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 0.2mg/kg/hour 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.

Rights

The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Cite as

Quinn, T., Gaughan, E., Bruce, A., Antonelli, J., O'Connor, R., Li, F., McNamara, S., Koch, O., Mackintosh, C., Dockrell, D., Walsh, T., Blyth, K., Church, C., Schwarze, J., Boz, C., Valanciute, A., Burgess, M., Emanuel, P., Mills, B., Rinaldi, G., Hardisty, G., Mills, R., Gwyer Findlay, E., Jabbal, S., Duncan, A., Plant, S., Marshall, A., Young, I., Russell, K., Scholefield, E., Nimmo, A., Moore, A., Finlayson, K., Shankar-Hari, M., Parker, R., Akram, A., Dear, J., Hirani, N. & Dhaliwal, K. 2022, 'Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics', EBioMedicine, 76, article no: 103856. https://doi.org/10.1016/j.ebiom.2022.103856

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Last updated: 16 June 2022
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