The AGILE Clinical Trial Platform

In 2020 the COVID-19 pandemic spread across the world, impacting the entire globe on unprecedented levels. The effects it had on public health and the world economy are still present years after the outbreak.

With infection rates accelerating and no intervention proven effective, there was an urgent need to understand the virus. This included finding the best ways to treat those infected and how to prevent the spread.

Many COVID-19 trial platforms were set up to investigate if existing drugs may be effective in treating the virus. Yet, there was a need to investigate early phase novel drugs that are safe and efficacious.

Challenge

It was clear that conventional drug development practice was too slow to be effective in fighting a pandemic. Traditionally it takes several years to go through the rigorous development processes required to get new drugs into healthcare programmes. In this case, the timeframe was simply unfeasible.

Vaccines were quickly developed, but they were not the only solution needed. There are people who cannot or will not receive a vaccine, they can be less effective in some people, and rapid mutations of the virus meant that future variants may not have been covered. Antiviral drugs were urgently needed to ease the burden on healthcare programmes worldwide.

The research for this study was even more challenging due to COVID-19 restrictions. Infection control meant that lab space and other facilities were limited, as were the number of scientists allowed to occupy these areas. This added more complications to an already challenging environment.

Solution

To meet this urgent need, a consortium led by the University of Liverpool and comprising of Liverpool University Hospital Foundation Trust, NIHR Clinical Research Facilities across the UK, the NIHR Southampton Clinical Trials Unit, Liverpool School of Tropical Medicine and the University of Cambridge came together to establish AGILE - a new type of clinical trial platform designed to be fast, flexible and fit for purpose.

The AGILE platform is a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment. This represents a new way of doing drug development. It adopts a Bayesian approach which is more flexible, efficient, and informative compared to traditional clinical trial designs. This approach is particularly suited for evaluating multiple treatments and adapting to new information as it emerges during the trial process – essential in a pandemic.

Experts recommended several different treatments thought to be strong candidates to treat patients as soon as they are showing symptoms of COVID-19. This would prevent them needing clinical care in hospital.

The trials started in phase I, where a safe dose for each new drug candidate was identified through rigorous clinical testing. Once a safe dose was proven, the candidate advanced to phase IIa. Here, the novel treatment was assessed against the current NHS standard of care, to see if there was a signal of benefit. If yes, that drug could be considered for inclusion into one of the existing UK later phase trial platforms. What makes the AGILE platform effective is that we can add many new drugs over time, supplying a pipeline of new potential COVID-19 drugs.

Advanced statistical analysis was adopted to speed up decision making, so only strong candidates advanced into phase III trials. Weaker candidates would be eliminated from the platform. This novel approach meant that we were not spending valuable resources on drugs that wouldn’t be effective.

Impact

Molnupiravir was one of the drugs assessed in the AGILE trial. During phase I, several dosages were analysed to determine the optimal dose for treating COVID-19. WE established the drug was well-tolerated and defined the optimal dose for testing in larger scale studies.

This data was shared with Ridgeback Biotherapeutics and their collaborators Merck, who subsequently undertook pivotal late-phase licensing trial in unvaccinated patients. AGILE meanwhile continued with phase II trials in the wider population of both vaccinated and unvaccinated patients, enrolling across the NIHR Clinical Research Facilities in Liverpool, Southampton, Manchester, Lancashire, and London.

In November 2021, Molnupiravir received regulatory approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating unvaccinated people with mild to moderate COVID-19 who are at increased risk of developing severe disease. Our study reported significant but relatively modest viral load changes, and proof that the primary mechanism of action was so-called lethal mutagenesis, where the drug induced mutations in the virus which reduced the amount of viral replication.

The subsequent definitive trial of molnupiravir in the UK, which was the largest treatment trial of a COVID-19 antiviral (PANORAMIC) failed to show a significant effect of molnupiravir on hospitalisation and mortality.

AGILE has undertaken the first evaluations of the monoclonal antibody Vir-7832 and intravenous favipiravir in COVID-19. We have evaluated use of high doses of nitazoxanide for treating COVID-19 in South Africa. The clinical trial platform has also completed an evaluation of the combination molnupiravir plus nirmatrelvir/ritonavir (Paxlovid).

The AGILE clinical trial platform’s impact goes beyond COVID-19. We have pioneered a new way of delivering clinical trials and redefined their speed, flexibility, and responsiveness. AGILE is an exceptional study that has heralded a new age for drug development and clinical trials.