Molnupiravir (Lagevrio, Merck Sharpe & Dohme) does not reduce frequency of hospital admissions or deaths in vaccinated, high-risk patients with COVID-19 in the community, according to latest results from the ongoing, UK-based, Platform Adaptive trial of NOvel antiviRals for eArly treatMent of COVID-19 In the Community (PANORAMIC).
Hospitalisations and deaths were recorded in a similar proportion of participants (1%) in both arms of the study that compared molnupiravir with standard NHS care.
However, molnupiravir did help patients recover faster, by approximately 4 days, and showed early sustained recovery compared with those on standard care, with fewer general practitioner consultations.
Patients on molnupiravir also showed a lower level of detectable virus and viral load 7 days after starting the drug.
The study, published online in today's edition of The Lancet, included people who had been vaccinated against COVID-19, largely reflecting the current situation in the UK where between 58% and 73% of people in age brackets upwards of 60 years are estimated to have received their autumn booster.
Of note, PANORAMIC is one of only around 20% of COVID-19 studies that are set in the community. Co-chief Investigator, Dr Chris Butler, professor of primary care in the Nuffield Department of Primary Care Health Sciences, University of Oxford, explained: "It is in the community where treatments could have their widest reach and impact." Although molnupiravir did not reduce hospital admissions and deaths, it "may have other benefits when being used to treat COVID-19, such as a faster recovery time and reduced follow up with health services".
He said: "This could help to ease the burden on UK health services through the treatment of selected patients at home, during times of high disease burden and pressure on key services."
In a comment published to accompany the research paper, Dr Michael Kidd, deputy chief medical officer at the Australian Government Department of Health and Aged Care, Canberra, who was independent of the study, noted that study participants "were already at low frequency of hospitalisation and death" but that patients were "not necessarily the highest risk, extremely vulnerable patients".
However, he added that, "the shortened and sustained symptom reduction, together with the effects on viral clearance, could be an important consideration in high-risk settings, such as care homes, in terms of potentially minimising the spread of infection among high-risk people. Molnupiravir might also provide benefits to health-care systems, especially during community surges, by potentially allowing health workers to return safely to work sooner."
Large, Community-Based, UK Study Population
Data in the primary analysis were drawn from 25,054 community-based participants who were either aged over 50 years and not in an at-risk group, or aged 18 and over with underlying health conditions. Over 120,000 patients were screened to participate in the study, sourced from 4509 GP practices across the UK.
Mean age of participants was 56.6 years, with 58.6% female, around 6% from minority ethnic groups, and around 10% from the UK's most deprived areas. Nearly all (98.9%) participants had received at least one dose of the SARS-CoV-2 vaccine, while 92.6% had received three doses.
Participants were randomised 1:1 to either molnupiravir (n=12,821; 800 mg dose twice daily for five days plus usual care), or standard NHS care (n=12,962), and treatment was initiated within 5 days of symptoms onset. Over 90% completed the full course.
The primary endpoint was whether molnupiravir reduced the risk of hospitalisation or death, while the secondary endpoints included recovery time and symptoms. Results were self-reported online during a 28-day follow-up and gathered between December 2021 and April 2022, during a time of Omicron variant dominance in the UK.
This was not a regulatory efficacy trial, emphasised Prof Butler. "We aimed to rapidly provide a policy-relevant answer as to whether prescribing the drug did more good than harm, compared with not prescribing the drug."
No Effect on Hospitalisations and Deaths, but Shorter Time to Recovery
No difference was found in hospitalisations or deaths, with 105 (1%) of 12,529 participants in the molnupiravir group compared with 98 (1%) of 12,525 in the standard care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]) either being hospitalised or dying.
"There was absolutely no difference, statistically speaking, and we ruled out a 20% difference in hospital admission or death, while the probability of molnupiravir being superior was very low," Prof Butler said. He added: "Vaccination is a powerful tool, which is why the trial included so many people so that we could feel confident that the study would show a difference [if it exists]."
A sub-group analysis also showed no differences in effect between patients on molnupiravir and those on standard care, he added.
Length of illness was shorter in those patients treated with molnupiravir compared with those on standard care (9 days versus 15 days respectively), while molnupiravir was calculated to be associated with reduced time to recovery overall (estimated at 4.2 days shorter than the control group) and for key individual symptoms.
"People who reported feeling better, stayed better more often [on the drug]," attesting to some sustained effect of improvement.
Fewer patients on the drug sought primary care services (20% of molnupiravir patients compared with 24% of the control group). A sub-group of patients on molnupiravir showed reduced viral load on day 7 after randomisation.
Serious adverse events were found in 0·4% of patients on molnupiravir compared with 0·3% of those on standard care, but none were considered related to molnupiravir. "There was a slight increase in gastrointestinal problems which fits with what we know about the drug," added Prof Butler.
PANORAMIC – Generating Evidence by Bringing Research to the People
The ongoing PANORAMIC trial is a platform adaptive trial, meaning that it is testing multiple drugs in parallel, and aims to identify which groups of higher risk people were most likely to benefit from new antiviral treatments for COVID-19.
Prof Butler highlighted the importance of basing pandemic treatments on evidence from RCTs. He drew a distinction with treatments used in the swine flu pandemic of 2009, where treatments were not informed by RCTs, and COVID-19. "This trial [PANORAMIC] represents a sea change in preparedness for evaluating treatments for epidemic and pandemic infections, because here we've managed to generate evidence from within a pandemic to use in that pandemic."
He also explained how PANORAMIC reversed the so-called inverse care (research) law whereby research often struggled to include the participants who have most to gain from the outcomes. "There are over 8000 general practices in the UK and often people are excluded from research because of where they live," he highlighted. "In the PANORAMIC trial, we have widened the research base considerably, because we took the research to the patient, and in some cases, they could participate without having to leave home, and this is important when people are too sick to travel to a trial site."
Sir Martin Landray, professor of medicine and epidemiology, Oxford Population Health, University of Oxford, and co-lead on the RECOVERY COVID-19 study, commentedthat the study design across 65 study hubs based in general practice was, "interesting and important".
"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 five-day course). And data for the primary outcome were available in over 97% of participants."
Prof Sir Jonathan Van-Tam, pro-vice-chancellor for the Faculty of Medicine and Health Sciences at the University of Nottingham and study co-author, remarked on the difference between molnupiravir in unvaccinated and vaccinated patients. "While molnupiravir was originally found to work well to reduce hospitalisation in patients with COVID, these were unvaccinated patients." This study treated a highly vaccinated population, "demonstrating that the vaccine protection is so strong that there is no obvious benefit from the drug in terms of further reducing hospitalisation and deaths".
However, Prof Van-Tam added that the symptom duration and virus shedding were both markedly reduced on molnupiravir, and that future results would shed light on any effects on long COVID.
PANORAMIC will conduct a cost effectiveness analysis in the near future.
The trial was published in today's edition of The Lancet.
COI: Dr Butler has declared no financial conflicts. JSN-V-T was seconded to the Department of Health and Social Care, England from October, 2017, to March, 2022, and reports lecture fees from Gilead and fees for participation on an advisory board forF Hoffmann-La Roche. KH is a member of the Health Technology Assessment General Committee and Funding Strategy Group, and Research Professors Funding Committee at the UK National Institute for Health and Care Research (NIHR), received a grant from AstraZeneca(paid to their institution) to support a trial of Evusheld for the prevention of COVID-19 in high-risk individuals, and is an independent member of the independent data monitoring committee for the OCTAVE-DUO trial of vaccines in individuals at high risk of COVID-19. DML has received grants or contracts from LifeArc, the UK Medical Research Council, Bristol Myers Squibb, GlaxoSmithKline, the British Society for Antimicrobial Chemotherapy, and Blood Cancer UK, personal fees orhonoraria from Biotest UK, Gilead, and Merck, consulting fees from GlaxoSmithKline (paid to their institution), and conference support from Octapharma. DBR has received consulting fees from OMASS Therapeutics and has a leadership and fiduciary role in the Heal-COVID trial TMG. BRS, JM, MAD, CTS, NSB, and MF report grant money paid to their employer from the University of Oxford for the statistical design and analyses of the PANORAMIC trial.