Nafamostat in hospitalized patients with moderate to severe COVID-19 pneumonia: a randomised Phase II clinical trial

Abstract

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).

The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment

“…However, the results are still pending (NCT04657497). A phase II clinical trial of NM was conducted in 104 hospitalized patients who suffered from COVID-19 pneumonia and required oxygen supplementation [189]. Overall, intravenous administration of NM (4.8 mg/kg/day for 10 days) failed to improve the time to clinical improvement and recovery compared with the SOC group [189].…”

“…A phase II clinical trial of NM was conducted in 104 hospitalized patients who suffered from COVID-19 pneumonia and required oxygen supplementation [189]. Overall, intravenous administration of NM (4.8 mg/kg/day for 10 days) failed to improve the time to clinical improvement and recovery compared with the SOC group [189]. However, a subgroup analysis of patients with worsened baseline clinical status revealed more rapid clinical improvement and a higher recovery rate in the study population treated with NM [189].…”

Association between Nafamostat Mesylate and In-Hospital Mortality in Patients with Coronavirus Disease 2019: A Multicenter Observational Study

“…Recently, a phase 2 open-label RCT in patients requiring nasal high-flow oxygen therapy and/or non-invasive mechanical ventilation with COVID-19 showed NM did not shorten the time to clinical improvement [ 9 ]. The result of the study supports our findings but further validation may be needed by larger RCTs.…”

“…Recent previous basic experimental [ 5 ] and case reports or series [ 2 , 6 , 7 , 8 ] have suggested the potential effectiveness of NM against COVID-19. However, to our knowledge, neither clinical trials nor observational studies, except for a recent small phase 2 open-label, randomized controlled trial (RCT) [ 9 ] have demonstrated an association between NM and reduced mortality. Therefore, we aimed to evaluate the effect of NM in patients with COVID-19 using a large-scale in-patient database in Japan.…”

SARS-CoV-2 and the Host Cell: A Tale of Interactions

“…However, even though TMPRSS2 and lysosomal cathepsins have been both demonstrated to have cumulative effects with furin on activating SARS-CoV-2 entry, inhibition of TMPRSS2 was found to be sufficient to prevent SARS-CoV-2 entry in lung cell lines and primary lung cells (148), raising hopes for their future use as antivirals in vivo. Accordingly, promising preclinical results obtained with Nafamostat, another TMPRSS2 inhibitor (149,150), are currently awaiting clinical confirmation (151).…”