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).

Keywords: COVID-19; Coronavirus disease 2019 (Covid-19); Nafamostat; Nafamostat mesilate; Pneumonia; Russia; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); randomized clinical trial.

Fig. 1

Trial profile.

Fig. 2

Achievement of clinical improvement following nafamostat or Standard of Care (SOC). Kaplan–Meier Estimates are shown in the overall FAS population (A), in population aged over 65 years (B), in patients with NEWS ≥6 (C) and in patients with NEWS ≥7 (D). Deaths before day 28 were considered to be right censored at day 28. NEWS, National Early Warning Score; N, number of patients

Fig. 3

Time to clinical improvement (A) and recovery (B) according to subgroup. Forest plots are shown in time to clinical improvement (A) and time to recovery (B) according to subgroup: age, 7-category ordinal scale, NEWS at baseline and concomitant standard care including antiviral and anti-inflammatory agents which were considered according to treatment guidelines. 7-category ordinal scale 4 (hospitalization, requiring supplemental oxygen); 5 (hospitalization, requiring nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation) *NE denotes not possible to estimate. CI, Confidential Interval; NEWS, National Early Warning Score; SOC, Standard of care