Title: Double-blinded randomised controlled trial of early low dose steroids in patients admitted to hospital with influenza infection during a pandemic
Funder: Department of Health and Social Care

Abstract: Design: Pragmatic mutli-centre double-blind randomized trial. Setting: Hospital in-patient services in England, Scotland and Wales Target Population: Adults (> 16 years old) hospitalized with an influenza-like illness during a pandemic. Health Technologies being assessed: Dexmethasone 6 mg once daily for 5 days from the day of hospital admission, given as adjuvant therapy, in addition to standard care. Based on current national guidelines, standard care will be expected to comprise of supportive measures (fluid and oxygen supplementation), antivirals and antibiotics as appropriate. Measurement of outcomes: The choice of primary outcome measure takes account of the need for simplicity in a trial conducted during a pandemic and of how pandemic severity influences clinical priorities. For a high severity pandemic, a high proportion will be admitted to intensive care, and/or die and so in this situation the primary outcome would be the composite measure of death or admission to intensive care. For a low/ moderate severity pandemic, severe adverse outcomes are less likely, and the primary outcome would be length of stay in hospital. Secondary outcomes include length of stay in intensive care unit > 7 days, readmission within 30 days of hospital discharge, GP consultation within 30 days of hospital discharge, death in hospital. Sample size: Our planned sample size of 2,200 patients is based on the range of possible scenarios that might be encountered during a pandemic. With 2,200 patients, the study will have 90% power to detect a 15% relative reduction in the primary outcome (admission to intensive care or death) in a high severity pandemic. A sample size of 1000 patients will have 90% power to detect a 20% relative reduction in length of stay in a low/moderate severity pandemic.

Lay abstract: During a pandemic, influenza infection can be severe because the population has little or no immune protection to the new virus. In such circumstances, severe influenza may lead to hospitalization, admission to intensive care or death. A pandemic also poses challenges for health care systems which may be over-stretched leading to further detrimental impacts on patient care. Current treatment options for influenza, including antivirals, are only partly effective at reducing adverse outcomes. There is much debate over whether steroids, given in addition to antivirals, are beneficial or harmful to patients. No trials have been successfully conducted to answer this question. The proposed trial will establish whether low-dose steroids given at the time of hospital admission for 5 days to adults hospitalized with influenza infection during a pandemic is beneficial. The trial will be conducted in hospitals in England, Scotland and Wales. In a severe pandemic associated with high death rates, the main outcome of the study will be whether steroids reduce the number of admissions to intensive care, or reduce the number of deaths. In a mild pandemic, rates of death or intensive care admission will be low. Therefore, the main outcome of the study will be whether steroids reduce the duration of hospital stay in those who do not die. In both instances, secondary outcome measures include hospital re-admission rates and General Practitioner consultation rates 30 days after hospital discharge to ensure there are no longer term risks associated with steroids. The trial is simple and the trial drug is of low-risk. The main ethical challenge of the trial relates to obtaining consent in an emergency setting within a pandemic. Pandemic-specific factors that impact the approach to consent in this study include: A) Patients admitted to hospital with severe pandemic influenza constitute a medical emergency. Such patients can deteriorate rapidly (within hours admission to hospital) and dramatically; the average time from hospital admission to ICU admission was 1 day in the 2009 pandemic. B) The context of a pandemic means that acute health care resources will be exceptionally stretched through a combination of high healthcare demand and high levels of staff sickness. C) The UK Pandemic Plan (2011) describes a proportionate response to pandemics of different impact. In moderate and high impact circumstances, it is recognised that hospital services may not be able to continue all usual activity; this may of necessity be accompanied by alterations in clinical priorities. D) Even in a low impact situation, the UK Pandemic Plan acknowledges that maximal effort by hospital services may be necessary to cope with the increased pressures of a pandemic situation. In line with the UK Pandemic Plan, the approach to consent will be proportionate to the impact of the pandemic. In a low impact situation, verbal assent on admission with deferred written consent within 72 hours will be obtained. In a high impact situation when health services are no longer able to conduct all usual activity, the consent process will involve informed verbal assent on admission with provision for withdrawal thereafter. The study is built on 3 phases - set up, hibernation and activation. By the end of the set up phase (12 months), 30- 50 participating sites will be identified, all regulatory approvals will be in place and processes for manufacture of trial drug/placebo established. The study will then enter the hibernation phase. Trial readiness will be reviewed annually at all participating sites during hibernation. The trial will be activated when a pandemic is declared following communication and agreement with NIHR and the TSC at the time. The aim will be to complete the trial within the first wave of a pandemic and for trial results to be available to inform national policy in the management of the on-going pandemic. The Research Team is multidisciplinary bringing together experts from respiratory medicine, infectious diseases, public health and Clinical Trials.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION