PROphylaxis for paTiEnts at risk of COVID-19 infecTion (PROTECT-V)

**Background:** Despite widespread vaccination against SARS-CoV-2, several patient groups remain vulnerable due to underlying health conditions, immunosuppressive treatments, or suboptimal vaccine responses. No vaccine is completely effective, and emerging variants continue to pose risks. The PROTECT-V platform trial was designed to evaluate pre-exposure prophylactic agents in these high-risk populations, bringing efficiency through a master protocol with shared placebo groups, unified oversight, and adaptive features.

**Methods:** PROTECT-V is a platform trial conducted in hospital settings across approximately 40 UK sites (niclosamide and ciclesonide arms) and 20–30 UK sites (sotrovimab arm), with a parallel niclosamide arm in India sponsored by The George Institute for Global Health. Eligible participants are aged ≥18 years and belong to vulnerable populations including end-stage renal failure on dialysis, kidney transplant recipients, vasculitis/SLE, glomerulonephritis, immunodeficiency, oncology/haematology patients, and autoimmune disease patients on immunosuppression. The sotrovimab arm additionally requires absent or suboptimal antibody response (Roche Elecsys Anti-SARS-CoV-2 assay <400 AU/mL) except for individuals on immunoglobulin replacement therapy. Three agents are approved: intranasal niclosamide (1% ethanolamine solution, 140 μL per nostril twice daily, total 5.6 mg/day), inhaled and intranasal ciclesonide (320 μg inhaled + 160 μg intranasal once daily), and intravenous sotrovimab (2000 mg single dose). Each intervention has a matched placebo. Randomisation is stratified by disease sub-group, age, and site using a web-based system (Sealed Envelope). The primary endpoint is confirmed symptomatic SARS-CoV-2 infection. For niclosamide and ciclesonide, the primary analysis uses Cox proportional hazards model in the ITT population with a 2-sided alpha of 0.045, requiring a maximum of 235 events for 90% power (estimated 15% 6-month infection rate in placebo, 10% in treatment; HR 0.648). The sotrovimab arm uses logistic regression at 12 weeks (2-sided alpha 5%), with a planned minimum of 1760 participants assuming 75% reduction from 2–3% placebo infection rate. The sotrovimab arm includes three lead-in cohorts (60 patients each) with progressive reduction in infusion time from 120 minutes to 30 minutes, monitored for severe infusion-related reactions.

**Key Results:** As of 31 October 2022, 1611 patients had been randomised to the niclosamide arm (1223 UK, 388 India). The ciclesonide arm was approved from May 2021 but could not secure drug supply. The sotrovimab arm opened in August 2022 after an 8-month delay for dose revision from 500 mg to 2000 mg due to emerging variants; 68 patients had been randomised. The niclosamide arm was anticipated to close at end of 2022 when required events accumulated. The sotrovimab arm expected recruitment completion by Q3 2023. No efficacy results are reported as the trial is ongoing.

**Clinical Implications:** PROTECT-V addresses a critical gap in COVID-19 prevention for immunocompromised patients who mount suboptimal vaccine responses. The platform design allows efficient evaluation of multiple prophylactic agents across diverse vulnerable populations, with adaptive features to respond to the evolving pandemic landscape (e.g., permitting lateral flow tests when PCR availability changed, increasing sotrovimab dose for emerging variants). The trial's pragmatic design minimises hospital visits through remote follow-up, medication delivery, and linkage with UKHSA data. If any agent demonstrates efficacy, it could provide an important pre-exposure prophylaxis option for patients who cannot rely on vaccination alone. The platform structure also allows future agents to be added as they become available.