Blinded randomised controlled trial of low-dose Adjuvant Steroids in Adults admitted to hospital with Pandemic influenza (ASAP): a trial 'in hibernation', ready for rapid activation

Study design

This is a pragmatic, blinded randomised placebo-controlled trial to determine whether or not during a pandemic, a 5-day course of dexamethasone, started within 24 hours of admission, in addition to standard care, is associated with a lower risk of death or admission to intensive care compared with placebo for adults (≥ 16 years) admitted to hospital with an influenza-like illness. This trial will be conducted at 30–40 sites across the UK during the first wave of the next influenza pandemic and will recruit 2200 participants, probably over a 6-week period.

The trial is set out in three phases: set-up, hibernation and activation. A summary of these phases is given in Appendix 1 (see section 6.1, figure 1). During the hibernation phase, regular review of trial procedures and sites will ensure that the trial is maintained in a state in which it can be rapidly activated to start recruitment in the event of a pandemic. When the NIHR activates the trial, it will move to a preactivation phase of 4–6 weeks. This final phase of trial set-up will include production and distribution of the trial drug and trial materials, finalisation of trial procedures, and a check of site readiness prior to beginning recruitment.

Participants

Adults with a clinical diagnosis of an influenza-like illness at the time of hospitalisation will be eligible for recruitment to the ASAP trial; a laboratory diagnosis of influenza will not be required. The definition of an influenza-like illness will be confirmed at the start of the pandemic and will conform to the definition provided by Public Health England at the time.

Adults known to be taking or requiring corticosteroids at the time of hospitalisation, and those on medication for the treatment of diabetes mellitus will not be eligible to participate in the trial.

Participants will be randomised (1 : 1 ratio) to receive dexamethasone or placebo. An overview of the trial design is given in Appendix 1 (see section 6.1, figure 2). Randomisation will be stratified by site. Each site will receive batches of sealed trial treatment packs in a consecutively numbered series. The treatment packs each contain (1) a 75-ml bottle of either dexamethasone 2 mg/5 ml or placebo (sufficient for 5 days of treatment); (2) instructions for the take home pack (for participants discharged within 5 days of admission); and (3) administration instructions. Trial treatment packs will be stored and available in each area where patients with influenza will be admitted during a pandemic. The two treatments, dexamethasone and placebo, are indistinguishable. Allocation to trial treatment will be by taking the next in the series of treatment packs in that area. Participants will be considered to be in the trial once the trial treatment pack label is completed regardless of whether or not they take any allocated treatment.

Intervention

The study intervention is dexamethasone administered as an oral liquid preparation, 6 mg once daily for 5 days. Dexamethasone 6 mg is equivalent to prednisolone 40 mg or hydrocortisone 160 mg.

Control

The study control is a matching placebo identical in colour, taste and consistency to the intervention.

In addition to the intervention/placebo, all patients will receive standard care for influenza, including oxygen supplementation, fluids, antivirals and antibiotics as appropriate.

Materials

Dexsol® (dexamethasone) 2 mg/5 ml oral solution manufactured by Rosemont Pharmaceuticals Ltd (PL 00427/0137) will be used in this trial.

A batch of matching placebo has been manufactured and is being stored by Rosemont Pharmaceuticals Ltd. A new batch of placebo will be manufactured to replace outdated stock as appropriate. Manufacturing time is approximately 4 weeks.

Three manufacturing units have been contracted to provide Investigational Medicinal Product (IMP) packaging and release services.

Outcomes

The design and analysis of the trial includes the flexibility to allow for pandemics of different severity. In a high-severity pandemic, the primary composite outcome is admission to intensive care or death by day 30. Secondary outcomes are (1) length of stay in the ICU; (2) readmission to hospital within 30 days of hospital discharge; (3) length of stay in hospital; (4) death within 30 days of admission to hospital; (5) admission to ICU within 30 days of admission to hospital; and (6) general practitioner consultations within 30 days of hospital discharge.

For the purposes of this trial, ‘admission to intensive care’ is defined as provision of level 3 care (usually involving mechanical ventilation); this includes the provision of such care in non-traditional level 3 environments as might be encountered under contingency or crisis situations during a pandemic. 27,28 This definition of ‘intensive care’ accords with the Department of Health planning assumptions. 29 Most patients who require critical care are likely to be mechanically ventilated at some point; during the low-severity 2009 pandemic, 77% of patients managed in critical care in the UK required advanced respiratory support. 30

In a low-/moderate-severity pandemic, the primary outcome is time to hospital discharge, right censored at 30 days.

At the outset of a pandemic, its severity will not necessarily be accurately appreciated. The ASAP trial is planned in anticipation of a high-severity pandemic; this represents the most challenging situation for trial execution and also the situation in which the trial results might have the largest public health impact. In addition, at the start of a pandemic, patients with more severe illness will be more readily identified and recognised compared with patients with mild or subclinical disease, hence potentially masking the true overall nature of the pandemic. Uncertainty regarding the severity of a pandemic will remain until sufficient data are gathered, which may not be until after the end of the first pandemic wave.

A review of pandemic severity will be conducted by the Trial Management Group and Trial Steering Committee (TSC) as the pandemic unfolds. Decisions regarding the final analysis plan and final primary outcome will rest with the TSC. These decisions are expected to be informed by discussions at the time with the Department of Health, NIHR and Public Health England, and will be made before any analyses of trial data are undertaken.

Current modelling estimates from the Department of Health are that for a high-severity pandemic, 35% of those admitted to hospital will die and 25% will be admitted to intensive care. It is anticipated that if these thresholds are not met, the pandemic will not be considered of ‘high severity’. For the purposes of the ASAP trial, thresholds defining a low-severity epidemic compared with a moderate-severity pandemic are less important.

Trial oversight

A TSC and a Data Monitoring Committee have been established. Yearly updates will be provided to these committees during the hibernation phase.

Statistical considerations

For a high-severity pandemic, with 1100 participants in each arm, the trial will have > 90% power to detect a 20% relative difference given a control event rate of 35%, or 80% power to detect a 15% relative difference given a control event rate of 40%, both with 5% two-sided alpha level. Further details of sample size estimates over a range of possible scenarios is given in Appendix 1 (see section 9.2).

For a low-/moderate-severity pandemic, a hazard ratio of 1.25, indicating an increased risk of discharge at any given time, is considered as the minimum clinically relevant change to detect. With 90% power and 1% two-sided alpha level, 5% censored in the control arm, up to 10% die in hospital in both arms, and 5% non-collection of primary outcome data, about 920 participants are required to be randomised for a low-/moderate-severity pandemic.

The initial target total sample size for the ASAP trial is 2200 participants. If the pandemic is of low or moderate severity, it is likely that fewer than 2200 participants will be randomised during the first wave of approximately 6 weeks’ duration, although this definition will not be available until after the end of the first wave. If more than 920 participants are randomised in a low-/moderate-severity pandemic then smaller effect sizes may be detectable.

We will compare numbers, age and sex of randomised participants with aggregate summary data of all patients who are admitted to hospital with influenza-like illness during the study period. We will compare baseline characteristics of the randomised arms using appropriate descriptive statistics. Between-group comparisons for primary and secondary outcomes will be conducted using an intention-to-treat (ITT) approach, implemented using appropriate regression models, and with results presented as point estimates, such as a ratio or difference comparing dexamethasone with placebo, with 95% CIs and p-values.

Secondary analyses will include additional adjustment for variables displaying an important imbalance at baseline. We anticipate little, if any, missing primary outcome data and therefore will use ITT without imputation as the main approach, and will investigate the influence of any missing data in sensitivity analyses, including multiple imputation. All analyses will be conducted using Stata version 13 or higher (StataCorp LP, College Station, TX, USA) or MLwiN 2.10 or higher (MLwiN, Centre for Multilevel Modelling, Bristol, UK).

A planned early analysis focused on the primary end points will be performed to provide rapid data to the UK Department of Health prior to the start of the second pandemic wave.

Preplanned subgroup analyses will be conducted for the primary outcome, based on the following baseline factors: (1) duration of symptoms; (2) clinical diagnosis of pneumonia; (3) underlying comorbid illness; and (4) severity of influenza. Outcomes will be reported descriptively by subgroup category and treatment arm, and formally estimated by fitting interaction terms in the regression models. It is recognised that power to detect subgroup effects is likely to be low, and these analyses will be regarded as exploratory and interpreted with due caution.

Substudy

In parallel with the ASAP trial, we have set up a mechanistic substudy to be conducted at six pre-selected trial-participating sites. The substudy will collect biological samples from 200 ASAP trial participants in order to determine the interaction of steroid therapy and the host, and to apply this in interpreting the clinical outcomes measured.

All patients recruited into the ASAP trial at substudy sites will be given the opportunity to participate in the substudy. Consent for participation in the substudy will be taken separately to the ASAP trial. Two blood samples and one nasal swab for subsequent transcriptomic and microbiological testing will be obtained from participants at baseline and 48 hours post first dose of ASAP trial medication.

Pressure on NHS resources

In the event of a high-severity pandemic, the NHS will be under considerable pressure to continue to deliver high-quality care to all patients. Under such circumstances, any additional non-essential work is likely to be deferred. This applies at the individual level as well.

The successful conduct of pragmatic acute care multicentre trials is challenging at the best of times. The need for any research-specific measurements requiring additional patient involvement or follow-up increases trial complexity and hence the burden of research, with potentially negative impacts on trial conduct. These challenges are magnified during a pandemic. 36 To reduce any extra work related to participation in the ASAP trial, trial processes and procedures were minimised to the bare essentials. No additional investigations or measurements are necessary for the ASAP trial; data required for all major outcome measures will be captured from routine medical data sources. 37

Co-enrolment of patients

At the time of reporting, there were at least four pandemic studies that were planning to recruit patients with influenza infection in the UK hospital setting: two are part of the NIHR pandemic portfolio. Of these four studies, the only clinical intervention trial is the ASAP trial; the others are observational cohort or biological sampling studies.

The chief investigators of these trials have agreed that there is no bar to co-enrolment of patients to the ASAP trial and another study. However, other pandemic studies may be set up in future, which may compete for the same patient pool. Even if a principle of co-enrolment could be observed, it may not be acceptable for patients to be approached to participate in multiple studies simultaneously.

An expansion of pandemic studies in future will likely require some degree of prioritisation of the delivery of such research. For instance, although patients entered into the ASAP trial will not be eligible to participate into another trial simultaneously, if a patient is admitted to intensive care and hence meets one of the primary composite end points for a high-severity pandemic, it may be reasonable to consider trial exit for that patient and subsequent enrolment in another trial. Such a decision would depend on a number of factors, including whether or not the severity of the pandemic had already been definitively declared, as this would affect the primary end point for the ASAP trial, the potential public health impact of different trials, the likelihood of completion of a trial, possible biological interactions and patient wishes.

Whether such prioritisation should be left to local sites or co-ordinated more centrally warrants exploration as part of pandemic preparedness planning. 38 The NIHR has established a CRN Urgent Public Health Group to help ensure that urgent public health studies can be set up and delivered quickly and effectively. 39 Commercial studies may apply for approval as relevant to the urgent public health risk. However, co-enrolment involving commercial studies, whether observational or interventional, may not meet with approval by industrial partners. The impact of allowing or disallowing co-enrolment should be carefully considered at the time of approval of studies for priority status within the CRN urgent public health research framework.

Engagement of sites

Maintaining the interest and focus of sites through the set-up process has required constant effort. Understandably, because of the perception that the ASAP trial may not be activated for an undefined period of years, there is less impetus to work on this trial compared with that of other trials that have more imminent datelines.

Establishing dialogue with a core team of local investigators at each site, and enabling them to better anticipate the potential barriers to conducting a trial during a pandemic, has coincided with the role of ‘pandemic champions’ promoted by the Infectious Diseases and Microbiology Specialty Group to the NIHR CRNs.

The support of the Specialty Group has been invaluable not only for establishing links with interested sites, but also in raising national awareness of the trial. To ensure the delivery of pandemic research, the Specialty Group has prepared a suite of documents around urgent public health research and how it will support delivery. The ASAP trial is a recognised urgent public health study; this has provided valuable reassurance to sites of their ability to conduct clinical research during such an emergency.

Site visits during the hibernation phase may be required to maintain study awareness and confirm pandemic preparedness. Including the delivery of NIHR-funded pandemic studies in individual NHS trust pandemic plans is a further desirable step towards integrating pandemic research into service delivery.

Site selection

Although it is anticipated that any future influenza pandemic would affect the whole of the UK, different regions may be more or less severely affected. The location and distribution of pandemic ‘hot spots’ is unpredictable. 1

The 40 sites participating in the ASAP trial are well distributed across the UK. Sites that do not experience much influenza activity during the first pandemic wave may not be activated. In addition, we have provided for a ‘flying squad’ of research nurses to respond to ‘hot spots’, in support of local research teams.

The occurrence of ‘hot spots’ increases the probability of patient transfers from one hospital to another to maintain patient flow and bed capacity. It is not possible to predict which hospitals might be involved in receiving patients. We are currently working on a generic site-specific information form for continuing care sites, to enable non-recruiting sites to continue IMP administration and data collection should a trial participant be transferred in.

Supply of Investigational Medicinal Product

A high-severity pandemic would not only place the NHS under considerable pressure, but also would affect other businesses, particularly through staff sickness. To improve resilience in the supply of IMP and placebo to participating trial sites, contracts with multiple manufacturing and distribution units have been established.

Training of local investigators

Local health-care workers (HCWs) will need to be actively involved in the identification of patients who are eligible for the ASAP trial and taking patient consent. Informing and training large numbers of local HCWs with regards to the ASAP trial in advance of a pandemic (i.e. in the interpandemic period) is unsustainable. More junior HCWs, in particular, will be likely to move on before the trial is activated and the remaining HCWs would require refresher training prior to trial activation.

A suite of trial-specific training material has been prepared jointly with Good Clinical Practice trainers, in consultation with the NIHR. This material has been designed to be easy to read and suitable for rapid dissemination in the preactivation phase to local HCWs who will be involved in the trial.

Command and control

During the severe acute respiratory syndrome outbreak in 2003, good command and control was identified as a major factor in the management of patients and hospital resources. 40 At the same time, undue reliance on any single individual or process is to be avoided.

The Nottingham Clinical Trials Unit (NCTU) has begun development of an internal pandemic plan to increase its resilience in the event of a pandemic, with special emphasis on the successful delivery of the ASAP trial. This includes the potential move of the trial team to an off-hospital site, away from clinical areas where patients with influenza will be managed. Online resources are being developed, both as a repository of information and a means for rapid updates to participating sites.

Changes during hibernation

The timing of a future pandemic is unpredictable. The ASAP trial has been set up with a hibernation phase of up to 10 years. There will inevitably be local and national infrastructural, policy and staff changes in this time. Maintaining trial readiness throughout these changes will require active management. As an example, in anticipation of a move overseas to take up a research directorship post, one of the trial co-investigators (SG) has already engaged another investigator (D Wootton) to take over responsibilities related to the ASAP trial. Such future-proofing strategies require forethought and long-term commitment.

Unforeseen changes that might undermine the integrity of the trial as it is currently set up may yet arise. Advances in the management of severe acute respiratory illnesses and the potential introduction of new therapies for severe influenza in particular may prompt alterations to the trial during the hibernation phase. An adaptive trial design to enable other treatment arms to be added to the ASAP trial is one consideration; any additional resources required may be justified in view of potential gains.

Lack of research staff

Current planning assumptions are that up to 50% of staff may be affected over the period of the pandemic, either directly by the illness or by caring responsibilities, thereby creating potential pressures on the response. 41 In addition to absenteeism, research staff may also be diverted to front-line clinical work. Lack of staff was identified as the main reason for poor recruitment in a pandemic trial that had to be terminated prior to completion during the 2009 pandemic. 42 To mitigate against this, we have designed the study to minimise the research sources required from sites for the conduct of this study; for instance, data collection and the Case Report Form have been designed with completion by trained administrative staff, and not necessarily by research nurses, in mind. Nevertheless, a minimum core team of local research investigators will be required at each participating site.

Employment of new research staff to support the conduct of the ASAP trial is unlikely to be feasible in view of the short time scale from recognition of a pandemic to trial activation. Redeployment of research staff from other areas of research will be required. The Comprehensive Local Research Network (CLRN) have prioritised the NIHR pandemic portfolio of studies. However, no standing agreement is in place between NIHR and other funding bodies, such as the Medical Research Council or Wellcome Trust.

High-level cross-organisational agreement is needed. Discussions held during the interpandemic period to agree on principles for prioritisation will help facilitate the more detailed discussions that will be required at the onset of a pandemic. Ultimately, the successful delivery of this trial will depend crucially on the timely and sufficient support by CLRN units at all participating sites during the pandemic.

Written informed consent

The process of taking written informed consent for a research study can potentially lead to delays in patient care with clinical consequences. This is most likely to occur when research is conducted in the context of emergency care. 43 Some patients with severe influenza will present to hospital in a state of emergency; the mean time from hospital admission to ICU transfer was 2 days during the 2009 pandemic. 2 In addition to individuals who require emergency care, a state of emergency will also prevail across the management of all patients because of the pressures on the NHS, particularly in the context of a high-severity pandemic.

The current legal requirement for a CTIMP, such as the ASAP trial, is for written informed consent, outside the waiver for emergency research. 44 This waiver applies only to individuals who require emergency care and does not include situations when the health service is in a state of emergency.

The consent approach for the ASAP trial (written informed consent) adheres to existing legal and regulatory standards for a CTIMP. However, as identified during PPI consultations, this may place it at odds with the opinions of patients and the public during a pandemic. Whether or not this will adversely impact on recruitment rates or patient management remains to be determined.

Public engagement: social media

The public’s perception of pandemics is variable. 45,46 Experience of the 2009 pandemic, which was less severe than initially portrayed, may alter how news regarding a future pandemic is received. The ASAP trial might receive wide media exposure during a pandemic and the tone of such media coverage could impact on the conduct of the trial. A public relations strategy for the NIHR pandemic portfolio of studies, including the ASAP trial, will be necessary from the time of activation.