{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:59:54Z","timestamp":1790873994893,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T00:00:00Z","timestamp":1697673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Compagnia San Paolo","award":["B\/2020\/0138"],"award-info":[{"award-number":["B\/2020\/0138"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Even though SARS-CoV-2 was declared by WHO as constituting no longer a public health emergency, the development of effective treatments against SARS-CoV-2 infection remains a critical issue to prevent complications, particularly in fragile patients. The protease inhibitor nafamostat, currently used in Japan and Korea for pancreatitis, owing to its anticoagulant properties for disseminated intravascular coagulation (DIC), is appealing for the treatment of COVID-19 infection, because it potently inhibits the transmembrane protease serine 2 (TMPRSS2) that, after virus binding to ACE-2, allows virus entry into the cells and replication. Moreover, it could prevent the DIC and pulmonary embolism frequently associated with COVID-19 infection. The goal of the RAndomized Clinical Trial Of NAfamostat (RACONA) study, designed as a prospective randomized, double-blind placebo-controlled clinical trial, was to investigate the efficacy and safety of nafamostat mesylate (0.10 mg\/kg\/h iv for 7 days), on top of the optimal treatment, in COVID-19 hospitalized patients. We could screen 131 patients, but due to the predefined strict inclusion and exclusion criteria, only 15 could be randomized to group 1 (n = 7) or group 2 (n = 8). The results of an ad interim safety analysis showed similar overall trends for variables evaluating renal function, coagulation, and inflammation. No adverse events, including hyperkalemia, were found to be associated with nafamostat. Thus, the RACONA study showed a good safety profile of nafamostat, suggesting that it could be usefully used in COVID-19 hospitalized patients.<\/jats:p>","DOI":"10.3390\/jcm12206618","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T05:43:28Z","timestamp":1697694208000},"page":"6618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["RAndomized Clinical Trial Of NAfamostat Mesylate, A Potent Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor, in Patients with COVID-19 Pneumonia"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3639-4086","authenticated-orcid":false,"given":"Teresa Maria","family":"Seccia","sequence":"first","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9877-1054","authenticated-orcid":false,"given":"Tungalagtamir","family":"Shagjaa","sequence":"additional","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8767-1995","authenticated-orcid":false,"given":"Margherita","family":"Morpurgo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical & Pharmacological Sciences, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3775-0011","authenticated-orcid":false,"given":"Brasilina","family":"Caroccia","sequence":"additional","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girolama","family":"Iadicicco","sequence":"additional","affiliation":[{"name":"Pharmacy, University Hospital of Padua, 35126 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Lococo","sequence":"additional","affiliation":[{"name":"Pneumology, University Hospital of Padua, 35126 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0263-0703","authenticated-orcid":false,"given":"Maria","family":"Mazzitelli","sequence":"additional","affiliation":[{"name":"Infectious Diseases, University Hospital of Padua, 35126 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Farnia","sequence":"additional","affiliation":[{"name":"Internal Medicine 3, University Hospital of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3445-0387","authenticated-orcid":false,"given":"Paola","family":"Fioretto","sequence":"additional","affiliation":[{"name":"Internal Medicine 3, University Hospital of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7996-3720","authenticated-orcid":false,"given":"Yusuke","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Yokohama City University, Yokohama 236-0027, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7906-0580","authenticated-orcid":false,"given":"Dario","family":"Gregori","sequence":"additional","affiliation":[{"name":"Biostatistics, Epidemiology and Public Health Unit, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7963-0931","authenticated-orcid":false,"given":"Gian Paolo","family":"Rossi","sequence":"additional","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13027-022-00451-1","article-title":"Bimodal antibody-titer decline following BNT162b2 mRNA anti-SARS-CoV-2 vaccination in healthcare workers of the INT\u2014IRCCS \u201cFondazione Pascale\u201d Cancer Center (Naples, Italy)","volume":"17","author":"Russo","year":"2022","journal-title":"Infect. Agents Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1080\/14760584.2023.2174529","article-title":"Understanding the mechanisms for COVID-19 vaccine\u2019s protection against infection and severe disease","volume":"22","author":"Yang","year":"2023","journal-title":"Expert. Rev. Vaccines"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1080\/14760584.2022.2092472","article-title":"Expert review on global real-world vaccine effectiveness against SARS-CoV-2","volume":"21","author":"Chuenkitmongkol","year":"2022","journal-title":"Expert. Rev. Vaccines"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.7326\/M22-0988","article-title":"Risk for Myocardial Infarction, Stroke, and Pulmonary Embolism Following COVID-19 Vaccines in Adults Younger Than 75 Years in France","volume":"175","author":"Botton","year":"2022","journal-title":"Ann. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1001\/jamainternmed.2022.3858","article-title":"Clinical and Genetic Risk Factors for Acute Incident Venous Thromboembolism in Ambulatory Patients with COVID-19","volume":"182","author":"Xie","year":"2022","journal-title":"JAMA Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.thromres.2022.08.021","article-title":"Thromboembolic events in deceased patients with proven SARS-CoV-2 infection: Frequency, characteristics and risk factors","volume":"218","author":"Voigtlaender","year":"2022","journal-title":"Thromb. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1161\/CIRCULATIONAHA.122.060785","article-title":"Association of COVID-19 with Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales","volume":"146","author":"Knight","year":"2022","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12959-020-00250-x","article-title":"Coagulation abnormalities in SARS-CoV-2 infection: Overexpression tissue factor","volume":"18","author":"Eslamifar","year":"2020","journal-title":"Thromb. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6532","DOI":"10.1128\/AAC.01043-16","article-title":"Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay","volume":"60","author":"Yamamoto","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"571","DOI":"10.5301\/IJAO.2011.8535","article-title":"Nafamostat mesilate as an anticoagulant during continuous veno-venous hemodialysis: A three-year retrospective cohort study","volume":"34","author":"Maruyama","year":"2011","journal-title":"Int. J. Artif. Organs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2392","DOI":"10.1097\/MD.0000000000002392","article-title":"Nafamostat Mesilate as an Anticoagulant during Continuous Renal Replacement Therapy in Patients with High Bleeding Risk: A Randomized Clinical Trial","volume":"94","author":"Choi","year":"2015","journal-title":"Medicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1097\/MPA.0000000000000310","article-title":"Nafamostat mesilate for prevention of post-ERCP pancreatitis: A meta-analysis of prospective, randomized, controlled trials","volume":"44","author":"Yu","year":"2015","journal-title":"Pancreas"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s12185-018-02567-w","article-title":"Comparison of gabexate mesilate and nafamostat mesilate for disseminated intravascular coagulation associated with hematological malignancies","volume":"109","author":"Minakata","year":"2019","journal-title":"Int. J. Hematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e77444","DOI":"10.7554\/eLife.77444","article-title":"Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry","volume":"11","author":"Kastenhuber","year":"2022","journal-title":"Elife"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1254\/jjp.35.203","article-title":"Pharmacological studies of FUT-175, nafamstat mesilate. I. Inhibition of protease activity in in vitro and in vivo experiments","volume":"35","author":"Aoyama","year":"1984","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0049-3848(94)90008-6","article-title":"Effect of nafamostat mesilate, a synthetic protease inhibitor, on tissue factor-factor VIIa complex activity","volume":"74","author":"Uchiba","year":"1994","journal-title":"Thromb. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Albert, J. (2009). Bayesian Computation with R, Springer.","DOI":"10.1007\/978-0-387-92298-0"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"256","DOI":"10.22237\/jmasm\/1383279240","article-title":"Comparison of Three Calculation Methods for a Bayesian Inference of P(\u03c01 > \u03c02)","volume":"12","author":"Kawasaki","year":"2013","journal-title":"J. Mod. Appl. Stat. Methods"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"778","DOI":"10.5964\/ejop.v7i4.163","article-title":"Doing Bayesian Data Analysis: A Tutorial with R and BUGS","volume":"7","author":"Barry","year":"2011","journal-title":"Eur. J. Psychol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1002\/sim.3680","article-title":"The BUGS project: Evolution, critique and future directions","volume":"28","author":"Lunn","year":"2009","journal-title":"Stat. Med."},{"key":"ref_22","unstructured":"R Development Core Team (2020, August 02). R: A Language and Environment for Statistical Computing. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1214\/ss\/1009212673","article-title":"Power prior distributions for regression models","volume":"15","author":"Chen","year":"2000","journal-title":"Stat. Sci."},{"key":"ref_24","first-page":"101169","article-title":"Nafamostat in hospitalized patients with moderate to severe COVID-19 pneumonia: A randomised Phase II clinical trial","volume":"41","author":"Zhuravel","year":"2021","journal-title":"E Clin. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gelman, A., Carlin, J.B., Stern, H.S., Dunson, D.B., Vehtari, A., and Rubin, D.B. (2013). Bayesian Data Analysis, Chapman and Hall\/CRC.","DOI":"10.1201\/b16018"},{"key":"ref_26","first-page":"21","article-title":"Acute eosinophilic pneumonia caused by camostat mesilate: The first case report","volume":"19","author":"Ota","year":"2016","journal-title":"Respir. Med. Case Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/01.ASN.0000043900.39397.48","article-title":"Inhibition of prostasin secretion by serine protease inhibitors in the kidney","volume":"14","author":"Iwashita","year":"2003","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Nimishakavi, S., Raymond, W.W., Gruenert, D.C., and Caughey, G.H. (2015). Divergent Inhibitor Susceptibility among Airway Lumen-Accessible Tryptic Proteases. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141169"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/0306-3623(95)00072-0","article-title":"Mechanisms of hyperkalemia caused by nafamostat mesilate","volume":"26","author":"Muto","year":"1995","journal-title":"Gen. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e57278","DOI":"10.7554\/eLife.57278","article-title":"Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients","volume":"9","author":"Rossi","year":"2020","journal-title":"eLife"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Quinn, T.M., Gaughan, E.E., Bruce, A., Antonelli, J., O\u2019Connor, R., Li, F., McNamara, S., Koch, O., MacKintosh, C., and Dockrell, D. (2022). Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b\/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics. EBio Med., 76.","DOI":"10.1016\/j.ebiom.2022.103856"},{"key":"ref_32","unstructured":"Dhawan, S. (2020). Sun Pharma Laboratories Limited, Mumbai, India, Unpublished work."},{"key":"ref_33","unstructured":"Kim, D. (2020). Korea Cancer Center Hospital, Seoul, Republic of Korea, Unpublished work."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"484","DOI":"10.7883\/yoken.JJID.2021.699","article-title":"Nafamostat Mesylate Monotherapy in Patients with Moderate COVID-19: A Single-Center, Retrospective Study","volume":"75","author":"Soma","year":"2022","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Inokuchi, R., Kuno, T., Komiyama, J., Uda, K., Miyamoto, Y., Taniguchi, Y., Abe, T., Ishimaru, M., Adomi, M., and Tamiya, N. (2021). Association between Nafamostat Mesylate and In-Hospital Mortality in Patients with Coronavirus Disease 2019: A Multicenter Observational Study. J. Clin. Med., 11.","DOI":"10.3390\/jcm11010116"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e00754-20","DOI":"10.1128\/AAC.00754-20","article-title":"Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19","volume":"64","author":"Hoffmann","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1007\/s00216-008-2054-4","article-title":"A method for quantifying the unstable and highly polar drug nafamostat mesilate in human plasma with optimized solid-phase extraction and ESI-MS detection: More accurate evaluation for pharmacokinetic study","volume":"391","author":"Cao","year":"2008","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"147","DOI":"10.2133\/dmpk.21.147","article-title":"Involvement of Human Blood Arylesterases and Liver Microsomal Carboxylesterases in Nafamostat Hydrolysis","volume":"21","author":"Yamaori","year":"2006","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1001\/jama.2018.6360","article-title":"Randomization in clinical trials: Permuted blocks and stratification","volume":"319","author":"Broglio","year":"2018","journal-title":"JAMA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1056\/NEJMsr2005760","article-title":"Renin\u2013Angiotensin\u2013Aldosterone System Inhibitors in Patients with Covid-19","volume":"382","author":"Vaduganathan","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1161\/CIRCRESAHA.120.317134","article-title":"Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients with Hypertension Hospitalized With COVID-19","volume":"126","author":"Zhang","year":"2020","journal-title":"Circ. Res."},{"key":"ref_42","unstructured":"World Health Organization (2020). WHO R&D Blueprint Informal Consultation on Prioritization of Candidate Therapeutic Agents for Use in Novel Coronavirus 2019 Infection."},{"key":"ref_43","unstructured":"Lesaffre, E. (2014). Understanding Evidence-Based Rheumatology, Springer."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"507","DOI":"10.2307\/2531201","article-title":"Evaluation of Sample Size and Power for Analyses of Survival with Allowance for Nonuniform Patient Entry, Losses to Follow-Up, Noncompliance, and Stratification","volume":"42","author":"Lachin","year":"1986","journal-title":"Biometrics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"ref_46","unstructured":"R_Core Team (2020, August 02). R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing: 2020. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_47","unstructured":"Keaven Anderson, K. (2020, August 02). gsDesign: Group Sequential Design. 30-1, Package Version; 2016. Available online: https:\/\/cranr-project.org\/package=gsdesign."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/20\/6618\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:09:43Z","timestamp":1760130583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/20\/6618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,19]]},"references-count":47,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["jcm12206618"],"URL":"https:\/\/doi.org\/10.3390\/jcm12206618","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,19]]}}}