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21/61 UK-wide antiviral clinical trial platform in non-hospitalised patients

Contents

Introduction

The Antivirals Taskforce (ATF) has been established by the Department of Health and Social Care (DHSC) to identify effective antiviral treatments for COVID-19 to augment the current vaccine and therapeutic programmes. Antivirals, if deployed rapidly, have the potential to break chains of transmission, reduce symptoms and hospitalisations, all of which will protect the vital gains of the vaccination programme, particularly if new Variants of Concern emerge which reduce vaccine efficacy. The emergence of the SARS-CoV2 virus has had a profound impact on the UK population, especially in relation to those more at risk groups. It is vital to ensure that a significant rise in infections and spread of the virus in the population is controlled as far as possible. The development of antiviral treatments is integral to our longer-term response to COVID-19 and will enhance pandemic preparedness in the years ahead. In addition to clinical data showing reductions in viral load and time to alleviation of symptoms or illness duration, other data are of great importance to ATF and DHSC in terms of national policy. These include data on reducing hospitalisations and mortality as well as data on reducing secondary transmission in households.

The ATF is seeking to make available oral (tablet or capsule) drugs that could be taken in non-hospitalised patients. The primary focus will be early treatment of confirmed (PCR positive) SARS-CoV2 infections in high-risk individuals to prevent hospitalisation, reduce symptoms, and speed up recovery, thus reducing clinical impact of the virus on individuals and the strain on NHS hospitals. Individuals where the vaccine is less effective, such as the immunosuppressed or the elderly are key targets for this type of treatment. Additionally, antivirals may be particularly useful in managing outbreaks, working alongside other public health interventions, to prevent infection in known contacts of positive cases and to offer protection to those who are not vaccinated or do not respond to vaccination.

The ATF is seeking to commission a research consortium that will be able to deliver a complex community-based clinical trial platform for antiviral candidates, focused primarily on major public health outcomes, notably reductions in hospitalisation and mortality. Proposals for hospital-based patients will not be required. Proposals focusing on primary outcomes related to illness duration or virus shedding (unless in the context of assessing secondary transmission and public health outcomes) will not be in scope. The ATF will identify and prioritise potential candidates for this study and the study team will be expected to set up a platform trial to evaluate the novel candidates and start recruiting patients into the platform trial by early October 2021 at the latest.

It is essential that the trial platform has a national scope that will ensure the inclusion of participants regardless of geographical location. The ATF will collaborate with organisations such as NIHR and NHSE&I to provide systemic support in order to deliver the trial at the required scale. The ATF will also provide support to connect the successful team to NHS Digital and the UK Health Security Agency (formerly NHS Test and Trace and Public Health England) to ensure rapid data sharing. The successful team will need to ensure that appropriate information governance for rapid sharing of person identifiable data is in place. Equitable access to the trial by a diverse range of the UK population will be critical and the successful team will be expected to develop resources such as a comprehensive clinical trial website and recruitment methods to enable this.

Potential teams will be assessed on the following criteria:

  1. Demonstration of capability in the team of delivering multi-centre interventional studies in community settings in the UK, including adaptive platform studies
  2. Demonstration of experience in the team of delivering a large multi-centre clinical trial of an Investigational Medicinal Product (CTIMP) in the UK
  3. Demonstration of ability to perform inclusive studies that identify and recruit from under-served populations and populations where outcomes of COVID-19 have been poor to date
  4. Experience in to establishing and coordinating data input from a wide variety of sites
  5. Demonstration of suitably skilled virology, public health, and epidemiology expertise within the team or consortium
  6. Track record in rapidly training sites to ensure robust completion of electronic case forms and data required to measure primary and secondary outcomes and pharmacovigilance data.

Primary Research Questions

Which drug interventions are most effective and safe in preventing hospitalisation in high-risk patients with a confirmed PCR positive SARS-CoV-2 test result?

How effective is the drug intervention in preventing transmission of SARS-CoV-2 to household contacts of index cases?

What impact do the antivirals have on viral load, time to virus clearance and an assessment of potential for development of resistance under drug selective pressure and transmission of resistant strains to contacts?

The successful proposal will address ALL the above questions, possibly through embedded sub-studies. Proposals ‘cherry picking’ just one of the primary questions are unlikely to be successful.

Proposed study design

A community-based, UK-wide adaptive platform for trialling antiviral candidates, identified by the ATF, in participants who can commence treatment within 5 days of symptom onset, to answer the primary research questions. A Bayesian analytical approach may be appropriate as there is a need to identify successful therapies very rapidly with a view to establishing appropriate national clinical standards in the shortest possible time frame. Potential investigators should ensure that appropriate measures are included in the trial design to generate large-scale safety data. It is also expected that data generated from the study will be able to inform views on the need for measures such as continuation or duration of self-isolation under therapy.

In addition, a virology sub-study will need to be conducted on a sufficiently large sample of patients to provide evidence on parameters such as rate of viral clearance and the potential development of viral resistance.

An embedded post-exposure prophylaxis (PEP) sub-study will also need to be conducted for household contacts of index cases.


Population of interest within the Community

  • Treatment:
    • Clinically vulnerable and clinically extremely vulnerable individuals over 18 years of age with a positive SARS-Cov-2 PCR test result
    • Individuals over 50 years of age with a positive SARS-Cov-2 PCR test result.
  • PEP:
    • Household members over the age of 18 of an index case with a PCR positive SARS-CoV-2 test result.

Intervention(s)

To be specified by the ATF – candidates initially will be oral antivirals with initial efficacy and safety data from phase II and / or small phase III trials.

Comparator

Standard of Care/Usual Care

Outcomes

Treatment:

The main outcome of interest is prevention of hospitalisation.

Applicants to define other practical primary and secondary outcomes.

The following are suggested: Prevention of severe disease, reduction in symptoms, speed of recovery and return to full function. PEP: Confirmed PCR positive SARS-CoV-2 infection amongst household contacts of confirmed cases.

Cost-effectiveness

Robust measures of healthcare utilisation, validated quality of life questionnaires and other relevant data should be collected to enable future cost effectiveness analyses. It is anticipated that this may include using quality adjusted life years and enabling incremental cost-effective ratios to be calculated, although other cost effectiveness measures may be proposed by applicants.

Duration and costs

Applicants should provide costs of setting up and running the platform study for 24 months in total and quickly starting recruitment, initially to up to three trial arms, once the interventions have been prioritised by ATF.

As other potential candidates are prioritised, additional study arms and their associated additional costs will be dealt with as a contract variations. Applicants should explain how they will be able expand the platform at pace and scale as new antivirals are prioritised by ATF.

After 24 months the requirement for the platform and the delivery of the team will be considered and a decision will be made by DHSC as to whether to extend the study for a further period.

Process for Assessment of Applications and Appointment of Successful team

Applicants should read the guidance notes.

Applicants will be asked to complete an application form and research plan. The research plan section of the form will be used by applicants to provide full clinical, scientific and methodological detail and explain and provide clear evidence that the team fulfils the criteria specified above.

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

Shortlisted applicants will be asked to present and discuss their application with a funding panel to be conducted virtually during the week commencing the 23rd August 2021 and applicants must be able to provide representation from their team – the panel will then decide the successful team.

A virtual information session for prospective applicants will be held on 29th July 2021 at 2pm. 

Enquiries can be made to the following email: nihrcovidcall@nihr.ac.uk

Closing date for applications

17th August 2021 at 1pm

We appreciate that the timescales for this call are extremely challenging, particularly over the Summer, and the difficulties that rapid calls create particularly in terms of convening a well-qualified and diverse team. However, we hope applicants will understand the urgency for this work and the rationale for this very short timescale given the current national crisis.

Additional Resources

Investigators my find the following guidance helpful:

NHS Digital Patient Risk Criteria

Joint Committee on Vaccination and Immunisation: advice on priority groups for COVID-19 vaccination

NICE Support for developers of medicinal products for COVID-19