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..