Title: A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) - Influenza
Funder: Department of Health and Social Care

Abstract: Before COVID-19, flu was the biggest cause of death from viral pneumonia each year. In the last two years the number of cases of flu has been low due to social distancing and mask wearing. Now as those restrictions are lifted there is concern that flu cases may rise to even higher numbers than recent years. We plan to use the lessons we learnt about evaluating treatments for COVID-19 to determine the best treatments to improve outcomes for all patients, adults and children, who are admitted to hospital due to flu. We will also determine which treatments provide the best use of NHS resources. REMAP-CAP is designed to test many treatments for all types of pneumonia, including COVID-19 and flu. It is known as an adaptive platform trial, which means it provides an ongoing platform where new treatments can be added for testing quickly and easily. It has many design features to provide answers efficiently. It uses a type of analysis called Bayesian, that allows answers to be reported as soon as clear results are reached, rather than waiting until fixed numbers of patients have been studied. It tests multiple different treatments at the same time and looks at how these treatments work together. As the trial progresses it also learns from the early results, allocating more patients to treatments that look most encouraging. In this way patients may benefit even before all the results are known. These innovative features have provided rapid proof of benefit or not on 14 different COVID-19 treatments. We now plan to use REMAP-CAP to determine the best treatments for flu. To start we will test two anti-viral drugs, oseltamivir and baloxavir that work against the flu virus in different ways. We will also compare the potential benefit of the combination of these two drugs and explore what is the right length of treatment. In COVID-19 we have shown that reducing inflammation save lives in severely ill patients, and we will test these same treatments now in flu. They include the steroid, dexamethasone, and for the sickest patients two drugs that modify the immune system, tocilizumab and baricitinib. We will test these drugs on their own and in combination to see which treatments save lives over and/or reduce the need for life support in intensive care. We will also measure how quickly patients leave hospital, and quality of life and disability after recovery, as these are important for patients. We will monitor if the flu virus becomes resistant to the anti-viral drugs and will establish an independent team of experts to advise about new treatments for future testing. We have brought together leading UK experts including specialists in intensive care, respiratory medicine, infectious diseases, virology, paediatricians and clinical trialists. We will work with the NIHR national research network and junior doctor networks to ensure recruitment from all areas of the UK. We are part of a wider international group already running the same trial helping to get answers quickly. We can start immediately in the UK. Patient groups have helped design this trial platform through workshops and interviews. They particularly liked the efficient design features and we will continue to work with them as the trial progresses. As well as providing a platform to provide answers quickly and efficiently about the best treatments for flu, REMAP-CAP is a collaborative platform that welcomes and supports young investigators as they develop their clinical research careers.

Lay abstract: -Research questions Overall platform: What are the most clinically and cost-effective pharmaceutical interventions for patients of all ages hospitalised with confirmed influenza? Domain specific (at outset): In adults and children hospitalised with confirmed influenza • What is the optimal anti-viral treatment strategy? • Do corticosteroids improve outcomes? • What is the optimal immune modulation strategy in the severely ill? -Design: An established UK multifactorial Bayesian adaptive platform trial for community acquired pneumonia, also recruiting internationally, using response adaptive randomisation. -Setting: 150 hospitals throughout the UK admitting patients with influenza including under-served regions and communities. -Target population: Adults and children admitted to hospital acutely unwell with confirmed influenza. Exclusion criteria: Patient is expected to be discharged from hospital today or tomorrow Previous participation in this trial within the last 90 days -Interventions being assessed at outset Influenza antiviral domain • Oseltamivir daily for 5 days • Oseltamivir daily for 10 days • Baloxavir on days 1 and 4 • Combination of Oseltamivir daily for 5 days and Baloxavir on days 1 and 4 • Combination of Oseltamivir daily for 10 days and Baloxavir on days 1 and 4 Initial comparator is no antiviral treatment. Corticosteroid domain • Dexamethasone for 10 days Comparator is no corticosteroid treatment Immune modulation domain • Tocilizumab • Baricitinib Initial comparator is no immune modulation treatment. The design allows comparative effectiveness between interventions in a domain to be estimated. The multi-factorial design allows interactions between treatments in different domains to be evaluated. Measurement of outcomes & costs: Primary: 28-day organ support-free days, including mortality Secondary: Symptom severity, WHO ordinal scale, need for intensive care (ICU) admission, need for ventilation, duration of ICU and hospital stay, 90- and 180-day mortality, serious adverse events / reactions, health-related quality of life (EQ-5D-5L), disability (WHODAS), cost effectiveness at 6 months. Development of anti-viral resistance. Statistical methods: A Bayesian hierarchical model, with pre-defined triggers for efficacy and futility (to control), superiority and equivalence (to other treatments). Stratification will allow separate treatment effects to be estimated for critically ill and non-critically ill patients, as well as adults and children. Timelines for delivery: International recruitment has begun (antiviral n=150, corticosteroids n=144). Approvals for UK ICU recruitment are in place. The adaptive Bayesian design allows conclusions as soon as triggers are reached rather than fixed sample sizes. International participation (Southern hemisphere) will ensure year-round recruitment and rapid results for a seasonal illness ahead of rises in UK cases. Anticipated impact and dissemination: REMAP-CAP changed practice globally, saving lives in severe COVID-19, and can impact influenza treatment in the same way.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION