RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial

DOI record: { "DOI": "10.3390/arm92030021", "ISSN": [ "2543-6031" ], "URL": "http://dx.doi.org/10.3390/arm92030021", "abstract": "<jats:p>Enisamium is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication. We evaluated the clinical efficacy of enisamium treatment combined with standard care in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. Hospitalized patients with laboratory-confirmed SARS-CoV-2 infection were randomly assigned to receive either enisamium (500 mg per dose, four times a day) or a placebo. The primary outcome was an improvement of at least two points on an eight-point severity rating (SR) scale within 29 days of randomization. We initially set out to study the effect of enisamium on patients with a baseline SR of 4 or 5. However, because the study was started early in the COVID-19 pandemic, and COVID-19 had been insufficiently studied at the start of our study, an interim analysis was performed alongside a conditional power analysis in order to ensure patient safety and assess whether the treatment was likely to be beneficial for one or both groups. Following this analysis, a beneficial effect was observed for patients with an SR of 4 only, i.e., patients with moderate COVID-19 requiring supplementary oxygen. The study was continued for these COVID-19 patients. Overall, a total of 592 patients were enrolled and randomized between May 2020 and March 2021. Patients with a baseline SR of 4 were divided into two groups: 142 (49.8%) were assigned to the enisamium group and 143 (50.2%) to the placebo group. An analysis of the population showed that if patients were treated within 4 days of the onset of COVID-19 symptoms (n = 33), the median time to improvement was 8 days for the enisamium group and 13 days for the placebo group (p = 0.005). For patients treated within 10 days of the onset of COVID-19 symptoms (n = 154), the median time to improvement was 10 days for the enisamium group and 12 days for the placebo group (p = 0.002). Our findings suggest that enisamium is safe to use with COVID-19 patients, and that the observed clinical benefit of enisamium is worth reporting and studying in detail.</jats:p>", "alternative-id": [ "arm92030021" ], "author": [ { "affiliation": [ { "name": "Department of Infectious Diseases, O.O. Bogomolets National Medical University, T. Shevchenko Blvd. 13, 01601 Kyiv, Ukraine" } ], "family": "Holubovska", "given": "Olga", "sequence": "first" }, { "affiliation": [ { "name": "State Expert Center, Smolenska Str. 10, 03057 Kyiv, Ukraine" } ], "family": "Babich", "given": "Pavlo", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-2630-1827", "affiliation": [ { "name": "Department of Respiratory and Other Viral Infections, L.V. Gromashevsky Institute of Epidemiology and Infectious Diseases of the NAMS of Ukraine, Amosova Str. 5a, 03083 Kyiv, Ukraine" } ], "authenticated-orcid": false, "family": "Mironenko", "given": "Alla", "sequence": "additional" }, { "affiliation": [ { "name": "Pharmalog Institut für Klinische Forschung GmbH, Oskar-Messter-Str. 29, 85737 Ismaning, Germany" } ], "family": "Milde", "given": "Jens", "sequence": "additional" }, { "affiliation": [ { "name": "Pharmaxi LLC, Filatova Str. 10A, 01042 Kyiv, Ukraine" } ], "family": "Lebed", "given": "Yuriy", "sequence": "additional" }, { "affiliation": [ { "name": "Pharmalog Institut für Klinische Forschung GmbH, Oskar-Messter-Str. 29, 85737 Ismaning, Germany" } ], "family": "Stammer", "given": "Holger", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-3633-1309", "affiliation": [ { "name": "Regenold GmbH, Zöllinplatz 4, 79410 Badenweiler, Germany" } ], "authenticated-orcid": false, "family": "Mueller", "given": "Lutz", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA" }, { "name": "Division of Virology, Department of Pathology, University of Cambridge Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK" } ], "family": "te Velthuis", "given": "Aartjan J. W.", "sequence": "additional" }, { "affiliation": [ { "name": "Farmak Joint Stock Company, Kyrylivska Str., 04080 Kyiv, Ukraine" } ], "family": "Margitich", "given": "Victor", "sequence": "additional" }, { "affiliation": [ { "name": "Farmak Joint Stock Company, Kyrylivska Str., 04080 Kyiv, Ukraine" } ], "family": "Goy", "given": "Andrew", "sequence": "additional" } ], "container-title": "Advances in Respiratory Medicine", "container-title-short": "ARM", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2024, 5, 6 ] ], "date-time": "2024-05-06T19:09:36Z", "timestamp": 1715022576000 }, "deposited": { "date-parts": [ [ 2024, 5, 6 ] ], "date-time": "2024-05-06T20:35:20Z", "timestamp": 1715027720000 }, "funder": [ { "DOI": "10.13039/100004440", "award": [ "206579/Z/17/Z" ], "doi-asserted-by": "publisher", "name": "joint Welcome Trust and Royal Society" } ], "indexed": { "date-parts": [ [ 2024, 5, 7 ] ], "date-time": "2024-05-07T00:33:18Z", "timestamp": 1715041998627 }, "is-referenced-by-count": 0, "issue": "3", "issued": { "date-parts": [ [ 2024, 5, 6 ] ] }, "journal-issue": { "issue": "3", "published-online": { "date-parts": [ [ 2024, 6 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2024, 5, 6 ] ], "date-time": "2024-05-06T00:00:00Z", "timestamp": 1714953600000 } } ], "link": [ { "URL": "https://www.mdpi.com/2543-6031/92/3/21/pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1968", "original-title": [], "page": "202-217", "prefix": "10.3390", "published": { "date-parts": [ [ 2024, 5, 6 ] ] }, "published-online": { "date-parts": [ [ 2024, 5, 6 ] ] }, "publisher": "MDPI AG", "reference": [ { "DOI": "10.1038/s41564-020-0695-z", "article-title": "The Species Severe Acute Respiratory Syndrome-Related Coronavirus: Classifying 2019-nCoV and Naming It SARS-CoV-2", "author": "Gorbalenya", "doi-asserted-by": "crossref", "first-page": "536", "journal-title": "Nat. 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