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

Autor:	Quinn TM; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Gaughan EE; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Bruce A; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Antonelli J; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., O'Connor R; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Li F; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., McNamara S; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Koch O; Regional Infectious Disease Unit, NHS Lothian, UK., MacKintosh C; Regional Infectious Disease Unit, NHS Lothian, UK., Dockrell D; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK; Regional Infectious Disease Unit, NHS Lothian, UK., Walsh T; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Blyth KG; Institute of Cancer Sciences, University of Glasgow, UK., Church C; Department of Respiratory Medicine, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde Health Board, Glasgow, UK., Schwarze J; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Boz C; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Valanciute A; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Burgess M; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Emanuel P; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Mills B; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Rinaldi G; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Hardisty G; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Mills R; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Findlay EG; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Jabbal S; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Duncan A; Regional Infectious Disease Unit, NHS Lothian, UK., Plant S; Regional Infectious Disease Unit, NHS Lothian, UK., Marshall ADL; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Young I; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Russell K; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Scholefield E; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Nimmo AF; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Nazarov IB; Latus Therapeutics, Oxford, UK; Department of Pharmacology, University of Oxford, Oxford, UK., Churchill GC; Department of Pharmacology, University of Oxford, Oxford, UK., McCullagh JSO; Department of Chemistry, University of Oxford, Oxford, UK., Ebrahimi KH; Institute of Pharmaceutical Science, King's College London, UK., Ferrett C; Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Templeton K; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Rannard S; Centre of Excellence for Long-acting Therapeutics, Materials Innovation Factory and Department of Pharmacology and Therapeutics, University of Liverpool, UK., Owen A; Centre of Excellence for Long-acting Therapeutics, Materials Innovation Factory and Department of Pharmacology and Therapeutics, University of Liverpool, UK., Moore A; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Finlayson K; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Shankar-Hari M; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK., Norrie J; Centre for Cardiovascular Science, Queen's Medical Research Institute, Bioquarter, University of Edinburgh, Edinburgh, UK., Parker RA; Edinburgh Clinical Trials Unit (ECTU), Usher Institute, University of Edinburgh, Edinburgh, UK., Akram AR; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Anthony DC; Department of Pharmacology, University of Oxford, Oxford, UK., Dear JW; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh,; Centre for Cardiovascular Science, Queen's Medical Research Institute, Bioquarter, University of Edinburgh, Edinburgh, UK., Hirani N; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh., Dhaliwal K; Centre for Inflammation Research, Queen's Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh,. Electronic address: Kev.Dhaliwal@ed.ac.uk.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2022 Feb; Vol. 76, pp. 103856. Date of Electronic Publication: 2022 Feb 11.
DOI:	10.1016/j.ebiom.2022.103856
Abstrakt:	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). Competing Interests: Declaration of interests The authors report no conflict of interests. (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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