Early Prednisolone for Suspected Community-acquired Acute Respiratory Tract Infection (PREDICATE): A Double-blind, Randomised, Multi-centre, Adaptive Platform, Controlled Trial

Introduction Acute Respiratory Infections (ARIs) are the fourth leading cause of death worldwide, third in China and second in Hong Kong. They are usually caused by bacteria or viruses and are associated with an early hyperinflammatory response. Evidence for the early detection of the disease and pathogen, risk-stratification and management are high priorities for the World Health Organisation (WHO).

The pathogens most likely to cause annual epidemics and pandemics are respiratory viruses although bacteria may cause up to 50% of ARI in hospitalised patients. Despite individual variation, the clinical course of ARIs generally involves an incubation period that lasts hours to days; and an early inflammatory prodrome which lasts days to a week and is characterised by symptoms such as a cough, fever, lethargy, headache (stage I). Whilst most patients recover, some progress to Stage II respiratory deterioration in the subsequent week; and Stage III severe respiratory failure may occur over subsequent weeks. The kinetics of bacterial and viral replication can last up to and even longer than 21 days. This prolonged and relatively slow progression provides several windows of opportunity in which early anti-inflammatory and immunomodulatory therapies could influence the course of the disease, reduce early hyperinflammation, facilitate recovery and well-being, and reduce hospital stay, disease progression, need for intensive care and mortality.

Usual care (UC) for patients with ARI presenting to EDs in Hong Kong is like other primary care settings in the world. For example, in Europe, early treatments are highly variable and consist of paracetamol, non-steroidal anti-inflammatory drugs, low-dose corticosteroids, over-the-counter medicines, fluids, rest, time off school/work, and antibiotics or antivirals. Rapid diagnostic tests (RDTs) are rarely available in the emergency department (ED) and even after admission a pathogen may not be identified in up to 70% of cases. Thus, treatment is usually begun and continued without an identifiable bacterial and/or viral pathogen. As many ARIs follow generic hyperinflammatory pathways, evaluating and repurposing existing anti-inflammatory drugs (e.g. prednisolone, 12) is a common and reasonable strategy which could have relevance not only for Hong Kong but worldwide.

Adaptive Platform Design and Response Adaptive Randomisation An adaptive platform trial (APT) is a trial in which multiple treatments for the same disease are tested simultaneously. New interventions can be added or replace existing ones during the course of the trial in accordance with pre-specified criteria. APTs offer innovations that could reshape clinical trials, and several APTs are now funded in various disease areas. APTs enhance research efficiency, shorten the duration of futile studies, and optimise sample size and study duration based on emerging data. The platform design allows for subsequent levels of randomisation if further treatments require evaluation.

The initial randomisation ratio is fixed 1:1 for a comparison between two trial arms, but the trial has the capability for these proportions to be altered according to participants' responses to interventions. Pre-specified decision criteria allow for dropping a treatment for futility, declaring a treatment superior, or adding a new treatment to be tested. If at any point a treatment is deemed superior to the usual care arm, the superior treatment may replace the usual care arm as the new standard of care.