A testing time: finding better treatments for COVID-19

Young scientist looking through a microscope

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While the world’s attention is fixed on coronavirus vaccines, it’s still vital that we continue to find more effective treatments for COVID-19.

With support from UK Research and Innovation (UKRI) and National Institute for Health Research (NIHR), pioneering clinical trials are testing brand new and established therapies across all stages of the disease.

This will help to preserve life and health here in the UK and around the world.

As we head into the second year of COVID-19, the eyes of the world are fixed on the new vaccines that are rolling out to tackle the pandemic.

But while vaccinations should help to bring cases under control, it’s important not to overlook the vital role that treatments play in the fight against this unpredictable new disease.

Treatments will always be needed

Peter Horby, Professor of emerging infectious diseases at the University of Oxford and co-chief investigator of the UK RECOVERY COVID-19 treatment trial says:

It’s clear that treatments will always be needed, particularly for viral respiratory infections like COVID.

Vaccines will never be a 100% solution, even when we reach widespread coverage. We could see evolution of the coronavirus so that there is a poor match between virus and vaccine, some people won’t respond to vaccination, while others won’t be able to be vaccinated or don’t want it.

So it’s almost certain that we will continue to have people falling seriously ill with COVID for a long time, perhaps forever.

Novel coronavirus

COVID-19 is a disease caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), so when the pandemic first struck doctors were unsure exactly how best to treat it.

There were lots of ideas – and, in the case of drugs like hydroxychloroquine, lots of media hype – but no solid data about how well any of them worked.

It was clear that clinical trials were urgently needed. But decisions would need to be made about which treatments to test and, importantly, any trials would need to be large enough to give definitive answers.

Building a strong platform for clinical trials

In partnership with NIHR and the NHS, UKRI has played a leading role in establishing and funding a rapid clinical research pipeline covering the entire ecosystem of COVID-19 treatments.

UKRI has had a wide involvement, from developing and testing brand new drugs to repurposing well-established therapies. Our work has covered all stages of the disease from prevention to aftermath.

The complex clinical trials needed to evaluate these therapies rely on a method known as adaptive trial design. UKRI-funded research has played a crucial role in implementing this innovative way of working into the UK clinical trials landscape.

Three large-scale national clinical trials

Central to this effort are three large-scale national clinical trials, each of which addresses a different part of the patient journey. These are:

There is also AGILE (AGILE trial website), which is for early-stage trials of novel drugs.

These are all so-called platform trials that allow patients to be efficiently recruited and randomised to receive one of a range of different treatments. There is the flexibility to swap therapies in or out as required.

Decisions therefore have to be made on an ongoing basis about which treatments to include in each of these trials. This task now falls to the UK COVID-19 Therapeutics Advisory Panel (UK-CTAP), managed by UKRI.

Anyone can suggest a potential treatment, old or new, for inclusion in any of the national platform trials.

Suggest a treatment for trial on the UK-CTAP web portal.

Evaluating all the proposed treatments

Patrick Chinnery, Chair of UK-CTAP and Medical Research Council Clinical Director, explains how the panel reaches its conclusions on which treatments to prioritise:

Although there are similarities with other respiratory illnesses like flu and pneumonia, COVID-19 is a bit different. As well as damaging the lungs, the disease can also have an overwhelming effect on the immune system and cause blood clots, so we’re looking at drugs covering a range of disease mechanisms and modes of action.

For each potential treatment we’ll examine whether there is a plausible mechanism of action against COVID-19 or its complications, any evidence that it might work in COVID-19 patients, and whether it’s being tested anywhere else in the world.

We’ll also consider whether it’s a medicine that could actually be used in the NHS if it works – is it available, affordable and able to be manufactured at scale?

UK-CTAP evaluates all the proposed treatments that are put forward, and only recommends those where there is a strong case based on objective scientific evidence. As might be expected, this means that there are many ideas that don’t pass the test.

Some people are convinced they have a COVID cure

Charlotte Summers, a lecturer in intensive care medicine at the University of Cambridge and a member of UK-CTAP said:

We get plenty of letters and emails from people who are convinced they have a COVID cure and some really quite strange stuff has ended up on my desk.

There was a man who offered to come from Belgium to show us his modern version of a divining rod – it was a contraption he wore on his body, and if you presented him with a range of therapies, he would be drawn towards the one that was most likely to work.

Putting COVID-19 treatments to the test

The NIHR Clinical Research Network has been central to delivering all of the trials across the NHS.

The rapid evaluation and approval of new drugs has enabled tens of thousands of patients to be recruited at an incredible pace. This has been done by the Medicines and Healthcare products Regulatory Agency (which looks at safety) and the Health Research Authority (which looks at the ethical aspects).

In turn, this speed and scale is leading to much-needed answers about which treatments do – and, importantly, don’t – help people with COVID-19.

The RECOVERY trial

In a matter of months after launching in April 2020, the RECOVERY trial had shown that the cheap, widely available steroid dexamethasone, could cut the risk of dying by a third in hospitalised patients who already require oxygen.

The dexamethasone steroid helps to calm down the severe immune response to the virus. This finding has saved an estimated 12,000 lives in the UK already and hundreds of thousands worldwide.

Conversely, the trial found that the antiviral combination lopinavir-ritonavir and the much-touted antimalarial drug hydroxychloroquine were both ineffective. By December 2020, the antibiotic azithromycin had joined the list of ineffective drugs.

RECOVERY also recently closed the trial arm testing blood plasma from patients who have recovered from COVID-19 (convalescent plasma), after preliminary results showed that there was no benefit from the treatment.

However, further analysis is ongoing to see if there are particular patient groups that might benefit from this therapy.

The REMAP-CAP and PRINCIPLE trials

Important results are also coming through from the other platform trials.

For example, there was recently a preliminary finding from REMAP-CAP that the arthritis medication tocilizumab and another drug called sarilumab can improve survival for COVID-19 patients and some patients in the ICU.

Both drugs modify the immune response by targeting the interleukin six receptor.

The PRINCIPLE trial has shown that the antibiotics azithromycin and doxycycline aren’t effective for people being treated at home.

Taken together, these results have had a game-changing impact on the way that COVID-19 patients are treated all over the world.

Getting a clear enough answer to change practices

Peter Horby said:

When we reviewed the treatment guidelines for COVID back in March 2020, a lot of countries were recommending hydroxychloroquine and lopinavir-ritonavir and advising against dexamethasone.

We ended up completely turning around all those treatment guidelines because we showed that the two things that were previously recommended didn’t work, and the one thing they said you shouldn’t use was clearly effective.

It highlights that the purpose of all these trials is to get a clear enough answer to change practices – obviously I’d like all results to be positive, but getting a negative result is just as important.

New treatments for a new disease

Given the need to get clinical trials up and running as fast as possible, RECOVERY, REMAP-CAP and PRINCIPLE are testing existing therapies that have been repurposed for COVID-19.

But there is still a need for entirely novel antiviral therapies, according to Saye Khoo, leader of the AGILE trial platform, which is taking brand new drugs into small-scale first-in-human trials.

Saye Khoo, Professor of Pharmacology at the University of Liverpool and leader of the AGILE trial platform said:

This is a new virus, so we need new treatments, particularly in the antiviral space.

When the pandemic hit us it was absolutely the right thing to test repurposed drugs first, but including these in large-scale trials without the level of evidence usually required meant that many of these treatments were likely to fail in clinical trials.

To see the kind of antiviral effect against coronavirus that we have for viruses like HIV or hepatitis C, we’re going to need new drugs that specifically target the SARS-CoV-2 virus.

Although AGILE is smaller than the other three national platform trials, it works in the same way, with new therapies being added according to recommendations from UK-CTAP.

Currently there is one new drug progressing through trials in Liverpool, with two more waiting to start and another in development. The trial will be expanding to five further centres in the UK thanks to funding from UKRI.

A pipeline of research

The UK’s suite of platform trials for COVID-19 treatments, underpinned by investment from UKRI and NIHR, has highlighted the benefits of a joined-up approach to clinical research that can extend far beyond the pandemic.

Saye Khoo said:

There’s nothing like it anywhere else – it’s a fantastic model for how drugs should be assessed in a pandemic and is unrivalled in the world.

UKRI’s support has been essential, not just for funding but by providing a way of prioritising drugs and linking together all the platforms so that promising treatments in AGILE can go forward into bigger trials, as well as unlocking administrative jams and building trust across the research community and industry.

Patrick Chinnery said:

I think the challenges of COVID-19 have shaken up the system in a very positive way and really highlighted some myths about how we do clinical research.

It’s shown us the speed at which we can move from having an initial concept through to launching a trial, which would typically take 18 months and we’ve managed to do in weeks.

Millions of people worldwide are affected by this disease right now and more will get it in the future, and they still need treatments. Everyone tends to focus on vaccines, but what gets lost is the fact that the UK has really excelled itself in testing treatments for COVID-19, and that should also be something to celebrate.

Last updated: 15 February 2021

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