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22/124 A platform trial to evaluate therapeutic interventions for Influenza specification document

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Published: 17 August 2022

Version: 1.0

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Rationale

Influenza, often called ‘flu’, is an acute respiratory infection typically caused by the influenza A or B viruses, within which different strains may be prevalent at a given time. Although most patients recover without treatment, the virus can lead to hospitalisation, long-term complications and death, particularly in those with known risk factors. Despite seasonal vaccines for influenza being well established and available through the NHS to those at the greatest risk, vaccine protection is incomplete and the number of severe flu cases resulting in hospital admission typically peaks over the winter months leading to significant morbidity and mortality, and pressures on the healthcare system.

In 2020 and 2021 there were considerably lower levels of influenza in the UK, which is thought in part to be the result of widespread public health measures employed to prevent the spread of COVID-19, such as face masks and social distancing. With the relaxation of these precautions, it is possible that cases of influenza may rise to or above previous levels in the winter months of 2022-23. Combined with co-circulation of COVID-19, high levels of influenza in the winter are expected to add to considerable pressures on the NHS and care systems.

For severe influenza infections, therapeutic interventions may be employed to manage symptoms, reduce complications and improve patient outcomes, including the need for intensive care; the need for invasive mechanical ventilation; the number of days in hospital prior to successful discharge; and mortality. Examples of therapeutic interventions include the neuraminidase inhibitors oseltamivir and zanamivir, however there is not clinical consensus on optimal antiviral management of hospitalised influenza patients (Bradbury et al, 2018. Clinicians’ attitude towards a placebo-controlled randomised clinical trial investigating the effect of neuraminidase inhibitors in adults hospitalised with influenza).

The place of novel antiviral agents such as baloxavir marboxil in influenza therapy also requires determination. Therefore, further research is needed to determine which interventions or combinations of interventions are most effective, particularly amongst those which can be easily administered. It is also possible that recent developments in the therapeutic management of COVID-19 may invite consideration for the role of corticosteroids in severe influenza.

Through this call, the Health Technology Assessment (HTA) Programme intends to commission a platform study that will efficiently generate high-quality evidence around the clinical and cost-effectiveness of multiple therapeutic interventions for complicated influenza for patients of all ages. The focus is on therapies which have demonstrated some evidence of clinical efficacy but which require further testing in a multi-centre, pragmatic Phase III trial to compare against current practice. It is proposed that this efficient approach may provide rapid evidence with the potential to improve health outcomes and also alleviate service pressures in the short term.

Primary research question

What are the most clinically and cost effective pharmaceutical interventions for patients hospitalised with confirmed influenza?

Population of interest

Patients admitted to hospital for confirmed influenza. Applicants should outline how proposals consider paediatric as well as adult patients.

Interventions

At the outset, the platform must define an adaptive protocol including the evaluation of the following interventions:

  1. Oseltamivir
  2. Baloxavir marboxil
  3. Dexamethasone

Further candidates may be proposed at application, where there is a strong rationale for their inclusion. At the outset, the successful research team should establish an Independent Scientific Advisory group. The study team may identify further candidate therapeutics in collaboration with the Independent Scientific Advisory group and others, including DHSC and UKHSA, during the conduct of the study.

Comparator

The comparator should be Standard Care or Usual Care.

Outcomes

Applicants to define practical and measurable primary and secondary outcomes, these should include: symptom severity; cost-effectiveness; need for intensive care and/or invasive mechanical ventilation; days in hospital prior to successful discharge; death.

Applicants should include proposals for monitoring the emergence of antiviral resistance during therapy, and monitoring signs of reduced therapeutic effectiveness against influenza viruses with pre-existing mutations that are considered to confer resistance.

Proposed study design

Pragmatic Adaptive Platform Trial to test the clinical and cost-effectiveness of therapies identified at application, with the flexibility to incorporate additional study arms to evaluate further candidates.

Duration and costs

We anticipate that a single platform will be commissioned for an initial period of 24 months. This study will be required to commence on 1 November 2022. Applications must therefore demonstrate the ability to set up the study within this timeframe.

Each Spring the requirement for the platform will be reviewed and a decision will be made by DHSC as to whether to extend the study for a further period.

Applicants are expected to provide a budget for setting up and running the platform for 24 months and quickly starting recruitment to specified intervention arms included at application.

As further potential therapies are prioritised by the Independent Scientific Advisory Group, additional study arms and their associated additional costs will be submitted for consideration to NIHR and, if agreed, amended payment schedules will be agreed.

Process for assessment of applications

This is a straight to Stage 2 (full application) funding opportunity. Applicants will be asked to complete an application form and research plan, providing clear evidence that the team fulfils the criteria specified below.

Groups that cannot confidently provide evidence for all criteria should not apply. Once applications are submitted, they will undergo a shortlisting process and any that do not meet the essential criteria will not be taken forward.

Assessment criteria

  • Scientific rigour
    • The study design would answer the research question proposed
    • The proposed study would be feasible and deliverable
  • Value for money
    • The proposed costs of the research are reasonable and commensurate with the proposed work involved
    • The costs to health and care services in supporting the research are reasonable in relation to the likely benefits of the research to decision-makers, patients and the public
  • Demonstration of experience in the team of delivering multi-centre interventional studies in the UK. Experience of innovative adaptive designs are likely to be particularly relevant.
  • A track record in working with members of the public, people who draw on services and in locations of greatest need to perform inclusive studies.
  • Evidenced plans to work closely in partnership – for example, within the consortia and with local NHS organisations
  • Ability to work effectively with industrial partners and deliver robust, independent and industrially relevant research
  • Ability to establish and coordinate data input from a wide variety of sites.

Applicants should also read the guidance notes.

Shortlisted applicants will be asked to present and discuss their application with a funding panel on 19 October 2022. Please ensure that the Chief Investigator and up to four members of the team are available on this date.

Enquiries can be made to the following email: hta.funding@nihr.ac.uk. The closing date for applications is: 13:00 on Thursday 29 September 2022.