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 et al., The Lancet, doi:10.1016/S0140-6736(22)02597-1 (date from preprint), PANORAMIC, ISRCTN30448031

Oct 2022

26,411 patient RCT in the UK, showing faster recovery but no significant difference in hospitalization/death or transmission. Improved recovery may be in part due to the open label design with self-reported symptomatic data. Viral load initially declined more quickly, but was higher at 14 days.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer Chamod, Hadj Hassine, Huntsman, Marikawa, Swanstrom, Waters, Zhou, Zibat. Multiple analyses have identified variants potentially created by molnupiravir Fountain-Jones, Kosakovsky Pond, Sanderson, twitter.com.

1. Chamod et al., Molnupiravir Metabolite--N4-hydroxycytidine Causes Cytotoxicity and DNA Damage in Mammalian Cells in vitro: N4-hydroxycytidine Induced Cytotoxicity DNA Damage, Asian Medical Journal and Alternative Medicine, 23:3, asianmedjam.com/index.php/amjam/article/view/1448.asianmedjam.com.

2. Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.sciencedirect.com, doi.org.

3. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

4. Huntsman, M., An assessment of the reproductive toxicity of the anti-COVID-19 drug molnupiravir using stem cell-based embryo models, Master's Thesis, scholarspace.manoa.hawaii.edu/items/cd11342c-b4dc-44c0-8b44-ce6e3369c40b.hawaii.edu.

5. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.com, doi.org.

6. Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.sciencedirect.com, doi.org.

7. Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.nature.com, doi.org.

8. Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.science.org, doi.org.

9. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

10. Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.wiley.com, doi.org.

11. Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.oup.com, doi.org.

12. Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.sciencedirect.com, doi.org.

Important missing comments or errors? Let us know.

risk of death, 40.0% lower, RR 0.60, p = 0.51, treatment 3 of 12,529 (0.0%), control 5 of 12,525 (0.0%), NNT 6260, day 28.

risk of death/hospitalization, 6.0% higher, RR 1.06, p = 0.69, treatment 105 of 12,529 (0.8%), control 98 of 12,525 (0.8%), odds ratio converted to relative risk, day 28, primary outcome.

risk of hospitalization, 7.3% higher, RR 1.07, p = 0.67, treatment 103 of 12,529 (0.8%), control 96 of 12,525 (0.8%), day 28.

risk of transmission, 1.9% lower, RR 0.98, p = 0.88, treatment 3,887 of 10,803 (36.0%), control 3,873 of 10,548 (36.7%), NNT 136, odds ratio converted to relative risk.

risk of no sustained recovery, 22.0% lower, RR 0.78, p < 0.001, treatment 3,856 of 12,403 (31.1%), control 4,838 of 12,140 (39.9%), NNT 11.

recovery time, 19.4% lower, relative time 0.81, p < 0.001, treatment 12,403, control 12,140, inverted to make RR<1 favor treatment, sustained recovery.

risk of no first recovery, 30.5% lower, RR 0.70, p < 0.001, treatment 2,675 of 12,403 (21.6%), control 3,766 of 12,140 (31.0%), NNT 11.

recovery time, 26.5% lower, relative time 0.74, p < 0.001, treatment 12,403, control 12,140, inverted to make RR<1 favor treatment, first recovery.

risk of viral load, 95.0% higher, RR 1.95, p = 0.01, treatment 21, control 11, all samples, day 14.

risk of viral load, 92.0% lower, RR 0.08, p < 0.001, treatment 33, control 26, all samples, day 5.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Butler et al., 6 Oct 2022, Randomized Controlled Trial, United Kingdom, peer-reviewed, mean age 56.6, 135 authors, study period 8 December, 2021 - 27 April, 2022, trial ISRCTN30448031 (PANORAMIC). Contact: christopher.butler@phc.ox.

This Paper Molnupiravir All

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

The Lancet, doi:10.1016/s0140-6736(22)02597-1

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.

References

Abdelnabi, Foo, Kaptein, The combined treatment of molnupiravir and favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model, EBioMedicine

Agarwal, Rochwerg, Lamontagne, A living WHO guideline on drugs for COVID-19, BMJ

Bernal, Da Silva, Musungaie, Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients, N Engl J Med

Burki, Omicron variant and booster COVID-19 vaccines, Lancet Respir Med

Butler, Yu, Dorward, Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, openlabel, adaptive platform trial, Lancet Respir Med

Caraco, Crofoot, Moncada, Phase 2/3 trial of molnupiravir for treatment of COVID-19 in nonhospitalized adults, NEJM Evidence

Cox, Wolf, Plemper, Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets, Nat Microbiol

Dorward, Yu, Hayward, Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial, Br J Gen Pract

Gastine, Pang, Boshier, Systematic review and patientlevel meta-analysis of SARS-CoV-2 viral dynamics to model response to antiviral therapies, Clin Pharmacol Ther

Hayward, Butler, Yu, Platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE): protocol for a randomised, controlled, open-label, adaptive platform, trial of community treatment of COVID-19 syndromic illness in people at higher risk, BMJ Open

Khoo, Fitzgerald, Fletcher, Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a phase I, openlabel, dose-escalating, randomized controlled study, J Antimicrob Chemother

Khoo, Fitzgerald, Saunders, Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial, Lancet Infect Dis, doi:10.1016/S1473-3099(22)00644-2

Laouénan, Guedj, Mentré, Clinical trial simulation to evaluate power to compare the antiviral effectiveness of two hepatitis C protease inhibitors using nonlinear mixed effect models: a viral kinetic approach, BMC Med Res Methodol

Lawrence, Mirchandani, Hill, Evaluation of publication bias for 12 clinical trials of molnupiravir to treat SARS-CoV-2 infection in 13 694 patients, doi:10.21203/rs.3.rs-1913200/v1(preprint

Little, Rumsby, Kelly, Information leaflet and antibiotic prescribing strategies for acute lower respiratory tract infection: a randomized controlled trial, JAMA

Little, Stuart, Moore, Amoxicillin for acute lowerrespiratory-tract infection in primary care when pneumonia is not suspected: a 12-country, randomised, placebo-controlled trial, Lancet Infect Dis

Lowe, Brown, Chowdhury, Favipiravir, lopinavirritonavir or combination therapy (FLARE): a randomised, double blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19, PLoS Med

Macpherson, Pragmatic clinical trials, Complement Ther Med

Malone, Campbell, Molnupiravir: coding for catastrophe, Nat Struc Mol Biol

Merck, Merck and Ridgeback's investigational oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50 percent compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of phase 3 study

Painter, Holman, Bush, Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2, Antimicrob Agents Chemother

Rosenke, Hansen, Schwarz, Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model, Nat Commun

Siemieniuk, Bartoszko, Ge, Drug treatments for COVID-19: living systematic review and network meta-analysis, BMJ

Singh, Mitra, Arora, Two Indian drugmakers to end trials of generic Merck pill for moderate COVID-19

Thorlund, Sheldrick, Meyerowitz-Katz, Singh, Hill, Making statistical sense of the molnupiravir MOVe-OUT clinical trial, Am J Trop Med Hyg

Urakova, Kuznetsova, Crossman, β-d-N 4-hydroxycytidine is a potent anti-alphavirus compound that induces a high level of mutations in the viral genome, J Virol

Wahl, Gralinski, Johnson, SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801, Nature

Wendler, Kington, Madans, Are racial and ethnic minorities less willing to participate in health research?, PLoS Med

Woodcock, Lavange, Master protocols to study multiple therapies, multiple diseases, or both, N Engl J Med

Download Image

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0