US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19
Finberg et al.,
US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19,
Open Forum Infectious Diseases, doi:10.1093/ofid/ofab56310
Small very late treatment RCT in the USA, with 25 favipiravir and 25 control patients, showing faster viral clearance with treatment. The benefit was only seen in patients <8 days from symptom onset. There were no significant differences in clinical outcomes. The death in the favipiravir group occurred after discharge and was believed to be unrelated to COVID-19 or favipiravir.
risk of death, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 25 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
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risk of mechanical ventilation, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 25 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
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hospitalization time, 19.8% higher, relative time 1.20, treatment 25, control 25.
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risk of no recovery, 58.1% lower, OR 0.42, p = 0.08, treatment 25, control 25, inverted to make OR<1 favor treatment, day 8 mid-recovery, 6-point ordinal scale, RR approximated with OR.
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risk of no recovery, 46.2% higher, OR 1.46, p = 0.54, treatment 25, control 25, inverted to make OR<1 favor treatment, day 15, 6-point ordinal scale, RR approximated with OR.
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recovery time, 42.9% lower, relative time 0.57, treatment 25, control 25, median time to aggregate NEWS2 score ≤2 or discharge.
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recovery time, 15.4% higher, relative time 1.15, treatment 25, control 25.
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time to viral-, 46.7% lower, relative time 0.53, p = 0.04, treatment 25, control 25, primary outcome.
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Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
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Finberg et al., 7 Dec 2021, Randomized Controlled Trial, USA, peer-reviewed, 10 authors, average treatment delay 8.4 days.
Abstract: Open Forum Infectious Diseases
MAJOR ARTICLE
US201 Study: A Phase 2, Randomized Proof-of-Concept
Trial of Favipiravir for the Treatment of COVID-19
Robert W. Finberg,1 Madiha Ashraf,2 Boris Julg,3 Folusakin Ayoade,4 Jai G. Marathe,5 Nicolas C. Issa,6 Jennifer P. Wang,1 Siraya Jaijakul,2
Lindsey R. Baden,6 and Carol Epstein7
1
University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA, 2Houston Methodist Research Institute, Houston, Texas, USA, 3Ragon Institute of Massachusetts General
Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA, 4University of Miami Miller School of Medicine, Miami, Florida, USA, 5Department
of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA, 6Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA, and 7FUJIFILM
Pharmaceuticals USA, Inc., Cambridge, Massachusetts, USA
Favipiravir, a nucleoside analog, is active against a broad spectrum of RNA viruses. The drug directly interacts with viral
polymerases to inhibit viral RNA transcription without affecting host polymerases. A major advantage of this drug is
that it can be orally administered and sustainable serum levels
achieved. Over 40 clinical trials for favipiravir have been conducted, and it is licensed in Japan to treat influenza virus that is
unresponsive to other agents.
In influenza studies, in vitro treatment with favipiravir leads
to inaccurate transcription of the virus, resulting in virus extinction via the accumulation of multiple detrimental mutations. Such “mutational meltdown” means that escape mutants
Received 13 October 2021; editorial decision 25 October 2021; accepted 1 November 2021;
published online 7 December 2021.
Correspondence: Jennifer Wang, MD, University of Massachusetts Medical School,
Department of Medicine, Diabetes Center of Excellence, ASC 7-2047, 368 Plantation St.,
Worcester, MA 01605 (jennifer.wang@umassmed.edu).
Open Forum Infectious Diseases®2021
© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society
of America. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted
reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
https://doi.org/10.1093/ofid/ofab563
are unlikely to occur and has been demonstrated in both in
vitro and in vivo studies with influenza [1, 2]. Importantly, in
vivo and in vitro studies with influenza indicate that favipiravir
does not select for resistant strains.
Several studies indicate that favipiravir-ribofuranosyl5’triphosphate (favipiravir-RTP) can be used against SARSCoV-2. Favipiravir has been shown to inhibit replication of
SARS-CoV-2 both in vitro and in a hamster model of infection [3,
4]. The drug binds to the SARS-CoV-2 RNA-dependent RNA polymerase [5–7] and suppresses viral replication by inhibiting the
incorporation of natural nucleosides [5]. In vitro studies demonstrate that favipiravir binds to the SARS-CoV-2 polymerase and
could mimic adenine and guanine [6], suggesting that its mechanism of action in inhibiting SARS-CoV-2 is analogous to the way
it inhibits influenza. In addition, by affecting transcription fidelity,
favipiravir appears to act on SARS-CoV-2 by generating mutations that are disadvantageous to the virus, possibly leading to
“mutational..
Late treatment
is less effective
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