Abstract: TYPE Clinical Trial PUBLISHED 24 February 2023 DOI 10.3389/fmed.2023.1095828 OPEN ACCESS EDITED BY Shisan (Bob) Bao, The University of Sydney, Australia REVIEWED BY Connor Bamford, Queen's University Belfast, United Kingdom Bryan D. Kraft, Duke University, United States *CORRESPONDENCE Raymond T. Chung chung.raymond@mgh.harvard.edu Peginterferon lambda for the treatment of hospitalized patients with mild COVID-19: A pilot phase 2 randomized placebo-controlled trial Myung-Ho Kim 1,2, Josh Elbaz 1,3, Nikolaus Jilg 4,5, Jenna L. Gustafson 1,5, Min Xu 1,5, Dilara Hatipoglu 5, Eric Nohelty 4,5, Arthur Y. Kim 4,5 and Raymond T. Chung 1,5* Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, 2 Department of Internal Korean Medicine, Woosuk University Medical Center, Jeonju, Republic of Korea, 3 Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States, 4 Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School Boston, Boston, MA, United States, 5 Department of Medicine, Massachusetts General Hospital, Boston, MA, United States 1 SPECIALTY SECTION This article was submitted to Infectious Diseases: Pathogenesis and Therapy, a section of the journal Frontiers in Medicine RECEIVED 11 November 2022 ACCEPTED 08 February 2023 PUBLISHED 24 February 2023 CITATION Kim MH, Elbaz J, Jilg N, Gustafson JL, Xu M, Hatipoglu D, Nohelty E, Kim AY and Chung RT (2023) Peginterferon lambda for the treatment of hospitalized patients with mild COVID-19: A pilot phase 2 randomized placebo-controlled trial. Front. Med. 10:1095828. doi: 10.3389/fmed.2023.1095828 COPYRIGHT © 2023 Kim, Elbaz, Jilg, Gustafson, Xu, Hatipoglu, Nohelty, Kim and Chung. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Background: This study aimed to investigate the efficacy and safety of subcutaneous injection of peginterferon lambda in patients hospitalized with COVID-19. Methods: In this study (NCT04343976), patients admitted to hospital with COVID-19 confirmed by RT-PCR from nasopharyngeal swab were randomly assigned within 48 h to receive peginterferon lambda or placebo in a 1:1 ratio. Participants were subcutaneously injected with a peginterferon lambda or saline placebo at baseline and day 7 and were followed up until day 14. Results: We enrolled 14 participants; 6 participants (85.7%) in the peginterferon lambda group and 1 participant (14.3%) in the placebo group were treated with remdesivir prior to enrollment. Fifty percent of participants were SARS-CoV-2 RNA negative at baseline although they tested SARS-CoV-2 RNA positive within 48h of randomization. Among participants who were SARS-CoV-2 positive at baseline, 2 out of 5 participants (40%) in the peginterferon lambda group became negative at day 14, while 0 out of 2 participants (0%) in the placebo group achieved negativity for SARS-CoV-2 by day 14 (p>0.05). The median change in viral load (log copies per ml) was +1.72 (IQR −2.78 to 3.19) in the placebo group and −2.22..