The anniversary also serves as a reminder that while vaccines have been developed and deployed to help prevent infection, there remains a need for new antiviral treatments to treat those who have already been infected.
The development of effective antiviral treatments for COVID-19 is crucial in reducing the burden of the disease on individuals and communities. Antiviral treatments target the virus at an early stage and can help to reduce the severity of symptoms, shorten the duration of illness, and decrease the spread of the virus.
Two trials led by Oxford University’s Primary Care Clinical Trials Unit have had significant implications for the COVID-19 pandemic response. Both PRINCIPLE and PANORAMIC trials aim to find treatments for COVID-19 for people at most risk of serious illness. The PRINCIPLE Trial focuses on testing repurposed drugs for COVID-19 in the community, whereas PANORAMIC tests novel, specific antiviral drugs.
Launched in March 2020, the Platform Randomised trial of Interventions against COVID-19 in older peoPLE (PRINCIPLE) trial tests pre-existing drugs for COVID-19 to reduce recovery time and prevent hospital admissions and deaths. PRINCIPLE was one of the first trials of COVID-19 treatments to take place in primary care, and recruited participants who are most at risk of serious COVID-19 illness, either due to their age, symptoms, or an underlying health condition.
All drugs tested in PRINCIPLE were commonly used to treat other illnesses. PRINCIPLE sought to understand whether they could also help people with COVID-19 in the community. It has tested five potential treatments so far, with a further two—favipiravir and ivermectin—still being studied in the trial.
PRINCIPLE found that two antibiotics (doxycycline and azithromycin) are not effective treatments for people with COVID-19. It also found that the anti-inflammatory drug colchicine did not help people get better any quicker. These drugs should not be used to treat people in the community who have COVID-19 as their usage exposes patients to unnecessary risks of side effects and contributes to the growing problem of antibiotic resistance. This finding was disseminated throughout the NHS in a Clinical Therapeutic Alert and has impacted clinical guidelines worldwide.
“Preventing ineffective antibiotic use is critical since there is a parallel pandemic—that of drug resistance,” said Professors Christopher Butler and Richard Hobbs, PRINCIPLE Co-Chief Investigators, Nuffield Department of Primary Care Health Services, University of Oxford.
In April 2021, PRINCIPLE showed that the commonly used asthma drug, inhaled budesonide, a steroid, was effective in reducing recovery time by around three days and that there was a high probability that it also reduced hospital admission.
Both PRINCIPLE and PANORAMIC are ‘platform trials’, which differ from conventional clinical trials that focus on evaluating a single treatment. The unique design of a platform trial enables the simultaneous assessment of multiple treatments.
PRINCIPLE is supported by a vast network of health and care professionals in care homes, pharmacies, NHS 111 Hubs, hospitals, and more than 1400 GP practices across England, Wales, Scotland, and Northern Ireland.
Launched in December 2021, the Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community trial (PANORAMIC) has already enlisted over 27,000 participants from across the nation in the quest to discover groundbreaking treatments that accelerate recovery from COVID-19 for patients at home and in the community, bypassing the need for hospitalisation.
PANORAMIC is investigating a range of potentially ground-breaking oral antiviral drugs, which can be taken at home by people in at-risk groups (aged 50 or over, or 18-49 with a pre-existing condition), in the early stages of COVID-19 infection.
In December 2022, PANORAMIC reported that molnupiravir, the first antiviral to be tested, did not reduce hospitalisations or deaths among higher risk, vaccinated adults with COVID-19 in the community. The treatment was, however, associated with a faster recovery time and reduced viral detection and load – participants who received molnupiravir reported feeling better compared to those who received usual care, and once well, more often stayed well.
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A new oral COVID-19 antiviral treatment—paxlovid—is now being trialled in the PANORAMIC trial.
Professor Paul Little, from the University of Southampton and Co-Chief Investigator, said:
“The PANORAMIC trial is one of the most ambitious ever undertaken in the community worldwide. The inclusion of Paxlovid in the trial is an exciting addition that will provide vital information about treatments to help the most vulnerable people in the ongoing fight against COVID-19.”
Professor Nick Lemoine CBE, National Institute for Health and Care Research (NIHR) said:
“While smaller-scale studies have already shown this new antiviral treatment to be highly effective against COVID-19 in the early stages of infection, additional evidence from much larger cohorts is needed to enable clinicians and health services to make best use of these exciting new treatments.”
The trial's second phase will involve approximately 17,000 participants in the UK. To compare the treatment's benefits to standard care, half of the participants will receive the antiviral treatment plus standard care, while the other half will receive standard care alone.
The study is open to adults over the age of 50 or those aged 18 to 49 with an underlying health condition that can increase the risk of developing severe COVID-19, who have received a positive test result, and who are experiencing symptoms that started in the previous five days.
Over 1,320 have already stepped forward to help us with this new branch of PANORAMIC. We need your help. If you have symptoms of COVID-19 and a positive PCR or LFT, please visit www.panoramictrial.org.
Participants may register for PANORAMIC via the central website or participating GP practices. If you are registered with one of our listed participating sites, you may be eligible to obtain a free Lateral Flow Test from your GP practice.
You can participate in your own home from anywhere in the UK. No face-to-face visits are required. The follow-up will be by answering questions each day online and/or telephone calls with the study team, who will be there to support you throughout the study.
Reflections on PRINCIPLE and PANORAMIC
Fewer than 1 in 5 therapeutic clinical trials in COVID-19 have been carried out in the community. Yet research can have its greatest impact outside of hospitals. “It is critically important that new treatments are tested on people and in the situation where they are intended to be used,” says Professor Chris Butler, Co-Lead of both the PANORAMIC and PRINCIPLE trials.
In both PRINCIPLE and PANORAMIC, researchers couriered medicines to participants, many of whom were too sick to collect their trial medications from a centre. This meant that people were able to join the trial regardless of where they live in the UK, making the findings highly generalisable. Indeed, PRINCIPLE was awarded the 2022 ‘Trial of the Year’ by the Thames Valley and South Midlands Clinical Research Network for its innovative use of primary care data and settings whilst working at pace and scale.
Moreover, both PRINCIPLE and PANORAMIC have focused on developing and maintaining grassroots partnerships with diverse community groups and places of worship across the UK.
“We know that Covid-19 minority ethnic groups in the UK more often get severely unwell when they become ill with Covid-19,” said Professor Butler. “It is so important that research involves those that stand to benefit the most from possible new treatments. PRINCIPLE and PANORAMIC are truly democratic, UK-wide clinical trials that strive to be as inclusive as possible. The findings of the studies will be so much more useful if we can include people in the trial who are representative of the UK's population as a whole.”
Professor Mahendra Patel OBE, the Pharmacy, and Inclusion and Diversity lead for both PRINCIPLE and PANORAMIC commented:
“We are determined to ensure that we are as inclusive as possible in our recruitment. To this effect, we have been working closely with national and local communities and religious organisations as well as community pharmacies UK-wide to help make the PRINCIPLE and PANORAMIC trials more visible and easily accessible to as many people as possible including from ethnically diverse communities.”
“I’m delighted to see how our recruitment strategy has been hugely successful across ethnicities and areas of high deprivation. This is an incredible testament to all those involved for their efforts in supporting the fastest and largest recruiting randomised interventional clinical trial in the world.”
Recruitment to PRINCIPLE is now closed. PRINCIPLE is funded by a grant to the University of Oxford from UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR).
PANORAMIC will investigate further antiviral drugs as they become available. For more information or to enrol, please visit www.panoramictrial.org. PANORAMIC is funded by the National Institute for Health and Care Research (NIHR), while delivery of the trial is supported by the NIHR Clinical Research Network.