Favipiravir in patients hospitalised with COVID-19 (PIONEER trial): a multicentre, open-label, phase 3, randomised controlled trial of early intervention versus standard care
Prof Pallav L Shah, Christopher M Orton, MD Beatriz Grinsztejn, Gavin C Donaldson, MD Brenda Crabtree Ramírez, James Tonkin, MD Breno R Santos, Sandra W Cardoso, Andrew I Ritchie, Francesca Conway, Maria P D Riberio, Dexter J Wiseman, Anand Tana, Bavithra Vijayakumar, Cielito Caneja, PhD Craig Leaper, MD Bobby Mann, MD Anda Samson, PhD Pankaj K Bhavsar, PhD Marta Boffito, Prof Mark R Johnson, PhD Anton Pozniak, Michael Pelly, Damon Foster, Nadia Shabbir, Simon Connolly, Andrea Cartier, Sajjida Jaffer, Carmen Winpenny, Doris Daby, Samuel Pepper, Christine Adamson, Jamie Carungcong, Kribashnie Nundlall, Serge Fedele, Pardina Samson-Fessale, Alexandra Schoolmeesters, Laura Gomes De Almeida Martins, Rhian Bull, Patricia Correia Da Costa, Carina Bautista, Maria Eleanor Flores, Shameera Maheswaran, Lester Macabodbod, Rosalie Houseman, Marie-Louise Svensson, Amrinder Sayan, Carrie Fung, Justin Garner, Dilys Lai, Mark Nelson, Luke Moore, Shewta Gidwani, Gary Davies, Beatrice Ouma, Clovis Salinos, Jad Salha, Redasaad Yassein, Abdul Abbasi, Metod Oblak, Angelica Steward, Mini Thankachen, Amy Barker, Candida Fernandes, Veronica Beatriz, Leah Flores, Alfredo Soler-Carracedo, Alessandra Rocca, Shameera Maheswaran, Carmela Martella, Charlotte Lloyd, Ciara Nolan, Latoya Horsford, Laura Martins, Lervina Thomas, Mark Winstanley, Miriam Bourke, Nicholas Branch, Orhan Orhan, Richard Morton, Sangeetha Saunder, Shashank Patil, Stephen Hughes, Wu Zhe, Ashley De Leon, Ayaan Farah, Grace Rya, Katrin Alizadeh, Kirsty Leong, Laure Trepte, Nupur Goel, Patrick Mcgown, Ursula Kirwan, Tamiris Vilela Baião, Luana Marins, Sandro Nazer, Raquel Malaguthi De Souza, Marcella Feitosa, Flavia Lessa, Elizabeth Silva De Magalhães, Jamile Costenaro, Rita De Cassia Alves Lira, Ana Carolina, Andréa Cauduro De Castro, Andre Machado Da Silva, Dimas Kliemann, Rita De Cassia Alves Lira, Gemma Walker, Donna Norton, Vicki Lowthorpe, Monica Ivan, Patrick Lillie, Nicholas Easom, Juan Sierra Madero, Álvaro López Iñiguez, Guadalupe Patricia Muñuzuri Nájera, Claudia Paola Alarcón Murra, Audelia Alanis Vega, Teresa Muñoz Trejo, Olivia Pérez Rodríguez
The Lancet Respiratory Medicine, doi:10.1016/s2213-2600(22)00412-x
Background COVID-19 has overwhelmed health services globally. Oral antiviral therapies are licensed worldwide, but indications and efficacy rates vary. We aimed to evaluate the safety and efficacy of oral favipiravir in patients hospitalised with COVID-19.
Methods We conducted a multicentre, open-label, randomised controlled trial of oral favipiravir in adult patients who were newly admitted to hospital with proven or suspected COVID-19 across five sites in the UK (n=2), Brazil (n=2) and Mexico (n=1). Using a permuted block design, eligible and consenting participants were randomly assigned (1:1) to receive oral favipiravir (1800 mg twice daily for 1 day; 800 mg twice daily for 9 days) plus standard care, or standard care alone. All caregivers and patients were aware of allocation and those analysing data were aware of the treatment groups. The prespecified primary outcome was the time from randomisation to recovery, censored at 28 days, which was assessed using an intention-to-treat approach. Post-hoc analyses were used to assess the efficacy of favipiravir in patients aged younger than 60 years, and in patients aged 60 years and older. The trial was registered with clinicaltrials.gov, NCT04373733.
Findings Between May 5, 2020 and May 26, 2021, we assessed 503 patients for eligibility, of whom 499 were randomly assigned to favipiravir and standard care (n=251) or standard care alone (n=248). There was no significant difference between those who received favipiravir and standard care, relative to those who received standard care alone in time to recovery in the overall study population (hazard ratio [HR] 1•06 [95% CI 0•89-1•27]; n=499; p=0•52). Post-hoc analyses showed a faster rate of recovery in patients younger than 60 years who received favipiravir and standard care versus those who had standard care alone (HR 1•35 [1•06-1•72]; n=247; p=0•01). 36 serious adverse events were observed in 27 (11%) of 251 patients administered favipiravir and standard care, and 33 events were observed in 27 (11%) of 248 patients receiving standard care alone, with infectious, respiratory, and cardiovascular events being the most numerous. There was no significant between-group difference in serious adverse events per patient (p=0•87). Interpretation Favipiravir does not improve clinical outcomes in all patients admitted to hospital with COVID-19, however, patients younger than 60 years might have a beneficial clinical response. The indiscriminate use of favipiravir globally should be cautioned, and further high-quality studies of antiviral agents, and their potential treatment combinations, are warranted in COVID-19. Funding LifeArc and CW+.
Ziekenhuis, Leuven, Belgium; and Andrew Hill, University of Liverpool, Liverpool, UK) for their oversight. We also thank Paul Cullinan for critical review of the manuscript, Lambert Assoumou for statistical support, and the patients for their altruism in participating in this trial. LifeArc awarded a grant for this study from a £10 million budget that the charity had set aside to fund research into existing or late-stage development therapies that could have the potential to be repurposed for patients with COVID-19. CW+ provided further funding for the study through philanthropic donations from XTX Markets, the Andrew and Belinda Scott Charitable Trust, the Pugh Family, Ageas Insurance, Cadogan, the David and Claudia Harding Foundation, and other private individuals. We are grateful to Fujifilm Toyama Chemical Co for supplying favipiravir, Richard H Kaszynski from Stanford Solutions, Stanford School of Medicine (Standford, CA, USA) for his expert consultation, and to Guy de Selliers for his assistance in the initiation of the study.
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