Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC): a randomised controlled trial
Victoria Harris, PhD Jane Holmes, Oghenekome Gbinigie-Thompson, Najib M Rahman, Duncan B Richards, Gail Hayward, Jienchi Dorward, David M Lowe, Prof Joseph F Standing, Prof Judith Breuer, Saye Khoo, PhD Stavros Petrou, Kerenza Hood, Haroon Ahmed, PhD Andrew Carson-Stevens, Prof Jonathan S Nguyen-Van-Tam, Prof Mahendra G Patel, PhD Benjamin R Saville, Nick Francis, Nicholas P B Thomas, Prof Philip Evans, Melissa Dobson, PhD May Ee Png, PhD Mark Lown, Oliver Van Hecke, Bhautesh D Jani, Nigel D Hart, Daniel Butler, Lucy Cureton, MS General Surgery, L-M Meena Patil, Monique Andersson, Maria Coates, Clare Bateman, PhD, I Jennifer C Davies, Ivy Raymundo-Wood, Andrew Ustianowski, F D Ly-Mee Yu, F D Richard Hobbs, Paul Little, Christopher C Butler, Areej Moftah, Anna Goodman, Rob Halifax, Chris Turnbull, Anand Sundaralingam, Akosua Agyeman, Divya Shah, Julianne Brown, Chris Thalasselis, Maximillian N J Woodall, Francis Yongblah, Aleksandra Howell, Kavil Patel, Iqbal Hussain, Ruth Penfold, Simon Hutchinson, Satveer Poonian, Marie Imlach, Olajide Popoola, Greg Irving, Alexander Pora, Nicholas Jacobsen, Vibhore Prasad, James Kennard, Rishabh Prasad, Umar Khan, Omair Razzaq, Kyle Knox, Scot Richardson, Christopher Krasucki, Simon Royal, Tom Law, Afsana Safa, Rem Lee, Satash Sehdev, Nicola Lester, Tamsin Sevenoaks, David Lewis, Aadil Sheikh, James Lunn, Vanessa Short, Claire Mackintosh, Baljinder Singh Sidhu, Mehul Mathukia, Ivor Singh, Patrick Moore, Yusuf Soni, Seb Morton, Pete Wilson, Daniel Murphy, David Wingfield, Rhiannon Nally, Michael Wong, Chinonso Ndukauba, Nick Wooding, Olufunto Ogundapo, Sharon Woods, Henry Okeke, Joanna Yong, Tanveer Ahmed, Damien Allcock, George Atherton, Adrian Beltran-Martinez, Oluseye Emmanuel Benedict, Nigel Bird, Laura Brennan, Gerard Burns, Mike Butler, Daniel Butler, PhD Andrew Carson-Stevens, 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, Alice Packham, Sarah Dowsell, Radhika Gulati, Amit Patel
The Lancet Infectious Diseases, doi:10.1016/s1473-3099(24)00431-6
Background No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation.
Methods This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included selfreported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation.
Findings Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89•2%) of 25 784 participants with 11 778 (91•9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86•6%) of 12 963 in the usual care group. 22 806 (99•1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1•6% [-2•6% to -0•6%]; probability superiority [p(sup)]>0•99; number needed to treat [NNT] 62•5; 6 months: -1•9% [-2•9% to -0•9%]; p(sup)>0•99, NNT 52•6) or persistent symptoms (3 months: adjusted risk difference -2•1% [-2•9% to -1•5%]; p(sup)>0•99; NNT 47•6; 6 months: -2•5% [-3•3% to -1•6%]; p(sup)>0•99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1•08 [0•65 to 1•53]; p(sup)>0•99; 6 months: 1•09 [0•63 to 1•55]; p(sup)>0•99). Ratings of wellness (3 months: adjusted mean difference 0•15 (0•11 to 0•19);..
reflect best care without the drug in question, reflecting what would happen under usual circumstances. 16 The trial therefore assesses whether there is added value to adding a new drug over and above usual care. An openlabel design does not allow one to estimate the contribution of either placebo or nocebo effects to any observed differences between the randomised groups. 17, 18 Knowing whether one is taking a treatment with proven efficacy or not can affect help seeking behaviour. Subjective measures such as symptom scores and participant rating of wellbeing are at potential risk from reporting bias due to the open-label trial design. However, although for many conditions, clearly there can be substantial placebo effects for acute respiratory infections, and even where beliefs in medication are high, the estimates from open-label trials with self-report outcomes (eg, sore throat, 19 acute bronchitis, 20 and otitis 21 ) suggest either no placebo effects or minimal effects when compared with placebo controlled trials in Cochrane reviews. [22] [23] [24] [25] We have found similar evidence for COVID-19 therapeutics: the PRINCIPLE trial, using a similar open-label design, found no clinically meaningful benefit from treatment for COVID-19 with azithromycin, doxycycline, and ivermectin, [26] [27] [28] a trend for harm from treatment with colchicine, 29 and of benefit form treatment with inhaled budesionide. 30 Effect sizes in open trials are generally similar to..
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