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

Butler et al., The Lancet, doi:10.1016/S0140-6736(22)02597-1, PANORAMIC, ISRCTN30448031, Oct 2022 (preprint)

https://c19early.org/butler2.html

26,411 patient RCT in the UK, showing faster recovery but no significant difference in hospitalization/death or transmission. Improved recovery may be in part due to the open label design with self-reported symptomatic data. Viral load initially declined more quickly, but was higher at 14 days. Longer-term results are from1.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity2-16. Multiple analyses have identified variants potentially created by molnupiravir17-21.

Standard of Care (SOC) for COVID-19 in the study country, the United Kingdom, is very poor with very low average efficacy for approved treatments22. The United Kingdom focused on expensive high-profit treatments, approving only one low-cost early treatment, which required a prescription and had limited adoption. The high-cost prescription treatment strategy reduces the probability of early treatment due to access and cost barriers, and eliminates complementary and synergistic benefits seen with many low-cost treatments.

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risk of death, 27.1% higher, RR 1.27, p = 0.50, treatment 20 of 11,778 (0.2%), control 15 of 11,230 (0.1%), day 180.

risk of death, 40.0% lower, RR 0.60, p = 0.51, treatment 3 of 12,529 (0.0%), control 5 of 12,525 (0.0%), NNT 6260, day 28.

risk of death/hospitalization, 6.0% higher, RR 1.06, p = 0.69, treatment 105 of 12,529 (0.8%), control 98 of 12,525 (0.8%), odds ratio converted to relative risk, day 28, primary outcome.

risk of hospitalization, 7.3% higher, RR 1.07, p = 0.67, treatment 103 of 12,529 (0.8%), control 96 of 12,525 (0.8%), day 28.

risk of transmission, 1.9% lower, RR 0.98, p = 0.88, treatment 3,887 of 10,803 (36.0%), control 3,873 of 10,548 (36.7%), NNT 136, odds ratio converted to relative risk.

risk of no sustained recovery, 22.0% lower, RR 0.78, p < 0.001, treatment 3,856 of 12,403 (31.1%), control 4,838 of 12,140 (39.9%), NNT 11.

recovery time, 19.4% lower, relative time 0.81, p < 0.001, treatment 12,403, control 12,140, inverted to make RR<1 favor treatment, sustained recovery.

risk of no first recovery, 30.5% lower, RR 0.70, p < 0.001, treatment 2,675 of 12,403 (21.6%), control 3,766 of 12,140 (31.0%), NNT 11.

recovery time, 26.5% lower, relative time 0.74, p < 0.001, treatment 12,403, control 12,140, inverted to make RR<1 favor treatment, first recovery.

risk of viral load, 95.0% higher, RR 1.95, p = 0.01, treatment 21, control 11, all samples, day 14.

risk of viral load, 92.0% lower, RR 0.08, p < 0.001, treatment 33, control 26, all samples, day 5.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

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Butler et al., 6 Oct 2022, Randomized Controlled Trial, United Kingdom, peer-reviewed, mean age 56.6, 135 authors, study period 8 December, 2021 - 27 April, 2022, trial ISRCTN30448031 (PANORAMIC). Contact: christopher.butler@phc.ox.

This Paper Molnupiravir All

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

Christopher C Butler, F D Richard Hobbs, Oghenekome A Gbinigie, Najib M Rahman, Gail Hayward, Duncan B Richards, Jienchi Dorward, David M Lowe, Joseph F Standing, Judith Breuer, Saye Khoo, PhD Stavros Petrou, Kerenza Hood, Jonathan S Nguyen-Van-Tam, Prof Mahendra G Patel, Benjamin R Saville, Joe Marion, Emma Ogburn, Julie Allen, Heather Rutter, Nick Francis, Nicholas P B Thomas, Philip Evans, Melissa Dobson, Tracie-Ann Madden, Jane Holmes, Victoria Harris, May Ee Png, Mark Lown, Oliver Van Hecke, Michelle A Detry, Christina T Saunders, Mark Fitzgerald, Nicholas S Berry, Lazaro Mwandigha, Ushma Galal, Sam Mort, Bhautesh D Jani, Nigel D Hart, Haroon Ahmed, Daniel Butler, Micheal Mckenna, Jem Chalk, Layla Lavallee, Elizabeth Hadley, Lucy Cureton, Magdalena Benysek, Monique Andersson, Maria Coates, Sarah Barrett, Clare Bateman, Jennifer C Davies, Ivy Raymundo-Wood, Andrew Ustianowski, Andrew Carson-Stevens, Ly-Mee Yu, Paul Little, Akosua A Agyeman, Tanveer Ahmed, Damien Allcock, Adrian Beltran-Martinez, Oluseye E Benedict, Nigel Bird, Laura Brennan, Julianne Brown, Gerard Burns, Mike Butler, Zelda Cheng, Ruth Danson, Nigel De Kare-Silver, Devesh Dhasmana, Jon Dickson, Serge Engamba, Stacey Fisher, Robin Fox, Eve Frost, Richard Gaunt, Sarit Ghosh, Ishtiaq Gilkar, Anna Goodman, Steve Granier, Aleksandra Howell, Iqbal Hussain, Simon Hutchinson, Marie Imlach, Greg Irving, Nicholas Jacobsen, James Kennard, Umar Khan, Kyle Knox, Christopher Krasucki, Tom Law, Rem Lee, Nicola Lester, David Lewis, James Lunn, Claire I Mackintosh, Mehul Mathukia, Patrick Moore, Seb Morton, Daniel Murphy, Rhiannon Nally, Chinonso Ndukauba, Olufunto Ogundapo, Henry Okeke, Amit Patel, Kavil Patel, Ruth Penfold, Satveer Poonian, Olajide Popoola, Alexander Pora, Vibhore Prasad, Rishabh Prasad, Omair Razzaq, Scot Richardson, Simon Royal, Afsana Safa, Satash Sehdev, Tamsin Sevenoaks, Divya Shah, Aadil Sheikh, Baljinder Vanessa Short, Baljinder S Sidhu, Ivor Singh, Yusuf Soni, Chris Thalasselis, Pete Wilson, David Wingfield, Michael Wong, Maximillian N J Woodall, Nick Wooding, Sharon Woods, Joanna Yong, Francis Yongblah, Azhar Zafar

The Lancet, doi:10.1016/s0140-6736(22)02597-1

Background The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031.

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DOI record: { "DOI": "10.1016/s0140-6736(22)02597-1", "ISSN": [ "0140-6736" ], "URL": "http://dx.doi.org/10.1016/S0140-6736(22)02597-1", "alternative-id": [ "S0140673622025971" ], "assertion": [ { "label": "This article is maintained by", "name": "publisher", "value": "Elsevier" }, { "label": "Article Title", "name": "articletitle", "value": "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" }, { "label": "Journal Title", "name": "journaltitle", "value": "The Lancet" }, { "label": "CrossRef DOI link to publisher maintained version", "name": "articlelink", "value": "https://doi.org/10.1016/S0140-6736(22)02597-1" }, { "label": "CrossRef DOI link to the associated document", "name": "associatedlink", "value": "https://doi.org/10.1016/S0140-6736(22)02593-4" }, { "label": "Content Type", "name": "content_type", "value": "article" }, { "label": "Copyright", "name": "copyright", "value": "© 2022 The Author(s). 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