Nafamostat in hospitalized patients with moderate to severe COVID-19 pneumonia: a randomised Phase II clinical trial
Nafamostat, a serine protease inhibitor, has been used for the treatment of disseminated intravascular coagulation and pancreatitis. In vitro studies and clinical reports suggest its beneficial effect in the treatment of COVID-19 pneumonia. This phase 2 open-label, randomised, multicentre, controlle...
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Published in | EClinicalMedicine Vol. 41; p. 101169 |
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01.11.2021
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Abstract | Nafamostat, a serine protease inhibitor, has been used for the treatment of disseminated intravascular coagulation and pancreatitis. In vitro studies and clinical reports suggest its beneficial effect in the treatment of COVID-19 pneumonia.
This phase 2 open-label, randomised, multicentre, controlled trial evaluated nafamostat (4.8 mg/kg/day) plus standard-of-care (SOC) in hospitalised patients with COVID-19 pneumonia (i.e., those requiring nasal high-flow oxygen therapy and/or non-invasive mechanical ventilation). The primary outcome was the time to clinical improvement. Key secondary outcomes included the time to recovery, rates of recovery and National Early Warning Score (NEWS). The trial is registered with ClinicalTrials.gov Identifier: NCT04623021.
A total of 104 patients, mean age 58.6 years were enrolled in 13 clinical centres in Russia between 25/9/2020 and 14/11/2020 and randomised to nafamostat plus SOC (n=53) or SOC alone (n=51). There was no significant difference in time to clinical improvement (primary endpoint) between the nafamostat and SOC groups (median 11 [interquartile range (IQR) 9 to 14) vs 11 [IQR 9 to 14] days; Rate Ratio [RR; the ratio for clinical improvement], 1.00; 95% CI, 0.65 to 1.57; p=0.953). In 36 patients with baseline NEWS ≥7, nafamostat was superior to SOC alone in median time to clinical improvement (11 vs 14 days; RR, 2.89; 95% CI, 1.17 to 7.14; p=0.012). Patients receiving nafamostat in this subgroup had a significantly higher recovery rate compared with SOC alone (61.1% (11/18) vs 11.1 % (2/18) by Day 11, p=0.002). The 28-day mortality was 1.9% (1/52) for nafamostat and 8.0% (4/50) for SOC (95% CI, -17.0 to 3.4; p=0.155). No case of COVID-19 related serious adverse events leading to death was recorded in the patients receiving nafamostat.
Our study found no significant difference in time to clinical improvement between the nafamostat and SOC groups, but a shorter median time to clinical improvement in a small group of high-risk COVID-19 patients requiring oxygen treatment. To assess the efficacy further, a larger Phase 3 clinical trial is warranted.
Korea Research Institute of Bioscience and Biotechnology [2020M3A9H5108928] and Chong Kun Dang (CKD) Pharm (Seoul, Korea). |
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AbstractList | Background: Nafamostat, a serine protease inhibitor, has been used for the treatment of disseminated intravascular coagulation and pancreatitis. In vitro studies and clinical reports suggest its beneficial effect in the treatment of COVID-19 pneumonia. Methods: This phase 2 open-label, randomised, multicentre, controlled trial evaluated nafamostat (4.8 mg/kg/day) plus standard-of-care (SOC) in hospitalised patients with COVID-19 pneumonia (i.e., those requiring nasal high-flow oxygen therapy and/or non-invasive mechanical ventilation). The primary outcome was the time to clinical improvement. Key secondary outcomes included the time to recovery, rates of recovery and National Early Warning Score (NEWS). The trial is registered with ClinicalTrials.gov Identifier: NCT04623021. Findings: A total of 104 patients, mean age 58.6 years were enrolled in 13 clinical centres in Russia between 25/9/2020 and 14/11/2020 and randomised to nafamostat plus SOC (n=53) or SOC alone (n=51). There was no significant difference in time to clinical improvement (primary endpoint) between the nafamostat and SOC groups (median 11 [interquartile range (IQR) 9 to 14) vs 11 [IQR 9 to 14] days; Rate Ratio [RR; the ratio for clinical improvement], 1.00; 95% CI, 0.65 to 1.57; p=0.953). In 36 patients with baseline NEWS ≥7, nafamostat was superior to SOC alone in median time to clinical improvement (11 vs 14 days; RR, 2.89; 95% CI, 1.17 to 7.14; p=0.012). Patients receiving nafamostat in this subgroup had a significantly higher recovery rate compared with SOC alone (61.1% (11/18) vs 11.1 % (2/18) by Day 11, p=0.002). The 28-day mortality was 1.9% (1/52) for nafamostat and 8.0% (4/50) for SOC (95% CI, -17.0 to 3.4; p=0.155). No case of COVID-19 related serious adverse events leading to death was recorded in the patients receiving nafamostat. Interpretation: Our study found no significant difference in time to clinical improvement between the nafamostat and SOC groups, but a shorter median time to clinical improvement in a small group of high-risk COVID-19 patients requiring oxygen treatment. To assess the efficacy further, a larger Phase 3 clinical trial is warranted. Funding: Korea Research Institute of Bioscience and Biotechnology [2020M3A9H5108928] and Chong Kun Dang (CKD) Pharm (Seoul, Korea). Nafamostat, a serine protease inhibitor, has been used for the treatment of disseminated intravascular coagulation and pancreatitis. In vitro studies and clinical reports suggest its beneficial effect in the treatment of COVID-19 pneumonia. This phase 2 open-label, randomised, multicentre, controlled trial evaluated nafamostat (4.8 mg/kg/day) plus standard-of-care (SOC) in hospitalised patients with COVID-19 pneumonia (i.e., those requiring nasal high-flow oxygen therapy and/or non-invasive mechanical ventilation). The primary outcome was the time to clinical improvement. Key secondary outcomes included the time to recovery, rates of recovery and National Early Warning Score (NEWS). The trial is registered with ClinicalTrials.gov Identifier: NCT04623021. A total of 104 patients, mean age 58.6 years were enrolled in 13 clinical centres in Russia between 25/9/2020 and 14/11/2020 and randomised to nafamostat plus SOC (n=53) or SOC alone (n=51). There was no significant difference in time to clinical improvement (primary endpoint) between the nafamostat and SOC groups (median 11 [interquartile range (IQR) 9 to 14) vs 11 [IQR 9 to 14] days; Rate Ratio [RR; the ratio for clinical improvement], 1.00; 95% CI, 0.65 to 1.57; p=0.953). In 36 patients with baseline NEWS ≥7, nafamostat was superior to SOC alone in median time to clinical improvement (11 vs 14 days; RR, 2.89; 95% CI, 1.17 to 7.14; p=0.012). Patients receiving nafamostat in this subgroup had a significantly higher recovery rate compared with SOC alone (61.1% (11/18) vs 11.1 % (2/18) by Day 11, p=0.002). The 28-day mortality was 1.9% (1/52) for nafamostat and 8.0% (4/50) for SOC (95% CI, -17.0 to 3.4; p=0.155). No case of COVID-19 related serious adverse events leading to death was recorded in the patients receiving nafamostat. Our study found no significant difference in time to clinical improvement between the nafamostat and SOC groups, but a shorter median time to clinical improvement in a small group of high-risk COVID-19 patients requiring oxygen treatment. To assess the efficacy further, a larger Phase 3 clinical trial is warranted. Korea Research Institute of Bioscience and Biotechnology [2020M3A9H5108928] and Chong Kun Dang (CKD) Pharm (Seoul, Korea). BACKGROUNDNafamostat, a serine protease inhibitor, has been used for the treatment of disseminated intravascular coagulation and pancreatitis. In vitro studies and clinical reports suggest its beneficial effect in the treatment of COVID-19 pneumonia. METHODSThis phase 2 open-label, randomised, multicentre, controlled trial evaluated nafamostat (4.8 mg/kg/day) plus standard-of-care (SOC) in hospitalised patients with COVID-19 pneumonia (i.e., those requiring nasal high-flow oxygen therapy and/or non-invasive mechanical ventilation). The primary outcome was the time to clinical improvement. Key secondary outcomes included the time to recovery, rates of recovery and National Early Warning Score (NEWS). The trial is registered with ClinicalTrials.gov Identifier: NCT04623021. FINDINGSA total of 104 patients, mean age 58.6 years were enrolled in 13 clinical centres in Russia between 25/9/2020 and 14/11/2020 and randomised to nafamostat plus SOC (n=53) or SOC alone (n=51). There was no significant difference in time to clinical improvement (primary endpoint) between the nafamostat and SOC groups (median 11 [interquartile range (IQR) 9 to 14) vs 11 [IQR 9 to 14] days; Rate Ratio [RR; the ratio for clinical improvement], 1.00; 95% CI, 0.65 to 1.57; p=0.953). In 36 patients with baseline NEWS ≥7, nafamostat was superior to SOC alone in median time to clinical improvement (11 vs 14 days; RR, 2.89; 95% CI, 1.17 to 7.14; p=0.012). Patients receiving nafamostat in this subgroup had a significantly higher recovery rate compared with SOC alone (61.1% (11/18) vs 11.1 % (2/18) by Day 11, p=0.002). The 28-day mortality was 1.9% (1/52) for nafamostat and 8.0% (4/50) for SOC (95% CI, -17.0 to 3.4; p=0.155). No case of COVID-19 related serious adverse events leading to death was recorded in the patients receiving nafamostat. INTERPRETATIONOur study found no significant difference in time to clinical improvement between the nafamostat and SOC groups, but a shorter median time to clinical improvement in a small group of high-risk COVID-19 patients requiring oxygen treatment. To assess the efficacy further, a larger Phase 3 clinical trial is warranted. FUNDINGKorea Research Institute of Bioscience and Biotechnology [2020M3A9H5108928] and Chong Kun Dang (CKD) Pharm (Seoul, Korea). |
ArticleNumber | 101169 |
Author | Burlaka, Oleg O Hong, Ka Young Gritsan, Alexey I Khmelnitskiy, Oleg K Goloshchekin, Boris M Kim, Seieun Zhuravel, Sergey V |
Author_xml | – sequence: 1 givenname: Sergey V surname: Zhuravel fullname: Zhuravel, Sergey V email: zhsergey5@gmail.com organization: State Budgetary Healthcare Institution "N.V. Sklifosovsky Research Institute for Emergency Medicine of Health Department of Moscow", Russia – sequence: 2 givenname: Oleg K surname: Khmelnitskiy fullname: Khmelnitskiy, Oleg K organization: St Petersburg State Budgetary Health Pokrovskaya City Hospital, St Petersburg, Russia – sequence: 3 givenname: Oleg O surname: Burlaka fullname: Burlaka, Oleg O organization: St Petersburg State Budgetary Healthcare Institution “City Aleksandrovskaya Hospital”, St Petersburg, Russia – sequence: 4 givenname: Alexey I surname: Gritsan fullname: Gritsan, Alexey I organization: V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Regional State Budgetary Healthcare Institution, “Krasnoyarsk Regional Clinical Hospital”, Krasnoyarsk, Russia – sequence: 5 givenname: Boris M surname: Goloshchekin fullname: Goloshchekin, Boris M organization: St Petersburg State Budget Healthcare Institution City Hospital 15, St Petersburg, Russia – sequence: 6 givenname: Seieun surname: Kim fullname: Kim, Seieun organization: Chong Kun Dang (CKD) Pharm., Seoul, South Korea – sequence: 7 givenname: Ka Young orcidid: 0000-0002-6079-8259 surname: Hong fullname: Hong, Ka Young organization: Chong Kun Dang (CKD) Pharm., Seoul, South Korea |
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Keywords | COVID-19 Nafamostat Pneumonia randomized clinical trial Coronavirus disease 2019 (Covid-19) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nafamostat mesilate Russia |
Language | English |
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Snippet | Nafamostat, a serine protease inhibitor, has been used for the treatment of disseminated intravascular coagulation and pancreatitis. In vitro studies and... BACKGROUNDNafamostat, a serine protease inhibitor, has been used for the treatment of disseminated intravascular coagulation and pancreatitis. In vitro studies... Background: Nafamostat, a serine protease inhibitor, has been used for the treatment of disseminated intravascular coagulation and pancreatitis. In vitro... |
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SubjectTerms | Coronavirus disease 2019 (Covid-19) COVID-19 Nafamostat Nafamostat mesilate Pneumonia randomized clinical trial Research paper Russia Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) |
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Title | Nafamostat in hospitalized patients with moderate to severe COVID-19 pneumonia: a randomised Phase II clinical trial |
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