Results from the PANORAMIC trial looking at the use of molnupiravir as early COVID-19 treatment for adults at increased risk of adverse outcomes have been published in the Lancet.
This Roundup accompanied an SMC Briefing.
Dr Janet Scott, Clinical Lecturer in Infectious Diseases, University of Glasgow, said:
“The PANORAMIC study has today published results in The Lancet of using molnupiravir plus usual care versus usual care alone for adults with increased risk of adverse outcomes.
“This is a large, well conducted study carried out across the UK, in the community. They recruited anyone over the age of 50, and people between 18-50 with relevant comorbidities which put them at a high risk of being hospitalised or dying should they get COVID-19. The UK population is very well vaccinated and 92-93% of volunteers had had 3 vaccine doses. Volunteers were sent the drug to be taken at home and then phoned to follow up on their symptoms.
“The conclusion of the paper says that “molnupiravir did not reduce the frequency of COVID-19 associated hospitalisations or death in high risk vaccinated adults in the community, but does result in a faster time to recovery and reduced contact with general practitioners”. The authors suggest in the light of their data that in our highly vaccinated population, reducing hospitalisation and death is primarily achieved via extensive vaccination.
“Rates of hospitalisation amongst vaccinated people is now low – most people who are at risk of severe acute COVID-19 and death are in the highest (rather than just high) risk category. For example, people with impaired immune systems. Many such people were not able to take part in this study since they were already prescribed specific antiviral treatment from the NHS, so the study was unable to comment on how useful the drug is for them.
“The vaccines are now doing their job and reducing the severity of infection in the high-risk groups – so the benefit of Molnupiravir is now more about time to recovery than reducing hospitalisation. This study provides robust data to guide clinical decisions in exactly what you are and are not likely to gain from taking Molnupiravir.
“Are the benefits worth the £577 it costs for the 5 day course? The answer to that may be in whether it reduces the number of people who go on to suffer from long COVID. Those results are still being analysed. An estimated 2 million people in the UK (3% of the population) currently have long COVID1, three times the prevalence of rheumatoid arthritis2.
“In my view there are currently two major challenges in COVID-19 treatment: the prevention and treatment of long COVID (analysis underway) and the prevention and treatment of acute COVID-19 in the highest risk groups including the immunosuppressed. This immunosuppressed group is likely going to require a bespoke study focusing on this issue.
“Current reports of a substantial new COVID-19 wave, coming out of China remind us that this virus continues to have the power to harm at a societal level, and remind us how very fortunate we are in the UK to have access to vaccines, therapeutics, and an integrated health care service to deliver them.”
1) ONS. (2022). Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 4 August 2022. R
2) NICE. (2021). Rheumatoid arthritis: How common is it?
Dr Sanjay Bhagani, Consultant Physician and Honorary Associate Professor in the Department of Infectious Diseases/HIV Medicine, Royal Free Hospital, said:
“Today we see the publication of one of the world’s largest community COVID-19 treatment trials.
“PANORAMIC is an exemplar of the strength of UK research in the COVID era; it demonstrates the ability to test interventions in a randomised-controlled trial representative of a ‘real-world’ setting; enrolling many thousands of patients in the community setting without the need for time-consuming, expensive research visits, and involving a diverse group of participants representative of the UK population.
“The results from the molnupiravir arm of the PANORAMIC trial teaches us many lessons; not least that as COVID evolves, in terms of variants and sub-variants (omicron this time round), and population immunity changes as a result of vaccinations and exposure, effectiveness (and ultimately cost-effectiveness) of antiviral therapies will change. Unlike the molnupiravir registration trial, MOVE-OUT, which enrolled unvaccinated ‘high-risk’ in the delta variant era, in this trial in the omicron-era, molnupiravir had no impact on prevention of hospitalisation or death in a highly vaccinated ‘high-risk’ population. It did, however, alleviate symptoms a few days faster, reduced viral shedding quicker, and reduced GP contacts. Whether it reduces progression to long COVID remains to be determined.
“We do need to note, however, that the trial excluded the ‘highest-risk’ population (i.e. immunocompromised patients) who had open access to therapies including monoclonal antibodies, and antiviral agents including ritonavir-boosted nirmatrelvir, remdesivir and molnupiravir. For this group, early interventions remain important.
“We look forward to further results from the PANORAMIC trial to help inform the utility of other antiviral therapies to prevent hospitalisation/death from COVID in the UK setting.”
Dr Kovilen Sawmynaden, Senior Principal Scientist at LifeArc, said:
“This PANORAMIC paper provides an update on the use of Molnupiravir in a now extensively vaccinated UK-based population. The baseline vaccine status in both the treatment and control groups are similar (notably > 90 % with at least 3 vaccines) and therefore provides a sound basis upon which to interpret the primary outcomes. It appears that that are no significant benefits in taking this antiviral, to prevent hospital-based care and/or people dying. Thus, it appears the vaccine prior is doing the ‘heavy-lifting’, in this respect. However, benefits in symptomatic improvement (correlating with reduced viral loads and shorter disease course) are noted as secondary outcomes and maybe be welcome in ‘outbreak-mode’ (either seasonal or local, such as clinics or care-homes).
“Overall, this study enables a more informed basis for patient stratification. This should improve the effectiveness of how and when Molnupiravir is prescribed. This study further reinforces the importance of population-based vaccination programmes. The extremely vulnerable groups (such as the immunocompromised) are correctly less represented in this study, due to a greater level of standard care required. However, vaccines remain poorly efficacious for them, and so the continued development of therapeutic antivirals (as well as prophylactic monoclonal antibodies) is critical to ensure we support the ongoing unmet medical need of this group.”
Prof Sir Martin Landray, Professor of Medicine & Epidemiology, Oxford Population Health, University of Oxford, said:
“These results come from a very large randomised controlled trial involving over 25,000 people with COVID-19 in the community (i.e. not in hospital).
“The study methods are interesting and important – participants were recruited from over via 65 Study Hubs based in General Practice as well as by online and telephone call with the central study team. Active treatment was issued to participants by mail. The principal means of follow-up was by online questionnaires. This is a good example of taking the trial to the patient rather than expecting the patient to come to the trial. Rates of adherence to the study treatment were excellent (over 95% patients allocated to receive molnupiravir completed the 5 day course). And data for the primary outcome were available in over 97% of participants.
“The challenge though is that these people were at very low risk of developing a serious acute complication of COVID-19 (i.e. the primary endpoint of hospital admission for any reason or death within 28 days of randomisation). The participants were relatively young (mean age 57 years) although about two-thirds had some form of background health condition (co-morbidity). Critically, the study was carried out in the UK over the winter of 2021/22 when the predominant circulating variant was omicron and following an extensive vaccination campaign – over 94% of participants had had 3 vaccine doses. Consequently the incidence of the primary outcome of death or hospitalisation was just 0.8% (8 per 10,000) overall.
“The ability of a trial to detect a treatment effect (if one exists) is dependent not on the number of people who go into the trial (over 25,000 in this case) but on the number of people in whom a primary outcome (death or hospitalisation) occurs (108 people in the molnupiravir arm and 98 in the usual care arm).
“The investigators also report that the time to resolution of symptoms and other markers of clinical improvement is better in those randomised to monupiravir. But beware – this is an open-label study – the participants in the active arm knew they were getting an anti-viral drug and the participants in the usual care arm knew for sure that they weren’t. Whilst this knowledge wouldn’t influence the hospital admission or death we have no way of knowing if or to what extent it might bias the findings on self-reported symptomatic outcomes.
“There is data on the effect of molnupiravir in a tiny subset of participants in this trial. This shows that molnupiravir reduces viral load (but that’s not a new finding – it is what we would expect it to do).
“What can we conclude from this:
– first, this study shows that in the context of widespread vaccination the risk of requiring hospital admission or dying is very low.
– secondly, the study doesn’t give us much in the way of new information about the actual impact of molnupiravir (the results are consistent with anything from a modest benefit to a modest harm).
– thirdly, rolling out a strategy of test and treat with molnupiravir for people in the general population would be a huge logistical and financial undertaking with no evidence of gain. (There are different issues, and possibly better treatment options, for patients with severe immunocompromise).
“Finally, it is great to see another really good example of the critical role that randomisation plays in clinical decision-making and in developing and implementing an effective, evidence-based public health response to a major health threat. It would have been so easy to just roll out molnupiravir as part of routine care, let doctors prescribe it as they saw fit, and learn nothing about whether we had done good, done harm, or simply wasted vast resources.”
‘Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial’ by Christopher C Butler et al. was published in the Lancet at 23:30 UK time on Thursday 22 December 2022.
Dr Janet Scott: “I am a co-investigator on a clinical trial of Favipiravir (a similar drug), and also a CoI on the ISARIC Global, PHOSP and CISS consortia which are researching long COVID.”
Dr Sanjay Bhagani: “I have been an investigator in the MSD sponsored MOVE-OUT trial of molnupiravir and have received research-funding and honoraria from MSD for Advisory Board participation.”
Dr Kovilen Sawmynaden: “Dr Kovilen Sawmynaden is Senior Principal Scientist at LifeArc. He was previously part of the Bioindustry Association (BIA) COVID-19 Antibody Taskforce and part of the founding team (on behalf of LifeArc) of RQ Biotechnology.”
Prof Sir Martin Landray: “In addition to the list of interests (below), please note that I am an employee of the University of Oxford (the sponsor of the PANORAMIC trial) and know many of the investigators as colleagues. However, I was not involved in the design, implementation, analysis or any other aspect of the trial.
Professor of Medicine & Epidemiology, Oxford Population Health (www.ndph.ox.ac.uk).
Chief Executive, Protas (www.protas.co.uk).
Co-lead RECOVERY trial (www.recoverytrial.net).
Grant funding to University of Oxford from MRC, NIHR, Wellcome, Novartis, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme.
Study drug for RECOVERY trial provided by Roche, Regeneron, AbbVie, GSK/Vir, Boehringer Ingelheim.
Grant funding to Protas (not-for-profit company) from NHS England, Schmidt Futures, Google Ventures, Flu Lab, Sanofi, Regeneron, Wellcome, Bill & Melinda Gates Foundation.
He has no financial interest/investment in, and does not accept, honoraria payments directly or indirectly from, the pharmaceutical, food, tobacco, or alcohol industries.”