Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics

Tom Quinn; Erin E Gaughan; Annya Bruce; Jean Antonelli; Richard A 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 Rinaldi; Gareth Hardisty; Ross Mills; Emily L Gwyer Findlay; Sunny  Jabbal; Andrew Duncan; Sinead  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 E Templeton; Steve Rannard; Andrew Owen; Anne Moore; Keith Finlayson; Manu Shankar-Hari; Ahsan R Akram; Richard A Parker; James W Dear; Nik Hirani; Kevin Dhaliwal

doi:10.1016/j.ebiom.2022.103856

Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics

Tom Quinn, Erin E Gaughan, Annya Bruce, Jean Antonelli, Richard A 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 L Gwyer Findlay, Sunny Jabbal, Andrew Duncan, Sinead 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 E Templeton, Steve Rannard, Andrew Owen, Anne Moore, Keith Finlayson, Manu Shankar-Hari, Ahsan R Akram, Richard A Parker, James W Dear, Nik Hirani, Kevin Dhaliwal^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	EBioMedicine
DOIs	https://doi.org/10.1016/j.ebiom.2022.103856
Publication status	Published - 10 Feb 2022

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10.1016/j.ebiom.2022.103856

Nafamostat manuscript EBM clean_Accepted author manuscript, 5.43 MBLicence: Creative Commons: Attribution (CC-BY)

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Quinn, T., Gaughan, E. E., Bruce, A., Antonelli, J., O'Connor, R. A., Li, F., McNamara, S., Koch, O., Mackintosh, C., Dockrell, D., Walsh, T., Blyth, K. G., Church, C., Schwarze, J., Boz, C., Valanciute, A., Burgess, M., Emanuel, P., Mills, B., ... 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. https://doi.org/10.1016/j.ebiom.2022.103856

@article{490ddbdb6bf14e68a6723bc961dc34bd,

title = "Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics",

abstract = "BackgroundMany 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.MethodsWe 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.FindingsData 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.InterpretationIn 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. ",

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

note = "Funding Information: Flow cytometry data was generated with support from the QMRI Flow Cytometry and cell sorting facility, University of Edinburgh. We thank Nichi-Iko (Japan) for kindly supplying Futhan (intravenous nafamostat) for the trial; The Clinical Research Facility and staff in the Royal Infirmary of Edinburgh; the EMERGE research team; the ACCORD team at NHS Lothian/ University of Edinburgh, the patients and their families for taking part; LifeArc (an independent medical research charity) for providing funding for the clinical trial under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230). Upon request to the corresponding author, certain anonymised data generated as part of this study will be made available, permitted there is a legitimate requirement and appropriate data sharing agreements are in place. Publicly created datasets or code are not available. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = feb,

day = "10",

doi = "10.1016/j.ebiom.2022.103856",

language = "English",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

Quinn, T, Gaughan, EE, Bruce, A, Antonelli, J, O'Connor, RA , Li, F, McNamara, S, Koch, O, Mackintosh, C, Dockrell, D , Walsh, T, Blyth, KG, Church, C, Schwarze, J, Boz, C, Valanciute, A , Burgess, M , Emanuel, P , Mills, B, Rinaldi, G, Hardisty, G, Mills, R, Gwyer Findlay, EL, Jabbal, S, Duncan, A, Plant, S, Marshall, ADL, Young, I, Russell, K , Scholefield, E, Nimmo, AF, Nazarov, IB, Churchill, GC, McCullagh, JSO, Ebrahimi, KH, Ferrett, C, Templeton, KE, Rannard, S, Owen, A, Moore, A, Finlayson, K, Shankar-Hari, M , Akram, AR , Parker, RA , Dear, JW , 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. https://doi.org/10.1016/j.ebiom.2022.103856

TY - JOUR

T1 - Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics

AU - Quinn, Tom

AU - Gaughan, Erin E

AU - Bruce, Annya

AU - Antonelli, Jean

AU - O'Connor, Richard A

AU - Li, Feng

AU - McNamara, Sarah

AU - Koch, Oliver

AU - Mackintosh, Claire

AU - Dockrell, David

AU - Walsh, Timothy

AU - Blyth, Kevin G

AU - Church, Colin

AU - Schwarze, Jürgen

AU - Boz, Cecilia

AU - Valanciute, Asta

AU - Burgess, Matthew

AU - Emanuel, Philip

AU - Mills, Bethany

AU - Rinaldi, Giulia

AU - Hardisty, Gareth

AU - Mills, Ross

AU - Gwyer Findlay, Emily L

AU - Jabbal, Sunny

AU - Duncan, Andrew

AU - Plant, Sinead

AU - Marshall, Adam D L

AU - Young, Irene

AU - Russell, Kay

AU - Scholefield, Emma

AU - Nimmo, Alastair F

AU - Nazarov, Islom B

AU - Churchill, Grant C

AU - McCullagh, James S.O.

AU - Ebrahimi, Kourosh H

AU - Ferrett, Colin

AU - Templeton, Kate E

AU - Rannard, Steve

AU - Owen, Andrew

AU - Moore, Anne

AU - Finlayson, Keith

AU - Shankar-Hari, Manu

AU - Akram, Ahsan R

AU - Parker, Richard A

AU - Dear, James W

AU - Hirani, Nik

AU - Dhaliwal, Kevin

N1 - Funding Information: Flow cytometry data was generated with support from the QMRI Flow Cytometry and cell sorting facility, University of Edinburgh. We thank Nichi-Iko (Japan) for kindly supplying Futhan (intravenous nafamostat) for the trial; The Clinical Research Facility and staff in the Royal Infirmary of Edinburgh; the EMERGE research team; the ACCORD team at NHS Lothian/ University of Edinburgh, the patients and their families for taking part; LifeArc (an independent medical research charity) for providing funding for the clinical trial under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230). Upon request to the corresponding author, certain anonymised data generated as part of this study will be made available, permitted there is a legitimate requirement and appropriate data sharing agreements are in place. Publicly created datasets or code are not available. Publisher Copyright: © 2022 The Authors

PY - 2022/2/10

Y1 - 2022/2/10

N2 - BackgroundMany 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.MethodsWe 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.FindingsData 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.InterpretationIn 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.

AB - BackgroundMany 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.MethodsWe 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.FindingsData 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.InterpretationIn 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.

U2 - 10.1016/j.ebiom.2022.103856

DO - 10.1016/j.ebiom.2022.103856

M3 - Article

SN - 2352-3964

JO - EBioMedicine

JF - EBioMedicine

ER -

Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics

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