Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics

Tom M. Quinn, Erin E. Gaughan, Annya Bruce, Jean Antonelli, Richard O'Connor, Feng Li, Sarah McNamara, Oliver Koch, Claire MacKintosh, David Dockrell, Timothy Walsh, Kevin G. Blyth, Colin Church, Jürgen Schwarze, Cecilia Boz, Asta Valanciute, Matthew Burgess, Philip Emanuel, Bethany Mills, Giulia RinaldiGareth Hardisty, Ross Mills, Emily Gwyer Findlay, Sunny Jabbal, Andrew Duncan, Sinéad Plant, Adam D.L. Marshall, Irene Young, Kay Russell, Emma Scholefield, Alastair F. Nimmo, Islom B. Nazarov, Grant C. Churchill, James S.O. McCullagh, Kourosh H. Ebrahimi, Colin Ferrett, Kate Templeton, Steve Rannard, Andrew Owen, Anne Moore, Keith Finlayson, Manu Shankar-Hari, John Norrie, Richard A. Parker, Ahsan R. Akram, Daniel C. Anthony, James W. Dear, Nik Hirani, Kevin Dhaliwal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

Background: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. Methods: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. Findings: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 – 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43–18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55–95% CI 0.31–0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. Interpretation: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. Funding: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Original languageEnglish
Article number103856
JournalEBioMedicine
Volume76
Early online date10 Feb 2022
DOIs
Publication statusPublished - Feb 2022

Keywords

  • Infectious diseases
  • Nafamostat mesylate
  • Respiratory medicine
  • SARS-CoV-2/COVID-19
  • Total manuscript word count

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