Nafamostat in hospitalized patients with moderate to severe COVID-19 pneumonia: a randomised Phase II clinical trial
Dr Sergey V Zhuravel, Oleg K Khmelnitskiy, Oleg O Burlaka, Alexey I Gritsan, Boris M Goloshchekin, Seieun Kim, Ka Young Hong
eClinicalMedicine, doi:10.1016/j.eclinm.2021.101169
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, 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.
Author Contributions SVZ was the coordinating investigator and OKK, OOB, AIG and BMG were principal investigators of the study. SVZ, OKK, OOB, AIG and BMG contributed to the implementation of the study and interpretation of the data. SVZ contributed revising the manuscript for important intellectual content and had final responsibility for the decision to submit for publication with agreement of all authors. SK and KYH were involved in the study design, analysis and interpretation of the data, and contributed to writing the manuscript. All authors reviewed and approved the final manuscript.
Declaration of Competing Interest SK and KYH are both employees of CKD Pharm. The Investigators declare that the research was supported by a grant from CKD Pharm, South Korea, and have no other relationships that could be construed as a potential conflict of interest.
Data sharing statement The datasets generated for this study and relevant documents including clinical study documents (e.g., study report, study protocol, statistical analysis plan) will be made available to be shared after publication of the manuscript in a peer-reviewed journal and if regulatory activities are complete, on requests directed to the corresponding author. Prior to providing data, documents will be examined, and, if necessary, redacted and the data will be de-identified, to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study..
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