Paxlovid (nirmatrelvir-ritonavir) does not reduce hospital admissions or deaths in vaccinated adults at higher risk of severe COVID-19, despite helping them recover faster, according to results from two national trials published today in the New England Journal of Medicine. With COVID-19 still causing significant illness and death, clinicians urgently need to know which patients benefit most from early antiviral treatment.
The findings, from 4,232 participants across the two trials, help clarify who should receive Paxlovid now that widespread vaccination has dramatically reduced the risk of severe outcomes.
The UK PANORAMIC trial, funded by the National Institute for Health and Care Research (NIHR) and led from the University of Oxford, enrolled 3,516 participants with COVID-19 across its Paxlovid arm (April 2022–March 2024). The Canadian CanTreatCOVID trial, led by Dr Andrew Pinto, director of Upstream Lab (Unity Health Toronto), enrolled 716 participants (January 2023–September 2024).
Both trials recruited adults aged 50 or over, or younger adults with additional conditions such as diabetes or asthma. Over 98% of all participants were vaccinated.
Paxlovid was approved in 2021 based on trials showing an 88% reduction in hospitalisation or death among unvaccinated high-risk adults. The two new trials tested the drug in mostly vaccinated higher-risk patients – a population very different from the one in which Paxlovid was originally studied. In May 2025, the National Institute for Health and Care Excellence (NICE) restricted routine NHS use to a narrower 'highest-risk' cohort (e.g. transplant recipients, severe liver disease), citing cost-effectiveness concerns.
"In today's highly vaccinated populations, the benefits of Paxlovid have fundamentally changed," said Professor Christopher Butler, Nuffield Department of Primary Care Health Sciences, University of Oxford, who led the UK trial. "While people feel better sooner from treatment with this important antiviral drug, we found no reduction in the already low rate of hospitalisations or deaths. This provides essential evidence for optimal, cost-effective targeting of this treatment."
The UK PANORAMIC trial was designed, coordinated and led by the University of Oxford's Primary Care Clinical Trials Unit, working with the NIHR Research Delivery Network across England and by Health and Care Research Wales, NHS Research Scotland, the Health and Social Care Board in Northern Ireland.
Across multiple treatments, the trial recruited over 29,000 participants. To complement recruitment through general practices, the Primary Care Clinical Trials Unit pioneered remote participation methods – online consent, medication dispatched through its in-house dispensing facility, and self-collected samples – removing many traditional barriers to taking part and thus ‘democratising trials research.’
Participants taking Paxlovid recovered substantially sooner. In PANORAMIC, median recovery time was 14 days with Paxlovid compared to 21 days with usual care. CanTreatCOVID found recovery at 6 days versus 9 days, respectively, but measures recovery in a slightly different way. Paxlovid also significantly reduced viral load by day 5, which may have implications for reduced opportunity for spread.
The safety profile matched what is already known about Paxlovid. In PANORAMIC, 90.4% reported at least one side effect – predominantly altered taste (dysgeusia) and gastrointestinal symptoms typical for this drug – with around 8% discontinuing treatment because of side effects. Serious adverse events remained rare in both groups.
"These trials demonstrate precisely what evidence-based policy and medical care should look like – rigorously testing treatments as conditions change," said Professor Jonathan Van-Tam, former UK Deputy Chief Medical Officer and Co-investigator, University of Nottingham. "The UK led the world in COVID treatment trials because we have unified health systems, strong academic trial units, and standing research infrastructure through the NIHR – capabilities that are critical for future pandemic preparedness."
Very few participants in either trial were hospitalised within 28 days. In PANORAMIC, rates were 0.8% with Paxlovid versus 0.7% with usual care. In CanTreatCOVID, rates were 0.6% versus 1.2%. Neither study found a statistically significant difference. There were no deaths in either trial during the Paxlovid recruitment period.
This joint publication demonstrates how independent trials using similar protocols can deliver more robust findings than multiple smaller studies.
Oxford's Primary Care Clinical Trials Unit and Toronto’s Upstream Lab are now applying these methods to trials of other respiratory infections through the ECRAID-Prime and TreatResp trials – carrying forward the research infrastructure developed during the pandemic to benefit broader public health and prepare for future outbreaks.
"These results demonstrate the value of rapid, large-scale evidence generation through NHS partnerships," said Professor Phil Evans, National Associate Director of Health and Care in the NIHR Research Delivery Network. "The UK's research infrastructure, built through the NIHR, and academic clinical trials units allowed us to generate this evidence quickly."
These findings apply specifically to higher-risk vaccinated adults (aged 50 or over, or aged 18 or over with comorbidities such as diabetes or chronic lung disease). They do not change recommendations for the highest-risk immunocompromised patients, for whom Paxlovid remains first-line treatment under current NICE guidance (TA878). Treatment should be started as soon as possible after symptom onset.
"Treatment decisions must evolve as the pandemic landscape changes," said Professor Butler. "The research infrastructure and methods developed through these trials provide a model for rapidly evaluating treatments during winter epidemics and future health emergencies."
ENDS
Notes to editors
Full citation: Butler CC, Pinto AD, Harris V, et al. Oral nirmatrelvir-ritonavir for COVID-19 in higher risk outpatients. N Engl J Med 2025
Contact:
For interview request please contect communications@phc.ox.ac.uk
About the trials:
Funding:
Current NICE guidance: The full NICE technology appraisal guidance (TA878) defining the highest-risk cohort eligible for Paxlovid is available at: https://www.nice.org.uk/guidance/ta878
Study design: Both were open-label, adaptive platform trials in community settings. Participants were eligible if they had a positive SARS-CoV-2 test, had been unwell for five days or less, and were randomised to receive either usual care plus Paxlovid (300mg nirmatrelvir/100mg ritonavir twice daily for 5 days) or usual care alone.
About the University of Oxford
Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the eighth year running, and number 3 in the QS World Rankings 2025. At the heart of this success are the twin pillars of our ground-breaking research and innovation and our distinctive educational offer.
Oxford is world-famous for research and teaching excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research alongside our personalised approach to teaching sparks imaginative and inventive insights and solutions.
Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine and life sciences, and it is home to the UK's top-ranked medical school. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.
Within the division, the Nuffield Department of Primary Care Health Sciences is the largest centre for academic primary care in the UK, and leads world-class research and training to rethink the way healthcare is delivered in general practice and other primary care settings. The department's main research focus is on the prevention, early diagnosis and management of common illness, bringing together academics from many different backgrounds to work together to produce benefits for the NHS, for populations and for patients. www.phc.ox.ac.uk
About Upstream Lab
The Upstream Lab , based at St. Michael’s Hospital in Toronto, Canada, is a research group focused on strengthening health systems through trials, AI, and approaches that address the social factors shaping health. Its work is guided by a commitment to generating knowledge that is focused on community priorities and ensuring that evidence is translated into meaningful improvements in real-world care.
The Upstream Lab supports a multidisciplinary team of clinicians, scientists, data experts, research staff, community partners, and individuals with lived experience. Research is conducted across a broad range of areas, including primary care, pandemic preparedness, community-based clinical trials, data-enabled tools, early warning systems, and interventions that advance more equitable health and social systems. This work emphasizes prevention, early support, and practical strategies that improve care in everyday clinical and community settings.
The Upstream Lab maintains strong collaborations with numerous primary care practice-based research networks, public health agencies, and community partners across the country and internationally. The Upstream Lab is based at St. Michael’s Hospital, an acute care hospital and research hub fully affiliated with the University of Toronto. St. Michael’s is part of Unity Health Toronto , a health care network spanning Toronto’s core and a national model for collaborative, integrated, high quality care aiming to build a stronger, resilient and equitable health system for all.
About the NIHR
The mission of the National Institute for Health and Care Research (NIHR) is to improve the health and wealth of the nation through research. We do this by: funding high quality, timely research that benefits the NHS, public health and social care; investing in world-class expertise, facilities and a skilled delivery workforce to translate discoveries into improved treatments and services; partnering with patients, service users, carers and communities, improving the relevance, quality and impact of our research; attracting, training and supporting the best researchers to tackle complex health and social care challenges; collaborating with other public funders, charities and industry to help shape a cohesive and globally competitive research system; funding applied global health research and training to meet the needs of the poorest people in low and middle income countries. NIHR is funded by the Department of Health and Social Care. Its work in low and middle income countries is principally funded through UK international development funding from the UK government.
New England Journal of Medicine
Randomized controlled/clinical trial
People
Oral nirmatrelvir-ritonavir for COVID-19 in higher risk outpatients
22-Apr-2026