Part 1: Inhaled repurposed agents 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.

Three vulnerable patient populations were enrolled initially: dialysis patients, kidney
transplant recipients and those with vasculitis or other auto-immune kidney disease such
as systemic lupus erythematosus (SLE) or glomerulonephritis (GN) These patient groups are
noted to be particularly vulnerable to COVID-19 infection by virtue of demographics,
underlying co-morbidities or as a consequence of treatments for these conditions, and
they are at exceptionally high risk of adverse outcomes. Additionally these groups are
known to mount sub-optimal responses to vaccination.

Approximately 1500 participants will be randomised to active treatment or placebo,
stratified by PROTECT sub-population, age and participating sites. Enrolment to the trial
will be via an online platform following informed consent with a face to face screening
visit. The screening visit will include assessment of eligibility (which will include
liver function tests and COVID-19 PCR test), randomisation, baseline data collection and
research serum sample collection to detect anti SARS-COV-2 antibodies. Subsequent
assessments, aside from an in person end of trial visit, will be done via email or
telephone together with utilising the routine collected health data thus reducing the
burden to participants as well as reducing their exposure to COVID-19. Telephone
consultations will be carried out at weeks 1, 2, 3, 4 and 6, followed by two weekly
self-reporting at week 8 onwards.

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.

If a participant develops symptoms suggestive of COVID-19 infection they should arrange
an urgent COVID-19 test. They should notify their trial physician. 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. 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.

A final safety assessment will be conducted in person, 4-6 weeks after the final
treatment. 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 into one of the other arms of the PROTECT-V trial platform. It is not permitted
for re-enrolment into the originally assigned arm.

Participants will continue allocated treatment until one of the following occurs:

1. The required number of the primary outcome events have occurred (for each
intervention)

2. The participant is hospitalised with COVID-19 (see 4.10.2.)

3. 28 Days after a diagnosis of COVID-19 if hospitalisation is not required

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. All Adverse Events and Adverse
Reactions will be recorded in the medical notes and in the appropriate section of the
case report form. Serious adverse events and serious adverse reactions should be reported
to the sponsor.

Niclosamide is a derivative of salicylic acid and has been used to treat tapeworm
infections. The exact target and mechanism of action is uncertain. 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. 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. Hepatic clearance is
the primary mechanism for elimination and there is anticipated low bioavailability,
therefore no dose adjustments are required for patients with renal impairment.
Side-effects (based on a phase 1 study in healthy volunteers) are minor nasal irritation,
sneezing or runny nose. 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.

Ciclesonide is an inhaled corticosteroid (ICS) that has been shown to possess in vitro
anti-SARS-CoV-2 activity. 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). ICS, particularly at higher doses, have been shown to reduce expression of
ACE2 and TMPRSS2 receptors, which mediate infection of host respiratory epithelial cells.
ICS have also been shown to inhibit in vivo production of IL-6, a key pro-inflammatory
cytokine in COVID-19 and a major predictor of severe disease and poor outcomes. 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-19. Ciclesonide and its active metabolite are metabolised and
excreted by hepatic mechanisms, therefore no dose adjustments are required for patients
with renal impairment, Side-effects may include cough, bronchospasm, bad taste and
application site reactions.

Part 2: Monoclonal antibodies and anti-viral agents

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. 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. Sotrovimab demonstrates
high affinity binding to the SARS-CoV-2 spike RBD. COMET-ICE 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. The primary endpoint, progression of COVID-19 at Day 29,
was reduced by 85% compared with placebo.

A single dose of 500 mg was selected for the study based on in vitro neutralisation data,
in vitro resistance data, and IV PK data from the COMET-ICE [NCT04545060] study. No dose
modification is required in renal or hepatic disease. The overall rate of AEs in
COMET-ICE was similar in those treated with sotrovimab compared to placebo. The known
side-effects of sotrovimab are hypersensitivity and anaphylaxis. 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.

An absent or suboptimal response (Roche Elecsys® Anti-SARS-CoV-2 assay result <400 AU/mL)
to COVID-19 vaccination, assessed at least 14 days after the vaccine was initially
require to be eligible for the sotrovimab arm of the study however, this have been remove
from the criteria. Additional patient groups with primary immunodeficiency, any
Haematology or Oncology patient who is currently receiving or has received chemotherapy
or who is immunocompromised as a result of their disease or treatment, those with a
diagnosis of an autoimmune or inflammatory disease receiving immunosuppression and also
haematopoietic stem cell transplant recipients have been added.

In addition to the core components of the screening visit previously listed the following
will also be conducted: ECG, serum antibody sample for Roche Elecsys® Anti-SARS-CoV-2
assay, full blood count, clotting profile, renal and liver function test (routine ALT/AST
tests performed up to 2 week before screening visit will be accepted to assess liver
function), and serum pregnancy test in women of child bearing potential, urine albumin:
creatinine ratio.

At the day 1 infusion visit, prior to commencing the IMP infusion, a blood sample to
measure anti-drug antibodies will be collected. Routine observations must be taken prior
to infusion, at the end of infusion and 1 hour after infusion and to be recorded. PK
samples to be taken within 1 hour after end of infusion.

Telephone consultations/remote telephone assessments will be carried out weekly for the
first 4 weeks, alternative weeks from week 6 to 24 and then every 4th week from week 28
to 36. In person assessments will occur during weeks 4, 12 and 24 and will include blood
sample collection for measurement of COVID-19 antibodies and PK sampling.