PROphylaxis for paTiEnts at Risk of COVID-19 infecTion
Phase: PHASE2
Conditions: Covid19
Sponsor: Cambridge University Hospitals NHS Foundation Trust

 
EudraCT Number: 2020-004144-28 
IRAS ID: 288652 
 
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PROTECT-V protocol V11.0 – 05/Sep/2023 
 
Clinical Trial Protocol 
 
 
Trial Title: 
PROphylaxis for paTiEnts at risk of COVID-19 infecTion (PROTECT-V). 
 
Protocol Number: 
CCTU0307 
 
EudraCT Number: 
2020-004144-28 
 
Investigational Product: 
Niclosamide, Ciclesonide, Sotrovimab 
 
Protocol Version: 
11 
 
Chief Investigator: 
Dr Rona Smith 
 
CI Address: 
Cambridge Clinical Trials Unit 
 
Box 401, Cambridge Biomedical Campus 
 
 
Hills Road 
 
Cambridge, CB2 0QQ 
 
Telephone: 
01223 336817 
 
Trial Sponsor: 
Cambridge University Hospitals NHS Foundation Trust and the 
 
University of Cambridge 
 
SAE Reporting: 
PROTECT-V Trial Office 
Email: 
add-tr.PROTECT@nhs.net 
 
 
 
 
 
 
 
 
 
 

 
EudraCT Number: 2020-004144-28 
IRAS ID: 288652 
 
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PROTECT-V protocol V11.0 – 05/Sep/2023 
 
Protocol Signatures: 
I give my approval for the attached protocol entitled “PROphylaxis for paTiEnts at risk of Covid-19 
infecTion (PROTECT-V)” Dated 05 SEP 2023   
 
Chief Investigator 
 
Name: 
Dr Rona Smith  
 
Signature: 
 
 
Date: 
05/09/2023 
 
 
Site Signatures  
 
I have read the attached protocol entitled “PROphylaxis for paTiEnts at risk of COVID-19 
infecTion. (PROTECT-V)” dated 05 SEP 2023 and agree to abide by all provisions set forth therein.  
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the 
European Clinical Trials Directives 2001/20/EC and 2005/28/EC, the Medicines for Human Use 
(Clinical Trials) Regulations 2004 (SI 2004/1031) and any subsequent amendments of the clinical 
trial regulations, the Sponsor’s SOPs, and other regulatory requirements as amended. 
 
I agree to ensure that the confidential information contained in this document will not be used for 
any other purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of the Sponsor  
 
Principal Investigator  
 
Name: ________________________________________  
 
Signature: ________________________________________  
 
Date: ____________________________  
 
 

 
EudraCT Number: 2020-004144-28 
IRAS ID: 288652 
 
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PROTECT-V protocol V11.0 – 05/Sep/2023 
 
Protocol Contributors 
Dr Rona Smith 
PROTECT-V Chief Investigator 
Lead for PROTECT-V 
Lead for vasculitis patients 
Senior Clinical Trials Fellow, Cambridge Clinical Trials 
Unit 
and 
Consultant 
Nephrologist, 
Cambridge 
University Hospitals NHS Foundation Trust 
Dr Thomas F Hiemstra 
 
Honorary Trials Methodologist, Cambridge CTU 
Director of Nephrology Clinical Development, GSK 
Honorary 
Consultant 
Nephrologist, 
Cambridge 
University Hospitals NHS Foundation Trust 
Professor Claire Sharpe 
Lead for transplant patients 
Professor of Renal Medicine, King’s College London 
and King’s College Hospital 
Professor Ian B. Wilkinson 
Head of Experimental Medicine & Immunotherapeutics, 
University of Cambridge & Director, Cambridge Clinical 
Trials Unit, Cambridge University Hospitals NHS 
Foundation Trust 
Dr Toby Humphrey 
Clinical Research Fellow, Division of Experimental 
Medicine 
& 
Immunotherapeutics, 
University 
of 
Cambridge 
Dr Kerrie Brusby 
Clinical Trials Coordinator, Cambridge Clinical Trials 
Unit 
Professor Indranil Dasgupta 
Professor of Nephrology and Hypertension, University 
of Warwick, Consultant Nephrologist, Birmingham 
Heartlands Hospital 
Dr Fergus Caskey 
Consultant Senior Lecturer, Population Health Science 
Institute, University of Bristol and Honorary Consultant 
Nephrologist, North Bristol NHS Trust 
Professor Patrick Mark 
Professor of Nephrology, Institute for Cardiovascular 
and Medical Sciences, University of Glasgow and 
Honorary Consultant Nephrologist, Glasgow Renal and 
Transplant Unit 
Professor James Burton 
Professor of Renal Medicine, University of Leicester 
and Honorary Consultant Nephrologist, Leicester 
General Hospital 
Professor Simon Davies 
Professor of Nephrology, Keele University and 
Consultant Nephrologist, Royal Stoke Hospital 

 
EudraCT Number: 2020-004144-28 
IRAS ID: 288652 
 
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PROTECT-V protocol V11.0 – 05/Sep/2023 
 
Dr Ragada El-Damanawi 
Renal Consultant, Sheffield Teaching Hospitals NHS 
Foundation Trust 
Dr Kate Bramham 
Senior Clinical Lecturer in Renal Medicine, King’s 
College London and Consultant Nephrologist, King’s 
College Hospital 
Professor Liz Lightstone 
Professor of Renal Medicine, Imperial College London 
and Honorary Consultant Nephrologist, Imperial 
College Healthcare NHS Trust 
Professor David Jayne 
Professor of Autoimmunity, University of Cambridge 
and Honorary Consultant Nephrologist, Cambridge 
University Hospitals NHS Foundation Trust 
Dr Silke Brix 
Consultant Nephrologist, Manchester University NHS 
Foundation Trust 
Dr Neil Basu 
Clinical Senior Lecturer, University of Glasgow and 
Honorary Consultant 
Dr Sapna Shah 
Consultant Nephrologist, King’s College Hospital 
Dr Kieran McCafferty 
Consultant Nephrologist, Barts Health NHS Trust 
Dr Mark Lambie 
Senior Lecturer in Renal Medicine, Keele University 
Dr Viyaasan Mahalingasivam 
Registrar in Renal Medicine, Barts Health NHS Trust 
Prof Martin Wilkie 
Professor of Nephrology, University of Sheffield 
 
 
Additional protocol contributors will be acknowledged in the relevant appendices. 
 
 
 

 
EudraCT Number: 2020-004144-28 
IRAS ID: 288652 
 
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PROTECT-V protocol V11.0 – 05/Sep/2023 
 
 
Trial Statistician: 
Dr Wendi Qian 
Cambridge Clinical Trials Unit (Box 111) 
Addenbrooke’s Hospital, Hills Road 
Cambridge, CB2 0QQ 
Telephone: 01223 256363 
E-mail: wq211@medschl.cam.ac.uk 
Professor James Wason 
Professor of Biostatistics 
Newcastle University 
Richardson Road 
Newcastle upon Tyne 
E-mail: james.wason@ncl.ac.uk  
Trial Manager: 
Francis Dowling 
Cambridge Trials Unit (Box 401) 
Addenbrooke’s Hospital, Hills Road 
Cambridge, CB2 0QQ 
Tel: 01223 254684 
Email: francis.dowling@nhs.net  
Trial Pharmacist: 
Robyn Staples 
Central Pharmacy, Box 55 
Cambridge University Hospitals Foundation Trust 
Cambridge Biomedical Campus 
Cambridge, CB2 0QQ 
Tel: 01223 216057 
Email: Robyn.Staples@nhs.net 
Sponsor: 
Cambridge University Hospitals NHS Foundation Trust and University of Cambridge 
Research & Development Department (Box 277) 
Addenbrooke’s Hospital, Hills Road 
Cambridge, CB2 0QQ 
Telephone: 01223 245151 
e-mail: cuh.ccturegulatory@nhs.net 
 
 

 
EudraCT Number: 2020-004144-28 
IRAS ID: 288652 
 
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Table of Contents 
Contents 
Protocol Signatures: ........................................................................................................................................... 2 
Protocol Contributors .......................................................................................................................................... 3 
Table of Contents ............................................................................................................................................... 6 
1. 
ABBREVIATIONS ....................................................................................................................................... 9 
2. 
INTRODUCTION ....................................................................................................................................... 11 
3. 
BACKGROUND AND RATIONALE .......................................................................................................... 12 
3.1. 
Setting ............................................................................................................................................... 12 
3.2. 
Clinical Course and current treatment options ................................................................................. 12 
3.3. 
Rationale for a trial ........................................................................................................................... 13 
3.4. 
A pre-exposure prophylaxis trial in vulnerable populations .............................................................. 14 
4. 
DESIGN AND PROCEDURES ................................................................................................................. 15 
4.1. 
Trial Population ................................................................................................................................. 15 
4.2. 
Eligibility ............................................................................................................................................ 15 
4.2.1. 
Inclusion Criteria ....................................................................................................................... 15 
4.2.2. 
Exclusion Criteria ...................................................................................................................... 17 
4.3. 
Participant Identification and Consent .............................................................................................. 17 
4.4. 
Screening .......................................................................................................................................... 18 
4.4.1. 
Screening Assessment – in person consultation ...................................................................... 18 
4.5. 
Randomisation .................................................................................................................................. 18 
4.6. 
Blinding ............................................................................................................................................. 18 
4.6.1. 
Emergency unblinding .............................................................................................................. 18 
4.6.1. 
Schedule of Assessments ........................................................................................................ 19 
4.7. 
Trial assessments ............................................................................................................................. 20 
4.7.1. 
Timing of assessments ............................................................................................................. 20 
4.7.1.1. 
Screening/Baseline ‘visit’ 1 (face to face) 
20 
4.7.1.2. 
Telephone consultations - weeks 1,2,3, 4 and 6 (±3 days) 
20 
4.7.1.3. 
Two-Weekly self-reporting - week 8 onwards 
20 
4.7.1.4. 
Final safety assessment 
22 
4.8. 
Duration of study .............................................................................................................................. 22 
4.9. 
Treatment withdrawal ....................................................................................................................... 22 
4.9.1. 
Treatment period ...................................................................................................................... 23 
4.9.2. 
Diagnosis of COVID-19 ............................................................................................................ 23 
4.10. 
Withdrawal of consent ...................................................................................................................... 24 
4.11. 
Objectives ......................................................................................................................................... 25 
4.11.1. 
Primary objective ...................................................................................................................... 25 

 
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4.11.2. 
Secondary objectives ............................................................................................................... 25 
4.11.3. 
Exploratory objectives .............................................................................................................. 25 
4.12. 
Outcomes ......................................................................................................................................... 25 
4.12.1. 
Primary Outcome ...................................................................................................................... 25 
4.12.1.1. Definition of the primary outcome event 
25 
4.12.2. 
Secondary Outcomes ............................................................................................................... 25 
4.12.3. 
Exploratory Outcomes .............................................................................................................. 26 
4.13. 
Sample management ....................................................................................................................... 26 
4.13.1. 
SARS-Cov-2 antibody testing ................................................................................................... 26 
4.14. 
Methods of analysis of each prophylactic intervention ..................................................................... 26 
4.14.1. 
Analysis populations ................................................................................................................. 26 
4.14.1.1. Intent-to-treat population (ITT) 
26 
4.14.1.2. · Safety population 
27 
4.14.2. 
Efficacy Analysis ....................................................................................................................... 27 
4.14.3. 
Safety Evaluation ...................................................................................................................... 27 
4.15. 
Method of analysis at the end of trial ................................................................................................ 28 
4.16. 
Sample size ...................................................................................................................................... 28 
4.17. 
Criteria for the premature termination of a prophylactic treatment ................................................... 28 
4.18. 
Trial restrictions ................................................................................................................................ 28 
5. 
SAFETY MONITORING AND REPORTING ............................................................................................. 29 
5.1. 
Adverse Event Definitions ................................................................................................................ 29 
5.2. 
Expected AEs or ARs ....................................................................................................................... 30 
5.3. 
Recording, Evaluating & Reporting of Serious Adverse Events / SARs .......................................... 30 
5.3.1. 
Assessment of Seriousness ..................................................................................................... 30 
5.3.2. 
Assessment of Causality .......................................................................................................... 31 
5.3.3. 
Clinical Assessment of Severity ............................................................................................... 31 
5.4. 
Assessment and onward reporting of SUSARs ................................................................................ 31 
5.4.1. 
Who should report and whom to report to? .............................................................................. 31 
5.4.2. 
Reference Safety Information (RSI) ......................................................................................... 31 
5.4.3. 
When to report SUSARs ........................................................................................................... 31 
5.4.3.1. 
Fatal or life-threatening SUSARs 
31 
5.4.3.2. 
Non-fatal and non-life-threatening SUSARs 
32 
5.4.4. 
How to report SUSARs? ........................................................................................................... 32 
5.4.4.1. 
Minimum criteria for initial expedited reporting of SUSARs 
32 
5.4.4.2. 
Follow-up reports of SUSARs 
32 
5.4.4.3. 
Format of the SUSARs reports 
32 
5.5. 
Pregnancy Reporting ........................................................................................................................ 32 
6. 
TRIAL COMMITTEES ............................................................................................................................... 33 

 
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6.1. 
Trial Management Group (TMG) ...................................................................................................... 33 
6.2. 
Trial Steering Committee (TSC) ....................................................................................................... 33 
6.3. 
Independent Data Monitoring Committee (IDMC) ............................................................................ 33 
7. 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 34 
7.1. 
Source Data ...................................................................................................................................... 35 
7.2. 
Data Protection & Participant Confidentiality .................................................................................... 35 
8. 
ETHICAL & REGULATORY CONSIDERATIONS .................................................................................... 35 
8.1. 
Ethical committee review .................................................................................................................. 35 
8.2. 
Regulatory Compliance .................................................................................................................... 35 
8.3. 
Protocol Amendments ...................................................................................................................... 36 
8.4. 
Peer Review ..................................................................................................................................... 36 
8.5. 
Declaration of Helsinki and Good Clinical Practice .......................................................................... 36 
8.6. 
GCP Training .................................................................................................................................... 36 
9. 
SPONSORSHIP, FINANCIAL AND INSURANCE .................................................................................... 36 
10. MONITORING, AUDIT AND INSPECTION .............................................................................................. 36 
11. PROTOCOL COMPLIANCE AND BREACHES OF GCP ......................................................................... 37 
12. PUBLICATIONS POLICY .......................................................................................................................... 37 
13. REFERENCES .......................................................................................................................................... 37 
APPENDIX A: NICLOSAMIDE ......................................................................................................................... 39 
APPENDIX B: CICLESONIDE ......................................................................................................................... 52 
APPENDIX C: SOTROVIMAB .......................................................................................................................... 67 
 
 
 

 
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1. ABBREVIATIONS 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ALT 
Alanine aminotransferase 
AR 
Adverse Reaction 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate aminotransferase 
CA 
Competent Authority 
CCTU 
Cambridge Clinical Trials Unit 
CI 
Chief Investigator 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
Con Med 
Concomitant Medication 
COVID-19 
Coronavirus Induced Disease 2019 
CRF 
Case Report Form (when used for data collection) 
CRF 
Clinical Research Facility 
CTA 
Clinical Trial Authorisation 
CTAP 
Coronavirus Treatment Acceleration Program 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic Case Report Form 
FDA 
Federal Drug Agency 
FSGS 
Focal Segmental Glomerular Sclerosis 
GP 
General Practitioner 
GFR 
Glomerular Filtration Rate 
GCP 
Good Clinical Practice 
GN 
Glomerulonephritis 
HCW 
Healthcare workers 
HD 
Haemodialysis 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICNARC 
Intensive Care National Audit and Research Centre 
IDMC 
Independent Data Monitoring Committee 
IgA 
Immunoglobulin A 
IMP 
Investigational Medicinal Product 
IRR 
Infusion Related Reaction 
ITT 
Intention to Treat 
LFT 
Lateral Flow Test 
MERS 
Middle East Respiratory Syndrome, MERS-coronavirus (MERS-CoV) 
MHRA 
Medicines and Healthcare products Regulatory Agency  
NAFLD 
Non alcoholic fatty liver disease 
NASH 
Non alcoholic steatohepatitis 
NIHR 
National Institute of Health Research 
ONS 
Office National Statistics 

 
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PCR 
Polymerase chain reaction 
PHE 
Public Health England 
PI 
Principle Investigator 
PID 
Patient Identifiable Data 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetic 
PTO 
PROTECT-V Trial Office 
R&D 
Research and Development 
RA 
Regulatory Agency 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
RRT 
Renal Replacement Therapy 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SARS-CoV-2 
Severe Acute Respiratory Syndrome coronavirus 2 
SD 
Standard Deviation 
SKP2 
S--Phase Kinase Associated Protein 2 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMG 
Trial Management Group 
TNF 
Tumour Necrosis Factor 
TPM 
Trial Procedure Manual 
TSC 
Trial Steering Committee 
UKHSA 
UK Health Security Agency 
WHO 
World Health Organisation 
WOCBP 
Woman of child bearing potential 
 
 
 

 
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IRAS ID: 288652 
 
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2. INTRODUCTION 
PROTECT-V is a platform trial to test prophylactic interventions against SARS-CoV2 infection in vulnerable 
patient populations at particularly high risk of COVID-19 and its complications, seeking to identify treatments 
that either might prevent the disease from occurring or may reduce the number of cases where the disease 
becomes serious or life-threatening. In PROTECT-V, multiple agents can be evaluated on the same platform 
across multiple vulnerable populations, with the option of adding additional treatments at later time points as 
these become available. The expectation is for as many sites as possible to recruit to all available trial 
treatments at any time, however, the platform structure and randomisation/data collection systems allow sites 
to open the trial treatment arms according to their capacity. 
 
The trial commenced with the first intervention, nasal niclosamide and matched placebo from February 2021.  
 
Potential future prophylactic agents will be introduced either through the CTAP pathway, or if identified by the 
PROTECT-V study investigators, which will be discussed with the Prophylaxis Taskforce. PROTECT-V is also 
able to restrict interventions to particular subpopulations or patient groups, as well as adding additional 
vulnerable patient groups at a later stage. The trial  started by enrolling vulnerable patients with kidney or 
autoimmune diseases, including patients in receipt of dialysis, kidney transplant recipients, individuals with 
vasculitis and glomerular disease receiving immunosuppression.  
  
 

 
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Study Schema 
3. BACKGROUND AND RATIONALE 
3.1. Setting  
In December 2019, a respiratory disease causing severe respiratory tract infection a novel coronavirus-induced 
disease (COVID-19) emerged in Wuhan, China.1 A month later the Chinese Centre for Disease Control and 
Prevention identified a new beta-coronavirus (SARS coronavirus 2, or SARS-CoV-2) as the aetiological agent 
and the disease now called COVID-19. COVID-19 was declared a global pandemic by the WHO on 11th March 
2020. To date, there have been > 157 million cases worldwide with 3.27 million deaths (WHO figures 9th May 
2021). 
3.2. Clinical Course and current treatment options 
The clinical manifestations of COVID-19 range from asymptomatic infection to mild, upper respiratory tract 
infections to severe viral pneumonia with associated respiratory failure and death. Some patients will also go 
on to develop multi-organ failure, with kidney, cardiac and neurological complications of SARS-CoV-2. The 
frequency of severe disease in hospitalised patients can be as high as 30%. Many potential treatments are 
being assessed in randomised treatment trials. The UK RECOVERY trial has demonstrated that 
dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 
0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). 
There was no benefit in patients not requiring ventilatory support. The ACCT-1 trial showed a shorter recovery 
time 11 days (95%CI, 9 to 12) versus 15 days 
 (95% CI, 13 to 19) in remdesivir-treated patients. A number of other treatment options have demonstrated no 
benefit, including hydroxychloroquine and lopinavir-ritonavir.  

 
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In contrast, there are no drugs proven to prevent COVID-19 or to reduce the severity of illness if given as 
prophylaxis. Although vaccines are now available, there remains a need for other prophylactic agents until 
vaccine use becomes widespread globally and effectiveness and durability is established, particularly in 
immunocompromised individuals for whom vaccine responses may be suboptimal. Efforts are underway to 
repurpose established drugs with well understood drug interactions and safety profiles. 
3.3. Rationale for a trial 
A considerable number of trials have been established at great speed in the wake of the global SARS-CoV-2 
outbreak. However, most assess treatments for established COVID-19.. Boulware and colleagues evaluated 
hydroxychloroquine versus placebo after known exposure to a confirmed case of COVID-19.2 This trial failed 
to show benefit from hydroxychloroquine, but the trial had serious methodological limitations, provided 
prophylaxis post-exposure and for a short duration, and excluded patients with significant kidney disease. A 
proposal to conduct a pre-exposure prophylaxis trial with hydroxychloroquine in patients with chronic kidney 
disease (CKD) receiving dialysis was rejected by the UK MHRA on safety grounds. Headline results from the 
PROVENT trial, published July 2021, a Phase III, randomised, double-blind, placebo-controlled, multi-
centre trial assessing the safety and efficacy of a single IM 300mg dose of AZD7442 (tixagevimab 
(AZD8895) and cilgavimab (AZD1061)) compared to placebo for the prevention of COVID-19 met its 
primary endpoint a statistically significant reduction in the incidence of symptomatic COVID-19. 
Several patient groups appear to be vulnerable to COVID-19 infection by virtue of demographics, underlying 
health conditions or as a consequence of treatments for these conditions, and they are at exceptionally high 
risk of adverse outcomes. Such vulnerable patients include those with kidney disease requiring dialysis, in 
receipt of a kidney transplant, or with auto-immune diseases that might affect kidney function and require 
immunosuppression (e.g. vasculitis and glomerular diseases). Despite the introduction of widespread 
vaccination, there remains a need for antigen independent prophylactic agents. No vaccine is completely 
effective, new variants of SARS CoV-2 are emerging, and many vulnerable individuals are 
immunocompromised, either as a result of underlying disease or treatments, and are known to mount a 
suboptimal response to vaccination against viruses. Individuals with kidney disease – those requiring dialysis, 
in receipt of a kidney transplant, or with auto-immune diseases that might affect kidney function and require 
immunosuppression (e.g. vasculitis and glomerular diseases) - are vulnerable to COVID-19 and at high risk of 
adverse outcomes. These patient groups are also known to mount a sub-optimal responses to vaccination 
against viruses3-5.  
Dialysis patients typically need to attend their dialysis centre 3 times per week for at least 4 hours at a time 
and travel to dialysis centres by ambulance, car or taxi. It is impossible for them to self-isolate. Further, patients 
receiving dialysis may be less likely to benefit from admission to intensive care due to their comorbidity and 
the perceived prognostically deleterious impact of end-stage kidney disease. Those dialysis patients 
contracting COVID-19 have a 26% risk of death from the disease. To date, 11% of the UK’s in-centre dialysis 
population has contracted COVID-19. 
Kidney transplant recipients are immunosuppressed and are at increased risk of infections (including viruses) 
with attendant morbidity.3 Chronic Kidney Disease is itself recognised as a risk factor for severe infections. The 
combination of immunosuppression and reduced GFR render kidney transplant recipients at particular risk of 
COVID-19 since regular healthcare contact is imperative for most patients. Most kidney transplant recipients 
have been shielding during the pandemic to date, but the need for monitoring and easing of shielding advice 
make exposure to COVID-19 a real risk. There have already been 1129 confirmed cases among transplant 
patients in England despite shielding (UK Renal Registry report 28 July 2021) with 158 deaths (14% case 
fatality rate). 
Vasculitis patients suffer with serious relapsing remitting auto-immune disease that results in the requirement 
for a considerable burden of immunosuppression. The disease itself often results in organ damage, particularly 
renal and pulmonary damage, and individuals have significant comorbidity. Whilst individual vasculitis 

 
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syndromes remain generally rare, the pool of vasculitides represent a considerable patient population thought 
to be at high risk of contracting COVID-19 leading to severe disease, and even death. There is a paucity of 
data on the occurrence of COVID-19 in this patient population to date, but of the 64 cases reported by mid 
June, 17 have died, equating to a 27% case fatality rate. 
Despite vaccination against SARS CoV-2, and the third dose and booster vaccination campaign, sub-optimal 
vaccine response and vulnerability to Covid-19 infection remains a major issue in clinically extremely 
vulnerable individuals, including immunocompromised renal patients. In July 2021, a synthesised review of 35 
studies looking at vaccine response in renal patients demonstrated 89% (85-91%) response in dialysis patients, 
and 35% (29-42%) in individuals with a renal transplant after two doses of SARS CoV-2 vaccine.6 The literature 
on vaccine response in individuals with autoimmune disease is more complicated in view of disease and 
treatment heterogeneity, but responses are also sub-optimal to healthy individuals. Data on the effect of third 
doses in the immunocompromised patient population is emerging, and approximately 50% of those individuals 
not protected after 2 doses mount a response after an additional dose.7,8 It is important to note that the majority 
of studies report absolute antibody titres, which does not indicate the functionality and neutralising capacity of 
the antibodies. In a study of 178 dialysis patients in the UK, AZD1222 alone in sero-naive individuals induces 
suboptimal neutralising antibody titres against all variants of concern (VOCs), including the delta variant that 
is dominant globally.9 As such, a greater proportion of the patient population other than those without detectable 
antibodies remain highly vulnerable to SARS CoV-2 infection. Furthermore, the occurrence of breakthrough 
infections, with some studies reporting that immunocompromised persons account for a high proportion (≥40%) 
of infections among fully vaccinated hospitalized persons is further evidence of sub-optimal vaccine 
response.10,11  
Addition of further vulnerable patient cohorts to the PROTECT-V trial platform is possible at later time points 
as wider networks are established. 
The urgent need for interventions that provide effective prophylaxis against SARS-CoV2 is emphasised by a 
recent report commissioned by the UK Government projected 119,000 in-hospital deaths from COVID19 
between September 2020 and June 2021 (95%CI 24,500 - 251,000).12 This suggests a ‘second wave’ could 
be considerably worse than the first. Outside the United 
Kingdom the pandemic is still accelerating. An effective 
prophylactic treatment could save thousands of lives. 
3.4. A pre-exposure prophylaxis trial in vulnerable 
populations 
PROTECT-V aims to enrol patients at particularly high risk of 
COVID-19 and its complications, seeking to test whether 
intranasal niclosamide might prevent the disease from 
occurring. The PROTECT-V trial platform brings greater 
efficiency, running multiple sub-trials within one master 
protocol. The core components of the PROTECT-V trial 
platform include: 
 
Central coordination trial management team  
 
Single data system, with linkage to UKHSA (formerly PHE), ONS, HES and ICNARC datasets 
 
Sponsor and regulatory oversight 
 
Single contract with participating sites for multiple interventions/populations 
 
Statistical efficiency – depending on specific interventions/populations, it may be possible to use 
Bayesian analysis methods that allow adaptive borrowing of information across populations. This will 

 
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mean in the case that there is a consistent effect across populations, the trial will have greater power 
to find significant differences for individual patient groups.  
Initially, participants will be randomised 1:1 to niclosamide or matching placebo. Additional treatment arms may 
be added if further promising treatments become available.  
 
4. DESIGN AND PROCEDURES 
4.1. Trial Population 
Participants will be enrolled from three vulnerable patient populations: dialysis patients, kidney transplant 
recipients and those with vasculitis or other auto-immune kidney disease such as systemic lupus 
erythematosus (SLE) or glomerulonephritis (GN).  
The provisional distribution between trial populations will be 1:1:1 (dialysis:transplant:vasculitis/SLE/GN). No 
capping for a specific subgroup will be implemented but it is expected to have a minimum of 150 patients in 
each subgroup per arm, or 300 patients per intervention plus placebo. However, the proportion of the total trial 
population represented by each subgroup may be adjusted depending on the event rate of the primary outcome 
measure within each patient group. The subgroup-specific event rate will be monitored monthly. 
4.2. Eligibility 
4.2.1. Inclusion Criteria 
To be included in the trial the participant must: 
 
Be aged 18 years or older 
 
Have given written informed consent 
 
Be a member of one of the following vulnerable patients populations 
○ 
Dialysis – including in centre haemodialysis, home haemodialysis and peritoneal dialysis 
○ 
Kidney transplant receiving at least one of the immunosuppressive medications listed in the table 
below 
○ 
Vasculitis (according to Chapel Hill Consensus Conference 2012 definitions) or systemic lupus 
erythematosus (SLE) receiving at least one of the immunosuppressive medications listed in the table 
below 
○ 
Glomerulonephritis* receiving at least one of the immunosuppressive medications listed in the table 
below  
 
* Glomerulonephritis includes prior histological confirmation of any of the following conditions - minimal change 
nephropathy, focal segmental glomerulosclerosis (FSGS), IgA nephropathy, primary membranous 
nephropathy, membranoproliferative glomerulonephritis or lupus nephritis. 
 
 

 
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Inclusion criteria 
Dialysis 
Kidney Transplant OR Vasculitis OR Glomerulonephritis 
or SLE receiving at least one of the following 
immunosuppressive medications 
Aged 18 years or older 
✓ 
✓ 
Written Consent  
✓ 
✓ 
In-centre haemodialysis or home 
haemodialysis or peritoneal dialysis 
✓ 
- 
Ciclosporin 
- 
✓ 
Tacrolimus 
- 
✓ 
Azathioprine 
- 
✓ 
Mycophenolate Mofetil or Mycophenolic 
Acid 
- 
✓ 
Belatacept 
- 
✓ 
Methotrexate 
- 
✓ 
Tocilizumab 
- 
✓ 
Abatacept 
- 
✓ 
Leflunomide 
- 
✓ 
Prednisolone (current dose) > 20mg daily 
for 8 weeks 
- 
✓ 
Anti-TNF 
(infliximab, 
adalimumab, 
etanercept) 
 
✓ 
Belimumab 
 
✓ 
Cyclophosphamide (within the last 6 
months) 
- 
✓ 
Rituximab (in the last 12 months) or 
Rituximab in the last 5 years and IgG level 
<5g/l 
- 
✓ 
Alemtuzumab (in the last 12 months) 
- 
✓ 
Sirolimus 
 
✓ 
 

 
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4.2.2. Exclusion Criteria 
The presence of any of the following will preclude participant inclusion: 
 
Inability to provide informed consent or to comply with trial procedures 
 
COVID-19 at time of enrolment – either positive SARS CoV-2 swab (PCR or lateral flow test; LFT) or 
symptoms highly suggestive of COVID-19 infection 
 
Allergy or hypersensitivity to any of the active IMPs, or to any of the excipients used 
 
Pregnant, trying to conceive, unwilling to use contraception or breastfeeding 
 
Current participation in another interventional prophylactic or vaccine trial* against COVID-19. 
 
*Patients remain eligible for enrolment if they have received SARS-COV-2 vaccination as part of routine 
care. 
Additional exclusion criteria specifically related to individual intervention or IMPs will be listed in the relevant 
appendices. 
 
4.3. Participant Identification and Consent 
Potential participants can be identified via a number of avenues including advertisements, word of mouth, trial 
specific invitation letter, face to face and existing cohort studies. 
● 
The PROTECT-V website will contain a video where one of the central trial physicians explains the study. 
● 
Additional information, including the detailed Participant Information Sheets will be available from the local 
site study team and on the study website.  
Consent will be obtained by the Principal Investigator at each trial site or by a suitably qualified and delegated 
health professional and member of the research team at each site.  
● 
Potential participants will be given a copy of the Patient Information Sheet to read through thoroughly, 
including the opportunity to take it home and discuss the trial with relatives/friends and other medical 
professional eg GP. 
● 
The Principal investigator or a suitably qualified and delegated health professional will explain the aims, 
methods, anticipated benefits, potential hazards and risk benefit balance of the intervention.  
● 
The participant will be allowed as much time as they need to consider all the information.  
● 
The Investigator will explain that participants are under no obligation to enter the trial and that they can 
withdraw at any time during the trial, without having to give a reason.  
● 
No trial specific procedures will be conducted prior to the participant giving consent by signing the Consent 
form. 
● 
Participants will be given a copy of their signed PIS and Informed Consent form to retain at home for future 
reference. Contact details for the local study team are included in the PIS should the participant have any 
further questions. 
If further safety information becomes available, the PIS and Informed Consent Form (ICF) will be reviewed 
and updated and submitted to the REC for approval. All participants that are actively enrolled in the study 

 
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will be informed of the updated information and will be required to sign the revised copy of the PIS/ICF in 
order to confirm their wish to continue on the study. 
The Informed Consent form must be approved by the REC and must be in compliance with GCP, local 
regulatory requirements and legal requirements. The investigator or designee must ensure that each trial 
participant is fully informed about the nature and objectives of the trial and possible risks associated with 
their participation. 
 
4.4. Screening 
4.4.1. Screening Assessment – in person consultation 
The screening and baseline visits may be readily combined in those patients who agree to participation in the 
trial. Screening will be conducted at participating sites. Participants attending the screening visit will be given 
a unique ID number to be used in all CRFs. 
All eligible participants who proceed to randomisation will be provided with the trial specific Patient ID Card 
which includes details of the trial IMPs and contact details of the local study team and Sponsor. 
4.5. Randomisation 
The PI or suitably qualified and delegated member of the study team will confirm the eligibility of a participant 
by entering their screening data into the PROTECT-V eCRF web portal. Once the full screening details have 
been entered and eligibility confirmed, the participant will be randomised. 
Randomisation will be carried out using a web-based randomisation system (Sealed Envelope) accessible via 
password-protected access. Randomisation will be stratified by PROTECT-V disease sub-group, age and site 
using a stratified block randomisation method. 
Immediate allocation of treatment will be performed, with documentation of the decision in a blinded 
confirmatory email. The notification will state what intervention a participant has been randomised to but not 
whether active or placebo drug has been assigned. The system will allocate the participant treatment pack 
code(s) which will relate uniquely to the first supply of IMP. Different treatment pack code(s) for every 
subsequent order of IMP supply will be allocated by the randomisation system.  
 
4.6. Blinding 
PROTECT-V will commence as a double blind placebo controlled study where neither the participant nor 
clinician will be aware of treatment allocation (whether active or placebo). As additional IMPs are added to the 
platform, the practicalities of blinding treatment and the need/availability of matched placebo will be evaluated 
on an individual basis. It may be necessary to restrict the number of IMPs in the platform if blinding is to be 
maintained. The independent DMC will regularly review the event rate in individual placebo arms to ensure 
they are comparable. In the participant’s information sheet, participants will be clearly informed that they will 
be blinded until the end of the trial or until a new standard care has been established, whichever occurs first. 
4.6.1. Emergency unblinding 
Treatment code break and unblinding must only occur in exceptional circumstances when knowledge of the 
actual treatment is essential for further management of a participant and their safety. If the investigator or 

 
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treating clinician deems unblinding to be necessary, the web-based randomisation system can be used by 
designated local investigators to unblind. The unblinder will not be shown the treatment allocation on-screen. 
Instead the allocation will be sent by email to the treating clinician and the unblinding notification without 
allocation should be printed and retained within the Investigator Site File. An email stating that an unblinding 
has taken place will be automatically sent to the coordination team and CI for oversight purposes. 
Unless it is necessary for the safety of the participant, the actual allocation must not be disclosed to the 
participant or other site personnel, either verbally or by any written correspondence. The CI/PI will also notify 
the Sponsor and the relevant authorities as necessary. 
4.6.1. Schedule of Assessments 
 
Assessment  
Schedule 
Screen/ 
Baseline 
visit 
Weekly 
(±3 days) 
% 
2-weekly (±3 
days) % 
  
As 
required 
data 
linkage 
Final 
assessment 
Eligibility check 
X 
 
 
 
 
 
Medical history  
 
X 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
 
 
 
Symptom checker 
questionnaire$ 
X 
X 
X 
 
 
 
SARS-CoV2 PCR or 
lateral flow test 
X 
 
 
X 
 
 
Serum sample for 
SARS-CoV2 Total Ab 
assay 
X 
 
 
 
 
X 
ALT/AST& 
X 
 
 
 
 
 
Pregnancy test# 
X 
 
 
 
 
 
SAR/SAE/SUSAR 
Reporting 
 
 
 
X 
 
 X  
Randomisation 
X 
 
 
 
 
 
COVID-19 infection 
 
 
 
 
X 
 
 
#A pregnancy test is required for WOCBP within 14 days prior to starting trial treatment. Women are considered 
WOCBP following menarche and until becoming post-menopausal unless permanently sterile (previous 
hysterectomy, previous bilateral salpingectomy and or oophorectomy). A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause. A serum pregnancy test is required for all 
WOCBP participants. 
% Weekly for one month and 2-weekly thereafter. Any participant testing positive for SARS-CoV-2 without 
symptom will be required to complete a COVID-19 symptom assessment at least weekly for 4 weeks after 
diagnosis, unless hospitalised. 
$ Telephone consultation will occur for the first 6 weeks. More details in sections 4.7.1.2 and 4.7.1.3. 

 
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& Routine ALT/AST tests performed up to 2 week before screening visit will be accepted to assess liver function 
Refer for each appendix for additional intervention specific assessments. 
 
 
4.7. Trial assessments 
The following sections describe the schedule of assessments that will be completed by participants. The 
Schedule of Assessments is shown in the table below. Further details are available in the trial procedures 
manual (TPM). 
PROTECT-V is a pragmatic trial. In view of the challenges of conducting clinical trials in a pandemic, research-
specific face-to-face visits as part of their trial participation will be kept to a minimum and aligned with routine 
clinical follow up whenever possible, as healthcare contact needs to be minimised during the COVID-19 
pandemic. Therefore, telephone follow-up and self-reporting of symptoms will be utilised. 
Data on the primary endpoint (COVID-19 infection) will be captured on a monthly basis via linkage with UKHSA 
(formerly PHE), and by direct reporting by sites or by participants. All subsequent assessments will consist of 
self-completed questionnaires online or post, or through telephone calls from the local trial team. Where 
possible, data will be collected in real time through linkage with NHS Digital or equivalent, ONS, ICNARC or 
other routine data sources as necessary. Data on death will be reported by sites or obtained via linkage.  
 
4.7.1. Timing of assessments 
4.7.1.1. 
Screening/Baseline ‘visit’ 1 (face to face) 
 
Eligibility 
 
Randomisation 
 
Baseline data collection 
o 
Medical history 
o 
Current medications 
o 
Vaccination history 
o 
Symptom checker self-assessment questionnaires 
 
Research serum sample collection to detect anti SARS-COV-2 antibodies 
 
IMP courier delivery arrangements (if necessary) and instruction on IMP administration, storage, dose 
recording (if necessary). 
 
4.7.1.2. 
Telephone consultations - weeks 1,2,3, 4 and 6 (±3 days) 
Participants will be telephoned by a member of the local research team and asked about the treatment received 
and symptoms suggestive of potential side effects of the trial treatment  or of COVID-19 infection, once every 
week for the first 4 weeks and then again on the sixth week from the start of the trial treatment. If concerns are 
raised about potential side effects of the IMP received, the information will be reviewed by the PI and a decision 
made whether to continue IMP. Participants will be asked to keep a diary of IMP administration (if self-
administering) with reasons for any missed doses.  
4.7.1.3. 
Two-Weekly self-reporting - week 8 onwards  
Participants will be asked to complete a short questionnaire regarding COVID-19 self-assessment/reporting 
and potential side effects of the IMP received, once every two weeks during trial conduct via email, in paper 
form via mail, or via telephone interview. Participants receiving in centre haemodialysis may be assessed 
during their dialysis sessions. The intention of two-weekly self-reporting is to provide participants with the 
opportunity to  

 
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● 
indicate any symptoms suggestive of COVID-19 infection, 
● 
side  effects of IMP administration, 
● 
report new concomitant medications 
● 
report vaccination against COVID-19 
If a participant has not submitted data for a period of approximately 6 weeks, they will be contacted by the local 
study team for a telephone interview to minimise loss to follow up. Failure to follow up a participant for more 
than 6 consecutive weeks will halt their trial treatment dispensation until communication has been restored. 
Failure to follow up a participant for more than 12 consecutive weeks will be considered loss of follow up and 
conclude their participation in the trial.  
Unscheduled assessment – “suspected COVID-19 infection” 
Should an individual develop symptoms suggestive of COVID-19 infection, which are listed in the Participant 
Information Sheet, they must inform the site team of their symptoms so these can be followed up and recorded 
within the electronic case report form (eCRF) pages. The participant should also take a COVID-19 lateral flow 
test (LFT), or preferably a PCR test if possible, depending on the tests available via the NHS.  
If they encounter any issues with organising the PCR or LFT, the participant should get assistance from the 
site team. Swabs (PCR or LFT) for COVID-19 (and swabs for influenza – see text below) should be performed 
as soon as possible after onset of symptoms. As soon as the result of the COVID-19 swab (PCR or LFT) and 
the influenza swab (if applicable) are known, the participant should inform the site team of these results. 
Importantly, if the participant’s LFT appears positive, the participant should: 
 
Take a photograph of the LFT result including the QR code  
 
Forward this photograph together with the date of the test and Trial ID number to the participating site 
team.  
 
Report their LFT result on the government website (currently this is https://www.gov.uk/report-covid19-
result.) 
The site team should then file a copy of the LFT result in the participants’ medical notes and within the ISF. If 
the LFT shows a positive result, a PCR test may also be arranged if these are available. Participants will also 
be required to notify their trial physician. 
Where possible, if the LFT is negative but the patient has symptoms consistent with COVID-19 infection, the 
team may then try to arrange a COVID-19 PCR test.   
For the niclosamide/matched placebo arm only, patients may also be swabbed for influenza at the same time, 
if they present to hospital. If this is not done routinely with the COVID-19 test in their area, the influenza test 
does not have to be completed. Where influenza swabs are available, the participant can self-swab, or ask a 
relative, or the individual performing the COVID-19 swab (PCR or LFT) may perform the test according to the 
instructions provided. The swab should be placed in the stamped addressed envelope and placed in a post 
box immediately to return to local site laboratories for testing. 
The individual should contact their local site to 
● 
Inform the site team of their symptoms so that these can be followed up and recorded in the eCRF pages 
● 
Get assistance should they be having difficulty organising a test (PCR or LFT) themselves. Swabs (PCR 
or LFT) for COVID-19 and swabs for influenza should be performed as soon after onset of symptoms as 
possible. 

 
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Inform the site team of the result of the COVID-19 swab (PCR or LFT), and receive the result of the influenza 
swab. If LFT is used, the individual should forward a photograph of the LFT result including the QR code, date 
of the test and their Trial ID number to the site trial team. The LFT result should also be reported on the 
government website (https://www.gov.uk/report-covid19-result). The site team may assist the patient with 
reporting their LFT result on the government website as necessary. 
Participants should continue taking trial medication (if self-administering medication) until advised to stop by a 
member of the trial team or admitted to hospital. 
Participants must follow the public health guidance for “suspected COVID-19 infection” current at that time 
Any participant testing positive for SARS-CoV-2 will be required to complete a COVID-19 symptom assessment 
at least weekly for 4 weeks after diagnosis, unless hospitalised. 
4.7.1.4. 
Final safety assessment 
PROTECT-V is an event driven platform trial. The anticipated median treatment duration per participant is 6 
months. However, the individual arm may conclude while some participants are in the trial for less than 6 
months if the required number of events are observed. Upon completion of the trial, participants randomised 
to the active IMP and matching placebo will be notified by email or by telephone depending on participant 
preference. Participants will be asked to stop taking IMP (if self-administering) and acknowledge receipt of 
end-of-trial arm notification. Patients will remain blinded.  
A final safety assessment will be conducted in person, 4-6 weeks after the final treatment (defined as date of 
last dose of IMP administered). Participants will be asked to return all completed medication diaries and IMP 
containers, if self-administering, for compliance assessment at this visit. Participants will be asked a series of 
questions to identify any additional adverse events or adverse reactions experienced since their last follow up 
assessment and a blood sample will be taken for a SARS-CoV2 total antibody assay, to detect asymptomatic 
cases of COVID-19 infection.  
At the final assessment, patients may be re-screened for consideration of enrolment (under a new subject 
ID) into one of the other arms of the PROTECT-V trial platform. It is not permitted for re-enrolment into 
the originally assigned arm. 
 
4.8. Duration of study 
PROTECT-V is an event driven trial. Duration for each IMP will be detailed in the relevant appendix.  
4.9. Treatment withdrawal 
Participants will be withdrawn from trial treatment at the discretion of the PI/CI if continuation in the trial is 
deemed to be against the participant’s best interest. 
Treatment will be withdrawn if: 
● 
Participants become pregnant 
● 
Participant is hospitalized for COVID-19 
● 
Participant experiences unacceptable drug reaction 
● 
Participant has not been followed up for more than 6 consecutive weeks (temporary halt) or for more than 
12 consecutive weeks (loss of follow up and trial withdrawal). 
 

 
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Participants who have been withdrawn from the trial treatment and are experiencing ongoing toxicity will be 
followed up until the adverse reaction comes to its conclusion. In the event of a Participant being withdrawn 
from the trial treatment, they will continue to receive the most appropriate standard of care treatment available 
under the guidance of their treating clinician. 
Following treatment withdrawal, at the final assessment, patients may be re-screened for consideration of 
enrolment (under a new subject ID) into one of the other arms of the PROTECT-V trial platform.  
 
4.9.1. Treatment period 
Participants will continue allocated treatment until one of the following occurs: 
a. The required number of the primary outcome events have occurred (for each intervention) 
b. The participant is hospitalised with COVID-19 (see 4.10.2.) 
c. 28 Days after a diagnosis of COVID-19 if hospitalisation is not required 
4.9.2. Diagnosis of COVID-19 
Participants may receive a diagnosis of COVID-19 during the course of participation in the trial, either as a 
result of routine testing or prompted by suggestive symptoms. Any participant diagnosed with COVID-19 should 
continue self-administering their randomised treatment, if applicable, for 28 days after the date of diagnosis, 
unless hospitalised. Participants hospitalised with a diagnosis of COVID-19 should stop the randomised 
treatment immediately. 

 
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Participants receiving a diagnosis of SARS-CoV-2 infection who are asymptomatic (most likely after routine 
screening) will be required to follow the above algorithm, continuing with treatment for 4 weeks unless 
hospitalised. If such participants remain asymptomatic, they will be judged not to have reached the primary 
endpoint for the trial. If they become symptomatic after diagnosis, they will be judged to have reached the 
primary endpoint of the trial. Under these circumstances, the primary endpoint date will remain the date of 
confirmed SARS-CoV-2 (the date of the test). 
Any participant testing positive for SARS-CoV-2 will be required to complete a COVID-19 symptom assessment 
at least weekly for 4 weeks after diagnosis, unless hospitalised. 
4.10. Withdrawal of consent 
Participants may withdraw consent for continuation in the trial at any point. Participants may choose to withdraw 
only from active trial participation (trial treatment and self-reporting questionnaires), allowing continuation of 
data collection through data linkage, or may choose to withdraw both from the trial and all further data linkage. 
No further trial procedures will be undertaken and no data or samples will be collected from the time of consent 
withdrawal, in line with the participant’s wishes. However, data and samples collected up to the time of consent 
withdrawal will be included in the data reported for the trial. The Investigator should inform the coordination 

 
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team as soon as possible and complete the End of Treatment Case Report Form (CRF), Trial Endpoint CRF 
and withdrawal CRF page if no further follow up is planned. 
Please note that the participant will be contacted for a safety assessment 4-6 weeks from last IMP dose 
regardless whether the participant withdrew from the further assessment.  
 
4.11. Objectives 
4.11.1. 
Primary objective 
The primary aim of the trial is to determine if prophylactic treatment reduces the risk of confirmed symptomatic 
COVID-19 infection in vulnerable renal and immunosuppressed patients participating in the study. 
4.11.2. 
Secondary objectives 
The trial also aims to: 
1) Determine if prophylactic treatment increases the time to confirmed SARS-Cov-2 infection from the date of 
randomisation including incidental asymptomatic cases in the vulnerable populations taking part in the study. 
2) Determine the safety of prophylactic treatments in this patient population 
3) Determine if prophylactic treatment reduces mortality and severity of COVID-19 infection in the vulnerable 
populations taking part in the study. 
4.11.3. 
Exploratory objectives 
 Determine if prophylactic treatment increases the proportion of individuals with antibodies to SARS-Cov-2 at 
the end of the trial in the vulnerable populations taking part in the study. 
 
4.12. Outcomes 
4.12.1. 
Primary Outcome 
The primary outcome for PROTECT-V is confirmed symptomatic COVID-19 infection during treatment. 
4.12.1.1. Definition of the primary outcome event 
The primary outcome event is defined as the presence of both 
● 
Confirmed SARS-CoV2 (by either PCR or lateral flow) and 
● 
One or more symptoms in keeping with COVID-19, including: 
○ 
Respiratory (Cough +/- sputum and shortness of breath) 
○ 
Constitutional (Pyrexia/chills, myalgia/arthralgia, fatigue, rash, headache, confusion) 
○ 
Gastrointestinal (nausea/vomiting, diarrhoea, abdominal pain, loss of appetite) 
The date (time) of the primary outcome event is defined as the date of the confirmed COVID-19 test. 
4.12.2. 
Secondary Outcomes 
Secondary outcomes include 
a. Time to confirmed SARS-Cov-2 infection from the date of randomisation including asymptomatic cases 

 
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b. Safety and All-cause mortality 
c. Severity of COVID-19 disease (assessed by PI 28 days after date of positive test) 
i. 
Adapted WHO ordinal scale (defined as the worst category 28 days from date of positive 
test or until date of discharge from hospital, whichever occurred later) 
1. Healthy carriers - confirmed SARS-CoV2 infection, no symptoms 
2. Very mild symptoms, no limitations 
3. Mild, limitations on activities 
4. Mild, hospitalised, no oxygen requirement 
5. Moderate, hospitalised, oxygen via mask or nasal cannulae 
6. Severe, non-invasive ventilation or high flow oxygen 
7. Very severe, intubation and mechanical ventilation 
8. Critical, ventilation and additional organ support (RRT/ECMO) 
9. Death 
ii. 
Length of inpatient stay 
iii. 
Common 
COVID-19 
complications 
(including 
ARDS, 
viral 
pneumonitis, 
myocarditis/myocardial injury, AKI) 
 
Additional information on longer term outcomes may be collected through review of medical records or linkage 
to medical databases such as those managed by NHS Digital, ICNARC, and UKHSA (formerly PHE). 
 
4.12.3. 
Exploratory Outcomes 
Exploratory outcomes will include 
1. 
Occurrence of antibodies to SAR-CoV-2 at the end of the trial 
 
4.13. Sample management 
Only authorised staff will have access to the trial samples. Full instructions for the collection, labelling and 
storage of samples are provided in the Trial Procedure Manual. 
4.13.1. 
SARS-Cov-2 antibody testing 
Serum samples will be taken at baseline and final assessment visits to test presence of antibodies against 
SARS-Cov-2. Samples will be stored and analysed in batch. Refer to laboratory section of trial procedure 
manual for full details of sample processing. 
 
4.14. Methods of analysis of each prophylactic intervention 
4.14.1. 
Analysis populations 
The following populations will be defined for efficacy and safety analyses for each of prophylactic intervention. 
4.14.1.1. Intent-to-treat population (ITT) 
The ITT population is defined as all participants randomised between the prophylactic intervention and the 
randomised placebo, regardless of whether they actually received trial treatment. The treatment group will be 
analysed as randomised. 

 
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4.14.1.2. · Safety population 
The safety population comprises all participants randomised between the prophylactic intervention and the 
placebo, and having received as least one dose of trial treatment. The treatment group will be analysed as 
treated. 
4.14.2. 
Efficacy Analysis  
The primary outcome measure, symptomatic COVID-19 infection, will be compared between each prophylactic 
treatment and the randomised placebo groups in the ITT population using a Cox proportional hazards model, 
considering adjustment for the following fixed effects   
· 
Age 
· 
Sex 
· 
Ethnicity 
· 
Patient population (dialysis, vasculitis/glomerulonephritis, transplant) 
· 
Known high-risk pre-existing conditions (e.g. cardiovascular disease, hypertension, diabetes mellitus), 
vs not. 
· 
Detectable anti SARS-COV-2 antibodies at baseline 
· 
Receipt of Covid-19 vaccination (a time-dependent covariate) 
· 
Randomisation option (one prophylactic treatment vs two prophylactic treatments) 
 
The hazard ratio will be determined and statistical significance will be declared using a 2-sided alpha-level of 
0.045 (adjusting for interim analyses, see sample Size section for details). There is no need to use a multiplicity 
adjustment for the treatment arms as these are considered independent comparisons. A 95% confidence 
interval for the hazard ratio from the Cox model will be provided. The estimand properties of the primary and 
sensitivity analyses of the primary endpoint will be detailed in the Statistical Analysis Plan 
Participants who did not develop symptomatic COVID-19, withdrew from the study, are lost to follow-up or died 
prior to developing symptomatic COVID-19 will be censored at the date of last treatment administered (for self-
administered IMP, otherwise last follow-up for all other participants). Further detail will be included in statistical 
analysis plan (SAP). Asymptomatic confirmed COVID-19 (either by PCR or LFT) participants will be followed 
up for a maximum of 4 weeks (this is consistent with the maximum of 4 week treatment after positive COVID-
19). If any protocol specified symptoms have occurred, the date of the positive COVID-19 test is the date of 
primary endpoint event; otherwise, the participant will be censored at the date of last follow up, or last treatment 
administered, if self-administering IMP. 
For the secondary outcome measure of time-to-confirmed SAR-Cov-2 infection (either by PCR or LFT) in the 
ITT population, the analysis will use a Cox proportional hazards model as described for the primary outcome 
measure. The median, 25th and 75th percentile and 95% Cis for time to confirmed SARS-CoV-2 infection (either 
by PCR or LFT) will be provided. The severity scale of COVID-19 disease will be compared using a proportional 
odds model for all COVID-19 infected participants. Length of inpatient stay will be compared using Fine and 
Gray approach with discharge alive as event of interest and hospital death as competing event for all 
hospitalised participants.. Common COVID-19 complications for all COVID-19 infected participants in the ITT 
population will be analysed using the standard chi-square test. The comparisons on the secondary outcome 
measures will be compared according to a pre-specified hierarchal order. Details will be included in the SAP.  
 
Different efficacy analysis will be included in an Appendix if required.  
4.14.3. 
Safety Evaluation 
The safety analyses will be based on the safety population for each prophylactic treatment. All safety 
parameters will be summarised. Summary tables will be presented for incidence rates of AEs, ARs, SAEs and 
SARs. 

 
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A full statistical analysis plan will be written before any analyses are undertaken. 
 
4.15. Method of analysis at the end of trial 
If efficacy is observed for more than one prophylactic intervention, comparisons between different prophylactic 
treatments will be performed at the end of trial in an exploratory manner.  
 
4.16. Sample size 
Details for each intervention will be included in the relevant appendix. The impact of vaccine response and 
infections rates in this patient population remains uncertain, and the assumption used in the sample size 
estimation will be monitored by the DMC. Sample size re-estimation will be considered with the process 
detailed in the DMC Charter.  
 
4.17. Criteria for the premature termination of a prophylactic treatment  
Each prophylactic intervention will be reviewed individually every 2 months by the Independent Data Monitoring 
Committee (DMC) for safety, combined primary outcome measure event rate and making a recommendation 
for performing efficacy analyses. A prophylactic treatment arm will be stopped early if there are any safety 
concerns. Depending on the specific requirements of each prophylactic treatment specified in the 
corresponding Appendix, a treatment could be stopped early for efficacy should there be sufficient evidence of 
beneficial effect comparing to the randomised placebo, or for futility if there is sufficient evidence of futile effect 
comparing to the randomised placebo. These decision will be based on the recommendation of independent 
Data Monitoring Committee with the detailed process included in the DMC charter and the approval from the 
Trial steering committee.  
Should one treatment arm be stopped earlier, future participants would be randomised between the remaining 
active prophylactic treatments and their matching placebos. 
 
4.18. Trial restrictions  
Women of childbearing potential are required to use effective contraception for the duration of the trial and for 
28 days after the completion of the last treatment. This includes: 
● 
Intrauterine Device (IUD) 
● 
Hormonal based contraception (pill, contraceptive injection or implant etc.) 
● 
Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap with spermicide) 
● 
True abstinence (where this is in accordance with the participant’s preferred and usual lifestyle) 
 

 
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5. SAFETY MONITORING AND REPORTING 
 
All Adverse Events (AEs) and Adverse Reactions (ARs) will be recorded in the medical notes and in the 
appropriate section of the CRF. SAEs and SARs should be reported to the sponsor as detailed in section 5.3. 
5.1. Adverse Event Definitions 
TABLE 1 
 Term  
Definition  
Adverse event  
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which is not necessarily caused by or related to this 
treatment.  
Adverse Reaction  
All untoward and unintended responses to an investigational medicinal product 
related to any dose administered. All adverse events judged by either the reporting 
investigator or the sponsor as having a reasonable causal relationship to a 
medicinal product qualify as adverse reactions. The expression ‘reasonable causal 
relationship’ means to convey, in general, that there is evidence or argument to 
suggest a causal relationship.  
Unexpected 
Adverse Reaction  
An adverse reaction, the nature, or severity of which is not consistent with the 
applicable reference safety information (RSI). When the outcome of the adverse 
reaction is not consistent with the applicable RSI this adverse reaction should be 
considered as unexpected. 
Serious 
Adverse 
Event 
(SAE) 
or 
Serious 
Adverse 
Reaction (SAR)  
Any untoward medical occurrence that at any dose:  
- results in death,  
- is life-threatening 
- requires hospitalisation or prolongation of existing inpatient hospitalisation  
- results in persistent or significant disability or incapacity, - is a congenital 
anomaly or birth defect.  
- is another important medical event  
Life-threatening in the definition of a serious adverse event or serious adverse 
reaction refers to an event in which the subject was at risk of death at the time of 
event; it does not refer to an event which hypothetically might have caused death if 
it were more severe. 
Suspected 
Unexpected Serious 
Adverse 
Reaction 
(SUSAR)  
A serious adverse reaction, the nature and severity of which is not consistent with 
the information set out in the RSI. 
  

 
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NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, the 
following note of clarification is provided: “Severe” is often used to describe intensity of a specific event, which 
may be of relatively minor medical significance. “Seriousness” is the regulatory definition supplied above. 
5.2. Expected AEs or ARs 
The Sponsor expects that adverse events are recorded from the point of Informed Consent regardless of 
whether a participant has yet received a medicinal product. Individual adverse events should be evaluated by 
the investigator. This includes the evaluation of its seriousness, and any relationship between the 
investigational medicinal product(s) and/or concomitant therapy and the adverse event (causality). All expected 
Adverse Reactions are listed in the latest MHRA approved version of the RSI as specified in section 5.4.2 This 
must be used when making a determination as to the expectedness of the adverse reaction. If the adverse 
reaction meets the criteria for seriousness, this must be reported as per section 5.3. 
All AEs and ARs, which are new or significantly worse since commencing the trial, should be recorded on the 
symptom checker questionnaire in the CRF and sent to the trial coordination centre within one month of the 
investigator becoming aware of the event. 
 
5.3. Recording, Evaluating & Reporting of Serious Adverse Events / SARs 
The Chief Investigator or PI is responsible for ensuring that the assessment of all SAEs for expectedness and 
relatedness is undertaken, (except for elective overnight admissions for pre-existing medical conditions, or 
complications directly related to vascular access, such as fistula thrombosis or central venous catheter infection 
or malfunction, or renal transplantation), and the onward notification of all SAEs and SARs to the Sponsor 
immediately but not more than 24 hours of first notification. A further review of expectedness will be undertaken 
by the Chief Investigator. The sponsor has to keep detailed records of all SAEs and SARs reported to them by 
the trial team. 
The Chief Investigator is also responsible for prompt reporting of all Serious Adverse Reactions to the 
competent authority (MHRA) if they could: 
● 
adversely affect the health of participants  
● 
impact on the conduct of the trial  
● 
alter the competent authority’s authorisation to continue the trial in accordance with Directive 2001/20/EC 
Details of where to report SAEs and SARs can be found in the PROTECT-V trial manual and on the front cover 
of the protocol. 
It will not be a requirement to report any SAE which occurs between final study visit in one arm of the trial, and 
date of consent to a subsequent arm of the trial. 
5.3.1. Assessment of Seriousness 
Seriousness is assessed against the criteria in the table 1 above.  

 
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5.3.2. Assessment of Causality 
The relationship of each adverse event to the trial medication must be determined by a medically qualified 
individual according to the following definition: 
Not related – where an event is not considered to be related to the IMP 
Related – the known effects of the IMP, its therapeutic class or based on challenge testing suggest that the 
IMP is the most likely cause. 
 
5.3.3. Clinical Assessment of Severity 
Mild 
The participant is aware of the event or symptom, but the event or symptom is easily 
tolerated  
Moderate: 
The participant experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity  
Severe: 
Significant impairment of functioning; the participant is unable to carry out usual activities 
and / or the participant’s life is at risk from the event.  
 
5.4. Assessment and onward reporting of SUSARs  
All suspected adverse reactions related to study IMP which occur in the PROTECT-V trial, and that are both 
unexpected and serious (SUSARs) are subject to expedited reporting.  
5.4.1. Who should report and whom to report to? 
The Sponsor delegates the responsibility of notification of SUSARs to the Chief Investigator. The Chief 
Investigator must report all the relevant safety information previously described, to the:  
● 
Sponsor  
● 
Competent authorities in the concerned member states (e.g. MHRA) 
● 
Ethics Committee in the concerned member states 
The Chief Investigator shall inform all investigators concerned of relevant information about SUSARs that could 
adversely affect the safety of participants. 
5.4.2. Reference Safety Information (RSI) 
RSI is a list of medical events that defines which reactions are expected for the IMP within a given trial and 
thus determining which Serious Adverse Reactions (SARs) require expedited reporting. 
RSI will be specified in each specific appendix. 
5.4.3. When to report SUSARs 
5.4.3.1. 
Fatal or life-threatening SUSARs 
The CI must inform the Sponsor of any fatal SUSAR immediately but within 24 hours of the site investigator 
awareness of the event. The MHRA and Ethics Committee must be notified as soon as possible but no 

 
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later than 7 calendar days after the trial team and Sponsor has first knowledge of the minimum criteria for 
expedited reporting. In each case relevant follow-up information should be sought and a report completed as 
soon as possible. It should be communicated to all parties within an additional 8 calendar days.  
5.4.3.2. 
Non-fatal and non-life-threatening SUSARs  
All other SUSARs and safety issues must be reported to the Sponsor immediately but within 24 hours of 
the site investigator awareness of the event. The MHRA and Ethics Committee must be notified as 
soon as possible but no later than 15 calendar days after first knowledge of the minimum criteria for expedited 
reporting. Further relevant follow-up information should be given as soon as possible.  
5.4.4. How to report SUSARs? 
5.4.4.1. 
Minimum criteria for initial expedited reporting of SUSARs 
Information on the final description and evaluation of an adverse reaction report may not be available within 
the required time frames for reporting. For regulatory purposes, initial expedited reports should be submitted 
within the time limits as soon as the minimum following criteria are met: 
a) a suspected investigational medicinal product 
b) an identifiable participant (e.g. trial participant code number) 
c) an adverse event assessed as serious and unexpected, and for which there is a reasonable suspected 
causal relationship 
d) an identifiable reporting source 
and, when available and applicable: 
- a unique clinical trial identification (EudraCT number or in case of non-European Community trials the 
sponsor's trial protocol code number) 
- a unique case identification (i.e. sponsor's case identification number) 
5.4.4.2. 
Follow-up reports of SUSARs 
In case of incomplete information at the time of initial reporting, all the appropriate information for an adequate 
analysis of causality should be actively sought from the reporter or other available sources. Further available 
relevant information should be reported as follow-up reports.  
In certain cases, it may be appropriate to conduct follow-up of the long-term outcome of a particular reaction.  
5.4.4.3. 
Format of the SUSARs reports 
Electronic reporting is the expected method for expedited reporting of SUSARs to the competent authority. The 
format and content as defined by the competent authority should be adhered to.  
 
5.5. Pregnancy Reporting 
All participant pregnancies within the trial or up to 1 month after the last dose should be reported to the Chief 
Investigator and the Sponsor using the relevant Pregnancy Reporting Form within 24 hours of notification.  
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded for the mother or 
child/foetus. If the outcome meets the serious criteria, this would be considered an SAE. 
 

 
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6.  TRIAL COMMITTEES 
6.1. Trial Management Group (TMG) 
The TMG will meet on a weekly basis during initial set up, and then two weekly face to face or by teleconference 
to oversee the running of the trial. TMG members will review SAEs which have occurred in the trial. If there 
are specific safety concerns these may be raised with the TSC and IDMC. TMG members will include co-
investigators, trial statistician, trial pharmacist, the trial co-ordinator and data manager at the Cambridge 
Clinical Trials Unit (CCTU). 
 
6.2. Trial Steering Committee (TSC) 
The Trial Steering Committee (TSC) is responsible for the review of the trial and related activities at regular 
intervals. The TSC also provides overall supervision for the trial, to ensure that it is conducted in accordance 
with the protocol and GCP and to provide advice through its independent chairman. The committee will aim to 
convene at regular intervals to review the data and discuss the recommendations from the Independent Data 
Monitoring Committee (IDMC). The details of the TSC are set out in the PROTECT-V Trial Steering Committee 
Charter. 
 
6.3. Independent Data Monitoring Committee (IDMC) 
The IDMC will comprise an unblinded independent group, as defined in the PROTECT-V Data Monitoring 
Committee Charter document, which will define the role of the IDMC. The IDMC will be responsible for the 
review of all safety (but not exploratory) data and will meet regularly whilst the trial is ongoing, from opening to 
recruitment until the final visit of the last participant.  
 

 
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Diagram of Relationships between Trial Committees and Group 
 
7. DATA HANDLING AND RECORD KEEPING 
All data will be transferred into an electronic Case Report Form (eCRF) which will be anonymised. All trial data 
in the CRF must be extracted from and be consistent with the relevant source documents. The eCRFs must 
be completed in a timely manner. Completeness and accuracy of the eCRF is the responsibility of the 
investigator. The eCRF will be accessible to trial coordinators, data managers, the Investigators, Clinical Trial 
Monitors, Auditors and Inspectors as required. 
Investigators must ensure that trial related documentation sent to the trial coordination centre contains no 
participant identifiable data. A trial specific data management plan will describe in detail the data management 
processes using the eCRF and the trial database.  
All trial assessments, including the questionnaires and the medication diary, will be emailed securely (using 
nhs.net email) to the local PI to enable records to be stored at participating sites. 
A copy of the data associated with a trial participant will be provided to the local PI at the end of the trial. 
All data entries will be made in the eCRF. It will not be possible to edit any data fields already marked as 
complete. Requests for corrections or additions will need to be made using the data change request form or 
logging a data change request in the eCRF.  
Study participants will provide explicit consent to the use of identifiable data for the purposes of the conduct of 
the study. The PROTECT-V trial management team will hold identifiable data on all participants including 
name, date of birth, gender, NHS number or equivalent, home address and postcode, telephone number and 
email address where applicable.  

 
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Personal identifiable data (PID) will be stored separately from anonymised study data on a secure server 
hosted within University of Cambridge School of Clinical Medicine Secure Data Hosting Service. PID will be 
accessible to the PROTECT-V trial team within the Cambridge Clinical Trials Unit, monitors, auditors and 
inspectors as required. It is necessary to 1) perform validation of NHS numbers and linkage to routinely 
collected datasets (NHS Digital, ONS), and 2) to generate datasets with participant details for mail merge 
creation of questionnaires, and is therefore imperative to the conduct of the study. 
 
7.1. Source Data 
To enable peer review, monitoring, audit and/or inspection, the investigator must agree to keep records of all 
participants (sufficient information to link records e.g., CRFs, hospital records and samples), all original signed 
informed consent forms and copies of the CRF pages. 
Source data may include but is not limited to:  
 
Informed Consent Form 
 
Relevant sections of the Case Report Form (written or electronic), as defined by the TPM 
 
Medical Records (written or electronic) 
 
On-line laboratory test results systems 
 
Photograph of the Lateral Flow Tests, together with the test date and patient Trial ID 
 
Participant Questionnaires (written or electronic) 
 
7.2. Data Protection & Participant Confidentiality 
All investigators and trial site staff involved in this trial must comply with the requirements of the Data Protection 
Act 2018 and Trust Policy with regards to the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles. 
8. ETHICAL & REGULATORY CONSIDERATIONS 
The consent information and consenting procedure is described under section 2.2, and will be approved by the 
REC. 
 
8.1. Ethical committee review 
Before the start of the trial or implementation of any amendment we will obtain approval of the trial protocol, 
protocol amendments, informed consent forms and other relevant documents e.g., advertisements and GP 
information letters if applicable from the REC. All correspondence with the REC will be retained in the Trial 
Master File/Investigator Site File. Annual reports will be submitted to the REC in accordance with national 
requirements. It is the Chief Investigator’s responsibility to produce the annual reports as required. 
 
8.2. Regulatory Compliance 
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from the MHRA. The protocol 
and trial conduct will comply with the Medicines for Human Use (Clinical Trials) Regulations 2004 and any 
relevant amendments. Development Safety Update Reports (DSURs) will be submitted to the MHRA in 
accordance with national requirements. It is the Chief Investigator’s responsibility to produce these reports as 
required. 

 
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8.3. Protocol Amendments 
Protocol amendments must be reviewed and agreement received from the Sponsor for all proposed 
amendments prior to submission to the REC and/or MHRA. The only circumstance in which an amendment 
may be initiated prior to REC and/or MHRA approval is where the change is necessary to eliminate apparent, 
immediate risks to the participants (Urgent Safety Measures). In this case, accrual of new participants will be 
halted until the REC and/or MHRA approval has been obtained. 
  
8.4. Peer Review 
The PROTECT-V trial protocol has been peer-reviewed by the CUH COVID-19 Trials Prioritisation Group, and 
independently peer reviewed by the COVID19 Research Committee of the UK Kidney Research Consortium.. 
  
8.5. Declaration of Helsinki and Good Clinical Practice 
The trial will be performed in accordance with the spirit and the letter of the declaration of Helsinki, the 
conditions and principles of good clinical practice, the protocol and applicable local regulatory requirements 
and laws.  
 
8.6. GCP Training 
All trial staff must hold evidence of appropriate GCP training or undergo GCP training prior to undertaking any 
responsibilities on this trial. This training should be updated every 2 years or in accordance with local Trust 
policies. 
9. SPONSORSHIP, FINANCIAL AND INSURANCE 
The trial is sponsored by Cambridge University Hospitals NHS Foundation Trust and the University of 
Cambridge.  
The study will be funded by LifeArc, Addenbrooke’s Charitable Trust and Kidney Research UK. Additional 
funders are acknowledged at the appendices.  
Cambridge University Hospitals NHS Foundation Trust, as a member of the NHS Clinical Negligence Scheme 
for Trusts, will accept full financial liability for harm caused to participants in the clinical trial caused through 
the negligence of its employees and honorary contract holders. There are no specific arrangements for 
compensation should a participant be harmed through participation in the trial, but no-one has acted 
negligently. The University of Cambridge will arrange insurance for negligent harm caused as a result of 
protocol design and for non-negligent harm arising through participation in the clinical trial. 
 
10. MONITORING, AUDIT AND INSPECTION 
The investigator must make all trial documentation and related records available should an MHRA Inspection 
occur. Should a monitoring visit or audit be requested, the investigator must make the trial documentation and 

 
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source data available to the Sponsor’s representative. All participant data must be handled and treated 
confidentially.  
The Sponsor’s monitoring frequency will be determined by an initial risk assessment performed prior to the 
start of the trial. A detailed monitoring plan will be generated detailing the frequency and scope of the monitoring 
for the trial. Throughout the course of the trial, the risk assessment will be reviewed and the monitoring 
frequency adjusted as necessary.  
On-site or remote monitoring will be conducted for all participating sites. The scope and frequency of the 
monitoring will be determined by the risk assessment and detailed in the Monitoring Plan for the trial.  
 
11. PROTOCOL COMPLIANCE AND BREACHES OF GCP 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK regulations on Clinical 
Trials and must not be used. Protocol deviations, non-compliances, or breaches are departures from the 
approved protocol. They can happen at any time, but are not planned. They must be adequately documented 
on the relevant forms and reported to the Chief Investigator and Sponsor immediately. Deviations from the 
protocol which are found to occur constantly again and again will not be accepted and will require immediate 
action and could potentially be classified as a serious breach. Any potential/suspected serious breaches of 
GCP must be reported immediately to the Sponsor without any delay.  
 
12. PUBLICATIONS POLICY 
On completion of each intervention of the trial the data will be analysed and tabulated and an Intervention 
Specific Final Trial Report prepared. The results of this trial may be published or presented at scientific 
meetings. Any reported serious breaches will be detailed in all publications in line with regulatory requirements. 
Authorship of final trial outputs will be assigned and funding acknowledged in accordance with guidelines set 
out by the International Committee of Medical Journal Editors. 
The statistician will also provide the Chief Investigator with the full summary of the trial results. The investigator 
is encouraged to share the summary results with the trial participants, as appropriate. The Trial team will 
provide the investigator with the randomisation codes for their site only after completion of the full statistical 
analysis. 
Trial information from this protocol will be posted on publicly available clinical trial registers before enrolment 
of participants begins. A results summary will also be posted to publicly available clinical trial registers and a 
manuscript developed for publication in a peer reviewed journal after completion of the trial. 
 
13. REFERENCES 
 
1. Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of 
Medicine 382, 727–733 (2020). 
2. Boulware, D. R. et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-

 
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19. New England Journal of Medicine (2020) doi:10.1056/NEJMoa2016638. 
3. Krueger, K. M., Ison, M. G. & Ghossein, C. Practical Guide to Vaccination in All Stages of CKD, Including 
Patients 
Treated 
by 
Dialysis 
or 
Kidney 
Transplantation. 
Am 
J 
Kidney 
Dis 
75, 
417-425, 
doi:10.1053/j.ajkd.2019.06.014 (2020). 
4. Bingham, C. O., 3rd et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: 
results from a controlled clinical trial. Arthritis Rheum 62, 64-74, doi:10.1002/art.25034 (2010). 
5. van Assen, S. et al. Humoral responses after influenza vaccination are severely reduced in patients with 
rheumatoid arthritis treated with rituximab. Arthritis Rheum 62, 75-81, doi:10.1002/art.25033 (2010). 
6. Carr, E.J. et al. Review of early immune responseto SARS CoV-2 vaccination among patients with CKD. 
Kidney Int Rep. 2021 Sep;6(9):2292-2304  
7. Kamar et al. Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. NEJM Aug 
2021; 385:661-662 
8. Caillard, S., Thaunat, O. COVID-19 vaccination in kidney transplant recipients. Nat Rev Nephrol. 2021. 
https://doi.org/10.1038/s41581-021-00491-7 
9. Carr, EJ. et al. Neutralising antibodies after COVID-19 vaccination in UK haemodialysis patients. Lancet. 
2021 Aug 12:S0140-6736(21)01854-7. doi: 10.1016/S0140-6736(21)01854-7. Epub ahead of print.  
10. Tenforde MW, et al. Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 
Hospitalizations in the United States. medRxiv. 2021 https://doi.org/10.1101/2021.07.08.21259776 
11. Brosh-Nissimov T et al. BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated 
hospitalized COVID-19 patients in Israel. Clin Microbiol Infect. 2021. 
12. Cowan, J. et al. Incidence Rate of Post-Kidney Transplant Infection: A Retrospective Cohort Study 
Examining Infection Rates at a Large Canadian Multicenter Tertiary-Care Facility. Can J Kidney Health Dis 5, 
2054358118799692 (2018).4.Academy of Medical Sciences. Preparing for a challenging winter 2020/2021. 
(2020).  
 
 

 
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APPENDIX A: NICLOSAMIDE 
APPENDIX A: NICLOSAMIDE ......................................................................................................................... 39 
Trial flowchart ................................................................................................................................................... 40 
1. 
INTRODUCTION ....................................................................................................................................... 40 
2. 
BACKGROUND ......................................................................................................................................... 41 
2.1. 
Rationale for niclosamide as a prophylactic measure ...................................................................... 41 
3. 
TRIAL TREATMENT - NICLOSAMIDE (UNI911) ..................................................................................... 43 
3.1. 
Niclosamide Name and description .................................................................................................. 43 
3.2. 
Niclosamide Legal status .................................................................................................................. 43 
3.3. 
Niclosamide Supply, dispensing and accountability ......................................................................... 43 
3.4. 
Niclosamide Packaging and Labelling .............................................................................................. 43 
3.5. 
Niclosamide Storage ........................................................................................................................ 44 
3.6. 
Niclosamide Treatment Duration ...................................................................................................... 44 
3.7. 
Niclosamide Dose ............................................................................................................................. 44 
3.8. 
Niclosamide Administration .............................................................................................................. 44 
3.9. 
Niclosamide Missed or Replacement Doses .................................................................................... 44 
3.10. 
Niclosamide Contraindications ......................................................................................................... 44 
3.11. 
Niclosamide side effects and concomitant medications ................................................................... 44 
3.12. 
Placebo to match niclosamide .......................................................................................................... 45 
3.13. 
Treatment Period .............................................................................................................................. 45 
3.14. 
Treatment Withdrawal ...................................................................................................................... 45 
4. 
ELIGIBILITY .............................................................................................................................................. 45 
5. 
BLINDING ................................................................................................................................................. 46 
6. 
RANDOMISATION .................................................................................................................................... 46 
7. 
SCHEDULE OF ASSESSMENTs ............................................................................................................. 47 
7.1 PHARMACOKINETIC ASSESSMENT ....................................................................................................... 48 
8. 
ADDITIONAL OBJECTIVES ..................................................................................................................... 48 
8.1. 
Exploratory Objectives ...................................................................................................................... 48 
9. 
ADDITIONAL OUTCOMES ....................................................................................................................... 48 
9.1. 
Exploratory Outcomes ...................................................................................................................... 48 
10. SAMPLE SIZE ........................................................................................................................................... 48 
11. CRITERIA FOR EARLY TERMINATION .................................................................................................. 49 
12. SAFETY REPORTING .............................................................................................................................. 49 
12.1. 
Recording, Evaluating & Reporting Serious Adverse Events / SARs .............................................. 49 
12.2. 
Reference Safety Information (RSI) ................................................................................................. 49 
12.3. 
Pregnancy Reporting ........................................................................................................................ 50 
13. ADDITIONAL FINANCIAL SUPPORT ...................................................................................................... 50 

 
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14. INTERNATIONAL PARALLEL PROTOCOL ............................................................................................. 50 
15. PUBLICATIONS POLICY .......................................................................................................................... 50 
16. APPENDIX A REFERENCES ................................................................................................................... 50 
 
 
Trial flowchart 
 
1. INTRODUCTION 
The trial commenced with the first intervention, nasal niclosamide and matched placebo from February 2021. 
The intended second intervention is nasal and inhaled ciclesonide. Participants are being randomised in a 1:1 
ratio until the second intervention is introduced. Once ciclesonide is introduced, participants who are eligible 
for ciclesonide will be randomised to niclosamide, ciclesonide, niclosamide matching placebo or ciclesonide 
matching placebo in a 2:2:1:1 ratio. The net result will be a 1:1:1 distribution between niclosamide, ciclesonide 
and placebo, with niclosamide-matching placebo and ciclesonide-matching placebo pooled for the analysis. In 

 
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this way, the PROTECT-V platform gains efficiency by reducing the overall sample size required to assess 
niclosamide and ciclesonide by around 25% from what would be required to conduct two independent trials. 
There will be a very small proportion of participants who will be not eligible for ciclesonide as there are 
additional exclusion criteria for this arm; these participants will be randomised to niclosamide and niclosamide 
matching placebo in a 1:1 ratio. 
 
2. BACKGROUND 
 
2.1. Rationale for niclosamide as a prophylactic measure  
 
Niclosamide is a derivative of salicylic acid. It is a cheap, safe drug that has been used for tapeworm 
infestations for decades and is on the WHO’s List of Essential Medicines. Although the exact target and 
mechanism of action is uncertain, niclosamide has pleiotropic activities and in vitro activity against a range of 
viruses and bacteria has been reported, including inhibition of SARS-CoV-1 replication, totally abolishing viral 
antigen synthesis.7 Potential mechanisms of action for niclosamide on SARS-CoV-2 include modulation of the 
pH gradient across endosomal membranes inhibiting viral escape, as well as autophagy related mechanisms8 
In the case of MERS, it is thought that niclosamide acts via SKP2 inhibition to reinstate autophagy.9  
Prior to the emergence of COVID-19, studies had suggested that niclosamide may have broader clinical 
applications aside from treatment of parasitic disease, such as a role inmalignancy, bacterial and viral 
infections, metabolic diseases (including Type II diabetes, NASH and NAFLD), and inflammatory conditions 
(rheumatoid arthritis, systemic sclerosis and atopic dermatitis).10 
In the context of COVID-19, niclosamide has been identified as the leading candidate for activity against SARS-
CoV-2 in two separate library screens of existing approved drugs (Giacca et al; 2020. Unpublished data). 
Furthermore, researchers at Institut Pasteur Korea have reported niclosamide as one of the most potent FDA 
approved inhibitors of SARS-Cov-2 in in vitro assays using vero cells, with IC50 of 0.28µM >25x higher than 
that of chloroquine and >40x higher than that of remdesivir.11 
 
 

 
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Left panel: drug library screens using syncythia assay showing that niclosamide is the most potent inhibitor of SARS-CoV2. 
NIC - niclosamide. CLO - chloroquine. Right panel: Dose-response of SARS-CoV-2 inhibition by niclosamide and 
remdesivor in vitro. The blue squares represent inhibition of virus infection (%) and the red triangles represent cell viability 
(%). Institut Pasteur Korea March 20, 2020. 
 
However, oral niclosamide is poorly absorbed from the gut with low bioavailability, thus meaning that re-
purposing as a therapy for COVID-19 is tricky, since the dose required to achieve sufficient exposure in target 
tissues is unknown. However, there are currently five clinical trials registered for testing oral niclosamide in 
COVID-19 infection, using the doses used to treat parasitic infection.  
Niclosamide primarily undergoes hepatic clearance after oral administration with the majority eliminated via 
the feces. When used to treat tapeworm infection, the dose of niclosamide is not adjusted in renal impairment. 
In humans, following a single oral dose of 2 grams of carbonyl 14C-niclosamide, only 2% to 25% is excreted in 
the urine over a 4-day period with the remainder eliminated in faeces.11 Excretion was essentially complete 
within 1-2 days. In urine, the glucuronides of 1) niclosamide, 2) 4’-nitro-reduced metabolite (2’,5-dichloro-4’-
amino-salicylanilide), and 3) the N‑ acetylated metabolite (2’,5-dichloro-4’-acetamino-salicylanilide) were 
reported by Andrews et al., 1982.12 The glucuronide metabolites found in urine are similar to those found in 
rats after oral administration of radiolabeled niclosamide (Griffiths and Facchini 1979), a species where oral 
doses up to 5000 mg/kg/day have been administered for 4 weeks without adverse findings.13 
Since aqueous solubility and oral bioavailability of niclosamide is poor there is reason to believe that other 
formulations, such as an inhaled preparation, would be advantageous for treating COVID-19. Union 
Therapeutics has developed a new stable liquid formulation (UNI911) of niclosamide. Related formulations 
have been tested topically in clinical trials for atopic dermatitis in over 600 subjects. These preparations have 
been re-purposed into an intranasal and nebulised formulation. A phase I escalating dose study in healthy 
volunteers using these formulations has recently been completed, with a favourable safety profile. 
In-vitro data indicating potent inhibition of SARS-COV2 replication and cellular penetration, together with 
evidence that SARS-COV2 initially replicates predominantly in the nasal epithelium, suggests nasal 
niclosamide is best placed as a prophylactic agent or for treatment of early stage COVID-19 disease when the 
viral load is a main issue.  
The PROTECT-V trial will administer 1% niclosamide ethanolamine solution via a nasal spray pump twice daily 
(140µL of a 1% niclosamide ethanolamine solution, equivalent to 1.4mg of niclosamide ethanolamine salt per 
nostril twice daily; total daily dose 5.6mg niclosamide ethanolamine salt (4.7mg free niclosamide acid). Even 
in a highly conservative approach, where 100% of the administered dose would be assumed to permeate and 
reach blood circulation, the maximal systemic exposure would still be approx. 40 times lower than the one 
reported with oral niclosamide at the approved dose (Yomesan chewable tablets) of 2g/day (based on the 
reported 10% bioavailability of oral niclosamide by Chang et al. 2006,14 i.e. 200 mg day-1 / 5.0 mg day-1 = 40). 
Based on 1) hepatic clearance as the primary mechanism for elimination of niclosamide, 2) the low human 
intranasal dose, 3) anticipated low bioavailability, 4) the lack of reported toxicity at high doses in animals, and 
5) a reported half-life of niclosamide of 1.3 to 5.6 hours, which suggests that steady state levels are reached 
within a few days, the proposed nasal application of UNI911 to renally impaired patients will not lead to 
appreciably high levels of niclosamide or its metabolites outside of those previously evaluated in animals 
following a single or short-term human dosing regimen and thus no dose adjustments are recommended for 
patients with renal impairment. 
UNI911 has been developed to maximise delivery of niclosamide to local tissues. In a non-clinical PK study 
UNI911 was administered by nebulisation to the lungs of sheep and sequential bronchoalveolar lavages were 
performed over a period of 8 hours after dosing. The study demonstrated a local exposure in the epithelial 
lining fluid in the deep lung above the SARS-CoV-2 IC50 value of niclosamide for the full 8 hour duration 

 
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supporting a twice daily regimen. On this basis, the proposed twice daily intranasal administration of UNI911 
to the nasal cavity should deliver a therapeutically active dose, considering that the dose delivered per surface 
area to the nasal cavity by intranasal spray pump exceeds that delivered to the lungs in the sheep PK study 
by nebulisation. The PK findings from the non-clinical study in sheep is also in agreement with PK findings in 
a recently completed Phase 1 study using UNI911 administered both by nebulisation to the lungs and intranasal 
spray pump to the nasal cavity.  
 
3. TRIAL TREATMENT - NICLOSAMIDE (UNI911) 
3.1. Niclosamide Name and description 
INN: 
 
 
 
Niclosamide Ethanolamine 
Chemical name (IUPAC): 
5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide.2 aminoethanol 
CAS registry number: 
 
1420-04-8 
Lab code: 
 
 
UNI911 
The IMPs niclosamide Nasal Spray 1% and matching Nasal Spray Placebo will be provided in 20 mL amber 
glass vials with nasal spray pumps, containing 8.5 mL of the respective solution, delivering 140 μL per spray 
shot. It is an isotonic and euhydric aqueous solution with red colour. 
 
3.2. Niclosamide Legal status 
Niclosamide is currently approved and marketed for the oral treatment of tapeworm infections in several 
European and developing countries but not the UK. Niclosamide ethanolamine has not previously been 
approved as a pharmaceutical drug and is used in this trial as an unlicensed product. 
 
3.3. Niclosamide Supply, dispensing and accountability 
Niclosamide Nasal Spray 1% and matching Nasal Spray Placebo will be provided by UNION therapeutics A/S, 
DK-Hellerup. Supply of the finished product to participating site pharmacies will be overseen by the trial co-
ordinator and distributed by a sponsor-appointed third party. Upon initial authorisation by the sponsor, an initial 
supply will be sent to sites; supplies thereafter will be distributed as detailed in the pharmacy manual.  
IMP will be dispensed at appropriate intervals, supplying the bottles labelled with kit numbers allocated. Full 
accountability records will be completed to document receipt, dispensing and destruction of expired and 
unused IMP at the end of the study. Further details of dispensing are detailed in the pharmacy manual. 
IMP will be collected by the participant during dialysis sessions or sent by courier to the participant. 
IMP for the trial will be provided free-of-charge for participating sites. 
 
3.4. Niclosamide Packaging and Labelling 
The IMPs niclosamide Nasal Spray 1% and matching Nasal Spray Placebo are packaged and labelled in single 
packs with one unit each. The outer carton and bottle label are blinded as to whether niclosamide or its 

 
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matching placebo is contained and complies with regulatory requirements. Each unit is labelled with an 
individual unique treatment pack number. The same number will appear on the bottle and carton label.  
3.5. Niclosamide Storage 
The IMPs niclosamide Nasal Spray 1% and matching Nasal Spray Placebo must be stored as per labelled 
storage conditions. Participants must only use each spray for a total of 14 days, even if there remains liquid in 
the bottle.  
 
3.6. Niclosamide Treatment Duration 
PROTECT-V will be an event driven trial, and continue until the required number of events are accrued. It is 
anticipated that the median treatment duration will be 6 months for each participant with a maximum treatment 
period of 9 months. 
 
3.7. Niclosamide Dose 
140µL of a 1% niclosamide ethanolamine solution in each nostril twice daily, equivalent to 1.4mg of niclosamide 
ethanolamine salt per nostril twice daily, approximately 12 hours apart. Total daily dose 5.6mg niclosamide 
ethanolamine salt (4.7mg free niclosamide acid). 
No dose modifications are permitted. 
 
3.8. Niclosamide Administration 
Single metered dose nasal pump spray per nostril twice daily. 
 
3.9. Niclosamide Missed or Replacement Doses 
Missed doses will not be replaced. A dose will be considered missed after 6 hours of usual administration time. 
 
3.10. Niclosamide Contraindications 
Niclosamide and placebo to match are contraindicated in subjects allergic or hypersensitive to niclosamide, its 
derivatives or any formulation excipients.  
 
3.11. Niclosamide side effects and concomitant medications 
The overall results from a phase 1 study in healthy volunteers receiving single or multiple escalating doses of 
the nebulized solution plus 150 μL of the intranasal formulation via spray showed no Serious Adverse Events 
and no early discontinuations. The Adverse Events, the most common of which was upper respiratory tract 

 
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irritation, were mild in intensity. After multiple dosing with 3 mL (Cohort 7) and 6 mL (Cohort 5) of inhaled 
niclosamide 1% there were some subjects who showed repeated asymptomatic drops in FEV1 (defined as a 
drop in FEV1 with more than 200 mL and 12%). These drops were all reversible, spontaneously or following 
dosing with short-acting beta2-agonist. 
The nasal administration was well tolerated with mild nasal irritation commonly reported. The irritation could 
be sensed as mild pain and/or a light burning sensation in the nose, sneeze or runny nose. The nasal irritation, 
with few exceptions, disappeared spontaneously within one hour after the administration. There was no 
moderate or severe pain or nosebleed reported. The nasal application was associated with some 
unpleasantness that became less evident as the multiple dosing progressed. It is highly unlikely that the nasal 
administration contributed to the decrease in FEV1 since there was an increase in these events with the inhaled 
dose level and because of the much lower drug administered through the nasal route. 
No formal drug-drug interaction studies with inhaled or intranasal niclosamide have been conducted. Given the 
expected low systemic exposure the risk for drug interactions is considered low. As a matter of precaution, 
administration of niclosamide should be made separately from any other drug administration. 
All standard of care medicines are to continue as per standard practice and will be recorded by the study team 
as described. 
 
3.12. Placebo to match niclosamide 
Placebo to match niclosamide will be supplied, stored, labelled, dispensed and dosed as for the active 
formulation. The placebo product is formulated to have the same appearance as the active solution.  
 
3.13. Treatment Period 
The median anticipated treatment period is 6 months with a maximum treatment period of 9 months. Last 
follow-up visit will be scheduled 4-6 weeks after last dose. After the end of the trial, Union Therapeutics will 
endeavour to make available to trial participants further supplies of the IMP in the event that the trial 
demonstrates benefit but this cannot be guaranteed. 
 
3.14. Treatment Withdrawal 
Unacceptable drug reactions for niclosamide include: 
● 
Moderate or severe pain in the nose 
● 
Severe itch or burning sensation in the nose 
● 
Spontaneous nose bleeding as result of nasal ulceration 
● 
Oedema that prevents breathing through the nose 
 
4. ELIGIBILITY  
Specific additional exclusion criteria 
 
Significant structural nasal disease in the opinion of the investigator 

 
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 
Prior participation in the niclosamide arm of the trial (if being re-screened for participation in a second 
interventional arm). 
5. BLINDING 
PROTECT-V-niclosamide will be a double blind placebo controlled study where neither the participant nor 
clinician will be aware of treatment allocation. 
 
6. RANDOMISATION 
A participant will be randomised to:  
 
niclosamide vs ciclesonide vs matching placebo to niclosamide vs matching placebo to ciclesonide in 
a 2:2:1:1 ratio, or 
 
niclosamide vs matching placebo to niclosamide in a 1:1 ratio if a participant is eligible for niclosamide 
but not ciclesonide, or 
 
ciclesonide vs matching placebo to ciclesonide in a 1:1 ratio if the recruitment of niclosamide 
intervention is completed as it is the first treatment commenced. 
The system will allocate the participant treatment pack code(s) which will relate uniquely to the first supply of 
IMP. Different treatment pack code(s) for every subsequent order of IMP supply will be allocated by the 
randomisation system.  
Participants and site teams will remain blinded to treatment allocation, i.e. whether active or placebo within a 
stated intervention. The allocated blinded IMP supply will be collected by participants when possible or sent at 
suitable intervals to their home by courier. 
 
 

 
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7. SCHEDULE OF ASSESSMENTs 
 
Assessment  
Schedule 
Screen/ 
Baseline 
Visit 
7 (±3) 
days  
PK 
* 
Weekly 
(±3 days) 
% 
2-weekly 
(±3 days) 
% 
  
14 (±3) 
days 
PK 
* 
21 (±3) 
days 
PK 
* 
As 
required 
data 
linkage 
Final 
assessm
ent& 
Eligibility check 
X 
 
 
 
 
 
 
 
 
Medical history  
 
X 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
 
X 
X 
 
 
 
 
 
Symptom checker 
questionnaire$ 
X 
 
X 
X 
 
 
 
 
 
SARS-CoV2 PCR or 
lateral flow test 
X 
 
 
 
 
 
X 
 
 
Serum sample for 
SARS-CoV2 Total Ab 
assay 
X 
 
 
 
 
 
 
 
X 
Medication diary£ 
X 
 
 
 
 
 
 
 
 
Influenza PCR 
 
 
 
 
 
 
X 
 
 
ALT/AST 
X 
 
 
 
 
 
 
 
 
Pregnancy test# 
X 
 
 
 
 
 
 
 
 
SAR/SUSAR 
Reporting 
 
 
 
 
 
 
X 
 
 X  
Randomisation 
X 
 
 
 
 
 
 
 
 
IMP supplied 
 
 
 
 
 
 
X€ 
 
 
COVID-19 infection 
 
 
X 
X 
 
 
 
X 
 
PK 
 
X 
 
 
X 
X 
 
 
 
* PK Cohort only 
# A pregnancy test is required for WOCBP within 14 days prior to starting trial treatment. Women are considered 
WOCBP following menarche and until becoming post-menopausal unless permanently sterile (previous 
hysterectomy, previous bilateral salpingectomy and or oophorectomy). A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause. A serum pregnancy test is required for all 
WOCBP participants. 
% Weekly for one month and 2-weekly thereafter. Any participant testing positive for SARS-CoV-2 without 
symptom will be required to complete a COVID-19 symptom assessment at least weekly for 4 weeks after 
diagnosis, unless hospitalised. 
$ Telephone consultation will occur for the first 6 weeks. 

 
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& Final assessment visit will occur 4-6 weeks after end of treatment 
€ IMP will be supplied at least 3-monthly, either at the dialysis centre or by courier. 
£ Local teams will instruct the participant on how to use the medication diary and add enough copies with each 
IMP dispensation to cover the treatment period 
7.1 PHARMACOKINETIC ASSESSMENT 
Population Pharmacokinetic (PK) assessment will be conducted in the first 30 participants receiving 
niclosamide for safety purposes, to exclude the unlikely possibility of accumulation of niclosamide during the 
course of the trial in patients receiving dialysis only. Given that participants and investigators will be blinded to 
treatment allocation, PK samples will maintain blinding by including the first 70 dialysis patients in the PK 
sampling cohort. Including 70 participants is necessary to exclude the scenario where a chance imbalance in 
treatment allocation early in the study results in fewer than 30 participants allocated to niclosamide. These 
participants will be identified as the ‘PK Cohort’. 
The PK Cohort will have a blood sample taken at the start of dialysis, before taking the IMP. PK Cohort 
participants receiving dialysis in the afternoon or evening may take the morning dose of IMP, but should omit 
the evening dose until the PK sample has been obtained. The procedure for obtaining PK samples is described 
in the trial procedures manual. 
PK samples will be obtained 7 (±3) days after the date of first IMP dose (or coincident with the 3rd dialysis 
session post-dating randomisation), 14 (±3) days and 21 (±3) days after date of first dose. 
 
8. ADDITIONAL OBJECTIVES 
8.1. Exploratory Objectives 
1) Determine if nasal niclosamide reduces the occurrence of other influenza infections in the vulnerable 
populations taking part in the study 
 
9. ADDITIONAL OUTCOMES 
9.1. Exploratory Outcomes 
1) Occurrence of other influenza infection (swab confirmed) 
2) Occurrence of other respiratory viral infections (aside from COVID-19 and influenza) 
3) Staphylococcus aureus infections (dialysis population only) 
 
10. 
SAMPLE SIZE 
For each prophylactic intervention, it is planned initially to randomise 1500 subjects between the prophylactic 
treatment and the placebo or the shared placebo for patients randomised to more than one prophylactic 
treatments option. This was based on that the estimated 6-month rate of confirmed symptomatic COVID-19 
infection was around 15% in the placebo group, and 10% in each treatment arm; this would correspond to a 

 
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hazard ratio of 0.648. With a 0.045 significance level (for an overall significance level of 0.05 with two interim 
analyses using a Lan-DeMets error-spending approach corresponding to symmetric 2-sided O’Brien-Fleming 
boundaries (https://doi.org/10.1002/sim.4780131308) and 90% power, the maximum total number events 
required would be 235. With a 3 month recruitment and a further continuation of 8 months (a total of 11 months), 
the number of events required would be observed with a total of 1275 subjects, allowing for a 15% 
noncompliance, a total of 1500 subjects. With a 6 month recruitment and a further continuation of 7 months (a 
total of 13 months), the number of events required will be observed with a total of 1278 subjects, allowing for 
a 15% noncompliance, a total of 1500 subjects. There are uncertainties and changes with the sample size 
assumptions with the development of the COVID 19 pandemic. Recruitment period will not be restricted by the 
assumptions. These assumptions are therefore monitored regularly by the independent data monitor 
committee (IDMC). Sample size re-estimation will be considered with the recommendation from the IDMC. 
 
11. 
CRITERIA FOR EARLY TERMINATION  
The study will be reviewed every 2 months by the independent Data Monitoring Committee (DMC) for safety, 
combined primary outcome measure event rate and making a recommendation for performing efficacy 
analyses. Should there be sufficient evidence of a difference in the primary outcome measure between the 
niclosamide arm and the matched placebo arm at one planned interim analysis, the DMC may consider 
recommending early termination of the study. As a guide to the DMC, considering the total duration of study is 
around 1 year, a maximum of two formal interim analyses, based the number of primary endpoint events, are 
to be performed using a Lan-DeMets error-spending approach corresponding to symmetric 2-sided O’Brien-
Fleming boundaries (https://doi.org/10.1002/sim.4780131308). The study will only be stopped earlier if there 
is sufficient evidence of benefit using the O’Brien-Fleming boundaries, that is, the value of the test statistic 
crosses the O’Brien-Fleming boundary of beneficial effect of niclosamide. 
As a potential pivotal study, it is not planned to stop the study for futility. The study will be stopped early if 
there are any safety concerns based on the recommendation of the independent Data Monitoring Committee 
and the approval from the Trial Steering Committee. As guidance, the study might be stopped early for safety 
concerns 
● 
if the rate of unacceptable toxicity in the niclosamide arm is over 20%, that is, the estimated lower limit 
of a 95% confidence interval is greater than 20%. In general, local intolerance should only be regarded 
as an unacceptable toxicity if the event fulfils criteria for a serious adverse event or is severe.  
● 
if the incidence of moderate/severe adverse events/symptoms is 15% more in the niclosamide arm 
with a minimum of 200 participants in each arm at a significance level of 0.05. 
 
12. SAFETY REPORTING 
12.1. Recording, Evaluating & Reporting Serious Adverse Events / SARs 
The Chief Investigator will ensure that all safety information is reported to Union Therapeutics when sponsor 
review is complete. 
12.2. Reference Safety Information (RSI) 
For this trial the Reference Safety Information is: Union Therapeutics Investigator Brochure for UNI911 
(Niclosamide nasal spray), Version 1.0, 26th August 2020 section 6.1.  

 
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12.3. Pregnancy Reporting 
The Chief Investigator will then report the pregnancy to UNION within 24 hours of notification 
13. ADDITIONAL FINANCIAL SUPPORT 
Trial medications and financial contributions are provided by UNION Therapeutics. 
 
14. INTERNATIONAL PARALLEL PROTOCOL 
A parallel niclosamide arm of the PROTECT-V study will be conducted in India. The George Institute for Global 
Health, India will sponsor PROTECT-V protocol in India. Trial medications and funding for the Indian arm of 
the study are provided by UNION Therapeutics. The overarching trial eCRF, statistical support and trial 
committees will be provided by the UK PROTECT-V infrastructure. Data on patients recruited in India will be 
entered directly into the PROTECT-V study database, and cumulative data from the parallel trial will contribute 
to the overall sample size and primary endpoint events. The study data from the parallel PROTECT-V protocols 
conducted in India and the UK will be shared via the trial eCRF throughout the trial and be reviewed by the trial 
committees listed in section 6 of the core protocol. The George Institute for global health, as Indian sponsor, 
is responsible for reporting all safety data to local authorities in accordance with local regulatory requirements 
and to Cambridge University Hospitals in periodic safety reports. This data will then be shared with Union 
therapeutics according to section 12.1 of Appendix A of the protocol. 
 
15. PUBLICATIONS POLICY 
All manuscripts or abstracts which present data from the niclosamide arm of the trial must be made available 
for review by Union Therapeutics before submission. This is to protect proprietary information and to provide 
comments. 
 
16. APPENDIX A REFERENCES 
7. Wu, C.-J. et al. Inhibition of Severe Acute Respiratory Syndrome Coronavirus Replication by 
Niclosamide. Antimicrob Agents Chemother 48, 2693–2696 (2004). 
8. Pindiprolu, S. K. S. S. & Pindiprolu, S. H. Plausible mechanisms of Niclosamide as an antiviral 
agent against COVID-19. Medical Hypotheses 140, (2020). 
9. Gassen, N. C. et al. SKP2 attenuates autophagy through Beclin1-ubiquitination and its 
inhibition reduces MERS-Coronavirus infection. Nature Communications 10, (2019). 
10. Chen, W., Mook, R. A., Premont, R. T. & Wang, J. Niclosamide: Beyond an antihelminthic drug. 
Cell Signal 41, 89–96 (2018). 
11. Jeon, S. et al. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-
approved drugs. Antimicrob Agents Chemother 64, 2020.03.20.999730 (2020). 
12. Andrews, P., Thyssen, J. & Lorke, D. The biology and toxicology of molluscicides, bayluscide. 
Pharmacology & Therapeutics 19, 245–295 (1982).11.WHO specifications and evaluations for 

 
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public health pesticides: Niclosamide.  
13. WHO specifications and evaluations for public health pesticides: Niclosamide} 
(https://www.who.int/neglected_diseases/vector_ecology/pesticide-
specifications/en/Niclosamide.pdf. accessed 14th July 2020)  
14. Chang, Y.-W. et al. Journal of Food and Drug Analysis (JFDA) - Articles & Issues - Food and Drug 
Administration, Department of Health. JFDA (2006). 
 
 

 
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APPENDIX B: CICLESONIDE 
 
Appendix B Protocol Contributors 
Prof Brian Lipworth 
Professor of Allergy and Respiratory Medicine, 
University of Dundee 
Prof Graeme Devereux 
Professor of Respiratory Medicine, Liverpool School of 
Tropical Medicine 
 
 
APPENDIX B: CICLESONIDE ...................................................................................................................... 52 
Trial Flowchart ............................................................................................................................................... 53 
1. 
INTRODUCTION .................................................................................................................................... 53 
2. 
BACKGROUND ...................................................................................................................................... 54 
2.1. 
Rationale for using ciclesonide for COVID-19 prophylaxis ........................................................... 54 
2.2. 
Dosing and administration of ciclesonide ...................................................................................... 55 
3. 
TRIAL TREATMENT - CICLESONIDE .................................................................................................. 56 
3.1. 
Ciclesonide Name and description ................................................................................................ 56 
3.2. 
Ciclesonide Legal status ................................................................................................................ 56 
3.3. 
Ciclesonide Supply, dispensing and accountability ....................................................................... 56 
3.4. 
Ciclesonide Packaging and Labelling ............................................................................................ 56 
3.5. 
Ciclesonide Storage ...................................................................................................................... 56 
3.6. 
Ciclesonide Treatment Duration .................................................................................................... 57 
3.7. 
Ciclesonide Dose and Administration ............................................................................................ 57 
3.8. 
Ciclesonide Missed or Replacement Doses .................................................................................. 57 
3.9. 
Ciclesonide Contraindications ....................................................................................................... 57 
3.10. 
Ciclesonide side effects and concomitant medications ................................................................. 57 
3.11. 
Placebo to match Ciclesonide ....................................................................................................... 58 
4. 
ELIGIBILITY ........................................................................................................................................... 58 
4.1. 
Additional Exclusion Criteria .......................................................................................................... 58 
5. 
BLINDING .............................................................................................................................................. 58 
6. 
RANDOMISATION ................................................................................................................................. 59 
7. 
SCHEDULE OF ASSESSMENTs .......................................................................................................... 59 
8. 
SAMPLE SIZE ........................................................................................................................................ 60 
9. 
CRITERIA FOR EARLY TERMINATION ............................................................................................... 60 
10. SAFETY REPORTING ........................................................................................................................... 61 

 
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10.1. 
Recording, Evaluating & Reporting of Serious Adverse Events / SARs ....................................... 61 
10.2. 
Reference Safety Information (RSI) .............................................................................................. 61 
10.3. 
Pregnancy Reporting ..................................................................................................................... 61 
11. RISK/BENEFIT ASSESSMENT ............................................................................................................. 61 
12. ADDITIONAL FINANCIAL SUPPORT ................................................................................................... 63 
13. APPENDIX B REFERENCES ................................................................................................................ 64 
 
Trial Flowchart 
 
1. INTRODUCTION 
The trial commenced with the first intervention, nasal niclosamide and matched placebo from February 2021. 
The intended second intervention is nasal and inhaled ciclesonide. Participants are being randomised in a 
1:1 ratio until the second intervention is introduced. Once ciclesonide is introduced, participants who are 

 
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eligible for ciclesonide will be randomised to niclosamide, ciclesonide, niclosamide matching placebo or 
ciclesonide matching placebo in a 2:2:1:1 ratio. The net result will be a 1:1:1 distribution between niclosamide, 
ciclesonide and placebo, with niclosamide-matching placebo and ciclesonide-matching placebo pooled for 
the analysis. In this way, the PROTECT-V platform gains efficiency by reducing the overall sample size 
required to assess niclosamide and ciclesonide by around 25% from what would be required to conduct two 
independent trials. There will be a very small proportion of participants who will be not eligible for ciclesonide 
as there are additional exclusion criteria for this arm; these participants will be randomised to niclosamide 
and niclosamide matching placebo in a 1:1 ratio. 
 
2. BACKGROUND 
2.1. Rationale for using ciclesonide for COVID-19 prophylaxis 
Inhaled corticosteroids (ICS) that are commonly used to treat asthma, COPD and allergic rhinitis have been 
proposed as a novel way of treating and preventing early COVID-191,2. Ciclesonide is an easily administered 
ICS licensed for the treatment of asthma and allergic rhinitis that has been shown to possess in vitro anti-
SARS-CoV-2 activity but has negligible systemic bioavailability even at higher doses. Consideration of these 
properties make it a leading candidate for testing as a COVID-19 primary prophylaxis intervention in 
vulnerable patient groups. 
Ciclesonide inhibits in vitro SARS-CoV-2 replication in cultured human bronchial epithelial cells via a novel 
mechanism on non-structural protein 15 (NSP-15)3,4,5. This effect is not seen with dexamethasone or 
commonly used ICS such as budesonide. Notably this effect was seen for SARS-CoV-2 but not other 
respiratory viruses such as influenza or respiratory syncytial virus (RSV). Ciclesonide has also been shown 
to form intracellular fatty acid conjugates6, which may help to inhibit viral lipid dependent attachment to host 
cells7.  
As an ICS, ciclesonide will also have pertinent class effects. Angiotensin converting enzyme 2 (ACE2), and 
transmembrane protease serine 2 (TMPRSS2) expression mediate SARS-CoV-2 infection of host respiratory 
epithelial cells. ICS, particularly at higher doses, have been shown to reduce expression of ACE2 and 
TMPRSS2 receptors8. ICS have also been shown to inhibit in vivo production of IL-69, a key pro-inflammatory 
cytokine in COVID-19 and a major predictor of severe disease and poor outcomes10,11,12. 
After inhalation, the major site of initial SARS-CoV-2 infection is the nasopharynx with subsequent micro-
aspiration leading to infection of the lower respiratory tract13. Reflecting this pattern of clinical disease ACE2 
expression is highest in the nose and decreases throughout the lower respiratory tract and is accompanied 
by a commensurate gradient of SARS-CoV-2 infection early on in the disease14,15. The proposed combination 
of prophylactic inhaled and intranasal ciclesonide will deliver early infection modifying therapy covering the 
entire respiratory epithelium, critical in the early stages of COVID-1916. A further advantage of ciclesonide is 
that due to its extra fine particle formulation and a particle size of 1.1um, ciclesonide achieves high levels of 
lung deposition especially in the peripheral airways and alveoli which is not seen with conventional ICS17. 
Hence unlike other ICS higher doses of inhaled ciclesonide are not needed to achieve adequate alveolar 
deposition. 
Ciclesonide has several novel pharmacological properties that distinguish it from other ICS commonly used 
to treat asthma and COPD. Ciclesonide is an inactive prodrug with low receptor binding affinity, which is 
activated on site by esterases within the respiratory mucosa to the highly potent active metabolite des-
ciclesonide18,Both ciclesonide and des-ciclesonide have been shown to bind to the active site of NSP-155. 
Des-ciclesonide forms intracellular lipid conjugates that promote pulmonary retention. It has a high a relative 
receptor binding affinity of 1200 compared to 100 for dexamethasone, consequently ciclesonide is licensed 

 
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for once daily dosing18. Ciclesonide and des-ciclesonide exhibit 99% first pass hepatic inactivation for the 
swallowed fraction and this, combined with 99% plasma protein binding (with no apparent saturation at high 
doses), results in negligible systemic effects at high inhaled doses (up to 1280µg/day), such as adrenal or 
bone suppression, even in the long term 19-22. Administration of supra-therapeutic doses of ciclesonide (2880 
μg) to healthy volunteers resulted in very low interstitial concentrations of unbound des-ciclesonide in skeletal 
muscle and adipose tissue below the lower limit of detection (<0.025 μg/L)18. In addition, because the active 
metabolite des-ciclesonide is generated on-site in the respiratory mucosa, there is minimal presence in the 
oropharynx or larynx, explaining the very low rate of local adverse effects such as oropharyngeal or laryngeal 
candidiasis when compared with conventional ICS18,23. 
Several uncontrolled case series of ciclesonide use in COVID-19 have been reported, but the lack of control 
groups, small size and concurrent testing of other potential antiviral agents limit interpretation8-10. A large 
retrospective study linking inhaled ICS usage with subsequent death from COVID-19 suggested that ICS-
users with COPD or asthma were at increased risk of death even after multiple covariate adjustment; 
nevertheless residual indication bias and lack of adequate adjustment mean that ICS may yet have a 
protective effect11,12. Several small-to-medium-sized trials of inhaled ciclesonide are planned or ongoing for 
the prevention or treatment of COVID-19. 
 
2.2. Dosing and administration of ciclesonide 
The maximal recommended daily dose of inhaled ciclesonide for asthma is 640µg with no adjustment for 
renal or hepatic impairment. The proposed inhaled dose of ciclesonide of 320µg once daily for the inhaled 
route has not been shown to be associated with any systemic adverse effects in patients with asthma in the 
long term19,20,24. A dose of 160µg once daily for the intranasal route will be used, which is similar to the 
recommended 200µg aqueous nasal spray dose, this also has no detectible systemic effects25. Nose bleeds 
are the most common adverse effect (4.9% 200µg ciclesonide vs 2.9% placebo) which is a dose related 
class effect of intranasal corticosteroids due to thinning of the nasal mucosa especially in the valve area 
albeit with the aqueous nasal spray 26. The doses of inhaled and intranasal ciclesonide have been chosen to 
achieve high local drug concentrations and are both in keeping with usual clinical recommended doses for 
asthma and allergic rhinitis.  
We propose to employ a pragmatic, easy to use delivery method for ciclesonide pMDI via Aerochamber 
spacer and facemask with mouth breathing for the inhaled route and nose breathing for the intranasal route. 
The proposed delivery devices will simplify drug administration and has been used as a technique to improve 
adherence27,28. Hence patients will not have the inconvenience of having to use two separate devices, one 
for the nose and one for the lungs. Administration of intranasal budesonide via spacer and nasal adaptor has 
already been shown, in two separate studies in adults and children with allergic rhinitis and asthma, to 
improve nasal peak inspiratory flow and nasal symptoms, thus proving that particles emitted from the spacer 
are trapped in the nose27,28. In both studies, asthma symptoms and oral peak expiratory flow also improved 
showing that, as expected, there is indeed some overspill of budesonide into the lungs. 
Ciclesonide and its active metabolite des-ciclesonide are metabolised and excreted by hepatic mechanisms. 
No dose modification is required for patients with renal disease. 
 

 
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3. TRIAL TREATMENT - CICLESONIDE 
3.1. Ciclesonide Name and description 
Chemical name (IUPAC): 
2-[(1S,2S,4R,8S,9S,11S,12S,13R)-6-cyclohexyl-11-hydroxy-9,13-
dimethyl-16-oxo-5,7-dioxapentacycloicosa-14, 
17-dien-8-yl]- 
2-oxoethyl 
2-methylpropanoate 
CAS registry number: 
141845-82-1 
Matched placebo contains the same solvent and propellant as the active product but no drug substance.  
3.2. Ciclesonide Legal status 
The ciclesonide product being supplied for use in the trial is an unlicensed formulation identical to that of the 
UK licensed formulation. Ciclesonide (by inhalation of aerosol) is currently licensed in the UK as a treatment 
to control persistent asthma in adults and adolescents (12 years and older). It is a pressurised solution, 
intended for inhalation use and commercialised under the brand Alvesco. The recommended dose of 
ciclesonide is 160µg once daily, which leads to asthma control in the majority of patients. However, this may 
be increased if necessary to 320µg twice daily, in severe asthma. 
 
3.3. Ciclesonide Supply, dispensing and accountability 
Ayrton Saunders will distribute supplies of ciclesonide and matched placebo to a sponsor appointed third 
party who will be responsible for the labelling and final packaging of the product into clinical trial supplies. 
Supply of the finished product to participating site pharmacies will be overseen by the trial co-ordinator and 
distributed by a sponsor-appointed third party. Upon initial authorisation by the sponsor, an initial supply will 
be sent to sites; supplies thereafter will be distributed as detailed in the pharmacy manual.  
IMP will be dispensed at appropriate intervals, supplying the inhalers labelled with allocated kit numbers. Full 
accountability records will be completed to document receipt, dispensing and destruction of expired and 
unused IMP at the end of the study. Further details of dispensing are detailed in the pharmacy manual. 
IMP will be collected by the participant during dialysis sessions or sent by courier to the participant. 
IMP for the trial will be provided free-of-charge for participating sites. 
 
3.4. Ciclesonide Packaging and Labelling 
The IMPs ciclesonide and matching placebo are packaged and labelled in single packs with one unit each. 
The outer carton and bottle label are blinded and complies with regulatory requirements. Each unit is labelled 
with an individual unique treatment pack number. The same number will appear on the inhaler and carton 
label. Each patient will also require a single AeroChamber Plus spacer with attached face mask for 
administration of the IMP throughout the entire study. 
 
3.5. Ciclesonide Storage 
The IMPs ciclesonide and matching ciclesonide Placebo must be stored as per labelled storage conditions. 
Store below 25°C out of direct sunlight in accordance with the manufacturer’s instructions. Do not use or 

 
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store near open flame or heat; do not puncture canisters. Exposure to temperatures >49°C may cause 
canister to burst; do not throw canister into fire or incinerator. 
 
3.6. Ciclesonide Treatment Duration 
PROTECT-V will be an event driven trial, and continue until the required number of events are accrued. It is 
anticipated that the median treatment duration will be 6 months for each participant with a maximum 
treatment period of 9 months. 
 
3.7. Ciclesonide Dose and Administration 
Participants will be prescribed ciclesonide once daily, administered as follows: 
 
Two puffs (320 µg) inhaled via mouth sequentially.  
 
One puff (160 µg) inhaled via nose.  
No dose modifications are permitted. 
 
3.8. Ciclesonide Missed or Replacement Doses 
Missed doses will not be replaced. A dose will be considered missed after 12 hours of usual administration 
time. 
 
3.9. Ciclesonide Contraindications 
Ciclesonide and placebo to match are contraindicated in subjects allergic or hypersensitive to ciclesonide, 
its derivatives or any formulation excipients.  
 
3.10. Ciclesonide side effects and concomitant medications 
The following are known side-effects (taken from Summary of Product Characteristics for ciclesonide inhaler 
and aerosol) and will be collected within the case report form: 
 
Incidence 
Side-effect 
Uncommon 
(>1/1,000, <1/100) 
Nausea, vomiting*, bad taste, application site reactions (including nasal 
discomfort and epistaxis), application site dryness, oral fungal infections*, 
headache*, 
dysphonia, 
cough 
after 
inhalation*, 
paradoxical 
bronchospasm*, eczema and rash 

 
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Rare or very rare 
(>1/10,000 
– 
1/1,000) 
Palpitations**, abdominal pain*, dyspepsia*, angioedema, hypersensitivity, 
hypertension  
Unknown 
Psychomotor 
hyperactivity, 
sleep 
disorders, 
anxiety, 
depression, 
aggression, behavioural changes (predominantly in children) 
* similar or lower incidence when compared with placebo 
** palpitations were observed in clinical trials in cases mostly confounded with concomitant medication with 
known cardiac effects (e.g. theophylline or salbutamol) 
All standard of care medicines are to continue as per standard practice and will be recorded by the study 
team as described. 
 
3.11. Placebo to match Ciclesonide 
Placebo to match ciclesonide will be supplied, stored, labelled, dispensed and dosed as for the active 
formulation.  
 
4. ELIGIBILITY 
4.1. Additional Exclusion Criteria 
In addition to the core exclusion criteria in the master protocol, the presence of any of the following will 
preclude participant inclusion: 
1. Significant structural nasal disease in the opinion of the investigator 
2. Prior participation in the ciclesonide arm of the trial (if being re-screened for participation in a second 
interventional arm). 
3. Currently taking inhaled corticosteroids - beclometasone dipropionate (aerosol inhaler and dry powder 
inhaler), budesonide (dry powder inhaler and single-dose units for nebulization), ciclesonide (aerosol 
inhaler), fluticasone propionate (dry powder inhaler, aerosol inhaler, and single-dose units for 
nebulization), mometasone furoate (dry powder inhaler). 
4. Received a live vaccine within last 14 days - ciclesonide increases risk of generalised infection: influenza, 
MMR, rotavirus, typhoid, varicella-zoster (shingles), yellow fever. 
5. Taking one of the following medications 
○ 
Systemic Ketoconazole, itraconazole, ritanovir, nelfinavir 
 
5. BLINDING 
PROTECT-V-ciclesonide will be a double blind placebo controlled study where neither the participant nor 
clinician will be aware of treatment allocation. 

 
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6. RANDOMISATION 
A participant will be randomised to:  
 
niclosamide vs ciclesonide vs matching placebo to niclosamide vs matching placebo to ciclesonide 
in a 2:2:1:1 ratio, or 
 
niclosamide vs matching placebo to niclosamide in a 1:1 ratio if a participant is eligible for 
niclosamide but not ciclesonide, or 
 
ciclesonide vs matching placebo to ciclesonide in a 1:1 ratio if the recruitment of niclosamide 
intervention is completed as it is the first treatment commenced. 
The system will allocate the participant treatment pack code(s) which will relate uniquely to the first supply of 
IMP. Different treatment pack code(s) for every subsequent order of IMP supply will be allocated by the 
randomisation system. Participants and site teams will remain blinded to treatment allocation, i.e. whether 
active or placebo within a stated intervention. The allocated blinded IMP supply will be collected by 
participants when possible or sent at suitable intervals to their home by courier. 
 
7. SCHEDULE OF ASSESSMENTs 
 
Assessment  
Schedule 
Screen/ 
Baseline 
visit 
Weekly 
(±3 
days) % 
2-weekly 
(±3 days) % 
  
As 
required 
data 
linkage 
Final 
assessment& 
Eligibility check 
X 
 
 
 
 
 
Medical history  
 
X 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
 
 
 
Symptom checker 
questionnaire$ 
X 
X 
X 
 
 
 
SARS-CoV2 PCR or 
lateral flow test 
X 
 
 
X 
 
 
Serum sample for 
SARS-CoV2 Total Ab 
assay 
X 
 
 
 
 
X 
ALT/AST 
X 
 
 
 
 
 
Pregnancy test# 
X 
 
 
 
 
 
Medication diary€ 
X 
 
 
 
 
 
SAR/SAE/SUSAR 
Reporting 
 
 
 
X 
 
 X  
Randomisation 
X 
 
 
 
 
 

 
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IMP supplied 
 
 
 
X€ 
 
 
COVID-19 infection 
 
X 
X 
 
X 
 
 
#A pregnancy test is required for WOCBP within 14 days prior to starting trial treatment. Women are 
considered WOCBP following menarche and until becoming post-menopausal unless permanently sterile 
(previous hysterectomy, previous bilateral salpingectomy and or oophorectomy). A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A serum pregnancy test is required 
for all WOCBP participants. 
% Weekly for one month and 2-weekly thereafter. Any participant testing positive for SARS-CoV-2 without 
symptom will be required to complete a COVID-19 symptom assessment at least weekly for 4 weeks after 
diagnosis, unless hospitalised. 
$ Telephone consultation will occur for the first 6 weeks. 
& Final assessment visit will occur 4-6 weeks after end of treatment 
€ Local teams will instruct the participant on how to use the medication diary and add a copy with the first 
IMP dispensation 
 
8. SAMPLE SIZE 
For each prophylactic intervention, it is planned initially to randomise 1500 subjects between the prophylactic 
treatment and the placebo or the shared placebo for patients randomised to more than one prophylactic 
treatments option. This was based on that the estimated 6-month rate of confirmed symptomatic COVID-19 
infection was around 15% in the placebo group, and 10% in each treatment arm; this would correspond to a 
hazard ratio of 0.648. With a 0.045 significance level (for an overall significance level of 0.05 with two interim 
analyses using a Lan-DeMets error-spending approach corresponding to symmetric 2-sided O’Brien-Fleming 
boundaries (https://doi.org/10.1002/sim.4780131308) and 90% power, the maximum total number events 
required would be 235. With a 3 month recruitment and a further continuation of 8 months (a total of 11 
months), the number of events required would be observed with a total of 1275 subjects, allowing for a 15% 
noncompliance, a total of 1500 subjects. With a 6 month recruitment and a further continuation of 7 months 
(a total of 13 months), the number of events required will be observed with a total of 1278 subjects, allowing 
for a 15% noncompliance, a total of 1500 subjects. There are uncertainties and changes with the sample 
size assumptions with the development of the COVID 19 pandemic. Recruitment period will not be restricted 
by the assumptions. These assumptions are therefore monitored regularly by the independent data monitor 
committee (IDMC). Sample size re-estimation will be considered with the recommendation from the IDMC. 
 
9. CRITERIA FOR EARLY TERMINATION  
The study will be reviewed every 2 months by the independent Data Monitoring Committee (DMC) for safety, 
combined primary outcome measure event rate and making a recommendation for performing efficacy 
analyses. Should there be sufficient evidence of a difference in the primary outcome measure between the 
ciclesonide arm and the placebo arm at one planned interim analyses, the DMC may consider recommending 
early termination of the ciclesonide arm of the study. As a guide to the DMC, considering the total duration 
of study is around 1 year, a maximum of two formal interim analyses, based the number of primary endpoint 

 
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events, are to be performed using a Lan-DeMets error-spending approach corresponding to symmetric 2-
sided O’Brien-Fleming boundaries (https://doi.org/10.1002/sim.4780131308). The study will be stopped 
earlier if there is sufficient evidence of benefit using the O’Brien-Fleming boundaries, that is, the value of the 
test statistic crosses the O’Brien-Fleming boundary of beneficial effect of ciclesonide. Condition power and 
predictive power will also be estimated and reviewed by the independent DMC, the study might be stopped 
early for futility. The detailed stopping guidance will be included in the DMC charter. 
The study will be stopped early if there are any safety concerns based on the recommendation of the 
independent Data Monitoring Committee and the approval from the Trial Steering Committee. As guidance, 
the study might be stopped early for safety concerns 
● 
if the rate of unacceptable toxicity in the ciclesonide arm is over 20%, that is, the estimated lower 
limit of a 95% confidence interval is greater than 20% 
● 
if the incidence of moderate/severe adverse events/symptoms is 15% more in the ciclesonide arm 
with a minimum of 200 participants in each arm at a significance level of 0.05. 
 
10. SAFETY REPORTING 
10.1. Recording, Evaluating & Reporting of Serious Adverse Events / SARs 
The Chief Investigator will ensure that all safety information is reported to Ayrton Saunders at the same time 
as notification to the Sponsor. 
 
10.2. Reference Safety Information (RSI) 
For this trial the Reference Safety Information is section 4.8 of the Alvesco (160mcg ciclesonide) summary 
of product characteristics. The applicable SmPC version will be the latest version that has been approved by 
the MHRA for use in this trial.  
 
10.3. Pregnancy Reporting 
The Chief Investigator will ensure that all pregnancies are reported to Ayrton Saunders when sponsor review 
is complete. 
 
11. RISK/BENEFIT ASSESSMENT 
1. Is there still a need to add another agent to a pre-exposure prophylaxis platform study in light 
of the Covid-19 vaccination program (including third primary doses and booster doses)? 
  
The PROTECT-V study protocol is clear that all patients should receive SARS CoV-2 vaccination as 
part of standard of care, and that includes third primary dose and/or booster doses as appropriate. 
However, many studies have shown that immunocompromised renal patients mount sub-optimal 
responses to vaccination.  

 
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In July 2021, a synthesised review of 35 studies looking at vaccine response in renal patients 
demonstrated 89% (85-91%) response in dialysis patients and 35% (29-42%) in individuals with a renal 
transplant after two doses of SARS CoV-2 vaccine29. Although, third doses lead to a response in 
approximately 50% of those individuals not protected after 2 doses, a considerable number of 
immunocompromised patients remain vulnerable to SARS CoV-2 infection30,31. The literature on vaccine 
response in individuals with autoimmune disease is more complicated in view of disease and treatment 
heterogeneity, but responses are also sub-optimal to healthy individuals. Table 1 shows the vaccine 
response from 695 patients in Cambridge, UK (unpublished data) and demonstrates not only the 
proportion of patients responding to vaccination, but the sub-optimal magnitude of response (threshold 
of protection for this assay 1896; healthy control titres >30,000). 
It is also important to note that the majority of studies report absolute antibody titres, which does not 
indicate the functionality and neutralising capacity of the antibodies. In a study of 178 dialysis patients 
in the UK, AZD1222 alone in sero-naive individuals induces suboptimal neutralising antibody titres 
against all variants of concern (VOCs), including the delta variant that is dominant globally32. As such, 
a greater proportion of the patient population other than those without detectable antibodies who remain 
highly vulnerable to SARS CoV-2 infection. Furthermore, the occurrence of breakthrough infections, with 
some studies reporting that immunocompromised persons account for a high proportion (≥40%) of 
infections among fully vaccinated hospitalized persons is further evidence of sub-optimal vaccine 
response33,34. 
Therefore, despite vaccination, and the third dose and booster vaccination campaign, sub-optimal 
vaccine response and vulnerability to Covid-19 infection remains a major issue in immunocompromised 
renal patients. 
Table 1: Vaccine response in three groups of immunocompromised renal patients in Cambridge. 
Threshold of protection for this assay is 1896. 
 
 
 
 
 
 
 
2.  Addition of systemic lupus erythematosus to inclusion criteria 
 
Systemic lupus erythematosus patients are another sub-group of the vulnerable renal patient population, 
receiving the very similar immunosuppressive agents as the renal transplant and vasculitis/GN patients. 
They will be stratified within the Vasculitis/GN cohort.  
 
3. Rationale for using unlicensed formulation of ciclesonide; the dose and route of 
administration 
 

 
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We considered using a licensed form of ciclesonide for the PROTECT-V trial, but since Ayrton Saunders 
were able to provide matched placebo, we opted for this formulation, as placebo control is so important 
in these prophylaxis studies.  
 
The maximal recommended daily dose of inhaled ciclesonide for asthma is 640µg with no adjustment for 
renal or hepatic impairment. The proposed inhaled dose of ciclesonide of 320µg once daily for the inhaled 
route has not been shown to be associated with any systemic adverse effects in patients with asthma in 
the long term19,20,24. A dose of 160µg once daily for the intranasal route will be used, which is similar to 
the recommended 200µg aqueous nasal spray dose, this also has no detectible systemic effects25. The 
proposed combination of prophylactic inhaled and intranasal ciclesonide will deliver early infection 
modifying therapy covering the entire respiratory epithelium, critical in the early stages of COVID-1916. 
Furthermore, ciclesonide has a high relative receptor binding affinity and is licensed for once daily 
dosing18.  
 
We propose to employ a pragmatic, easy to use delivery method for ciclesonide pMDI via the standard 
of care Aerochamber spacer and facemask with mouth breathing for the inhaled route and nose breathing 
for the intranasal route. The proposed delivery devices will simplify drug administration and has been 
used as a technique to improve adherence27,28. Hence patients will not have the inconvenience of having 
to use two separate devices, one for the nose and one for the lungs.  
 
4. Justification for the intensity of scheduled follow up 
 
The intensity and manner of follow up for the ciclesonide arm has been carefully considered to minimise 
healthcare interactions with clinically extremely vulnerable individuals, but to ensure that there is 
sufficient monitoring to ensure patient safety. Ciclesonide is widely used for the treatment of asthma at 
doses greater than those proposed for this study, and for a longer duration without major adverse effects. 
The safety profile is well established and we believe the proposed remote follow-up schedule provides 
sufficient safety monitoring. Subjects are seen in person at the screening/baseline visit to discuss the 
trial, provide informed consent, undergo screening blood tests and be educated about the IMP and trial. 
All patients then have a weekly telephone call with a member of the study team to ask about potential 
adverse events related to the IMP for the first 6 weeks of the study. Follow up questionnaires are then 
completed every 2 weeks throughout the study by the patient and submitted/returned to the trial team.  
5. Justification for use of Alvesco SMPC as reference safety information  
The IMPD describes the product development strategy taken by Ayrton to demonstrate therapeutic 
equivalence to the Reference Medical Product (RMP), Alvesco®, via in vitro data only, in line with section 
5.2 of CPMP/EWP/4151/00 Rev.1. This includes testing to justify a waiver from conducting in vivo 
studies. A Quality Target Product Profile is outlined (Table 2.1-1), defined after analysis of the SmPC, 
PIL and applicable patents of the RMP, and Critical Quality Attributes were considered and evaluated to 
identify product characteristics that might impact quality (Table 2.1-2). A Control Strategy has been 
developed to ensure manufacturing consistency of a product of required quality. It is therefore, 
considered that use of the SmPC for Alvesco® is acceptable for use in this study. Section 4.8 of the 
Alvesco is stated as the reference safety information in Section 10.2 of appendix B. 
 
12. ADDITIONAL FINANCIAL SUPPORT 
Trial medications are provided by Department of Health and Social Care funding, and this arm of the trial is 
supported by funding from the National Institute of Health Research. 

 
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13. APPENDIX B REFERENCES 
1. Lipworth B, Kuo CR, Lipworth S, et al. Inhaled Corticosteroids and COVID-19. Am J Respir Crit Care 
Med 2020;202(6):899-900. doi: 10.1164/rccm.202005-2000LE [published Online First: 2020/07/16] 
2. Lipworth B, Chan R, Kuo CR. Use of inhaled corticosteroids in asthma and coronavirus disease 2019: 
Keep calm and carry on. Ann Allergy Asthma Immunol 2020 doi: 10.1016/j.anai.2020.06.026 [published 
Online First: 2020/06/26] 
3. Matsuyama S, Kawase M, Nao N, et al. The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA 
replication by targeting the viral 2 replication -transcription complex in cultured cells. J. Virol. 2020 
doi:10.1128/JVI.01648-20. 
4. Jeon S, Ko M, Lee J, et al. Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-
Approved 
Drugs. 
Antimicrobial 
agents 
and 
chemotherapy 
2020;64(7):e00819-20. 
doi: 
10.1128/aac.00819-20 
5. Kimura H, Kurusu H, Sada M, et al. Molecular pharmacology of ciclesonide against SARS-CoV-2. J 
Allergy Clin Immunol 2020;146(2):330-31. doi: 10.1016/j.jaci.2020.05.029 [published Online First: 
2020/07/01] 
6. Nave R, Meyer W, Fuhst R, et al. Formation of fatty acid conjugates of ciclesonide active metabolite 
in the rat lung after 4-week inhalation of ciclesonide. Pulm Pharmacol Ther 2005;18(6):390-6. doi: 
10.1016/j.pupt.2005.02.012 [published Online First: 2005/09/24] 
7. Baglivo M, Baronio M, Natalini G, et al. Natural small molecules as inhibitors of coronavirus lipid-
dependent attachment to host cells: a possible strategy for reducing SARS-COV-2 infectivity? SARS-
COV-2 lipid-dependent attachment to host cells. Acta Bio Medica Atenei Parmensis 2020;91(1):161-64. 
doi: 10.23750/abm.v91i1.9402 
8. Peters MC, Sajuthi S, Deford P, et al. COVID-19–related Genes in Sputum Cells in Asthma. 
Relationship to Demographic Features and Corticosteroids. Am J Respir Crit Care Med 2020;202(1):83-
90. doi: 10.1164/rccm.202003-0821OC 
9. Lipworth B, Chan R, Lipworth S, et al. Weathering the Cytokine Storm in Susceptible Patients with 
Severe 
SARS-CoV-2 
Infection. 
J 
Allergy 
Clin 
Immunol 
Pract 
2020;8(6):1798-801. 
doi: 
10.1016/j.jaip.2020.04.014 [published Online First: 2020/04/21] 
10. Lipworth B, Chan R, Kuo CR. Predicting Severe Outcomes in COVID-19. J Allergy Clin Immunol 
Pract 2020;8(8):2582-84. doi: 10.1016/j.jaip.2020.06.039 [published Online First: 2020/07/03] 
11. Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of IL-6 and CRP predict the need for 
mechanical ventilation in COVID-19. J Allergy Clin Immunol 2020;146(1):128-36 e4. doi: 
10.1016/j.jaci.2020.05.008 [published Online First: 2020/05/20] 
12. Zhang J, Hao Y, Ou W, et al. Serum interleukin-6 is an indicator for severity in 901 patients with 
SARS-CoV-2 infection: a cohort study. J Transl Med 2020; 18, 406. https://doi.org/10.1186/s12967-020-
02571-x 
13. Wölfel R, Corman VM, Guggemos W. et al. Virological assessment of hospitalized patients with 
COVID-2019. Nature 2020; 581, 465–469. https://doi.org/10.1038/s41586-020-2196-x 

 
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14. Hou YJ, Okuda K, Edwards CE, et al. SARS-CoV-2 Reverse Genetics Reveals a Variable Infection 
Gradient in the Respiratory Tract. Cell 2020;182(2):429-46 e14. doi: 10.1016/j.cell.2020.05.042 
[published Online First: 2020/06/12] 
15. Chen M, Shen W, Rowan NR, et al. Elevated ACE2 expression in the olfactory neuroepithelium: 
implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. Eur Respir J 2020 
doi: 10.1183/13993003.01948-2020 [published Online First: 2020/08/21] 
16. Lipworth B, Chan R, RuiWen Kuo C. COVID-19: Start with the nose. J Allergy Clin Immunol 2020 
doi: 10.1016/j.jaci.2020.06.038 [published Online First: 2020/08/24] 
17. Newman S, Salmon A, Nave R, et al. High lung deposition of 99mTc-labeled ciclesonide 
administered via HFA-MDI to patients with asthma. Respiratory medicine 2006;100(3):375-84. doi: 
10.1016/j.rmed.2005.09.027 [published Online First: 2005/11/09] 
18. Derendorf H. Pharmacokinetic and pharmacodynamic properties of inhaled ciclesonide. J Clin 
Pharmacol 2007;47(6):782-9. doi: 10.1177/0091270007299763 [published Online First: 2007/04/07] 
19. Lipworth BJ, Kaliner MA, LaForce CF, et al. Effect of ciclesonide and fluticasone on 
hypothalamicpituitary-adrenal axis function in adults with mild-to-moderate persistent asthma. Annals of 
Allergy, Asthma & Immunology 2005;94(4):465-72. 
20. Anderson WJ, McFarlane LC, Lipworth BJ. Prospective follow-up of novel markers of bone turnover 
in persistent asthmatics exposed to low and high doses of inhaled ciclesonide over 12 months. J Clin 
Endocrinol Metab 2012;97(6):1929-36. doi: 10.1210/jc.2011-3410 [published Online First: 2012/03/23] 
21. Lee DK, Fardon TC, Bates CE, et al. Airway and systemic effects of hydrofluoroalkane formulations 
of high-dose ciclesonide and fluticasone in moderate persistent asthma. Chest. 2005;127:851-860. 
22. Szefler S, Rohatagi S, Williams J, et al. Ciclesonide, a novel inhaled steroid, does not affect 
hypothalamic-pituitary-adrenal axis function in patients with moderate-to-severe persistent asthma. 
Chest. 2005;128:1104-1114. 
23. Manning P, Gibson PG, Lasserson TJ. Ciclesonide versus other inhaled steroids for chronic asthma 
in children and adults. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD007031. 
DOI: 10.1002/14651858.CD007031. 
24. Lipworth BJ, Short PM, Williamson PA, et al. A randomized primary care trial of steroid titration 
against 
mannitol 
in 
persistent 
asthma: 
STAMINA 
trial. 
Chest 
2012;141(3):607-15. 
doi: 
10.1378/chest.11-1748 [published Online First: 2011/10/15] 
25. Chervinsky P, Kunjibettu S, Miller DL, et al. Long-term safety and efficacy of intranasal ciclesonide 
in adult and adolescent patients with perennial allergic rhinitis. Ann Allergy Asthma Immunol 
2007;99(1):69-76. doi: 10.1016/S1081-1206(10)60624-2 [published Online First: 2007/07/27] 
26. Nasal ciclesonide spc: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/022004lbl.pdf 
27. Pedersen W, Hjuler I, Bisgaard H, et al. Nasal inhalation of budesonide from a spacer in children 
with perennial rhinitis and asthma. Allergy 1998;53(4):383-7. doi: 10.1111/j.1398-9995.1998.tb03909.x 
[published Online First: 1998/05/09] 

 
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28. Pedersen B, Dahl R, Lindqvist N, et al. Nasal inhalation of the glucocorticoid budesonide from a 
spacer for the treatment of patients with pollen rhinitis and asthma. Allergy 1990;45(6):451-6. doi: 
10.1111/j.1398-9995.1990.tb01096.x [published Online First: 1990/08/01] 
29. Carr, E.J. et al. Review of early immune responseto SARS CoV-2 vaccination among patients with 
CKD. Kidney Int Rep. 2021 Sep;6(9):2292-2304  
30. Kamar et al. Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. NEJM 
Aug 2021; 385:661-662 
31. Caillard, S., Thaunat, O. COVID-19 vaccination in kidney transplant recipients. Nat Rev Nephrol. 
2021. https://doi.org/10.1038/s41581-021-00491-7 
32. Carr, EJ. et al. Neutralising antibodies after COVID-19 vaccination in UK haemodialysis patients. 
Lancet. 2021 Aug 12:S0140-6736(21)01854-7. doi: 10.1016/S0140-6736(21)01854-7. Epub ahead of 
print.  
33. Tenforde MW, et al. Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 
Hospitalizations in the United States. medRxiv. 2021;https://doi.org/10.1101/2021.07.08.21259776 
34. Brosh-Nissimov T et al. BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully 
vaccinated hospitalized COVID-19 patients in Israel. Clin Microbiol Infect. 2021.  

 
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APPENDIX C: SOTROVIMAB 
Appendix C Protocol Contributors 
Dr Davinder Dosanjh 
Consultant Respiratory Physician, University Hospitals 
Birmingham NHS Foundation Trust 
Ms Robyn Staples 
Clinical Trials Pharmacist, Cambridge Clinical Trials 
Unit 
Prof Alex Richter 
Professor 
and 
Honorary 
Consultant 
in 
Clinical 
Immunology, University of Birmingham 
Dr Benjamin Sutton 
Consultant Respiratory Physician, University Hospitals 
Birmingham NHS Foundation Trust 
 
 
Prof Paul Cockwell 
Consultant 
Nephrologist, 
University 
Hospitals 
Birmingham NHS Foundation Trust 
 
 
APPENDIX C: SOTROVIMAB ....................................................................................................................... 67 
Trial Flowchart ............................................................................................................................................... 70 
1. 
BACKGROUND ...................................................................................................................................... 70 
1.1. 
Rationale for using sotrovimab for COVID-19 prophylaxis ............................................................ 70 
1.2. 
Dose Rationale .............................................................................................................................. 72 
2. 
TRIAL TREATMENT – SOTROVIMAB .................................................................................................. 74 
2.1. 
Sotrovimab Name and description ................................................................................................ 74 
2.2. 
Placebo to match sotrovimab ........................................................................................................ 74 
2.3. 
Sotrovimab Legal status ................................................................................................................ 74 
2.4. 
Sotrovimab Supply, dispensing and accountability ....................................................................... 75 
2.5. 
Sotrovimab Packaging and Labelling ............................................................................................ 75 
2.6. 
Sotrovimab Storage ....................................................................................................................... 75 
2.7. 
Sotrovimab Treatment Duration .................................................................................................... 76 
2.8. 
Sotrovimab Dose and Administration ............................................................................................ 76 
2.9. 
Sotrovimab Contraindications........................................................................................................ 78 
2.10. 
Sotrovimab side effects and concomitant drug interactions .......................................................... 78 
3. 
ELIGIBILITY ........................................................................................................................................... 79 
3.1. 
Additional Inclusion Criteria ........................................................................................................... 79 

 
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3.2. 
Additional Exclusion Criteria .......................................................................................................... 79 
4. 
BLINDING .............................................................................................................................................. 79 
4.1. 
Emergency unblinding ................................................................................................................... 80 
5. 
RANDOMISATION ................................................................................................................................. 80 
6. 
SCHEDULE OF ASSESSMENTS .......................................................................................................... 81 
6.1. 
Trial Assessments ......................................................................................................................... 83 
6.1.1. 
Screening ............................................................................................................................... 83 
6.1.2. 
Day 1 infusion visit ................................................................................................................. 83 
6.1.3. 
Day 4 safety bloods visit ........................................................................................................ 83 
6.1.4. 
Telephone follow-up assessments ........................................................................................ 84 
6.1.5. 
Day 29 (week 4) (+/- 3 days), week 12 (+/- 7 days) and week 24 (+/- 7 days) in- person 
assessments .......................................................................................................................................... 84 
6.1.6. 
PK and ADA assessment ...................................................................................................... 84 
6.2. 
Assessments in the event of a patient developing symptomatic, confirmed COVID-19 infection 
(either by PCR or lateral flow test) ............................................................................................................. 85 
If COVID-19 infection is confirmed either by PCR or lateral flow test (LFT): ............................................. 85 
6.3. 
Trial Restrictions (monoclonal arm) ............................................................................................... 85 
7. 
ADDITIONAL OBJECTIVES .................................................................................................................. 85 
7.1. 
Additional exploratory objectives ................................................................................................... 86 
8. 
ADDITIONAL OUTCOMES .................................................................................................................... 86 
8.1. 
Primary Outcomes ......................................................................................................................... 86 
8.2. 
Secondary Outcomes .................................................................................................................... 86 
8.3. 
Additional exploratory outcomes ................................................................................................... 86 
9. 
EXPERIMENTAL MEDICINE SAMPLES ............................................................................................... 87 
10. STATISTICS ........................................................................................................................................... 87 
10.1. 
Statistical methods ........................................................................................................................ 87 
10.1.1. 
Efficacy Analyses................................................................................................................... 88 
10.1.1.1. Primary Efficacy Analysis 
88 
10.2. 
Number of patients to be enrolled ................................................................................................. 88 
10.3. 
Interim Analyses ............................................................................................................................ 89 
11. CRITERIA FOR EARLY TERMINATION ............................................................................................... 89 
12. SAFETY REPORTING ........................................................................................................................... 90 
12.1. 
Recording, Evaluating & Reporting Serious Adverse Events / SARs ........................................... 90 
12.2. 
Reference Safety Information (RSI) .............................................................................................. 91 
12.3. 
Pregnancy Reporting ..................................................................................................................... 91 
13. JUSTIFICATION OF STUDY DESIGN AND RISK/BENEFIT ASSESSMENT FOR ADDITION OF 
SOTROVIMAB TO THE PROTECT-V PLATFORM ...................................................................................... 91 

 
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13.1. 
Is there still a need for an additional arm in the PROTECT-V platform in light of the COVID-19 
vaccination program (including third primary doses and booster doses) as well as other non-vaccine 
agents? ...................................................................................................................................................... 91 
13.2. 
Broadening inclusion criteria to include non-renal patients who have mounted sub-optimal vaccine 
responses .................................................................................................................................................. 93 
13.3. 
Justification for the intensity of scheduled follow up ..................................................................... 94 
13.4. 
Collection of Adverse Events up to Day 29 only ........................................................................... 95 
13.5. 
Rationale for revision of event rate (symptomic COVID-19 infection) ........................................... 95 
13.6. 
Justification of a 12-week primary endpoint .................................................................................. 95 
13.7. 
Management of individuals who develop COVID-19 infection during the study ........................... 96 
13.8. 
Concerns about monoclonal antoantibodies driving viral evolution .............................................. 96 
13.9. 
Concerns about waning of sotrovimab concentrations as the study progresses .......................... 96 
14. ADDITIONAL FINANCIAL SUPPORT ................................................................................................... 97 
15. PUBLICATIONS POLICY ....................................................................................................................... 97 
16. REFERENCES ....................................................................................................................................... 98 

 
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Trial Flowchart 
 
1Day 3 (24-72 hours post infusion) telephone call only necessary for lead-in cohorts 
2Day 4 (48-96 hours post-infusion) in person assessment will only be done for lead-in cohort one and will 
be a home-visit  
 
1. BACKGROUND 
 
1.1. Rationale for using sotrovimab for COVID-19 prophylaxis 
Sotrovimab is a fully human IgG1κ monoclonal antibody (mAb) derived from the parental mAb S309, a potent 
neutralising mAb directed against the spike protein of SARS-CoV-2 (1). S309 binds to a highly conserved 
epitope of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domain (RBD) and inhibits SARS-
CoV-2 infection in vitro (1). The amino acid sequence of the complementarity determining regions of 
sotrovimab is identical to the parent molecule S309, with the exception of one amino acid modification (N55Q) 
introduced to aid antibody developability.  
 
Sotrovimab demonstrates high affinity binding to the SARS-CoV-2 spike RBD. Sotrovimab neutralises SARS-
CoV-2 virus in vitro with a half maximal effective concentration (EC50) of 100.1 ng/mL and effectively 
neutralises pseudotyped virus containing the SARS-CoV-2 spike. 
  
Sotrovimab was also examined for the potential for antibody dependent enhancement (ADE) using a series 
of in vitro studies. Using moDCs, PBMCs, and U937 cells sotrovimab showed no enhancement of viral 
uptake, no enhancement of viral replication, and no effect on infection-associated cytokine production. These 
in vitro data did not identify an elevated concern that sotrovimab will demonstrate ADE in a clinical setting. 
In addition, in vivo antiviral activity was evaluated in a hamster model of SARS-CoV-2 infection using a 

 
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version of the mAb that lacks the ‘LS’ modification (VIR-7831-WT). VIR-7831-WT showed a dose-dependent 
improvement in all measured outcomes, with no evidence of disease exacerbation that would indicate a 
potential for ADE at fully neutralising and sub-neutralising doses. 
Clinical Trial data: COMET-ICE  
This is a Phase II/III randomised, double-blind, placebo-controlled study which evaluated sotrovimab as 
treatment for COVID-19 infection in non-hospitalised patients at high risk of medical complications of the 
disease. Patients included were aged 18 years and older with at least one of the following comorbidities: 
diabetes, obesity (BMI>30), chronic kidney disease, congestive heart failure, chronic obstructive pulmonary 
disease, moderate to severe asthma, or were aged 55 years and older. The study included patients with 
symptoms for ≤ 5 days, oxygen saturation on room air ≥94% and SARS-CoV-2 infection, as confirmed by 
local laboratory tests and/or point of care tests. Patients with severe COVID-19 requiring supplemental 
oxygen or hospitalisation were excluded from the trial. Patients were treated with a single 500 mg infusion of 
sotrovimab (N=291) or placebo (N=292) over 1 hour (Intent to Treat (ITT), [interim analysis (IA)] population). 
The median age of the overall randomised population was 53 years (range: 18-96). The three most common 
pre-defined risk factors or comorbidities were obesity (63%), 55 years of age or older (47%) and diabetes 
requiring medication (23%). The efficacy of sotrovimab was evaluated in a pre-planned interim analysis and 
the study was recommended to be stopped by the Independent Data Monitoring Committee (IDMC) for 
profound efficacy. The primary endpoint, progression of COVID-19 at Day 29, was reduced by 85% compared 
with placebo (adjusted relative risk reduction) in recipients of sotrovimab vs placebo (p=0.002).  
Hospitalisation for more than 24 hours or death occurred in 1% (3 out of 291) of patients who received 
sotrovimab and 7% (21 out of 292) of those who received placebo. The adjusted relative risk reduction for 
the full ITT (Day 29) population (sotrovimab: 528; placebo: 529) was 79% (p<0.001). Risk reduction was 
consistent in magnitude between the ITT (IA) and ITT (Day 29) populations. The proportion of patients 
reporting adverse events was similar between treatment groups; sotrovimab was well tolerated, and no new 
safety concerns were identified. 
Monoclonal antibodies as prophylactic agents in COVID-19 
Other monoclonal antibodies have been investigated for their use as prophylaxis against COVID-19 infection 
and have been proven to be effective.   
The PROVENT Phase III prophylaxis trial met its primary endpoint in preventing COVID-19 infection, with 
administration of Evusheld (tixagevimab/cilgavimab, AZD7442) reducing the risk of developing symptomatic 
COVID-19 by 77% compared to placebo at 6 months, though the data is yet to be published or independently 
peer-reviewed (2). Evusheld has now been issued with Conditional Marketing Authorisation by the UK MHRA 
for pre-exposure prophylaxis of COVID-19 in adults who are not currently infected with SARS-CoV-2 and 
who are unlikely to mount an adequate immune response to COVID-19 vaccination, or for whom COVID-19 
vaccination is not recommended (3). Of note, the MHRA recognises that the duration of protection provided 
by Evusheld for the Omicron BA.1 and BA.1.1 variants is currently not known.   
Ronapreve (casirivimab/imdevimab) has been authorised for use by the MHRA as a prophylactic agent 
against COVID-19 based on the Phase III COV-2069 trial which demonstrated an 81% relative risk reduction 
in the development of COVID-19 with Ronapreve versus placebo in individuals who had experienced 
exposure to COVID-19 from a household contact (4).  
Rationale for using sotrovimab in PROTECT-V trial platform 
Sotrovimab may have advantages as a prophylactic agent, compared to the other available monoclonal 
antibodies that target COVID-19: 
 
Prolonged half-life: The Fc domain of sotrovimab includes the 2 amino acid “LS” modification that 
extends antibody half-life and is also expected to enhance distribution to the respiratory mucosa 

 
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(5-7), thus the LS modification allows for less frequent dosing, an important characteristic for a 
product intended to be used in the prophylaxis setting. 
 
Increased respiratory mucosal distribution: Transcytosis of IgG across mucosal surfaces 
including respiratory epithelium has been shown to be FcRn dependent (8, 9), and therefore the LS 
modification may also increase respiratory mucosal distribution, an important consideration in 
respiratory diseases (10) such as COVID-19. Moreover, FcRn can also play an important role in 
processing of endocytosed multimeric IgG immune complexes by dendritic cells, thereby 
contributing to CD4+ and CD8+ T cell responses (11, 12). 
 
Effective against all known COVID-19 variants of concern: Sotrovimab targets a highly 
conserved spike epitope, with amino acid conservation > 99.99% for all amino acids based on 
>2,100,000 available sequences. Variants at two positions, E340 and P337, resulted in significant 
half maximal effective concentration (EC50) shifts indicating reduced susceptibility to sotrovimab. 
E340 and P337 are >99.99% conserved among sequences in the GISAID database (16 July 2021). 
In vitro neutralization data using pseudotyped virus carrying mutations from the B.1.1.7 (Alpha, UK 
origin), B.1.351 (Beta, South Africa origin), P.1 (Gamma, Brazil origin), B.1.427/B.1.429 (Epsilon, 
California origin), B.1.526 (Iota, New York origin), B.1.617.1 (Kappa, India origin), B.1.617.2 (Delta, 
India origin), AY.1 (Delta Plus, India origin), AY.2 (Delta Plus, India origin), C.37 (Lambda, Peru 
origin), B.1.621 (Mu, Colombia origin), and B.1.1.529 (Omicron, South Africa origin) variants 
demonstrated fold-changes in sotrovimab EC50 values of less than 3-fold as compared to WT spike, 
suggesting sotrovimab retains antiviral activity against variants of concern. Note that EC90 values 
were not calculated from pseudotype virus testing. Additionally, in vitro neutralisation data from 
authentic SARS-CoV-2 variant viruses indicate sotrovimab retains activity against the B.1.1.7, 
B.1.351, P.1, B.1.617.1, and B.1.616.2 variants.  
 
High barrier to viral resistance: Sotrovimab neutralised SARS-CoV-2 live virus with an average 
EC90 value of 186.3 ng/mL (range: 125.8 – 329.5 ng/mL) (PC-7831-0105). In resistance analyses, 
no viral breakthrough was observed through 10 passages at fixed concentrations of antibody, 
indicating the potential for sotrovimab to have a high barrier to resistance (PC-7831-0109). Using 
an increasing concentration selection method to force resistance emergence, E340A was identified 
as a monoclonal antibody-resistant mutant (MARM) conferring a >100-fold reduction in 
susceptibility to sotrovimab. Notably, E340 is 99.9% conserved among available SARS-CoV-2 
sequences.  
 
The PROTECT-V team is aware of other studies assessing the efficacy of both Ronapreve and AZD7442 in 
similar patient groups. These are not related to this study. 
 
1.2. Dose Rationale 
A single dose of 2000 mg was selected for the study based on pseudotype and live virus neutralisation data, 
and sotrovimab clinical PK data from multiple clinical studies evaluating the 500 mg IV dose. 
 
A preliminary population PK model was developed using data across several studies including COMET-ICE, 
COMET-PEAK, BLAZE-4 and a PK study in individuals of Japanese and Caucasian descent. The predicted 
median (10th, 90th percentile) serum concentrations of sotrovimab at week 12 following a single 2000 mg IV 
dose are 84.3 (52.8, 126.7) µg/mL. 
 
A 2000 mg IV dose was selected to ensure that sotrovimab concentrations in the lung tissue are maintained 
at or above levels anticipated to be neutralising for the duration of the treatment window. Live virus assays 
indicated that, compared to wild type EC90 (0.288 μg/mL), Omicron BA.1 and BA.2 confer a 3.5-fold and 35-
fold shift in EC90, respectively (PC-7831-0155) (13). Results from in vitro pseudotyped virus assays indicated 
that, compared to wild type EC90, BA.3 confers a 9-fold shift in EC90. Tissue-adjusted EC90 values were 
calculated using two different assumptions for lung:serum ratio of 25% (based on measured data (Report: 

 
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2021N472605) (14-17) and 10% (based on literature reports for mABs in general (18-23)); and were used to 
estimate coverage above tissue-adjusted EC90 following a 2000 mg IV dose of sotrovimab. 
 
When assuming a lung:serum ratio of 25%, a 2000 mg IV dose is expected to provide coverage against BA.1, 
BA.2 and BA.3 with serum concentrations achieving 13x, 1.4x and 5.6x lung tissue adjusted EC90 in 90% of 
patients at Week 12, respectively. When we use a more conservative lung:serum ratio of 10%, a 2000 mg 
IV dose is expected to maintain serum levels at or above 5.3x, 0.56x, and 2.23x lung tissue adjusted EC90 at 
Week 12 in 90% of patients for BA.1, BA.2 and BA.3 variants, respectively.  
Under the 10% and 25% lung:serum ratio assumptions, concentrations of sotrovimab at week 12 following a 
2000 mg IV dose are expected to provide adequate protection in  90% of patients against variants that 
confer up to 20-fold and 49-fold shift in EC90 compared to WT, respectively. Similarly, this dose of sotrovimab 
at week 12 is expected to achieve adequate coverage for 50% of patients against variants that confer up to 
31- and 78-fold shift in EC90 compared to WT when lung:serum ratio are assumed to be 10% and 25%, 
respectively. 
There is currently no available PK or immunogenicity data on a 2000 mg IV dose. Since sotrovimab exhibits 
dose proportional PK, exposures would be expected to be dose proportional between a 500 mg and 2000 
mg IV doses. In the GLP repeat dose IV monkey toxicology study there were no toxicity findings at doses up 
to 500 mg/kg, the highest dose tested and the NOAEL [TX-7831-0102]. Assuming dose proportional increase 
in exposures at 2000 mg, sotrovimab Cmax and AUC in patients are expected to be 15.5 and 13.5-fold lower 
than Cmax and AUC values from the toxicology study at the NOAEL, supporting the evaluation of sotrovimab 
at the higher clinical dose of 2000 mg IV. The 500 mg IV dose is being evaluated in the clinical studies: 
COMET-ICE and ACTIV-3-TICO (NCT04501978). 
The overall rate of AEs in COMET-ICE was similar in those treated with sotrovimab compared to placebo 
(sotrovimab: 114/523 [22%]; placebo: 123/526 [23%]). Serious AEs were numerically more common in the 
placebo arm than in the sotrovimab arm (32 of 526 [6%] vs., 11 of 523 [2%] respectively). The difference in 
SAE rates between the arms was mostly due to hospitalisations due to COVID-19–related causes, which 
were reported more frequently in the placebo group. The nature of SAEs was generally consistent with that 
expected in the COVID-19 population being evaluated and/or the underlying co-morbidities in the study 
population. No deaths and no SAEs considered related to treatment by the investigator were reported in the 
sotrovimab arm of the study. The 250 mg and 500 mg IM doses are evaluated in COMET-TAIL 
(NCT04913675). So far, reported AEs were not found to be dose-dependent, suggesting a large increase in 
rate of AEs with 2000 mg IV of sotrovimab is unlikely. 
Immunogenicity data at doses higher than 500 mg IV are not available. Sotrovimab is considered low risk for 
immunogenicity based on intrinsic product characteristics (i.e. quality of GMP manufacturing controls and 
release specifications), extrinsic factors (i.e. administered as a single dose) and patient population (i.e. no 
apparent heightened risk of immune response). Limited preliminary analysis of immunogenicity data through 
Day 29 is available from 391 and 38 subjects given 500 mg IV in COMET-ICE and Japan-PK studies, 
respectively [ref EUA 000100, Response to FDA Feb 03, 2022 Clin Pharm IR, submitted Feb 08, 2022, Seq 
No. 0090]. In COMET-ICE, the post-dose rate of antibodies to sotrovimab was 3% (10/391 participants) by 
Day 29 of the study. Four of the 10 participants were positive for anti-sotrovimab antibodies (ADA) at baseline 
with no boosting in titre values at Day 29 and therefore were not considered to have treatment-induced ADA. 
In the Japan-PK study, no post-dose treatment-emergent ADA responses have been observed. To date, the 
incidence of treatment-emergent ADA responses has remained low, with no detectable impact on safety or 
efficacy. These clinical findings align with the low immunogenicity risk profile and the risk prediction would 
not be expected to change substantially at higher doses when the product is administered as a single dose 
by the same route and for the same intended patient population and indication. Therefore, the current risk-
based bioanalytical strategy for immunogenicity analysis (i.e. screening, confirmation, titration and 
neutralisation assays) is considered appropriate for higher doses as well. 
No metabolism studies have been conducted with sotrovimab. As a human IgG1 monoclonal antibody, 
sotrovimab is expected to be eliminated via catabolism in the same manner as endogenous IgG. No active 

 
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metabolite is expected for sotrovimab.  As such no dose modification is recommended in individuals with 
renal or hepatic disease. 
 
 
   
2. TRIAL TREATMENT – SOTROVIMAB 
The trial treatments in this study are sotrovimab and placebo to match. 
 
2.1. Sotrovimab Name and description 
Name   
 
 
Sotrovimab, VIR-7831, GSK4182136 
Dosage Form 
 
 
Sterile solution for intravenous infusion 
Concentration  
 
62.5 mg/mL 
Route of administration  
Intravenous infusion 
Physical description 
 
Colourless or yellow to brown, liquid solution 
Formulation 
20 mM histidine, 7% sucrose (w/v), 0.04% PS80 (w/v), 5 mM L-methionine 
at pH 6.0 
 
Sotrovimab drug product is provided as a sterile solution and contains no preservatives. Each single-use, 8 
mL vial contains 500 mg of sotrovimab. Four vials will be required for a 2000 mg dose. 
 
 
2.2. Placebo to match sotrovimab 
This will be in the form of 0.9% sodium chloride 100mL for infusion and will be sourced from commercially 
available stock by the site. It may be procured and stored as per sites usual procedures and only requires 
handling as an IMP upon dispensing and labelling. Please refer to the pharmacy manual for bag material 
compatibility information. 
 
2.3. Sotrovimab Legal status 
Sotrovimab has received provisional marketing approval in Australia and Special Approval in an Emergency 
in Japan.  Emergency use authorisation has been granted in the United States of America on 26 May 2021 
(Emergency Use Authorization). Temporary authorisations have also been approved in Canada (interim 
Order), Singapore (pandemic Special Access), Italy, United Arab Emirates, Bahrain, Kuwait, Oman, Qatar 
Brazil, Switzerland, Thailand and Egypt. 
In the European Union (EU) a procedure similar to an application for an emergency use/temporary 
authorisation was initiated on 14 April 2021. This was a referral procedure under Article 5(3) of Regulation 
726/2004. This procedure concluded on 20 May 2021 with a positive scientific opinion being issued by the 
Committee for Medicinal Products for Human Use (CHMP) and a Conditions of Use document is in the 
process of being issued. 

 
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The UK MHRA has issued a Conditional Marketing Authorisation for sotrovimab for the treatment of 
symptomatic adults and adolescents (aged 12 years and over and weighing at least 40kg) with acute COVID-
19 infection who do not require oxygen supplementation and who are at increased risk of progressing to 
severe COVID-19 infection (26). 
 
2.4. Sotrovimab Supply, dispensing and accountability 
Vir Biotechnology will distribute supplies of sotrovimab to a sponsor appointed third party who will be 
responsible for labelling and QP release of the final product. Supply of the finished product to participating 
site pharmacies will be overseen by the trial co-ordinator and distributed by a sponsor-appointed third party. 
Upon initial authorisation by the sponsor, an initial supply will be sent to sites; supplies thereafter will be 
distributed as detailed in the pharmacy manual.  
IMP will be dispensed by delegated pharmacy staff that will either be responsible for preparing the product 
in the aseptic unit or dispensing vials directly to an unblinded nurse for ward level preparation as per the 
sites’ own policies and procedures with regards to preparation of mAbs.  No unblinded members of staff will 
have direct contact with the participant. The IMP will be administered by a blinded member of staff.1 Full 
accountability records will be completed to document receipt, dispensing and destruction of expired and 
unused IMP at the end of the study. Further details of dispensing are detailed in the pharmacy manual. 
Active IMP for the trial will be provided free-of-charge for participating sites. Placebo will need to be sourced 
by site. All IMP received by site will be unblinded. Blinding will only occur once the product is prepared in the 
final IV bag.  
1 Where site policies and procedures require that the individual who prepared an IV drug also attaches it to 
the patient, an exception may be permitted. In such instances, sites should contact the PROTECT-V Trial 
Office providing their policy/Site unblinding plan before commencement of recruitment to the sotrovimab arm. 
 
2.5. Sotrovimab Packaging and Labelling 
Sotrovimab will be provided in single-use vials in an individual carton and labelled as required in 
accordance with MHRA requirements for clinical trials. The primary container closure system consists of a 
Type I glass vial, a Teflon‑faced chlorobutyl 20mm stopper, and a flip-off aluminium seal. 
 
 
2.6. Sotrovimab Storage 
The drug product should be stored upright in the carton at 2‑8 °C and protected from light. 
Investigative site staff must confirm appropriate temperature conditions have been maintained during transit 
for all active study drug received. All active study drug must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labelled storage conditions with access 
limited to the investigator and authorised investigative site staff. All excursions from specified storage 
requirements should be notified to the sponsor. 
 
 

 
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2.7. Sotrovimab Treatment Duration 
There will be a single infusion of sotrovimab or placebo administered at the beginning of the study. Based 
on the pharmacokinetics of the drug, it is predicted that the single infusion will remain efficacious for 
approximately 16 weeks, and possibly up to 48 weeks.   
 
 
2.8. Sotrovimab Dose and Administration 
2000mg of sotrovimab solution (32mL) will be diluted in 68mL of 0.9% sodium chloride and administered by 
intravenous infusion. The IMP should be infused with a 0.2 m inline filter. The giving set should be flushed 
after the infusion is completed to ensure the entire IMP is administered.   
Placebo will be in the form of 100mL 0.9% sodium chloride.   
No dose modifications are permitted. Please refer to the pharmacy manual for dose preparation, equipment 
and drug compatibilities. 
There will be three lead-in cohorts to establish the most appropriate infusion time (See Figure A1). 

 
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Figure A1. Infusion and observation timings for each lead-in cohort. IMP: Investigational medicinal product. 
IRR: Infusion related reaction.  
1Day 4 post-infusion, routine haematology and biochemistry results will also be used to inform this decision.  
2Post-infusion observation period to remain at 60 minutes. 
 
The time provided in this protocol for infusions length for cohorts 1, 2 & 3 and onwards are approximate 
(90, 60 and 30 respectively). Infusion time windows are: 10 minutes under cohort infusion time to up to 60 
mins over the cohort infusion time.  
Infusion and observation times will begin as per Cohort One in Figure A1. After 60 patients have been 
recruited a safety analysis will be carried out assessing whether any participants had suffered from a severe 
IRR.  
A severe IRR is defined as 1) requiring IMP treatment termination or 2) requiring hospitalisation for 
interventional management of an IRR within 24 hours. Admission to hospital for observation after a 
mild/moderate IRR and completion of the infusion will not meet this definition of a severe IRR.  

 
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Any severe IRR in Cohort One will be reviewed by the IDMC to evaluate the IRR, and make recommendations 
to the TMG regarding whether to adjust the infusion time further, implement any other measures, or delay 
progress to Cohort Two. If no severe IRRs are noted from the first 60 patients recruited, and the Day 4 routine 
haematological and biochemical assessments do not demonstrate any clinically significant abnormalities, 
then sites will be instructed to alter the IMP infusion time in-line with Cohort Two. 
After 60 patients have been recruited to Cohort Two, data will be reviewed by the IDMC to evaluate the IRR, 
and make recommendations to the TMG regarding whether to adjust the infusion time further, implement any 
other measures, or delay progress to Cohort Three. If there is no severe IRR, then sites will be instructed to 
alter the IMP infusion time in-line with Cohort Three.  
After 60 patients have been recruited to Cohort Three, data will be reviewed by the IDMC to evaluate any 
IRR, and make recommendations to the TMG regarding whether to adjust the infusion time further, or 
implement any other measures. If there are no severe IRRs then the infusion and observation times will 
remain as per Cohort Three for the remainder of the study.  
There will be no pause in recruitment whilst the safety analyses are being carried out between cohorts. 
Progression to the next Cohort will not occur until the safety analysis has been reviewed by the IDMC. 
 
2.9. Sotrovimab Contraindications 
Sotrovimab is contraindicated and should not be used in subjects with a history of anaphylaxis to sotrovimab 
or any of the excipients present in the investigational product. Individuals with these conditions will not be 
eligible for the study. 
 
 
2.10. Sotrovimab side effects and concomitant drug interactions 
The known side-effects of sotrovimab are hypersensitivity (such as skin reactions, bronchospasm, and 
infusion-related reactions) and anaphylaxis. 
There have been two episodes of anaphylaxis for patients who have received sotrovimab 500mg IV.  One 
incident was as part of the ACTIV-3-TICO study evaluating sotrovimab in patients with COVID-19 that 
required 
hospitalisation, 
and 
the 
other 
was 
following 
administration 
as 
treatment 
under 
Emergency/Temporary authorisation of use.  Both individuals had COVID-19 infection at the time of drug 
administration.  Both reactions were within 4 hours of receiving sotrovimab. 
 
No pharmacokinetic drug interaction studies have been conducted with sotrovimab. In vitro combination 
experiments using sotrovimab and remdesivir showed an additive antiviral effect. Notably, no antagonism 
was observed between the two agents. 
 
There are no safety concerns associated with co-administration of sotrovimab and any vaccine (including 
COVID-19 vaccines). 
 
Whilst there are no concerns regarding interaction between sotrovimab and chimeric antigen receptor T-cell 
(CAR-T) therapy infusions, due to the risk of cytokine release syndrome associated with CAR-T therapy, it is 
advised to wait 4 weeks from a CAR-T therapy infusion before administering sotrovimab. 
 

 
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3. ELIGIBILITY 
 
3.1. Additional Inclusion Criteria 
 
 
Be a member of an immunocompromised population, which includes but is not limited to those 
groups listed in the core protocol as well as the following: 
o 
Immunodeficiency (primary and secondary immunodeficiencies)* 
o 
Any Oncology, Haematology-Oncology or Haematology patient who is currently 
receiving or has received chemotherapy or who is immunocompromised as a result of 
their disease or treatment 
o 
Have a diagnosis of an autoimmune/inflammatory disease currently receiving 
immunosuppression including those individuals currently on Prednisolone ≥20mg daily 
for at least 4 weeks. Those who have received Rituximab or Alemtuzumab within the 
last 12 months would also be eligible. 
o 
Solid organ and haematopoietic stem cell transplant recipients  
 
 
If a participant is not eligible for the sotrovimab arm, but still wishes to take part in the PROTECT-V study, 
their eligibility may be assessed for the other available arms of the PROTECT-V platform.  The participant 
should be re-screened using a new subject ID.   
 
No capping for a specific subgroup will be implemented. 
 
3.2. Additional Exclusion Criteria 
In addition to the core exclusion criteria in the master protocol, the presence of any of the following will 
preclude participant inclusion: 
 
If in the opinion of the PI it is not in the best interests of the participant to take part in the study  - for 
example due to limited life expectancy (≤12 months) due to pre-existing co-morbidities 
 
History of hypersensitivity reaction to sotrovimab, one of its excipients or any other monoclonal 
antibody targeting SARS CoV-2  
 
Known chronic liver disease or hepatic dysfunction as evidenced by ALT or AST > 3x upper limit of 
the normal range 
 
History of receiving any monoclonal antibody targeting SARS CoV-2 within the last 6 months 
 
Admission to hospital for acute, unplanned care at the time of randomisation or in the two weeks 
prior to screening 
 
History of receiving chimeric antigen receptor T-cell (CAR-T) therapy less than 4 weeks prior to 
consenting to take part in the study  
 
*If a potential participant is using any prophylactic agent for COVID-19 other than a licensed SARS-CoV-2 
vaccination, their participation must be discussed with the CI prior to randomisation. 
 
4. BLINDING 
 

 
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PROTECT-V-Sotrovimab will be a double blind placebo controlled study arm where neither the participant 
nor clinician will be aware of treatment allocation. Sites will need to have unblinded members of the study 
team in order to dispense and prepare the IMP.  Only blinded members of staff will have contact with the 
participants and administer the IMP dose (see section 2.4). A site blinding plan should be in place to cover 
the methods used by the site to ensure the blinded study team members are not inadvertently informed of 
the treatment allocation. 
 
4.1. Emergency unblinding 
Please refer to section 4.6.1. of the core protocol for details of the emergency unblinding procedure. 
 
5. RANDOMISATION 
 
At sites where the sotrovimab arm of the study is running, participants wishing to take part in the study will 
be assessed for eligibility for the sotrovimab arm first. If deemed eligible, they will be recruited to and 
screened for this arm of the trial. If they remain eligible after screening assessments, participants will be 
randomised to sotrovimab vs matching placebo in a 1:1 ratio.   
At sites where the sotrovimab arm is not running, or if a participant is not eligible to take part in the sotrovimab 
arm, participants can be screened for the other available arms of the PROTECT-V platform. 
Randomisation will be carried out using a web-based randomisation system (Sealed Envelope) accessible 
via password-protected access. Randomisation for the sotrovimab arm will be stratified by PROTECT-V 
disease sub-group, age and site using a stratified block randomisation method. 
Immediate allocation of treatment will be performed, with documentation of the decision in a blinded 
confirmatory email to blinded staff and an unblinded email to unblinded staff. The system will specify whether 
the participants are allocated to sotrovimab or placebo.  
Participants and blinded members of the site teams will remain blinded to treatment allocation, i.e. whether 
active or placebo within a stated intervention.  
If a patient declines to participate in the sotrovimab arm or has consented to the sotrovimab arm but then is 
deemed a ‘screen-fail’, then their eligibility for the other open arms of the trial can still be assessed.  
Participants may be consented for screening, and if eligible, randomised into one of those arms of the study. 
Participants will be allocated a new subject identifier if they are being re-screened for another arm. 
 

 
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6. SCHEDULE OF ASSESSMENTS 
 
 
Assessment  
Schedule 
Screening 
visit 
Day 11 
 
Day 32 
(±1 day) 
Day 43  
(±1 day) 
Day 8 
(±3 days) 
Day 15 
(±3 days) 
Day 29 
(±3 days) 
Every 14 
days 
(±7 days) 
Day 85 
(±7 days) 
Every 28 
days 
(±7 days) 
Day 169 
(±7 days) 
Every 28 
days (±7 
days) 
Day 253 
(±7 days) 
 
Day 337 
(±7 days) 
Final 
Study 
Visit 
Confirmed 
COVID19 
infection5 
(+4 days) 
28 days 
post 
COVID19 
infection17 
(±7 days) 
28 days 
post 
COVID 
vaccine6 
(±7 days) 
As 
required 
Eligibility check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medications4 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 PCR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sample for central 
SARS-CoV-2 ab assay 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
Blood tests (FBC, U+E, 
LFTs19, clotting,  
immunoglobulins) 
X20 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
ECG 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy status 
assessment 
X7 
 
 
 
 
 
 
 
 
 
X14 
 
X15 
X15 
 
 
 
 
Urine ACR 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Randomisation 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Experimental Work Bloods 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Vital signs (HR, Temp, BP, 
RR, Sats) 
 
X10 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
IMP administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up questionnaire, 
AE/SAE collection4, 11 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Sampling 
 
X12 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X17 
X 
 
 
Anti-drug antibody 
assessment 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X17 
X 
 
 
SAR/SUSAR 
Reporting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weekly SARS-CoV-2 PCR 
until tests negative4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
COVID19 severity 
assessment 
questionnaire4,13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Saliva samples16 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Stool Samples18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 

 
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1Day 1 visit to take place within 14 days of the screening visit. Day 1 procedures may take place on the same day as screening if all required screening 
investigations are available prior to randomisation. 
2Day 3 visit only required whilst lead-in cohorts are being assessed. May be done 24-72 hours post-infusion. Sites will be informed when this visit is no longer 
required. 
3Day 4 visit only required for lead-in Cohort 1, and will be a home-visit. May be done 48-96 hours post-infusion. Sites will be informed when this visit is no 
longer required. 
4Assessment can be carried out remotely (by phone or video-link) if no other assessment requires on-site presence. 
5PCR or LFT confirmed COVID19 infection at any point after randomisation into the trial, during the follow-up period. 
6Only applicable if patient received COVID19 vaccination after randomisation into the trial. 
7A serum pregnancy test is required for WOCBP within 14 days prior to starting trial treatment. Women are considered WOCBP following menarche and until 
becoming post-menopausal unless permanently sterile (previous hysterectomy, previous bilateral salpingectomy and or oophorectomy). A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause.  
8Randomisation may occur prior to day 1, assuming the participant has met the eligibility criteria, as assessed at the screening visit and following central 
laboratory SARS CoV-2 antibody assessment. 
9Experimental medicine samples to be taken prior to IMP administration. 
10Observations to be taken pre-infusion, at the end of infusion, 1 hour post-infusion and for lead-in cohort 1, 2 hours post the infusion (see Figure A1). 
11All Adverse Events will be collected up to and including Day 28. Following Day 28, only SUSARs, SARs, SAEs and adverse events of special interest (AESIs) 
will be collected. See section 12 of Appendix C for further detail. 
12PK sample to be taken within 1 hour of end of IMP infusion. 
13To be completed by all participants who have a positive PCR test for COVID19. If symptomatic, to be completed weekly until resolution of COVID19-related 
symptoms, until 28 days after PCR confirmation of infection or hospitalisation, whichever is sooner. If asymptomatic, to be completed weekly for two weeks. If 
asymptomatic, but then becomes symptomatic, to be completed weekly until resolution of COVID19-related symptoms, until 28 days after PCR confirmation 
of infection or hospitalisation, whichever is sooner.   
14Urine pregnancy test is adequate. 
15Pregnancy assessment based on history from participant is adequate. 
16These samples will only be taken at Cambridge & University Hospitals Birmingham NHS Foundation Trust sites. 
17PK and ADA samples at the time of PCR-confirmed COVID19 infection will only be taken from participants who will be attending site for this visit. 
18Stool samples only to be taken where possible and feasible to do so 
19Routine ALT/AST tests performed up to 2 week before screening visit will be accepted to assess liver function 
20see section 6.1.1. 
 

 
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6.1. Trial Assessments 
6.1.1. Screening 
In addition to the core components of the screening visit listed in section 4.7.1.1. of the master protocol, the 
following will be conducted: 
 
ECG 
 
Serum antibody sample for Roche Elecsys® Anti-SARS-CoV-2 assay. This will be processed in a 
central laboratory (refer to trial procedure manual for further details) 
 
Full blood count, clotting profile, renal and liver function 
 
serum pregnancy test in women of child bearing potential 
 
Urine albumin:creatinine ratio 
 
Immunoglobulins 
Results of liver function test (permitted within the preceding 2 weeks), pregnancy test and COVID 
PCR/Lateral Flow test are required prior to eligibility confirmation, randomisation and IMP administration. 
The screening assessment should be less than 14 days prior to date of planned IMP administration. 
It is permissible for screening investigations that are not essential for determining eligibility (such as ECG, 
full blood count, clotting profile, renal function, urine albumin creatinine ratio and immunoglobulins) to be 
taken on Day 1 prior to IMP infusion, although every effort should be made to take at screening visit.  It is 
permitted to conduct a screening and Day 1 visit on the same day, provided the site has facility to obtain 
results of essential screening investigations, randomise the patient and administer IMP on the same day. 
6.1.2. Day 1 infusion visit 
Prior to commencing the IMP infusion, a blood sample to measure ADA will be collected. Blood samples (up 
to 70mL in total), will be taken for the additional experimental medicine work packages. Saliva samples will 
be taken at selected sites local to Cambridge and Birmingham only. Refer to the sample collection section of 
the trial procedure manual and Section 9 of Protocol Appendix C.  Where possible, blood will be drawn at 
the time of intravenous cannula insertion, or from pre-existing vascular access lines. 
Observations (pulse, blood pressure, temperature, respiratory rate and oxygen saturations) must be taken 
prior to infusion, at the end of infusion, 1 hour after infusion and for lead-in Cohort One, at 2 hours after 
infusion. All observations must be recorded in the eCRF. 
PK samples to be taken within 1 hour after end of infusion (see PK section 6.1.15). 
 
6.1.3. Day 4 safety bloods visit 
A blood sample will be taken for all participants enrolled into lead-in Cohort One, 48-96 hours (3-5 days) 
post-infusion for FBC, renal and liver function tests and clotting profile. This will be a home-visit and will 
consist of a single blood-draw only. Sites must book this visit with the home-nursing team (see PROTECT-V 
Sotrovimab arm Trial Procedure Manual and Homecare Manual). Sites should continue to book the Day 4 
visit with the home-nursing team until they have notification from the PROTECT-V Trial Office that these 
assessments are no longer necessary. 
 

 
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6.1.4. Remote follow-up assessments 
Please refer to section 4.7.1.2 of the core protocol.   
Remote assessments will be made at week 1 (day 8 +/- 3 days from the day of IMP dose), week 2 (day 15 
+/- 3 days),  every 2 weeks from week 6 (day 43 +/- 7 days) to week 12 (day 85+/- 7 days), and every 4 
weeks from week 12 (day 85+/- 7 days) to week 36 (day 253 +/- 7 days). The final telephone assessment 
will take place at week 48 (day 337 +/- 7 days).  
An additional Day 3 telephone assessment (24-72 hours (1 to 3 days) after the infusion) for adverse events 
only will be required for participants within the lead-in cohorts. Sites should continue performing Day 3 
telephone assessments until they have notification from the PROTECT-V Trial Office that these assessments 
are no longer necessary.   
Telephone, email or electronic medical record communication systems (such as MyChart via EPIC) can be 
used according to local site preference. 
  
While week 12 is the primary endpoint (efficacy of sotrovimab in prevention of symptomatic confirmed 
COVID-19 (either by PCR or lateral flow test; LFT) over 12 weeks), and primary endpoint efficacy analyses 
will commence following the last subject reaching week 12 or the last infection + 28 days for WHO severity 
determination, whichever is later - the week 48 phone call is intended to assess safety, concomitant 
medications, and pregnancy status in WOCBP. 
See section 4.7.1.2 of the core protocol. All data will be collected as specified in the core protocol, but the PI 
will not need to make a decision regarding continuation of IMP since it is a single IV infusion. The follow up 
assessment will collect information on COVID-19 infection status, new medications and vaccinations. 
 
6.1.5. Day 29 (week 4) (+/- 3 days), week 12 (+/- 7 days) and week 24 (+/- 7 days) in- person 
assessments  
Activities as detailed in the schedule of assessments will be conducted including: 
 
Blood draw (for routine blood tests, PK sampling and ADA sampling [ADA sampling week 4 and 
week 24 only]),  
 
ECG (day 29 only) 
 
Urine sample for albumin/creatinine ratio 
 
Saliva sample collection (for selected sites local to Cambridge and Birmingham only, please see 
trial procedure manual for further details) 
 
Vital signs 
 
Adverse event check 
 
6.1.6. PK and ADA assessment  
Refer to trial procedure manual and schedule of assessments for full details. All equipment for collecting 
PK and ADA samples will be supplied to site. 
 

 
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6.2. Assessments in the event of a patient developing symptomatic, confirmed COVID-19 
infection (either by PCR or lateral flow test) 
If COVID-19 infection is confirmed either by PCR or lateral flow test (LFT): 
a) Participants will be asked to complete a COVID-19 severity assessment questionnaire. This should 
be completed weekly, via a telephone call with the local research team, until symptoms have 
resolved, until 28 days following COVID-19 infection confirmation, or until hospitalisation, whichever 
is sooner. 
b) Participants will be asked to undergo blood-sampling for routine safety investigations as well as 
immunoprofiling work, as set out in sections 7.1 and 9 below. 
c) Participants who are attending sites for this assessment will also have PK and ADA samples taken.  
d) Participants will be supplied with COVID-19 PCR swabs to be completed weekly and returned to 
the central study laboratory for viral load determination and sequencing to evaluate viral evolution 
until the PCR result is negative. 
e) Where possible a stool sample will also be collected. 
 
Participants should continue to attend scheduled study visits (in person and telephone). 
In the event of discordant PCR/LFT results, the result of the positive test, whichever that may be, will be used 
to trigger the primary endpoint of the study. 
Participants will be eligible to receive established standard of care treatments for SARS-CoV-2 infection (e.g. 
dexamethasone, anti-SARS-CoV-2 mAb, remdesivir or other antivirals) at the discretion of the local 
investigator or their usual practitioner. 
28 days post confirmed infection, all participants will undergo blood-sampling for SARS-CoV-2 antibody titres, 
PK and ADA measurement, and where possible, will also have stool samples collected. 
6.3. Trial Restrictions (monoclonal arm) 
Women of childbearing potential are required to use effective contraception for the duration of the trial for at 
least 48 weeks after treatment infusion. This includes: 
● 
Intrauterine Device (IUD) 
● 
Hormonal based contraception (pill, contraceptive injection or implant etc.) 
● 
Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap with spermicide) 
● 
True abstinence (where this is in accordance with the participant’s preferred and usual lifestyle) 
 
Where possible the administration of prophylactic agents for COVID-19, should be deferred until at least 12 
weeks after IMP infusion. In the event that a randomised participant commences a prophylactic agent for 
COVID-19 other than a licensed SARS-CoV-2 vaccination, their ongoing participation must be discussed 
with the CI. It is at the discretion of the CI as to whether the participant is to continue in the study, or whether 
they must be withdrawn. 
 
7. ADDITIONAL OBJECTIVES 
 

 
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7.1. Additional exploratory objectives 
a) To describe the effect, if any, of sotrovimab therapy on SARS-CoV-2 viral evolution, and monitor for 
any emergence of a variant of concern as a result of sotrovimab therapy 
b) To describe the development of anti-sotrovimab antibodies (immunogenicity) in this patient group 
and their potential association with PK levels and efficacy 
c) To describe the PK of sotrovimab over a 24 week period 
d) Immunoprofiling of individuals who develop COVID-19 infection despite sotrovimab therapy pre-, 
during and post-SARS CoV-2 infection 
e) To describe the effect of antibody titre on rates of SARS CoV-2 infection 
 
8. ADDITIONAL OUTCOMES 
 
8.1. Primary Outcomes 
The primary outcome for the PROTECT-V sotrovimab arm is confirmed symptomatic COVID-19 infection at 
12 weeks (85±7 days) from date of IMP administration. 
The primary outcome event (symptomatic COVID-19 infection) is defined in section 4.12.1.1 of the core 
protocol. 
 
8.2. Secondary Outcomes 
In addition to secondary outcomes referenced in section 4.12.2 of the core protocol, the following additional 
outcome will be assessed: 
Confirmed, symptomatic COVID-19 infection at 16 weeks (113±7 days) from date of IMP administration. 
Confirmed, symptomatic COVID-19 infection at 24 weeks (169±14 days) from date of IMP administration. 
Confirmed, symptomatic COVID-19 infection at 36 weeks (253±14 days) from date of IMP administration. 
Confirmed, symptomatic COVID-19 infection at 48 weeks (337±14 days) from date of IMP administration. 
 
8.3. Additional exploratory outcomes 
In addition to those outcomes listed in the core protocol, the following exploratory outcomes will be evaluated: 
a) Viral load and sequencing in patients who develop SARS-CoV-2 infection by week 48 
b) Occurrence of anti-drug antibodies in trial participants (immunogenicity) 
c) Description of the PK profile of sotrovimab over a 24 week period  
d) Description of individual participant’s immunological profile at baseline, the time of SARS-CoV-2 
infection and 1 month post-infection, in participants who developed infection by week 48 
e) Serum antibody titres to SARS-CoV-2 at baseline will be correlated with the development of SARS 
CoV-2 infection 

 
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9. EXPERIMENTAL MEDICINE SAMPLES 
 
These samples will be used to address exploratory outcomes in section 8.3 above.  
Please refer to the sample section of the trial procedure manual (includes details about sample collection, 
preparation, storage and transport) and the experimental medicine SOP for further details. 
Saliva samples will only be collected at sites local to Cambridge and Birmingham.  
Where possible the following samples will be collected at the Day 1 infusion visit in all participants in the 
sotrovimab arm, and in those subjects that develop COVID-19 infection and 28 days later:  
Serum, plasma, PBMC, DNA, RNA (up to 70mL blood in total).    
Samples will be collected as close as possible to when the participant tests COVID-19 positive (either by 
PCR or LFT) (ideally within 96 hours) and then 28 days (+/- 7 days) later. 
Samples will be labelled with the subject’s unique trial identifier. These samples will be shipped immediately 
for centrally processing at the University of Cambridge or the University of Birmingham, and appropriately 
stored for future analyses including but not confined to B and T cell immunophenotyping, functional B and T 
cell assays, anti-cytokine assays, evaluation of the role of mucosal immunity and neutrophil function 
analyses. 
Hypotheses include: 
1. Is there an immunological signature associated with SARS CoV-2 infection in individuals who have 
failed to mount a protective vaccine response? 
 
2. Can this signature also be identified at baseline in individuals treated with sotrovimab, who develop 
SARS CoV-2 infection? 
 
3. How does the immune profile of individuals who develop infection change from baseline? 
 
4. What is the impact of sotrovimab on the immediate immune response to SARS CoV-2 infection? 
 
5. Is the longer term immune response to SARS Cov-2 infection influenced by sotrovimab? 
 
10. STATISTICS 
 
10.1. Statistical methods 
Please refer to section 4.14 of the core protocol for 4.14.1 Analysis populations and 4.14.3 Safety evaluation.  

 
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10.1.1. 
 Efficacy Analyses 
 
10.1.1.1. Primary Efficacy Analysis 
 
The primary efficacy analysis of this trial will be a analysis for the difference in the distribution of symptomatic 
COVID-19 infection at 12 weeks between the sotrovimab group and the placebo group (two-sided at an α-
level of 5%), that is, to test the following hypotheses: 
 
H0:  there is no treatment difference between sotrovimab and placebo in proportion of patients who 
develop symptomatic COVID-19 infection  
Vs.   
H1:  there is a treatment difference between sotrovimab and placebo in proportion of patients who 
develop symptomatic COVID-19 infection  
 
The odds ratio or the relative risk with the corresponding 95% confidence interval will be presented as 
appropriate. The disease sub-group and age at randomisation will be adjusted for as fixed effects in the 
analyses.  
 
Primary efficacy analyses will be performed according to ITT in participants who have received any IMP.. If 
the statistical significance at a 2-sided 0.05 level is established for the primary efficacy outcome measure, a 
hierarchical testing procedure will be applied to the key secondary efficacy outcome measures at a 2-sided 
0.05 significance level. The order of testing sequence for key secondary outcome measures is 1) Confirmed, 
symptomatic COVID-19 infection at 16 weeks (113±7 days) from date of IMP administration 2) Confirmed, 
symptomatic COVID-19 infection at 24 weeks (169±14 days) from date of IMP administration; 3) Confirmed, 
symptomatic COVID-19 infection at 36 weeks (253±14 days) from date of IMP administration; 4) Confirmed, 
symptomatic COVID-19 infection at 48 weeks (337±14 days) from date of IMP administration. Further detail 
will be documented in the Statistical Analysis Plan (SAP).  
 
Every effort will be made to reduce missing data and it is anticipated that missing data on the primary outcome 
measure will occur in a very small proportion of participants as the primary endpoint data will also be obtained 
via linkage to UK Health Security Agency (UKHSA; formerly PHE) data. Methods to assess missing data and 
missing data sensitivities will be detailed in the analysis plan. The estimand properties of the primary and 
sensitivity analyses of the primary endpoint will be detailed in the Statistical Analysis Plan. 
 
10.2. Number of patients to be enrolled 
The primary outcome measure is symptomatic COVID-19 infection at 12 weeks (85±7 days) from the date of 
IMP administration. It is anticipated that there will be a reduction of 75% in symptomatic COVID-19 infection 
with sotrovimab treatment compared with the placebo arm. With the estimated symptomatic COVID-19 
infection rate at 12 weeks around 5% to 9% in the placebo arm using currently available blinded data from 
this arm and unblinded data from the niclosamide arm of PROTECT-V (Appendix A), the table below is a 
range of sample sizes using the Fisher's exact test with a 5% significance level, 90% power and two-sided 
test to detect a 75% reduction.  
 
 

 
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Symptomatic COVID-19 infection rate  at 12 weeks 
Total number of patients 
required 
Total sample size 
allowing for 10% 
non-compliance 
placebo arm 
Sotrovimab arm with a 75% 
reduction 
5% 
1.25% 
932 
1036 
6% 
1.5% 
772 
858 
7% 
1.75% 
658 
732 
8% 
2% 
574 
638 
9% 
2.25% 
506 
562 
 
Considering the significant uncertainty in the anticipated infection rate during the study period, the sample 
size assumption will be monitored and reviewed regularly by the independent Data Monitoring Committee 
(IDMC) in a blinded manner. The study team will consult with the IDMC regarding timing of performing 
efficacy analyses with consideration of an event driven strategy (Zou G. A modified poisson regression 
approach to prospective studies with binary data. Am J Epidemiol. 2004;159(7):702-6.).  Approval will be 
obtained from both the IDMC and TSC prior to performing the primary endpoint analysis. 
 
10.3. Interim Analyses 
An independent Data Monitoring Committee (IDMC) will review data, by treatment group on safety of patients 
in the trial. The IDMC will meet approximately every two months until the end of the trial. In addition, during 
the initial three lead-in cohort period and prior to the final infusion time being established, the IDMC will review 
severe Infusion related reaction (IRR) events whenever they are observed and have additional meetings as 
required.  
There are no plans to stop the trial early for efficacy and therefore no interim analyses for efficacy or futility. 
Efficacy data, by treatment arm, will therefore not be routinely provided. The IDMC can request efficacy data, 
by treatment group, confidentially from the Trial Steering Committee (TSC) if changes to the protocol are 
considered and these data are required by the IDMC in order to reach decisions about the ongoing 
risk/benefit to patients in the trial. If efficacy data are reviewed, a Haybittle-Peto boundary may be used.  Full 
details will be given in the IDMC charter.  
 
11. CRITERIA FOR EARLY TERMINATION  
 
The study will be reviewed approximately every 2 months by the independent Data Monitoring Committee 
(IDMC). The detailed stopping guidance will be included in the IDMC charter. 
The study will be stopped early if there are any safety concerns based on the recommendation of the 
independent Data Monitoring Committee and the approval from the Trial Steering Committee. As guidance, 
the study might be stopped early for safety concerns 
● 
if the rate of unacceptable toxicity attributable to study drug in the sotrovimab arm is over 20%, that 
is, the estimated lower limit of a 95% confidence interval is greater than 20% 

 
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● 
if the incidence of moderate/severe adverse events in the sotrovimab arm is 15% greater than that 
of the placebo arm, at 12 weeks (85±7 days from date of randomisation) at a significance level of 
0.05 for the first 20% patients recruited and followed up for 12 weeks from the date of IMP 
administration. 
 
12. SAFETY REPORTING 
 
12.1. Recording, Evaluating & Reporting Serious Adverse Events / SARs 
The Chief Investigator will ensure that all safety information is reported to GSK at the same time as 
notification to the Sponsor.  The Sponsor will be informed of any SAE/SAR reported to the CI immediately 
but not more than 24 hours after the CI is first notified. GSK will be informed of any SAE/SAR reported to the 
CI not more than 72 hours after the CI is first notified. 
All AEs (serious and non-serious) will be reported until Day 29 of the study as these are most likely to be 
potentially related to study drug. Data regarding any AE reported prior to Day 29 will be gathered until 
resolution of the AE. The population that will take part in this study are multi-morbid and suffer from numerous 
fluctuating chronic symptoms. Recording all symptoms as possible AEs beyond day 29 would likely lead to 
an inability to identify any meaningful trends in the AE analysis. 
Beyond Day 29, all SAEs and adverse events of special interest (AESI) (whether serious or non-serious) will 
continue to be assessed until the final study visit on week 48 or day 337. All of these events will be followed 
to resolution, are otherwise explained or the patient is lost to follow-up. These have been defined based on 
potential risks associated with the mAb class of therapeutics administered via intravenous infusion and the 
data available from the COMET-ICE study, and include the following: 
 
Hypersensitivity reactions (including skin reactions and bronchospasm) at any time after IMP infusion 
– will be solicited through week 12. 
 
Infusion-related reactions within 24 hours after IMP infusion (including pyrexia, chills, dizziness and 
dyspnoea) 
 
Antibody dependent enhancement (ADE) of disease in those who reach the primary end-point will 
be assessed 
ADE is a theoretical risk with vaccines and antiviral antibodies and has been best described in 
association with some vaccine development programs. ADE can occur via one of three previously 
described mechanisms: 
 
By facilitating viral entry into host cells and enhancing viral replication in these cells; 
 
By increasing viral fusion with target host cells, enhancing viral replication in these cells; 
 
By enhancing disease pathology from viral antigen-antibody related immune complex 
deposition or complement activation and immune cell recruitment in target organs.  
The first two mechanisms are hypothesised to occur at sub-neutralising antibody concentrations. 
The third mechanism is hypothesised to occur at high levels of antigen (i.e., viral load) and antibody 
potentially leading to immune complex deposition and complement activation in tissue sites of high 
viral replication. This may manifest as acute deterioration in clinical status temporally associated with 
sotrovimab infusion or as increased severity or duration of illness in sotrovimab-treated participants 
who reach the primary end-point, compared to what would be clinically expected. 

 
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New SAE reporting for patients enrolled to the sotrovimab arm will stop at the time of the final study visit.  
However, for those who withdraw from the trial prior to the final study visit, new SAE reporting will cease at 
Day 29 or date of withdrawal, whichever is the latter. SAEs reported prior to these dates will be followed up 
to closure. 
 
12.2. Reference Safety Information (RSI) 
For this trial the Reference Safety Information is:  
1. VIR Investigator’s Brochure for VIR-7831 – Treatment and prevention of COVID-19, Edition 3, 
November 2021, Section 6.6.2. 
 
12.3. Pregnancy Reporting 
The Chief Investigator will ensure that all pregnancies of female participants are reported to Sponsor and 
GSK within 24 hours of awareness. 
 
13. 
JUSTIFICATION 
OF 
STUDY 
DESIGN 
AND 
RISK/BENEFIT 
ASSESSMENT FOR ADDITION OF SOTROVIMAB TO THE 
PROTECT-V PLATFORM 
 
13.1. Is there still a need for an additional arm in the PROTECT-V platform in light of the COVID-
19 vaccination program (including third primary doses and booster doses) as well as other 
non-vaccine agents? 
Preventing infection due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of 
COVID-19, is an urgent public health priority. Prevention of COVID-19 with therapeutic interventions has the 
potential to significantly reduce disease-associated morbidity and mortality, as well as transmission in the 
community.  A number of vaccines for the prevention of COVID-19 have been approved globally. While these 
currently available vaccines have been shown to be highly efficacious in the general patient population in 
which the clinical trials were conducted, there are limited data on efficacy in patient populations where 
immunogenicity may potentially be impaired.  
Patients who receive systemic immunosuppression or have an underlying immunodeficiency are at high risk 
of morbidity and mortality from COVID-19. Solid organ transplant recipients had a 3.53 (95% CI 2.77-2.49) 
increased risk of COVID-19-related death in the first wave in the UK, the highest increased risk of all medical 
conditions incorporated in the OpenSAFELY analysis (27). A case series undertaken by the UK Primary 
Immunodeficiency network found that infection-associated fatality rates were significantly higher in primary 
immunodeficiency (20%) and secondary immunodeficiency (33.3%) than the general population (28). 
In addition, there is mounting evidence that many of these individuals mount sub-optimal responses to 
vaccines.  In July 2021, a synthesised review of 35 studies looking at vaccine response in renal patients; 
only 35% (29-42%) of individuals with a renal transplant mounted a protective response after two doses of 

 
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SARS CoV-2 vaccine (29).  Although, third doses lead to a response in approximately 50% of those 
individuals not protected after 2 doses, a considerable number of immunocompromised patients remain 
vulnerable to SARS CoV-2 infection (30, 31).   
Less data is available on patients with autoimmune disease. Figure A2 compares SARS CoV-2 vaccine 
responses in patients also with malignancy or receiving immunosuppressive therapies (32). The literature on 
vaccine response in individuals with autoimmune disease is more complicated in view of disease and 
treatment heterogeneity, but responses are also sub-optimal compared to healthy individuals.  Table A1 
shows the vaccine responses from 695 patients in Cambridge, UK (unpublished data) and demonstrates not 
only the proportion of patients responding to vaccination, but the sub-optimal magnitude of response 
(threshold of protection for this assay 1896; healthy control titres >30,000). 
It is important to note that the majority of studies report absolute antibody titres, which does not indicate the 
functionality and neutralising capacity of the antibodies.  In a study of 178 dialysis patients in the UK, the 
Astra-Zeneca vaccine (AZD1222) when administered alone in sero-naive individuals induced suboptimal 
neutralising antibody titres against all variants of concern (VOCs), including the delta variant that is currently 
dominant globally (33).  We considered using a neutralising measure as an eligibility criterion rather than 
antibody titres alone.  However, as a screening tool, this is not possible due to limited availability and high 
cost. It is also unlikely to become routinely available which would limit rapid translation into practice, should 
the trial show a positive result. 
 
 
 
 
 
 
Table A1: Vaccine response in three groups of immunocompromised renal patients in Cambridge. Threshold of protection for 
this assay is 1896. 
 
 
 

 
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Figure A2: Percent of subjects with antibody response after two mRNA vaccine doses by immunocompromising condition 
and study (n=63) (32). 
 
Furthermore, some studies have reported that immunocompromised persons account for a high proportion 
(≥40%) of infections among fully vaccinated, hospitalised persons, providing further evidence of sub-optimal 
vaccine response (34, 35). 
Therefore, despite vaccination, and the third dose and booster vaccination campaign, sub-optimal vaccine 
response and vulnerability to COVID-19 infection remains a major issue in immunocompromised patients. 
There are currently limited non-vaccine agents that are approved for use in immunocompromised patients. 
In the UK, the anti-SARS-CoV-2 mAb casirivimab/imdevimab (Ronapreve) recently received a conditional 
marketing authorisation for the prevention and treatment of COVID-19. Use of Ronapreve for prophylaxis 
was based on efficacy shown in an RCT trial evaluating the subcutaneous administration of Ronapreve for 
prevention of SARS-CoV-2 infection in seronegative individuals with a household exposure (36). Notably, 
this study was conducted during a time period with less widespread vaccination and less circulation of 
COVID-19 variants of concern. 
Evusheld has now been issued with Conditional Marketing Authorisation by the UK MHRA for pre-exposure 
prophylaxis of COVID-19 in adults who are not currently infected with SARS-CoV-2 and who are unlikely to 
mount an adequate immune response to COVID-19 vaccination, or for whom COVID-19 vaccination is not 
recommended, though we are not aware of any published data evaluating its efficacy as a prophylactic agent 
in the patient population being evaluated in this study, or against the Omicron variants that are currently 
prevalent in the UK.     
Some novel oral antiviral agents targeting COVID-19 are being developed. Molnupiravir (Lagevrio), has 
recently been approved by the UK’s MHRA for the treatment of mild to moderate COVID-19 disease (37).  
Paxlovid (PF-07321332; ritonavir) has also recently been reported to reduce the risk of hospitalisation or 
death by 89% compared to placebo in non-hospitalised high risk adults with COVID-19.  Data is only available 
on the efficacy of these drugs in patients with confirmed COVID-19 disease, and their efficacy as a 
prophylactic agent is currently unknown (38).   
Therefore, there is an urgent need for development of effective modalities for pre-exposure prophylaxis with 
conserved activity against emerging SARS-CoV-2 variants in the immunocompromised patient population.   
 
13.2. Broadening inclusion criteria to include non-renal patients who have mounted sub-optimal 
vaccine responses 
The PROTECT-V trial platform is designed to study agents for pre-exposure prophylaxis in vulnerable 
individuals. The trial commenced prior to the COVID-19 vaccine program, and as such vaccine response 
was not considered in eligibility criteria. The trial commenced recruiting renal patients, as dialysis patients 
were severely impacted early in the pandemic, and were unable to shield. Furthermore, an existing network 
of renal sites and investigators were selected to facilitate rapid set-up, and renal transplant patients and 
individuals with autoimmune renal disease were also included as they were managed by the same clinicians 
and identified as being clinically extremely vulnerable. 
 
Response to vaccination has clearly modified the risk profile of COVID-19 infection. Defining vaccine 
response is complicated but serological tests are now available to measure antibody titres, and identify those 
individuals with sub-optimal or absent serological responses. Although neutralisation assays would offer a 
functional measure, they are not practical screening tests for a clinical trial, and are unlikely to become widely 
available as part of routine care to guide the use of monoclonal antibodies should they demonstrate benefit. 

 
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Now that the platform is established, a network has been developed with clinicians beyond the renal 
community enabling the following clinically extremely vulnerable patients to be enrolled 
o 
Primary immunodeficiency  
o 
Any Oncology, Haematology-Oncology or Haematology patient who has received 
chemotherapy or who is immunocompromised as a result of their disease or treatment 
o 
Have a diagnosis of an autoimmune/inflammatory disease currently receiving 
immunosuppression  
o 
Solid organ and haematopoietic stem cell transplant recipients 
Inclusion of these vulnerable patients at this stage of the pandemic is also a timely intervention. Due to 
relaxation of UK-government COVID-19 restrictions, these patients are no longer shielding to the same extent 
that they were at the beginning of the pandemic, when PROTECT-V was first launched, increasing the 
possibility of COVID-19 disease in this patient cohort. 
In order to effectively expand recruitment into these patient groups, a strategy to recruit from these new 
patient cohorts has been implemented. National leads have been appointed to drive recruitment across all 
centres for their allocated patient cohorts. The individuals are leading physicians in their respective fields and 
have established links with physicians across the country who would be able to recruit these patients. 
Individual sites will take different approaches to recruitment, however, we recommend identifying clinician 
sub-investigators at each site with expertise in managing patients from each cohort in order to create an 
effective recruitment strategy. 
 
13.3. Justification for the intensity of scheduled follow up 
The intensity and manner of follow up has been carefully considered to minimise healthcare interactions with 
clinically extremely vulnerable individuals, but to ensure that there is sufficient monitoring to ensure patient 
safety.  Since an antibody titre is required for eligibility, and a central laboratory is being used to standardise 
the assay, it is not possible to conduct the screening and infusion on the same day. Three further in person 
visits at weeks 4, 12 and 24 are required for safety monitoring in order to draw blood samples for safety 
bloods and PK assays.  All other assessments will be conducted via telephone (online and postal 
questionnaires are not permitted for this arm, as sotrovimab is a novel drug, and this approach is being taken 
to minimise any loss to follow up) initially weekly for the first 4 weeks, fortnightly during weeks 4-24 and then 
4 weekly until week 36 with a final call at week 48. 
This study will be the first time a 2000 mg dose will be used in humans. There are no theoretical safety 
concerns for the use of this dose, based on the NOAEL data. Data from previous in-human studies using a 
500mg dose of sotrovimab suggests infusion-related reactions are the most likely adverse events to occur. 
Given this, we have introduced three lead-in cohorts with consecutive reductions in infusion times to evaluate 
the most appropriate rate of drug infusion as well as the observation period thereafter (see Figure A1). There 
will also be an additional telephone assessment 24-48 hours after the infusion for participants within these 
three lead-in cohorts. For lead-in Cohort One, there will also be an additional set of routine safety bloods on 
Day 4. Progression of recruitment from one cohort to the next will not occur until independent review of the 
safety data by the IDMC.   
 

 
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13.4. Collection of Adverse Events up to Day 29 only 
Sotrovimab has been administered to tens of thousands of individuals and has a very favourable safety 
profile. However, it is a novel agent, and therefore all adverse events (AEs) (new symptoms or clear 
deterioration of pre-existing symptoms) will be collected up until day 29 post dose. The population that will 
take part in this study are often multi-morbid and suffer from numerous chronic symptoms (e.g. fatigue, 
nausea). Recording all symptoms as possible AEs beyond day 29 would likely lead to an inability to identify 
any meaningful differences in the AE analysis. Therefore, only SAEs and AESIs will be collected from Day 
29 onwards.   
 
 
13.5. Rationale for revision of event rate (symptomic COVID-19 infection) 
Predicting the event rate is extremely difficult as it is affected by so many variables – public health measures, 
circulating levels of virus, and variants. Furthermore, the event rate is non-linear. Public Health England data 
from existing patients recruited to PROTECT-V indicates a 13% attack rate in the last 24 weeks. These 
patients do tend to shield when able, but as the pandemic continues, many are of working age with 
dependents, and cannot continue formal shielding, especially as current government guidance does not 
recommend continuation of shielding. It must also be noted that there has been a reduction of mask-wearing 
and loss of other public health measures designed to reduce COVID-19 transmission. These changes must 
be counter-balanced with the shortening in primary end-point from 24 weeks to 12 weeks. Given this level of 
uncertainty, we believe having a range of 5-9% event rate at 12 weeks within the protocol to be the most 
appropriate way of representing the recruitment target for this study.  
The study is powered to detect a 75% risk reduction of symptomatic COVID-19 infection.  The event rate will 
be monitored by the independent Data Monitoring Committee (IDMC), who within their charter can make 
recommendations regarding sample size re-calculation should the event rate be different than anticipated.  
Together with the recruitment monitored regularly, the IDMC will also make recommendations regarding the 
timing of performing efficacy analyses with consideration of an event driven strategy. 
 
13.6. Justification of a 12-week primary endpoint 
The primary outcome measure and clinical study report (CSR) will be based on the data from the first 12 
weeks of study. The primary endpoint was updated based on new population PK analyses that incorporated 
data across several studies evaluating a sotrovimab 500 mg IV dose. Based on these preliminary PK 
analyses, as well as the shift in EC50 with the Omicron sub-variants, the predicted median (5th, 95th percentile) 
serum concentrations of sotrovimab at 12, 16 and 24 weeks following dosing were evaluated. While the 2000 
mg IV dose is expected to maintain adequate coverage above tissue-adjusted EC90 (for WT and for variants 
with <22-fold shift in potency) through 24 weeks, the primary endpoint was changed from 24 weeks to 12 
weeks to ensure the highest likelihood of demonstrating efficacy, particularly with the current BA.2 variance 
predominance. PK sampling will be conducted within 1 hour post-infusion and at days 29, 85 and 163 in the 
trial to provide further supporting evidence. Secondary endpoint analyses will include time to event and 
response at 16 week, 24 week, 36 week and 48 week measures, so these analyses coupled with the PK 
data will be able to demonstrate any waning effect of sotrovimab. There will be an additional addendum to 
the CSR, including all safety and follow-up data collected up until week 48 of the study. 
 

 
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13.7. Management of individuals who develop COVID-19 infection during the study 
Individuals who develop COVID-19 infection during the trial should be treated according to standard of care 
at that time, including the receipt of monoclonal antibody therapy if it is indicated. If it is possible, the 
remaining protocol assessments should be assessed for patients with positive ‘COVID19’.   
We considered unblinding patients that develop COVID-19 during the study, and administering sotrovimab 
to those who had received placebo.  However, we felt that it is ethically sound and logistically more 
straightforward to recommend standard of care treatment, without unblinding, especially given the rapidly 
changing nature of COVID-19 therapeutics. There is no theoretical safety concern of interaction between two 
anti-SARS-CoV-2 monoclonal antibodies, and it may be determined to be beneficial by a patient’s treating 
clinician to administer another mAb as standard of care, even in those who were previously randomised to 
sotrovimab. In the BLAZE-4 study (NCT04634409), a clinical trial with multiple arms evaluating anti-SARS-
CoV-2 mAbs from Eli Lilly and Company and GSK/Vir, sotrovimab was used in combination with 
bamlanivimab in one arm. 
 
Given sotrovimab’s mode of action, there is no theoretical indication that it would interact with the oral anti- 
SARS-CoV-2 agents mentioned above. 
 
There is also no theoretical risk of receiving a further 500mg dose of sotrovimab having received 2000mg 
already (according to the available NOAEL data). 
 
13.8. Concerns about monoclonal antoantibodies driving viral evolution 
Immunocompromised individuals may be slow to clear the virus, and have been reported to shed virus for 
many weeks, allowing opportunity for development of mutations. Therefore, the prevention of COVID-19 
infection in these individuals is key. However, since there is concern that monoclonal antibodies such as 
sotrovimab may drive this process, a robust viral screening process is integrated into the protocol. Individuals 
who develop COVID-19 infection will continue weekly nasopharyngeal PCR swabs, which will undergo deep 
sequencing to address the question of viral evolution, until PCR negative.   
 
13.9. Concerns about waning of sotrovimab concentrations as the study progresses 
The dose of sotrovimab (2000mg) and anticipated duration of efficacy (12 weeks) have been calculated using 
intensive PK analysis and advanced modelling taking into account the Omicron (B.1.1.529) VOC (as 
described in ‘Section 1.2 Dose Rationale’). In order to ensure sotrovimab levels remain at the anticipated 
concentrations, we plan to undertake PK sampling at days 1, 29, 85 and 169. This will allow us to confirm 
sotrovimab concentrations remain at therapeutic levels throughout the study period.  In case of unexpected 
early falls in sotrovimab levels, the efficacy at earlier time points will be investigated guided by the PK 
sampling results. We will also be measuring PK levels in some patients who develop symptomatic COVID-
19 infection in order to assess sotrovimab concentrations in those with break-through infection. 
13.10  Removal of antibody threshold of <400 IU/ml as an inclusion criterion 
When the sotrovimab arm of PROTECT-V was designed in 2021, the majority of potential participants had 
received just 2 doses of vaccine against SARS CoV-2.  Based on the data available at the time, an antibody 
threshold of <400 IU/mL was set for inclusion into the study, with the rationale that those with a titre less than 
this would be most at risk of developing symptomatic COVID-19 infection.  However, as of January 
2023, most patients have received at least 4 vaccine doses if not 5 or 6.  Despite vaccination, the 
immunocompromised populations remain at risk of symptomatic infection with worse outcomes, but antibody 
titres have been higher than anticipated, leading to a higher screen fail rate in those who have been enrolled 

 
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to the sotrovimab arm of PROTECT-V thus far.  In addition, there is no data to suggest that anti-spike 
antibody levels are a correlate of protection in the immunocompromised population. 
  
There is a balance between timely recruitment to the trial, and the theoretical risk of dilution of an effect size 
with a higher antibody threshold (though a direct clinical correlate of antibody titres and different thresholds 
is yet to be established in the literature).  Furthermore, the situation is complicated with emerging variants, 
where higher antibody titres may be required to have a comparable neutralising effect.  It is becoming clear 
that rather than a definitive threshold of complete protection vs no protection, there is a spectrum of 
protection, and PROTECT V is in an ideal situation to evaluate this spectrum within the trial design. 
  
Therefore, given the lack of evidence for antibody levels being a direct correlate of protection, the antibody 
titre as a requirement for inclusion has been removed.  All those in an at-risk groups currently included in the 
PROTECT-V trial would be eligible, regardless of their antibody level.  The antibody levels would still be 
measured at recruitment in order to enable a pre-defined, secondary analysis of efficacy effect according to 
antibody titre. Once implemented, those previously screened and deemed ineligible due to raised antibody 
titre may be re-approached and re-screened using a new study ID number.  
 
14. ADDITIONAL FINANCIAL SUPPORT 
 
Trial medication and additional funding for this arm of this trial is provided by GSK and Vir Biotechnology. 
As part of this support GSK will be provided the following: 
 
All DMC/TSC aggregated anonymised open session reports related to the Sotrovimab protocol will 
be shared within 30 days of the meetings.  
 
Any emerging safety findings with the IMP identified by the DMC meetings will be reported to GSK 
within 24 hours 
 
The study database on the date of database hardlock, in a link anonymised form, to GSK, at the 
end of the study for regulatory filings, for further research or other purposes. 
 
15. PUBLICATIONS POLICY 
 
The analysis of the primary outcome measure will be performed when all randomised patients have 
completed week 12 or up to 4 weeks post the date of the last confirmed positive COVID-19 result to allow for 
symptom collection, for those cases that occur between week 8 and week 12. The efficacy on key secondary 
outcome measures analyses will be when there are a sufficient number of patients that have completed week 
16, week 24, week 36 and week 48 (or up to 4 weeks post the date of last confirmed positive COVID-19 
result), using a hierarchical testing procedure. The details will be documented in the SAP. The results will be 
published as soon as possible. 
 
Individual clinicians must not publish data concerning their patients that are directly relevant to questions 
posed by the trial until the report on the trial is published. The Appendix C Management Group will form the 
basis of the writing group and advise on the nature of publications. All requests for data will be approved by 
the TSC. 
 
All publications shall include a list of all investigators. The members of the TSC and IDMC will be listed with 
their affiliations in the Acknowledgements/Appendix of the main publication.  

 
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All manuscripts or abstracts which present data from the sotrovimab arm of the trial will be made available 
for review by GSK/Vir. These will also be made available for review prior to publication to the TMG and IDMC 
members. This is to protect proprietary information and to provide comments. 
 
16. REFERENCES 
 
1. 
Pinto D, Park YJ, Beltramello M, Walls AC, Tortorici MA, Bianchi S, et al. Cross-
neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature. 
2020;583(7815):290-5. 
2. 
AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing 
COVID-19 [press release]. https://www.astrazeneca.com/media-centre/press-
releases/2021/azd7442-prophylaxis-trial-met-primary-endpoint.html2021. 
3. 
Medicines & Healthcare Products Regulatory Agency. Decision. Summary of Product 
Characteristics of Evusheld https://www.gov.uk/government/publications/regulatory-approval-of-
evusheld-tixagevimabcilgavimab/summary-of-product-characteristics-for-evusheld2022 [Available 
from: https://www.gov.uk/government/publications/regulatory-approval-of-evusheld-
tixagevimabcilgavimab/summary-of-product-characteristics-for-evusheld. 
4. 
Summary of Product Characteristics - Ronapreve. In: Medicines and Healthcare products 
Regulatory Agency, editor. 
https://assetspublishingservicegovuk/government/uploads/system/uploads/attachment_data/file/1
012415/revised-gb-spc-ronapreve-clean-120mg-ml12aug2021docxpdf. 
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/fil
e/1012415/revised-gb-spc-ronapreve-clean-120mg-ml12aug2021docx.pdf2021. 
5. 
Ko SY, Pegu A, Rudicell RS, Yang ZY, Joyce MG, Chen X, et al. Enhanced neonatal Fc 
receptor function improves protection against primate SHIV infection. Nature. 
2014;514(7524):642-5. 
6. 
Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IW, Sproule TJ, et al. Enhanced 
antibody half-life improves in vivo activity. Nat Biotechnol. 2010;28(2):157-9. 
7. 
Gaudinski MR, Coates EE, Houser KV, Chen GL, Yamshchikov G, Saunders JG, et al. 
Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A 
Phase 1 open-label clinical trial in healthy adults. PLoS Med. 2018;15(1):e1002493. 
8. 
Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, et al. 
Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional 
expression of FcRn in the mammalian lung. J Exp Med. 2002;196(3):303-10. 
9. 
Heidl S, Ellinger I, Niederberger V, Waltl EE, Fuchs R. Localization of the human neonatal 
Fc receptor (FcRn) in human nasal epithelium. Protoplasma. 2016;253(6):1557-64. 
10. 
Hope T. Mutliscale imaging of Therapeutic Antibody Distribution and Localization 
https://www.iasociety.org/web/webcontent/file/HIV_Cure_Forum_2019/Session5/FT5-2Hope.pdf: 
The International AIDS Society; 2019 [Available from: 
https://www.iasociety.org/web/webcontent/file/HIV_Cure_Forum_2019/Session5/FT5-2Hope.pdf. 
11. 
Qiao SW, Kobayashi K, Johansen FE, Sollid LM, Andersen JT, Milford E, et al. 
Dependence of antibody-mediated presentation of antigen on FcRn. Proc Natl Acad Sci U S A. 
2008;105(27):9337-42. 

 
EudraCT Number: 2020-004144-28 
IRAS ID: 288652 
 
Page 99 of 100 
PROTECT-V protocol V11.0 – 05/Sep/2023 
 
12. 
Baker K, Rath T, Lencer WI, Fiebiger E, Blumberg RS. Cross-presentation of IgG-
containing immune complexes. Cell Mol Life Sci. 2013;70(8):1319-34. 
13. 
Cathcart AL, Havenar-Daughton C, Lempp FA, Ma D, Schmid MA, Agostini ML, et al. The 
dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in 
vivo activity against SARS-CoV-2. BioRxiv. 2021. 
14. 
Baxter LT, Zhu H, Mackensen DG, Jain RK. Physiologically based pharmacokinetic model 
for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human 
tumor xenografts in nude mice. Cancer Res. 1994;54(6):1517-28. 
15. 
Covell DG, Barbet J, Holton OD, Black CD, Parker RJ, Weinstein JN. Pharmacokinetics of 
monoclonal immunoglobulin G1, F(ab')2, and Fab' in mice. Cancer Res. 1986;46(8):3969-78. 
16. 
Datta-Mannan A. Mechanisms Influencing the Pharmacokinetics and Disposition of 
Monoclonal Antibodies and Peptides. Drug Metab Dispos. 2019;47(10):1100-10. 
17. 
Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. 
J Pharm Sci. 2004;93(11):2645-68. 
18. 
Magyarics Z, Leslie F, Bartko J, Rouha H, Luperchio S, Schörgenhofer C, et al. 
Randomized, double-blind, placebo-controlled, single-ascending-dose study of the penetration of 
a monoclonal antibody combination (ASN100) targeting Staphylococcus aureus cytotoxins in the 
lung epithelial lining fluid of healthy volunteers. Antimicrobial Agents and Chemotherapy. 
2019;63(8):e00350-19. 
19. 
Chigutsa E, Jordie E, Riggs M, Nirula A, Elmokadem A, Knab T, et al. A Quantitative 
Modeling and Simulation Framework to Support Candidate and Dose Selection of Anti‑SARS‑
CoV‑2 Monoclonal antibodies to Advance Bamlanivimab into a First‑in‑Human Clinical Trial. 
Clinical Pharmacology & Therapeutics. 2022;111(3):595-604. 
20. 
Chigutsa E, O’Brien L, Ferguson‑Sells L, Long A, Chien J. Population Pharmacokinetics 
and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients 
With Mild to Moderate COVID‑19 Infection. Clinical Pharmacology & Therapeutics. 
2021;110(5):1302-10. 
21. 
Jones BE, Brown-Augsburger PL, Corbett KS, Westendorf K, Davies J, Cujec TP, et al. 
The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman 
primates. Science translational medicine. 2021;13(593):eabf1906. 
22. 
Jadhav SB, Khaowroongrueng V, Fueth M, Otteneder MB, Richter W, Derendorf H. 
Tissue distribution of a therapeutic monoclonal antibody determined by large pore microdialysis. 
Journal of pharmaceutical sciences. 2017;106(9):2853-9. 
23. 
Shah DK, Betts AM, editors. Antibody biodistribution coefficients: inferring tissue 
concentrations of monoclonal antibodies based on the plasma concentrations in several 
preclinical species and human. MAbs; 2013: Taylor & Francis. 
24. 
Kearns P, Siebert S, Willicombe M, Gaskell C, Kirkham A, PIrrie S, et al. Examining the 
immunological effects of COVID-19 vaccination in patients with conditions potentially leading to 
diminished immune response capacity - the OCTAVE trial. Preprints with The Lancet. 2021. 
25. 
Protective Immunity from T Cells in Healthcare Workers (PITCH) Study https://www.pitch-
study.org/ [Available from: https://www.pitch-study.org/. 
26. 
Summary of Product Characteristics for Xevudy. In: Medicines and Healthcare products 
Regulatory Agency, editor. https://wwwgovuk/government/publications/regulatory-approval-of-
xevudy-sotrovimab/summary-of-product-characteristics-for-xevudy. 
https://www.gov.uk/government/publications/regulatory-approval-of-xevudy-sotrovimab/summary-
of-product-characteristics-for-xevudy2021. 
27. 
Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors 
associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430-6. 

 
EudraCT Number: 2020-004144-28 
IRAS ID: 288652 
 
Page 100 of 100 
PROTECT-V protocol V11.0 – 05/Sep/2023 
 
28. 
Shields AM, Burns SO, Savic S, Richter AG, Consortium UPC-. COVID-19 in patients with 
primary and secondary immunodeficiency: The United Kingdom experience. J Allergy Clin 
Immunol. 2021;147(3):870-5 e1. 
29. 
Carr EJ, Kronbichler A, Graham-Brown M, Abra G, Argyropoulos C, Harper L, et al. 
Review of Early Immune Response to SARS-CoV-2 Vaccination Among Patients With CKD. 
Kidney Int Rep. 2021;6(9):2292-304. 
30. 
Kamar N, Abravanel F, Marion O, Couat C, Izopet J, Del Bello A. Three Doses of an 
mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. N Engl J Med. 2021;385(7):661-
2. 
31. 
Caillard S, Thaunat O. COVID-19 vaccination in kidney transplant recipients. Nat Rev 
Nephrol. 2021;17(12):785-7. 
32. 
Prevention. CfDCa. Science Brief: COVID-19 Vaccines and Vaccinations 
https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/fully-vaccinated-
people.html2021 [Available from: https://www.cdc.gov/coronavirus/2019-ncov/science/science-
briefs/fully-vaccinated-people.html. 
33. 
Carr EJ, Wu M, Harvey R, Wall EC, Kelly G, Hussain S, et al. Neutralising antibodies after 
COVID-19 vaccination in UK haemodialysis patients. Lancet. 2021;398(10305):1038-41. 
34. 
Tenforde MW, Patel MM, Ginde AA, Douin DJ, Talbot HK, Casey JD, et al. Effectiveness 
of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 Hospitalizations in the United States. 
medRxiv. 2021:2021.07.08.21259776. 
35. 
Brosh-Nissimov T, Orenbuch-Harroch E, Chowers M, Elbaz M, Nesher L, Stein M, et al. 
BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized 
COVID-19 patients in Israel. Clin Microbiol Infect. 2021;27(11):1652-7. 
36. 
O’Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan K-C, Sarkar N, et al. Subcutaneous 
REGEN-COV Antibody Combination to Prevent Covid-19. New England Journal of Medicine. 
2021;385(13):1184-95. 
37. 
Medicines & Healthcare Products Regulatory Agency. Decision. Summary of Product 
Characteristics for Lagevrio 2021 [updated 4/11/2021. Available from: 
https://www.gov.uk/government/publications/regulatory-approval-of-lagevrio-
molnupiravir/summary-of-product-characteristics-for-lagevrio. 
38. 
Pfizer's novel COVID-19 oral antiviral treatment candidate reduced risk of hospitalisation 
or death by 89% in interim analysis of Phase 2/3 EPIC-HR study [press release]. 
https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-
antiviral-treatment-candidate2021.