AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment:an update to the structured summary of a study protocol for a randomised platform trial letter

Griffiths, G.O. and FitzGerald, R. and Jaki, T. and Corkhill, A. and Reynolds, H. and Ewings, S. and Condie, S. and Tilt, E. and Johnson, L. and Radford, M. and Simpson, C. and Saunders, G. and Yeats, S. and Mozgunov, P. and Tansley-Hancock, O. and Martin, K. and Downs, N. and Eberhart, I. and Martin, J.W.B. and Goncalves, C. and Song, A. and Fletcher, T. and Byrne, K. and Lalloo, D.G. and Owen, A. and Jacobs, M. and Walker, L. and Lyon, R. and Woods, C. and Gibney, J. and Chiong, J. and Chandiwana, N. and Jacob, S. and Lamorde, M. and Orrell, C. and Pirmohamed, M. and Khoo, S. and investigators, on behalf of the AGILE (2021) AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment:an update to the structured summary of a study protocol for a randomised platform trial letter. Trials, 22 (1). ISSN 1745-6215

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Abstract

Background: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods/design: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. Discussion: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial registration: EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183 19 February 2021 ISRCTN reference: 27106947

Item Type:
Journal Article
Journal or Publication Title:
Trials
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Export Date: 26 August 2021 Correspondence Address: Griffiths, G.O.; Southampton Clinical Trials Unit, Southampton, United Kingdom; email: G.O.Griffiths@soton.ac.uk Funding details: AstraZeneca Funding details: Merck Funding details: Roche Funding details: Wellcome Trust, WT Funding details: University Hospital Southampton NHS Foundation Trust Funding details: UCB Funding details: UK Research and Innovation, UKRI, EP/R024804/1 Funding details: Gilead UK and Ireland Corporate Contributions Funding details: Medical Research Council, MRC Funding details: Engineering and Physical Sciences Research Council, EPSRC Funding details: National Institute for Health Research, NIHR Funding details: Cancer Research UK, CRUK Funding details: University of Southampton Funding details: University of Liverpool, UoL Funding details: Chienkuo Technology University, CTU Funding details: UCLH Biomedical Research Centre, NIHR BRC, BRC-1215-20014, MC_UU_00002/14, NIHR300576 Funding text 1: We acknowledge Cancer Research UK (CRUK) who, during the COVID-19 crisis, allowed its staff at Southampton CTU to work with the National Institute for Health Research (NIHR) community (e.g. Southampton CTU, Liverpool CRF & Southampton Biomedical Research Centre) to develop this phase I/II trial platform. We acknowledge the University Hospital Southampton NHS Foundation Trust, Liverpool University Hospitals NHS Foundation Trust, University of Southampton and the University of Liverpool who supported and collaborated in the development of AGILE. We acknowledge the Global Health Trials Unit within the Liverpool School of Tropical Medicine who are leading in developing AGILE international trials with our international partners in South Africa and Uganda. We also acknowledge The Wellcome Trust and the Medical Research Council (MRC)/UK Research and Innovation (UKRI) for core funding this project. Funding text 2: We acknowledge Cancer Research UK (CRUK) who, during the COVID-19 crisis, allowed its staff at Southampton CTU to work with the National Institute for Health Research (NIHR) community (e.g. Southampton CTU, Liverpool CRF & Southampton Biomedical Research Centre) to develop this phase I/II trial platform. We acknowledge the University Hospital Southampton NHS Foundation Trust, Liverpool University Hospitals NHS Foundation Trust, University of Southampton and the University of Liverpool who supported and collaborated in the development of AGILE. We acknowledge the Global Health Trials Unit within the Liverpool School of Tropical Medicine who are leading in developing AGILE international trials with our international partners in South Africa and Uganda. We also acknowledge The Wellcome Trust and the Medical Research Council (MRC)/UK Research and Innovation (UKRI) for core funding this project. Funding text 3: The development of the AGILE master protocol, electronic data capture system, randomisation and eConsent was funded using Cancer Research UK (CRUK) core funding and National Institute for Health Research (NIHR) CTU support funding at the Southampton Clinical Trials Unit. NIHR funding at the Royal Liverpool and Broadgreen Clinical Research Facility and staff at the University of Liverpool and Lancaster also supported the development of the master protocol and its associated documentation (e.g. participant information sheets, case report forms). Funding for each CST protocol is a mixture of core funding and investigator-initiated research grants from pharmaceutical companies supplying the candidate. Funding for CST3 was provided by Unitaid and preclinical evaluation of nitazoxanide was supported by UKRI using funding repositioned from EP/R024804/1 as part of the UK emergency response to COVID-19. We have core funding from The Wellcome Trust and the Medical Research Council (MRC)/UK Research and Innovation (UKRI). TJ was supported by the NIHR, Cambridge Biomedical Research Centre (BRC-1215-20014) and by UK Medical Research Council (grant number: MC_UU_00002/14). PM was supported by NIHR Advanced Fellowship (NIHR300576).The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Funding text 4: AO is a Director of Tandem Nano Ltd and co-inventor of patents relating to drug delivery. Also unrelated, AO has received research funding from ViiV, Merck, Janssen and consultancy from Gilead, ViiV and Merck. MP receives research funding from various organisations including the MRC and NIHR. He has also received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis), a PhD studentship jointly funded by EPSRC and Astra Zeneca and grant funding from Vistagen Therapeutics. He has also unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol-Myers Squibb and UCB. He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. He is part of the IMI Consortium ARDAT ( www.ardat.org ). None of these of funding sources have been used for the current paper. 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158873
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Deposited On:
01 Sep 2021 12:20
Refereed?:
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Published
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06 Oct 2021 08:26