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, Christopher C; Hobbs, F D Richard; Gbinigie, Oghenekome A.; Rahman, Najib M; Hayward, Gail; Richards, Duncan B; Dorward, Jienchi; Lowe, David M.; Standing, Joseph F.; Breuer, Judith; Khoo, Saye; Petrou, Stavros; Hood, Kerenza; Nguyen-Van-Tam, Jonathan S; Patel, Mahendra G; Saville, Benjamin R; Marion, Joe; Ogburn, Emma; Allen, Julie L.; Rutter, Heather; Francis, Nick; Thomas, Nicholas P. B.; Evans, Philip; Dobson, Melissa E; Madden, Tracie-Ann; Holmes, Jane; Harris, Victoria; Png, May Ee; Lown, Mark; Van Hecke, Oliver; Detry, Michelle A; Saunders, Christina T; FitzGerald, Mark; Berry, Nicholas S.; Mwandigha, Lazaro Mwakesi; Galal, Ushma; Mort, Sam; Jani, Bhautesh D.; Hart, Nigel D; Ahmed, Haroon; Butler, Daniel; McKenna, Micheal; Chalk, Jem; Lavallee, Layla; Hadley, Elizabeth; Cureton, Lucy; Benysek, Magdalena; Andersson, Monique Ingrid; Coates, Maria Veronica; Barrett, Sarah Elizabeth; Bateman, Clare; Davies, Jennifer C; Raymundo-Wood, Ivy; Ustianowski, Andrew A; Carson-Stevens, Andrew; Yu, Ly-Mee; Little, Paul

doi:10.1016/S0140-6736(22)02597-1

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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

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Author(s): Christopher C Butler , Prof, FMedSci ^a ^, ^* ^, ^* , F D Richard Hobbs , Prof, FMedSci ^a ^, ^* , Oghenekome A Gbinigie , DPhil ^a , Najib M Rahman , Prof, DPhil ^b ^, ^c ^, ^e , Gail Hayward , DPhil ^a , Duncan B Richards , Prof, DM ^d , Jienchi Dorward , MBChB ^a ^, ^f , David M Lowe , PhD ^g , Joseph F Standing , Prof, PhD ^h ^, ⁱ , Judith Breuer , Prof, MD ^h , Saye Khoo , Prof, FRCP ^j , Stavros Petrou , Prof, PhD ^a , Kerenza Hood , Prof, PhD ^k , Jonathan S Nguyen-Van-Tam , Prof, FMedSci ^m , Mahendra G Patel , Prof, PhD ^a , Benjamin R Saville , PhD ⁿ ^, ^o , Joe Marion , PhD ⁿ , Emma Ogburn ^a , Julie Allen , BA ^a , Heather Rutter , BSc ^a , Nick Francis , Prof, PhD ^p , Nicholas P B Thomas , FRCGP ^q ^, ^r ^, ^s , Philip Evans , Prof, FRCGP ^t ^, ^u , Melissa Dobson , BSc ^b , Tracie-Ann Madden , PhD ^k , Jane Holmes , PhD ^a , Victoria Harris , PhD ^a , May Ee Png , PhD ^a , Mark Lown , PhD ^p , Oliver van Hecke , DPhil ^a , Michelle A Detry , PhD ⁿ , Christina T Saunders , PhD ⁿ , Mark Fitzgerald , PhD ⁿ , Nicholas S Berry , PhD ⁿ , Lazaro Mwandigha , PhD ^a , Ushma Galal , MSc ^a , Sam Mort , PGCert ^a , Bhautesh D Jani , PhD ^v , Nigel D Hart , Prof, MD ^w , Haroon Ahmed , PhD ^l , Daniel Butler , MBChB ^w , Micheal McKenna , BSc ^a , Jem Chalk , PhD ^a , Layla Lavallee , MPH ^a , Elizabeth Hadley , MSc ^a , Lucy Cureton , BSc ^a , Magdalena Benysek , MSc ^a , Monique Andersson , MD ^x , Maria Coates ^a , Sarah Barrett ^a , Clare Bateman , BA ^a , Jennifer C Davies , PhD ^a , Ivy Raymundo-Wood , BSc ^a , Andrew Ustianowski , Prof, PhD ^y , Andrew Carson-Stevens , Prof, PhD ^l , Ly-Mee Yu , DPhil ^a ^, ^† , Paul Little , Prof, FMedSci ^p ^, ^† , PANORAMIC Trial Collaborative Group

Publication date (Electronic): 22 December 2022

Journal: Lancet (London, England)

Publisher: The Author(s). Published by Elsevier Ltd.

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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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Most cited references 32

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Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

Angélica Jayk Bernal, Monica M. Gomes da Silva, Dany Musungaie … (2021)

Abstract Background New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. Results A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. Conclusions Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.)

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A living WHO guideline on drugs for covid-19

Francois Lamontagne, Thomas Agoritsas, Helen Z. MacDonald … (2020)

What is the role of drug interventions in the treatment and prevention of covid-19? The first version on this living guidance focuses on corticosteroids. It contains a strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, and a weak or conditional recommendation against systemic corticosteroids in patients with non-severe covid-19. Corticosteroids are inexpensive and are on the World Health Organisation list of essential medicines. this guideline was created This guideline reflects an innovative collaboration between the WHO and the MAGIC Evidence Ecosystem Foundation, driven by an urgent need for global collaboration to provide trustworthy and living covid-19 guidance. A standing international panel of content experts, patients, clinicians, and methodologists, free from relevant conflicts of interest, produce recommendations for clinical practice. The panel follows standards, methods, processes, and platforms for trustworthy guideline development using the GRADE approach. We apply an individual patient perspective while considering contextual factors (that is, resources, feasibility, acceptability, equity) for countries and healthcare systems. A living systematic review and network meta-analysis, supported by a prospective meta-analysis, with data from eight randomised trials (7184 participants) found that systemic corticosteroids probably reduce 28 day mortality in patients with critical covid-19 (moderate certainty evidence; 87 fewer deaths per 1000 patients (95% confidence interval 124 fewer to 41 fewer)), and also in those with severe disease (moderate certainty evidence; 67 fewer deaths per 1000 patients (100 fewer to 27 fewer)). In contrast, systemic corticosteroids may increase the risk of death in patients without severe covid-19 (low certainty evidence; absolute effect estimate 39 more per 1000 patients, (12 fewer to 107 more)). Systemic corticosteroids probably reduce the need for invasive mechanical ventilation, and harms are likely to be minor (indirect evidence). The panel made a strong recommendation for use of corticosteroids in severe and critical covid-19 because there is a lower risk of death among people treated with systemic corticosteroids (moderate certainty evidence), and they believe that all or almost all fully informed patients with severe and critical covid-19 would choose this treatment. In contrast, the panel concluded that patients with non-severe covid-19 would decline this treatment because they would be unlikely to benefit and may be harmed. Moreover, taking both a public health and a patient perspective, the panel warned that indiscriminate use of any therapy for covid-19 would potentially rapidly deplete global resources and deprive patients who may benefit from it most as potentially lifesaving therapy. This is a living guideline. Work is under way to evaluate other interventions. New recommendations will be published as updates to this guideline. This is version 1 of the living guideline, published on 4 September ( BMJ 2020;370:m3379) version 1. Updates will be labelled as version 2, 3 etc. When citing this article, please cite the version number. August 28 August 31

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Drug treatments for covid-19: living systematic review and network meta-analysis

Reed Siemieniuk, Jessica Bartoszko, Long Ge … (2020)

Abstract Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources US Centers for Disease Control and Prevention COVID-19 Research Articles Downloadable Database, which includes 25 electronic databases and six additional Chinese databases to 20 July 2020. Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, a bayesian random effects network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. Results 23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference −4.5 days, low certainty), remdesivir (−2.6 days, moderate certainty), and lopinavir-ritonavir (−1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation. Conclusion Glucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations. Systematic review registration This review was not registered. The protocol is included as a supplement. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

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Author and article information

Journal

Journal ID (nlm-ta): Lancet

Journal ID (iso-abbrev): Lancet

Title: Lancet (London, England)

Publisher: The Author(s). Published by Elsevier Ltd.

ISSN (Print): 0140-6736

ISSN (Electronic): 1474-547X

Publication date PMC-release: 22 December 2022

Publication date (Electronic): 22 December 2022

Affiliations

[a ]Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK

[b ]Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK

[c ]Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK

[d ]Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

[e ]Oxford National Institute for Health and Care Research Biomedical Research Centre, Oxford, UK

[f ]Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu–Natal, Durban, South Africa

[g ]Institute of Immunity and Transplantation, University College London, London, UK

[h ]Infection, Inflammation and Immunology, UCL Great Ormond Street Institute of Child Health, London, UK

[i ]Department of Pharmacy, Great Ormond Street Hospital for Children, London, UK

[j ]Department of Pharmacology, University of Liverpool, Liverpool, UK

[k ]Centre for Trials Research, Cardiff University, Cardiff, UK

[l ]Division of Population Medicine, Cardiff University, Cardiff, UK

[m ]Lifespan and Population Health Unit, University of Nottingham School of Medicine, Nottingham, UK

[n ]Berry Consultants, Austin, TX, USA

[o ]Department of Biostatistics, Vanderbilt School of Medicine, Nashville, TN, USA

[p ]Primary Care Research Centre, University of Southampton, Southampton, UK

[q ]Windrush Medical Practice, Witney, UK

[r ]National Institute for Health and Care Research Clinical Research Network: Thames Valley and South Midlands, Oxford, UK

[s ]Royal College of General Practitioners, London, UK

[t ]Faculty of Health and Life Sciences, University of Exeter, Exeter, UK

[u ]National Institute for Health and Care Research Clinical Research Network, Leeds, UK

[v ]General Practice and Primary Care, School of Health and Wellbeing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK

[w ]School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK

[x ]Department of Microbiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

[y ]and Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK

Author notes

[* ]Correspondence to: Prof Christopher C Butler, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK

[*]

These authors contributed equally

[†]

These authors contributed equally

[‡]

Members listed at end of paper

Article

Publisher Item ID: S0140-6736(22)02597-1

DOI: 10.1016/S0140-6736(22)02597-1

PMC ID: 9779781

PubMed ID: 36566761

SO-VID: 8774fb2a-35a3-480a-b88a-8f85fb631eed

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Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 32

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

A living WHO guideline on drugs for covid-19

Drug treatments for covid-19: living systematic review and network meta-analysis

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