PROphylaxis for paTiEnts at Risk of COVID-19 infecTion -V

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.