Randomized Controlled Trial

. 2023 Jan 28;401(10373):281-293.

doi: 10.1016/S0140-6736(22)02597-1. Epub 2022 Dec 22.

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 Butler¹, F D Richard Hobbs², Oghenekome A Gbinigie², Najib M Rahman³, Gail Hayward², Duncan B Richards⁴, Jienchi Dorward⁵, David M Lowe⁶, Joseph F Standing⁷, Judith Breuer⁸, Saye Khoo⁹, Stavros Petrou², Kerenza Hood¹⁰, Jonathan S Nguyen-Van-Tam¹¹, Mahendra G Patel², Benjamin R Saville¹², Joe Marion¹³, Emma Ogburn², Julie Allen², Heather Rutter², Nick Francis¹⁴, Nicholas P B Thomas¹⁵, Philip Evans¹⁶, Melissa Dobson¹⁷, Tracie-Ann Madden¹⁰, Jane Holmes², Victoria Harris², May Ee Png², Mark Lown¹⁴, Oliver van Hecke², Michelle A Detry¹³, Christina T Saunders¹³, Mark Fitzgerald¹³, Nicholas S Berry¹³, Lazaro Mwandigha², Ushma Galal², Sam Mort², Bhautesh D Jani¹⁸, Nigel D Hart¹⁹, Haroon Ahmed²⁰, Daniel Butler¹⁹, Micheal McKenna², Jem Chalk², Layla Lavallee², Elizabeth Hadley², Lucy Cureton², Magdalena Benysek², Monique Andersson²¹, Maria Coates², Sarah Barrett², Clare Bateman², Jennifer C Davies², Ivy Raymundo-Wood², Andrew Ustianowski²², Andrew Carson-Stevens²⁰, Ly-Mee Yu², Paul Little¹⁴; PANORAMIC Trial Collaborative Group

Collaborators, Affiliations

Collaborators

PANORAMIC Trial Collaborative Group:
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, 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

Affiliations

¹ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK. Electronic address: christopher.butler@phc.ox.ac.uk.
² Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
³ Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK; Oxford National Institute for Health and Care Research Biomedical Research Centre, Oxford, UK.
⁴ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁵ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
⁶ Institute of Immunity and Transplantation, University College London, London, UK.
⁷ Infection, Inflammation and Immunology, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Pharmacy, Great Ormond Street Hospital for Children, London, UK.
⁸ Infection, Inflammation and Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.
⁹ Department of Pharmacology, University of Liverpool, Liverpool, UK.
¹⁰ Centre for Trials Research, Cardiff University, Cardiff, UK.
¹¹ Lifespan and Population Health Unit, University of Nottingham School of Medicine, Nottingham, UK.
¹² Berry Consultants, Austin, TX, USA; Department of Biostatistics, Vanderbilt School of Medicine, Nashville, TN, USA.
¹³ Berry Consultants, Austin, TX, USA.
¹⁴ Primary Care Research Centre, University of Southampton, Southampton, UK.
¹⁵ Windrush Medical Practice, Witney, UK; National Institute for Health and Care Research Clinical Research Network: Thames Valley and South Midlands, Oxford, UK; Royal College of General Practitioners, London, UK.
¹⁶ Faculty of Health and Life Sciences, University of Exeter, Exeter, UK; National Institute for Health and Care Research Clinical Research Network, Leeds, UK.
¹⁷ Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁸ General Practice and Primary Care, School of Health and Wellbeing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.
¹⁹ School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
²⁰ Division of Population Medicine, Cardiff University, Cardiff, UK.
²¹ Department of Microbiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
²² and Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK.

PMID: 36566761
PMCID: PMC9779781
DOI: 10.1016/S0140-6736(22)02597-1

Randomized Controlled Trial

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 et al. Lancet. 2023.

. 2023 Jan 28;401(10373):281-293.

doi: 10.1016/S0140-6736(22)02597-1. Epub 2022 Dec 22.

Authors

Collaborators

PANORAMIC Trial Collaborative Group:
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, 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

Affiliations

¹ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK. Electronic address: christopher.butler@phc.ox.ac.uk.
² Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
³ Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK; Oxford National Institute for Health and Care Research Biomedical Research Centre, Oxford, UK.
⁴ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁵ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
⁶ Institute of Immunity and Transplantation, University College London, London, UK.
⁷ Infection, Inflammation and Immunology, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Pharmacy, Great Ormond Street Hospital for Children, London, UK.
⁸ Infection, Inflammation and Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.
⁹ Department of Pharmacology, University of Liverpool, Liverpool, UK.
¹⁰ Centre for Trials Research, Cardiff University, Cardiff, UK.
¹¹ Lifespan and Population Health Unit, University of Nottingham School of Medicine, Nottingham, UK.
¹² Berry Consultants, Austin, TX, USA; Department of Biostatistics, Vanderbilt School of Medicine, Nashville, TN, USA.
¹³ Berry Consultants, Austin, TX, USA.
¹⁴ Primary Care Research Centre, University of Southampton, Southampton, UK.
¹⁵ Windrush Medical Practice, Witney, UK; National Institute for Health and Care Research Clinical Research Network: Thames Valley and South Midlands, Oxford, UK; Royal College of General Practitioners, London, UK.
¹⁶ Faculty of Health and Life Sciences, University of Exeter, Exeter, UK; National Institute for Health and Care Research Clinical Research Network, Leeds, UK.
¹⁷ Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁸ General Practice and Primary Care, School of Health and Wellbeing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.
¹⁹ School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
²⁰ Division of Population Medicine, Cardiff University, Cardiff, UK.
²¹ Department of Microbiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
²² and Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK.

PMID: 36566761
PMCID: PMC9779781
DOI: 10.1016/S0140-6736(22)02597-1

Abstract

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.

Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.

Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community.

Funding: UK National Institute for Health and Care Research.

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Conflict of interest statement

Declaration of interests 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 for F 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 or honoraria 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. JM has also participated on data and safety monitoring boards as part of his employment with Berry Consultants. ML is a member of the data monitoring and ethics committee of RAPIS-TEST (NIHR efficacy and mechanism evaluation). SK reports grants from GlaxoSmithKline, ViiV, Ridgeback Biotherapeutics, Vir, Merck, the UK Medical Research Council, and the Wellcome Trust (all paid to his institution), speaker's honoraria from ViiV, and donations of drugs for clinical studies from ViiV Healthcare, Toyama, and GlaxoSmithKline. JFS has participated on a data safety monitoring board for GlaxoSmithKline. MA has received grants from the Blood and Transplant Research Unit, Janssen, Pfizer, Prenetics, Dunhill Medical Trust, the BMA Trust (Kathleen Harper Fund), and Antibiotic Research UK (all of which were paid to their institution), and consultancy fees from Prenetics and OxDx. MA reports a planned patent for Ramanomics, has participated on data safety monitoring boards or advisory boards for Prenetics, and has an unpaid leadership or fiduciary role in the E3 Initiative. NPBT has received payment for participation on an advisory board from MSD (before any knowledge or planning of this trial). OvH has received consulting fees from MindGap (fees paid to Oxford University lnnovation), has participated on data safety monitoring boards or advisory boards for the CHICO trial, and has an unpaid leadership or fiduciary role in the British Society of Antimicrobial Chemotherapy. AU has received consulting fees and payment or honoraria from MSD, GlaxoSmithKline, and Gilead. NF has received consulting fees from Abbott Diagnostics and GlaxoSmithKline, is a member of the PRINCIPLE trial data safety monitoring board and the NIHR Health Technology Assessment General Funding Committee, and has stocks in Synairgen. JB has received consulting fees from GlaxoSmithKline (paid to her institution). All other authors declare no competing interests.

Figures

**Figure 1**
Trial profile *Results related to these groups are not discussed in this Article.

**Figure 2**
Forest plot of subgroup analyses of hospitalisation or death, or both 95% BCI=95% Bayesian credible interval.

**Figure 3**
Time from randomisation to first reported recovery from COVID-19

**Figure 4**
Forest plot of subgroup analysis of time to first reported recovery from COVID-19

See this image and copyright information in PMC

Comment in

PANORAMIC: important insights into molnupiravir use in COVID-19.
Kidd MR, Kelly PM. Kidd MR, et al. Lancet. 2023 Jan 28;401(10373):250-251. doi: 10.1016/S0140-6736(22)02593-4. Epub 2022 Dec 22. Lancet. 2023. PMID: 36566762 Free PMC article. No abstract available.

References

1. Toots M, Yoon JJ, Cox RM, et al. Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci Transl Med. 2019;11 - PMC - PubMed
1. Fischer WA, 2nd, Eron JJ, Jr, Holman W, et al. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med. 2022;14 - PMC - PubMed
1. Malone B, Campbell EA. Molnupiravir: coding for catastrophe. Nat Struc Mol Biol. 2021;28:706–708. - PubMed
1. Cox RM, Wolf JD, Plemper RK. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol. 2021;6:11–18. - PMC - PubMed
1. Wahl A, Gralinski LE, Johnson CE, et al. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 2021;591:451–457. - PMC - PubMed

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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

Collaborators

Affiliations

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

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Conflict of interest statement

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