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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

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
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

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

0140-6736
281-293
Butler, Christopher C
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PANORAMIC Trial Collaborative Group
Butler, Christopher C
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PANORAMIC Trial Collaborative Group (2023) 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. The Lancet, 401 (10373), 281-293. (doi:10.1016/S0140-6736(22)02597-1).

Record type: Article

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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e-pub ahead of print date: 22 December 2022
Published date: 28 January 2023
Additional Information: Funding Information: This study was funded by the NIHR (NIHR135366). KH and SP are co-investigators on this grant, and DMI was a co-applicant. CCB received support as an NIHR senior investigator, from the NIHR Community Healthcare Medtech and In-Vitro Diagnostics Co-operative, and from the NIHR Health Protection Research Unit on Health Care Associated Infections and Antimicrobial Resistance. FDRH is part-funded by the NIHR Applied Research Collaboration and the NIHR Community Healthcare Medtech and In-Vitro Diagnostics Co-operative. GH is funded by an NIHR advanced fellowship and by the NIHR Community Healthcare Medtech and In-Vitro Diagnostics Co-operative (MIC). JD is funded by the Wellcome Trust PhD programme for primary care clinicians (216421/Z/19/Z). SP receives support as an NIHR senior investigator (NF-SI-0616-10103) and from the UK NIHR Applied Research Collaboration Oxford and Thames Valley. OAG receives funding from the European Clinical Research Alliance on Infectious Diseases (project number 101046109). JB receives supports as an NIHR senior investigator and from the University College London Hospitals NIHR Biomedical Research Centre. JFS received a UK Medical Research Council project grant (MR/X004724/1) that contributed to the design of the virology study. HA is supported by an NIHR Advanced Fellowship funded by Health and Care Research Wales. JFS has received research grants from the UK Medical Research Council (MR/X004724/1, MR/W015560/1), the Wellcome Trust, NIHR, and the Drugs for Neglected Diseases Initiative, all of which were paid to his institution. OvH has received an NIHR Development and Skills Personal Award. T-AM reports grant funding from Cardiff University through an NIHR award to the University of Oxford. NF reports receiving NIHR grant funding. ML and PL report funding from the NIHR for PANORAMIC. We thank all participants in the study, all participating general practices, NHS COVID-19 treatment services, and other health and social care organisations supporting the trial for their work and support, our patient and public involvement contributors, the trial steering and data monitoring and safety committees, primary care colleagues in the NIHR Clinical Research Network (lead network: Thames Valley and South Midlands), Health and Care Research Wales, NHS Research Scotland, the Health and Social Care Board in Northern Ireland, the NIHR, and the Therapeutics Task Force, NHS DigiTrials, the Intensive Care National Audit and Research Centre, Public Health Scotland, the National Records Service of Scotland, the Secure Anonymised Information Linkage at the University of Swansea, and Health and Social Care Northern Ireland. The views expressed in this Article are the authors' and not necessarily those of the NIHR or the Department of Health and Social Care. Funding Information: This study was funded by the NIHR (NIHR135366). KH and SP are co-investigators on this grant, and DMI was a co-applicant. CCB received support as an NIHR senior investigator, from the NIHR Community Healthcare Medtech and In-Vitro Diagnostics Co-operative, and from the NIHR Health Protection Research Unit on Health Care Associated Infections and Antimicrobial Resistance. FDRH is part-funded by the NIHR Applied Research Collaboration and the NIHR Community Healthcare Medtech and In-Vitro Diagnostics Co-operative. GH is funded by an NIHR advanced fellowship and by the NIHR Community Healthcare Medtech and In-Vitro Diagnostics Co-operative (MIC). JD is funded by the Wellcome Trust PhD programme for primary care clinicians (216421/Z/19/Z). SP receives support as an NIHR senior investigator (NF-SI-0616-10103) and from the UK NIHR Applied Research Collaboration Oxford and Thames Valley. OAG receives funding from the European Clinical Research Alliance on Infectious Diseases (project number 101046109). JB receives supports as an NIHR senior investigator and from the University College London Hospitals NIHR Biomedical Research Centre. JFS received a UK Medical Research Council project grant (MR/X004724/1) that contributed to the design of the virology study. HA is supported by an NIHR Advanced Fellowship funded by Health and Care Research Wales. JFS has received research grants from the UK Medical Research Council (MR/X004724/1, MR/W015560/1), the Wellcome Trust, NIHR, and the Drugs for Neglected Diseases Initiative, all of which were paid to his institution. OvH has received an NIHR Development and Skills Personal Award. T-AM reports grant funding from Cardiff University through an NIHR award to the University of Oxford. NF reports receiving NIHR grant funding. ML and PL report funding from the NIHR for PANORAMIC. We thank all participants in the study, all participating general practices, NHS COVID-19 treatment services, and other health and social care organisations supporting the trial for their work and support, our patient and public involvement contributors, the trial steering and data monitoring and safety committees, primary care colleagues in the NIHR Clinical Research Network (lead network: Thames Valley and South Midlands), Health and Care Research Wales, NHS Research Scotland, the Health and Social Care Board in Northern Ireland, the NIHR, and the Therapeutics Task Force, NHS DigiTrials, the Intensive Care National Audit and Research Centre, Public Health Scotland, the National Records Service of Scotland, the Secure Anonymised Information Linkage at the University of Swansea, and Health and Social Care Northern Ireland. The views expressed in this Article are the authors' and not necessarily those of the NIHR or the Department of Health and Social Care. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Identifiers

Local EPrints ID: 474145
URI: http://eprints.soton.ac.uk/id/eprint/474145
ISSN: 0140-6736
PURE UUID: ec0ac215-118f-46ec-acc4-8b327b2265ef
ORCID for Nick Francis: ORCID iD orcid.org/0000-0001-8939-7312
ORCID for Mark Lown: ORCID iD orcid.org/0000-0001-8309-568X

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Date deposited: 14 Feb 2023 17:40
Last modified: 17 Mar 2024 03:58

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Contributors

Author: Christopher C Butler
Author: F D Richard Hobbs
Author: Oghenekome A Gbinigie
Author: Najib M Rahman
Author: Gail Hayward
Author: Duncan B Richards
Author: Jienchi Dorward
Author: David M Lowe
Author: Joseph F Standing
Author: Judith Breuer
Author: Saye Khoo
Author: Stavros Petrou
Author: Kerenza Hood
Author: Jonathan S Nguyen-Van-Tam
Author: Mahendra G Patel
Author: Benjamin R Saville
Author: Joe Marion
Author: Emma Ogburn
Author: Julie Allen
Author: Heather Rutter
Author: Nick Francis ORCID iD
Author: Nicholas P B Thomas
Author: Philip Evans
Author: Melissa Dobson
Author: Tracie-Ann Madden
Author: Jane Holmes
Author: Victoria Harris
Author: May Ee Png
Author: Mark Lown ORCID iD
Author: Oliver van Hecke
Author: Michelle A Detry
Author: Christina T Saunders
Author: Mark Fitzgerald
Author: Nicholas S Berry
Author: Lazaro Mwandigha
Author: Ushma Galal
Author: Sam Mort
Author: Bhautesh D Jani
Author: Nigel D Hart
Author: Haroon Ahmed
Author: Daniel Butler
Author: Micheal McKenna
Author: Jem Chalk
Author: Layla Lavallee
Author: Elizabeth Hadley
Author: Lucy Cureton
Author: Magdalena Benysek
Author: Monique Andersson
Author: Maria Coates
Author: Paul Little
Corporate Author: PANORAMIC Trial Collaborative Group

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