of Viral Load Log10 copies/mL 
Virology   Interim, 
Final 
1.2 
Median Viral Load Log10 copies/mL by VOC/VUI  
Safety   
Interim, 
Final 
1.3 
Median viral load Log10 copies/mL over time of Epitope Substitution 
by Residue 
Safety   
Interim, 
Final 
1.4 
Individual subjects profile plot of viral load Log10 copies/mL by 
VOC/VUI  
Safety   
Interim, 
Final 
1.5  
Kaplan-Meier Plot for All-Cause Hospitalization by VOC/VUI 
subvariants   
Safety    
Interim 
  
 
 


Statistical Analysis Plan (SAP)
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16. Index of Listings 
Listings
List of Interim and Final Reports
PopulationAnalysis
Listing1.1 
Subject Disposition 
Screened  Interim, Final
Listing1.2 
Demographics and Baseline Characteristics 
Safety   
Interim, Final
Listing1.3 
Listing of all Baseline and Post-baseline Spike protein Amino 
Acid Substitutions  Minority species (Allelic frequency >5%) Safety   
Interim, Final
Listing1.4 
Listing of all Baseline and Post-baseline Spike protein Amino 
Acid Substitutions  Consensus sequence (Allelic frequency 
>50%) 
Safety   
Interim, Final
Listing1.5 
Listing of all Baseline and Post-baseline Epitope Amino Acid 
Substitutions  Minority species (Allelic frequency >5%) 
Safety   
Interim, Final
Listing1.6 
Listing of all Baseline and Post-baseline Epitope 
Substitutions  Consensus Sequence (Allelic frequency 
>50%) 
Safety   
Interim, Final
Listing1.7 
Listing of all Treatment-emergent Spike protein Amino Acid 
Substitutions  Minority species (Allelic frequency >5%) 
Safety   
Interim, Final
Listing1.8 
Listing of all Treatment-emergent Spike protein Amino Acid 
Substitutions  Consensus sequence (Allelic frequency 
>50%) 
Safety   
Interim, Final 
Listing1.9 
Listing of all Treatment-emergent Epitope Amino Acid 
Substitutions  Minority species (Allelic frequency >5%)  
Safety   
Interim, Final 
Listing1.10 
Listing of all Treatment-emergent Epitope Amino Acid 
Substitutions  Consensus sequence (Allelic frequency 
>50%)  
Safety   
Interim, Final 
Listing1.11 
Listing of all Treatment-emergent Epitope Amino Acid 
Substitutions  Minority species (Allelic frequency >5%) by 
VOI/VUI 
Safety   
Interim 
Listing1.12 Listing of Variant of Concern/Under Investigation (VOC/VUI) Safety   
Interim, Final 


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Listing1.131Listing of Nasal/oropharyngeal swab SARS CoV2 Viral Load 
Safety  
Interim, Final 
Listing1.132Listing of Nasal/oropharyngeal swab SARS CoV2 Viral Load 
for subjects with missing baseline viral load 
Safety  
Interim, Final
Listing1.14 Listing of Nasal/oropharyngeal swab SARS CoV2 viral load by 
epitope substitution 
Safety   
Interim
Listing1.15 Listings of Hospital Admission
Safety  
Interim, Final
Listing1.16 Listings of ICU Hospital Admissions
Safety  
Interim, Final
Listing1.17 Listings of requirement for Oxygen Support, Non-invasive, 
Invasive ventilation, ECMO 
Safety   
Interim, Final
Listing1.18 Listings of Deaths
Safety  
Interim, Final
Listing1.19 Listings of All Adverse Events
Safety  
Interim, Final
Listing1.20 Listings of All Serious Adverse Events
Safety  
Interim, Final
Listing1.21 Listings of Hypersensitivity Adverse Reactions
Safety  
Interim, Final
Listing1.22 Listings of Anaphylactic Adverse Reactions
Safety  
Interim, Final
Listing1.23 Listings of All Serious Adverse Events 
Safety   
Interim, Final 
 
 
Additional Listings for Final Analysis 
 
 
Listing1.24 Listings of All Protocol Deviations 
Safety   
 Final 
Listing1.25 Listings of Medical History 
Safety   
 Final 
Listing1.26 Listings of Prior and Concomitant Medications 
Safety   
 Final 
Listing1.27 Listing of Nasal/oropharyngeal swab SARS CoV2 Viral Load 
of Participants Meeting Criteria for Viral Rebound 
Safety   
 Final 
Listing1.28 Listing of All S Protein Substitutions (Allelic frequency >1%) Safety   
 Final 
Listing1.29 Listing of Screen Failures
Safety   
 Final 
 
 


Statistical Analysis Plan (SAP)
Sponsor: GSK; Protocol No: 218407 
This document is confidential. 
Statistical Analysis Plan (SAP) text Version: Final 2.0 14-Jul-2023 
Controlled Document ID: 3903B.01, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 43 of 43 
17. Shells 
17.1 
Table Shells 
Please refer TLF shells document. 
17.2 
Figure Shells 
Please refer TLF shells document. 
 
18. Appendices 
Not Applicable. 


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