Molnupiravir Plus Usual Care Versus Usual Care Alone as Early Treatment for Adults with COVID-19 at Increased Risk of Adverse Outcomes (PANORAMIC): Preliminary Analysis from the United Kingdom Randomised, Controlled Open-Label, Platform Adaptive Trial

43 Pages Posted: 17 Oct 2022

See all articles by Christopher Butler

Christopher Butler

University of Oxford - Nuffield Department of Primary Care Health Sciences

Richard Hobbs

University of Oxford - Nuffield Department of Primary Care Health Sciences

Oghenekome Gbinigie

University of Oxford - Nuffield Department of Primary Care Health Sciences

Najib M. Rahman

University of Oxford - Oxford Respiratory Trials Unit; University of Oxford - NIHR Biomedical Research Unit Oxford; University of Oxford - Chinese Academy of Medical Science Oxford Institute (COI)

Gail Hayward

University of Oxford - Nuffield Department of Primary Care Health Sciences

Duncan Richards

University of Oxford - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS)

Jienchi Dorward

University of Oxford - Nuffield Department of Primary Care Health Sciences; University of KwaZulu-Natal - Centre for the AIDS Programme of Research in South Africa (CAPRISA)

David Lowe

University College London - UCL Institute of Immunity and Transplantation

Joseph F. Standing

University College London - Department of Infection, Inflammation and Immunity; Great Ormond Street Hospital for Children - Department of Pharmacy

Judith Breuer

University College London - Department of Infection, Inflammation and Immunity

Saye Khoo

University of Liverpool - Department of Pharmacology

Stavros Petrou

University of Oxford - Nuffield Department of Primary Care Health Sciences

Kerenza Hood

Cardiff University - Centre for Trials Research

Jonathan S. Nguyen-Van-Tam

University of Nottingham - Division of Epidemiology and Public Health

Mahendra Patel

University of Oxford - Nuffield Department of Primary Care Health Sciences

Benjamin R. Saville

Berry Consultants, LLC; Vanderbilt University - Department of Biostatistics

Joe Marion

Berry Consultants, LLC

Emma Ogburn

University of Oxford - Nuffield Department of Primary Care Health Sciences

Julie Allen

University of Oxford - Nuffield Department of Primary Care Health Sciences

Heather Rutter

University of Oxford - Nuffield Department of Primary Care Health Sciences

Nick Francis

University of Southampton - Primary Care Research Centre

Nicholas Thomas

Windrush Medical Practice; National Institute for Health and Care Research - CRN Thames Valley and South Midlands; Royal College of General Practitioners

Philip Evans

University of Exeter - Faculty of Health and Life Sciences; National Institute for Health and Care Research

Melissa Dobson

University of Oxford - Oxford Respiratory Trials Unit

Tracie-Ann Madden

Cardiff University - Centre for Trials Research

Jane Holmes

University of Oxford - Nuffield Department of Primary Care Health Sciences

Victoria Harris

University of Oxford - Nuffield Department of Primary Care Health Sciences

May Ee Png

University of Oxford - Nuffield Department of Primary Care Health Sciences

Mark Lown

University of Southampton - Primary Care Research Centre

Oliver van Hecke

University of Oxford - Nuffield Department of Primary Care Health Sciences

Michelle Detry

Berry Consultants, LLC

Christina Saunders

Berry Consultants, LLC

Mark Fitzgerald

Berry Consultants, LLC

Nicholas Berry

Berry Consultants, LLC

Lazaro Mwandigha

University of Oxford - Nuffield Department of Primary Care Health Sciences

Ushma Galal

University of Oxford - Nuffield Department of Primary Care Health Sciences

Bhautesh Jani

University of Glasgow - Institute of Health and Wellbeing

Nigel Hart

Queen's University Belfast - School of Medicine, Dentistry & Biomedical Science

Daniel Butler

Queen's University Belfast - School of Medicine, Dentistry & Biomedical Science

Jeremy Chalk

University of Oxford - Nuffield Department of Primary Care Health Sciences

Layla Lavallee

University of Oxford - Nuffield Department of Primary Care Health Sciences

Elizabeth Hadley

University of Oxford - Nuffield Department of Primary Care Health Sciences

Lucy Cureton

University of Oxford - Nuffield Department of Primary Care Health Sciences

Magdalena Benysek

University of Oxford - Nuffield Department of Primary Care Health Sciences

Monique Andersson

NHS Foundation Trust - Oxford University Hospitals

Maria Coates

University of Oxford - Nuffield Department of Primary Care Health Sciences

Sarah Barrett

University of Oxford - Nuffield Department of Primary Care Health Sciences

Clare Bateman

University of Oxford - Nuffield Department of Primary Care Health Sciences

Jennifer Davies

University of Oxford - Nuffield Department of Primary Care Health Sciences

Ivy Raymundo-Wood

University of Oxford - Nuffield Department of Primary Care Health Sciences

Andrew Ustianowski

North Manchester General Hospital - Regional Infectious Diseases Unit

Andrew Carson-Stevens

Cardiff University - Centre for Trials Research

Ly-Mee Yu

University of Oxford - Nuffield Department of Primary Care Health Sciences

Paul Little

University of Southampton - Primary Care and Population Science

Date Written: October 4, 2022

Abstract

Background: The safety, effectiveness and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, in patients in the community who are multiply-vaccinated and at increased risk of morbidity and mortality from COVID-19, has not been established. We aimed to determine whether molnupiravir added to usual care reduced hospital admissions/deaths among people at higher risk from COVID-19, and here report our preliminary analyses.

Methods: Participants in this UK multicentre, open-label, adaptive, multi-arm, platform, randomised controlled trial were aged ≥50, or ≥18 years with comorbidities, and unwell ≤5 days with confirmed COVID-19 in the community, and were randomised to usual care or usual care plus molnupiravir (800mg twice daily for 5 days). The primary outcome measure was all-cause hospitalisation/death within 28 days, analysed using Bayesian models. The main secondary outcome measure was time to first self-reported recovery. A sub-set of participants in each group were assessed for the virology primary outcome measure of day seven SARS-CoV-2 viral load. Trial registration: ISRCTN30448031

Findings: Between December 8, 2021 and April 27, 2022, 25783 participants were randomised to molnupiravir plus usual care (n=12821) or usual care alone (n=12962). Mean (range) age of participants was 56·6 years (18 to 99), 58·6% were female, and 99% had at least one dose of a SARS-CoV-2 vaccine. The median duration of symptoms prior to randomisation was two days (IQR 1 – 3), the median number of days from symptom onset to starting to take the medication was three days (IQR 3 – 4), 87% (11109/11997) received their medication within five days of symptom onset, and 95·4% (n=11857) of participants randomised to molnupiravir reported taking molnupiravir for five days. Primary outcome measure data were available in 25000 (97%) participants and included in this analysis. 103/12516 (0·8%) hospitalisations/deaths occurred in the molnupiravir group versus 96/12484 (0·8%) in usual care alone with a posterior probability of superiority of 0·34 (adjusted odds ratio 1·061 (95% Bayesian credible interval [BCI]) 0·80 to 1·40). Estimates were similar for all subgroups. The observed median (IQR) time-to-first-recovery from randomisation was 9 (5–23) days in molnupiravir and 15 (7–not reached) days in usual care. There was an estimated benefit of 4·2 (95% BCI: 3·8 – 4·6) days in time-to-first-recovery (TTR) giving a posterior probability of superiority of >0·999 (estimated median TTR 10·3 [10·2 – 10·6] days vs 14·5 [14·2 – 14·9] days respectively; hazard ratio [95% BCI], 1·36 [1·3–1·4] days), which met the pre-specified superiority threshold. On day 7, SARS-CoV-2 virus was below detection levels in 7/34 (21%) of the molnupiravir group, versus 1/39 (3%) in the usual care group (p=0.039), and mean viral load was lower in the molnupiravir group compared with those receiving usual care [(SD) of log10(viral load) 3·82 (1·40) in the molnupiravir group and 4.93 (1·38) in the usual care group, (P<0·001)]. 59 (0·4%) participants experienced serious adverse events in the molnupiravir group and 52 (0·4%) in usual care.

Interpretation: In this preliminary analysis, we found that molnupiravir did not reduce already low hospitalisations/deaths among higher risk, vaccinated adults with COVID-19 in the community, but resulted in faster time to recovery, and reduced viral detection and load.

Funding: This project is funded by the NIHR (NIHR135366). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Note:
Funding Information: This project is funded by the NIHR (NIHR135366). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Conflict of Interests: JSN-V-T was seconded to the Department of Health and Social Care, England (DHSC) from October 2017 to March 2022. The views expressed in this paper are those of its authors and not necessarily those of DHSC. Berry statisticians are paid by the University of Oxford for their statistical work on the unblinded analyses for PANORAMIC, but their compensation is not dependent on the outcomes of arms in the study. SK has received research support from ViiV, Merck, Ridgeback, GSK and Vir and honoraria from Pfizer unrelated to this work. UW has received speaker/advisory board fees from AZ, Gilead, GSK/ViiV and MSD/Merck. All other authors have nothing to declare.

Ethical Approval: The UK Medicines and Healthcare products Regulatory Agency and the South Central Berkshire Research Ethics Committee approved the trial protocol. Online informed consent is obtained from all participants. The authors vouch for the accuracy and completeness of the data and for fidelity to the protocol. An independent Trial Steering Committee (TSC), and Data and Safety Monitoring Committee (DSMC) provide trial oversight. I can confirm that the safety monitoring board has approved release of the data contained in the preprint.

Trial Registration: Trial registration: ISRCTN30448031

Keywords: COVID-19, clincial trial, antiviral agents, primary health care, molnupiravir

Suggested Citation

Butler, Christopher and Hobbs, F.D. Richard and Gbinigie, Oghenekome and Rahman, Najib M. and Hayward, Gail and Richards, Duncan and Dorward, Jienchi and Lowe, David and Standing, Joseph F. and Breuer, Judith and Khoo, Saye and Petrou, Stavros and Hood, Kerenza and Nguyen-Van-Tam, Jonathan S. and Patel, Mahendra and Saville, Benjamin R. and Marion, Joe and Ogburn, Emma and Allen, Julie and Rutter, Heather and Francis, Nick and Thomas, Nicholas and Evans, Philip and Dobson, Melissa and Madden, Tracie-Ann and Holmes, Jane and Harris, Victoria and Png, May Ee and Lown, Mark and van Hecke, Oliver and Detry, Michelle and Saunders, Christina and Fitzgerald, Mark and Berry, Nicholas and Mwandigha, Lazaro and Galal, Ushma and Jani, Bhautesh and Hart, Nigel and Butler, Daniel and Chalk, Jeremy and Lavallee, Layla and Hadley, Elizabeth and Cureton, Lucy and Benysek, Magdalena and Andersson, Monique and Coates, Maria and Barrett, Sarah and Bateman, Clare and Davies, Jennifer and Raymundo-Wood, Ivy and Ustianowski, Andrew and Carson-Stevens, Andrew and Yu, Ly-Mee and Little, Paul, Molnupiravir Plus Usual Care Versus Usual Care Alone as Early Treatment for Adults with COVID-19 at Increased Risk of Adverse Outcomes (PANORAMIC): Preliminary Analysis from the United Kingdom Randomised, Controlled Open-Label, Platform Adaptive Trial (October 4, 2022). Available at SSRN: https://ssrn.com/abstract=4237902 or http://dx.doi.org/10.2139/ssrn.4237902

Christopher Butler (Contact Author)

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

F.D. Richard Hobbs

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Oghenekome Gbinigie

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Najib M. Rahman

University of Oxford - Oxford Respiratory Trials Unit ( email )

Mansfield Road
Oxford, Oxfordshire OX1 4AU
United Kingdom

University of Oxford - NIHR Biomedical Research Unit Oxford ( email )

Oxford
United Kingdom

University of Oxford - Chinese Academy of Medical Science Oxford Institute (COI) ( email )

United Kingdom

Gail Hayward

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Duncan Richards

University of Oxford - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS) ( email )

Oxford
United Kingdom

Jienchi Dorward

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

University of KwaZulu-Natal - Centre for the AIDS Programme of Research in South Africa (CAPRISA) ( email )

2nd Floor, Doris Duke Medical Research Institute
719 Umbilo Road
Durban, 4041
South Africa

David Lowe

University College London - UCL Institute of Immunity and Transplantation ( email )

Gower Street
London, WC1E 6BT
United Kingdom

Joseph F. Standing

University College London - Department of Infection, Inflammation and Immunity ( email )

30 Guilford Street
London
United Kingdom

Great Ormond Street Hospital for Children - Department of Pharmacy ( email )

London
United Kingdom

Judith Breuer

University College London - Department of Infection, Inflammation and Immunity ( email )

30 Guilford Street
London
United Kingdom

Saye Khoo

University of Liverpool - Department of Pharmacology ( email )

Liverpool
United Kingdom

Stavros Petrou

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Kerenza Hood

Cardiff University - Centre for Trials Research

Cardiff
United Kingdom

Jonathan S. Nguyen-Van-Tam

University of Nottingham - Division of Epidemiology and Public Health

University Park
Nottingham, NG8 1BB
United Kingdom

Mahendra Patel

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Benjamin R. Saville

Berry Consultants, LLC ( email )

Austin, TX
United States

Vanderbilt University - Department of Biostatistics

2301 Vanderbilt Place
Nashville, TN 37240
United States

Joe Marion

Berry Consultants, LLC ( email )

Austin, TX
United States

Emma Ogburn

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Julie Allen

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Heather Rutter

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Nick Francis

University of Southampton - Primary Care Research Centre ( email )

United Kingdom

Nicholas Thomas

Windrush Medical Practice ( email )

Witney
United Kingdom

National Institute for Health and Care Research - CRN Thames Valley and South Midlands ( email )

United Kingdom

Royal College of General Practitioners ( email )

30 Euston Square
London
United Kingdom

Philip Evans

University of Exeter - Faculty of Health and Life Sciences ( email )

United Kingdom

National Institute for Health and Care Research ( email )

United Kingdom

Melissa Dobson

University of Oxford - Oxford Respiratory Trials Unit ( email )

Mansfield Road
Oxford, Oxfordshire OX1 4AU
United Kingdom

Tracie-Ann Madden

Cardiff University - Centre for Trials Research ( email )

Cardiff
United Kingdom

Jane Holmes

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Victoria Harris

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

May Ee Png

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Mark Lown

University of Southampton - Primary Care Research Centre ( email )

United Kingdom

Oliver Van Hecke

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Michelle Detry

Berry Consultants, LLC ( email )

Austin, TX
United States

Christina Saunders

Berry Consultants, LLC ( email )

Austin, TX
United States

Mark Fitzgerald

Berry Consultants, LLC ( email )

Austin, TX
United States

Nicholas Berry

Berry Consultants, LLC ( email )

Austin, TX
United States

Lazaro Mwandigha

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Ushma Galal

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Bhautesh Jani

University of Glasgow - Institute of Health and Wellbeing ( email )

Glasgow
United Kingdom

Nigel Hart

Queen's University Belfast - School of Medicine, Dentistry & Biomedical Science ( email )

Belfast
Ireland

Daniel Butler

Queen's University Belfast - School of Medicine, Dentistry & Biomedical Science ( email )

Belfast
Ireland

Jeremy Chalk

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Layla Lavallee

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Elizabeth Hadley

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Lucy Cureton

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Magdalena Benysek

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Monique Andersson

NHS Foundation Trust - Oxford University Hospitals ( email )

United Kingdom

Maria Coates

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Sarah Barrett

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Clare Bateman

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Jennifer Davies

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Ivy Raymundo-Wood

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Andrew Ustianowski

North Manchester General Hospital - Regional Infectious Diseases Unit ( email )

Manchester
United Kingdom

Andrew Carson-Stevens

Cardiff University - Centre for Trials Research ( email )

Cardiff
United Kingdom

Ly-Mee Yu

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Paul Little

University of Southampton - Primary Care and Population Science

Southampton, SO16 5ST
United Kingdom

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