Favipiravir in patients hospitalised with COVID-19 (PIONEER trial): a multicentre, open-label, phase 3, randomised controlled trial of early intervention versus standard care
et al., The Lancet Respiratory Medicine,
Favipiravir in patients hospitalised with COVID-19 (PIONEER trial): a multicentre, open-label, phase 3,..
, The Lancet Respiratory Medicine, doi:10.1016/S2213-2600(22)00412-X (date from earlier preprint), PIONEER, NCT04373733
PIONEER very late treatment RCT showing lower mortality and mechanical ventilation with favipiravir, without statistical significance.
The conclusion "favipiravir is not efficacious in treating hospitalised adult patients with COVID-19" is incorrect. Authors show 26% and 24% lower mortality and mechanical ventilation. While these results are not statistically significant, they predict efficacy, and cannot be used to rule out efficacy.
Favipiravir 1,800mg bid day 1, 800mg bid days 2-10.
risk of death, 26.0% lower, HR 0.74, p = 0.24, treatment 26 of 251 (10.4%), control 34 of 248 (13.7%), NNT 30.
risk of mechanical ventilation, 24.0% lower, HR 0.76, p = 0.21, treatment 251, control 248.
risk of no recovery, 5.7% lower, HR 0.94, p = 0.53, treatment 251, control 248, inverted to make HR<1 favor treatment.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Shah et al., 22 Sep 2022, Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, median age 58.9, 120 authors, study period 5 May, 2020 - 26 May, 2021, average treatment delay 8.9 days, trial NCT04373733 (history)
Favipiravir in patients hospitalised with COVID-19 (PIONEER
trial): a multicentre, open-label, phase 3, randomised
controlled trial of early intervention versus standard care
Pallav L Shah*, Christopher M Orton*, Beatriz Grinsztejn, Gavin C Donaldson, Brenda Crabtree Ramírez, James Tonkin, Breno R Santos,
Sandra W Cardoso, Andrew I Ritchie, Francesca Conway, Maria P D Riberio, Dexter J Wiseman, Anand Tana, Bavithra Vijayakumar,
Cielito Caneja, Craig Leaper, Bobby Mann, Anda Samson, Pankaj K Bhavsar, Marta Boffito, Mark R Johnson, Anton Pozniak, Michael Pelly,
for the PIONEER trial group†
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,
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+.
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
is less effective
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