A Randomized Trial of Nafamostat for Covid-19

Susan C. Morpeth; Balasubramanian Venkatesh; James A. Totterdell; Grace M. McPhee; Robert K. Mahar; Mark Jones; Methma Bandara; Lauren A. Barina; Bhupendra K. Basnet; Asha C. Bowen; Andrew J. Burke; Belinda Cochrane; Justin T. Denholm; Ashesh Dhungana; Gregory J. Dore; Ravindra Dotel; Eamon Duffy; Jack Dummer; Hong Foo; Timothy L. Gilbey; Naomi E. Hammond; Bernard J. Hudson; Vivekanand Jha; Purnima R. Jevaji; Oommen John; Rajesh Joshi; Gagandeep Kang; Baldeep Kaur; Seungtaek Kim; Santa Kumar Das; Jillian S.Y. Lau; Roberta Littleford; Julie A. Marsh; Ian C. Marschner; Gail Matthews; Michael J. Maze; Colin J. McArthur; James D. McFadyen; James H. McMahon; Zoe K. McQuilten; James Molton; Jocelyn M. Mora; Vijaybabu Mudaliar; Vi Nguyen; Matthew V.N. O’Sullivan; Suman Pant; Jaha E. Park; David L. Paterson; David J. Price; Nigel Raymond; Megan A. Rees; James O. Robinson; Benjamin A. Rogers; Wang-Shick Ryu; Joe Sasadeusz; Omar Shum; Thomas L. Snelling; Christine Sommerville; Nanette Trask; Sharon R. Lewin; Thomas E. Hills; Joshua S. Davis; Jason A. Roberts; Steven Y.C. Tong

doi:10.1056/evidoa2300132

A Randomized Trial of Nafamostat for Covid-19

Susan C. Morpeth
, Balasubramanian Venkatesh
, James A. Totterdell
, Grace M. McPhee
, Robert K. Mahar
, Mark Jones
, Methma Bandara
, Lauren A. Barina
, Bhupendra K. Basnet
, Asha C. Bowen
, Andrew J. Burke
, Belinda Cochrane
, Justin T. Denholm
, Ashesh Dhungana
, Gregory J. Dore
, Ravindra Dotel
, Eamon Duffy
, Jack Dummer
, Hong Foo
, Timothy L. Gilbey

Naomi E. Hammond, Bernard J. Hudson, Vivekanand Jha, Purnima R. Jevaji, Oommen John, Rajesh Joshi, Gagandeep Kang, Baldeep Kaur, Seungtaek Kim, Santa Kumar Das, Jillian S.Y. Lau, Roberta Littleford, Julie A. Marsh, Ian C. Marschner, Gail Matthews, Michael J. Maze, Colin J. McArthur, James D. McFadyen, James H. McMahon, Zoe K. McQuilten, James Molton, Jocelyn M. Mora, Vijaybabu Mudaliar, Vi Nguyen, Matthew V.N. O’Sullivan, Suman Pant, Jaha E. Park, David L. Paterson, David J. Price, Nigel Raymond, Megan A. Rees, James O. Robinson, Benjamin A. Rogers, Wang-Shick Ryu, Joe Sasadeusz, Omar Shum, Thomas L. Snelling, Christine Sommerville, Nanette Trask, Sharon R. Lewin, Thomas E. Hills, Joshua S. Davis, Jason A. Roberts, Steven Y.C. Tong

Health New Zealand - Te Whatu Ora
University of Auckland
University of Queensland
The George Institute for Global Health
University of Sydney
University of Melbourne
Murdoch Children's Research Institute
Bir Hospital
Perth Children’s Hospital
Telethon Kids Institute
Prince Charles Hospital
Camden and Campbelltown Hospitals
Western Sydney University
Royal Melbourne Hospital
University of New South Wales
St. Vincent’s Hospital
Blacktown Hospital
University of Otago
Dunedin Hospital
NSW Health Pathology
Wagga Wagga Base Hospital
Royal North Shore Hospital
Manipal Academy of Higher Education
Wellcome Trust Research Laboratory
Institut Pasteur Korea
Tribhuvan University Institute of Medicine
University of Western Australia
The Alfred Hospital
Baker IDI Heart and Diabetes Institute
Alfred Health
Monash University
Monash Health
Western Health
Westmead Hospital
Tribhuvan University Teaching Hospital
Chong Kun Dang Pharmaceutical
National University of Singapore
Royal Perth Hospital
PathWest Laboratory Medicine
Wollongong Hospital
University of Wollongong
Chartered Accountants Australia and New Zealand
Medical Research Institute of New Zealand
Auckland City Hospital
The University of Newcastle Australia
Menzies School of Health Research
Metro North Health
Royal Brisbane and Women's Hospital
Montpellier University

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

Abstract

Background: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry.

Methods: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients.

Results: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants.

Conclusions: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat.

Original language	English
Number of pages	14
Journal	NEJM Evidence
Volume	2
Issue number	11
Early online date	18 Oct 2023
DOIs	https://doi.org/10.1056/evidoa2300132
Publication status	Published - 24 Oct 2023
Externally published	Yes

Bibliographical note

Funding

ASCOT is supported by the Australian Partnership for Preparedness Research on Infectious Disease Emergencies, the BHP Foundation, Health Research Council (HRC) of New Zealand (HRC 20/1068), Hospital Research Foundation, the Macquarie Group Foundation, the Minderoo Foundation, the Pratt Foundation, Royal Brisbane and Women’s Hospital Foundation, the Common Good (the Prince Charles Hospital Foundation), Wesley Medical Research, Chong Kun Dang Pharmaceutical Corp., NSW Office for Health and Medical Research, Medical Research Future Fund (MRFF2002132 and MRF9200005), and the Russell and Womersley Foundation.

Funders	Funder number
Australian Partnership for Preparedness Research on Infectious Disease Emergencies
BHP Foundation
Health Research Council of New Zealand	HRC 20/1068
Hospital Research Foundation
Macquarie Group Foundation
Minderoo Foundation
Pratt Foundation
Royal Brisbane and Women’s Hospital Foundation
The Common Good
Wesley Medical Research
Chong Kun Dang Pharmaceutical
NSW Health and Medical Research
Australian Government	MRFF2002132, MRF9200005
Russell and Womersley Foundation

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10.1056/evidoa2300132

Cite this

Morpeth, S. C., Venkatesh, B., Totterdell, J. A., McPhee, G. M., Mahar, R. K., Jones, M., Bandara, M., Barina, L. A., Basnet, B. K., Bowen, A. C., Burke, A. J., Cochrane, B., Denholm, J. T., Dhungana, A., Dore, G. J., Dotel, R., Duffy, E., Dummer, J., Foo, H., ... Tong, S. Y. C. (2023). A Randomized Trial of Nafamostat for Covid-19. NEJM Evidence, 2(11). https://doi.org/10.1056/evidoa2300132

Morpeth, SC, Venkatesh, B, Totterdell, JA, McPhee, GM, Mahar, RK, Jones, M, Bandara, M, Barina, LA, Basnet, BK, Bowen, AC, Burke, AJ, Cochrane, B, Denholm, JT, Dhungana, A, Dore, GJ, Dotel, R, Duffy, E, Dummer, J, Foo, H, Gilbey, TL, Hammond, NE, Hudson, BJ, Jha, V, Jevaji, PR, John, O, Joshi, R, Kang, G, Kaur, B, Kim, S, Das, SK, Lau, JSY, Littleford, R, Marsh, JA, Marschner, IC, Matthews, G, Maze, MJ, McArthur, CJ, McFadyen, JD, McMahon, JH, McQuilten, ZK, Molton, J, Mora, JM, Mudaliar, V, Nguyen, V, O’Sullivan, MVN, Pant, S, Park, JE, Paterson, DL, Price, DJ, Raymond, N, Rees, MA, Robinson, JO, Rogers, BA, Ryu, W-S, Sasadeusz, J, Shum, O, Snelling, TL, Sommerville, C, Trask, N, Lewin, SR, Hills, TE, Davis, JS, Roberts, JA & Tong, SYC 2023, 'A Randomized Trial of Nafamostat for Covid-19', NEJM Evidence, vol. 2, no. 11. https://doi.org/10.1056/evidoa2300132

@article{5eb36793e92d4785bc5816d7328a5822,

title = "A Randomized Trial of Nafamostat for Covid-19",

abstract = "Background: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. Methods: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. Results: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11\%) of 73 patients with usual care and 4 (5\%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95\% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93\%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1\%) of 67 and 7 (9\%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1\%) of 73 and 7 (8\%) of 82 participants. Conclusions: Among hospitalized patients with Covid-19, there was a 93\% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat.",

author = "Morpeth, \{Susan C.\} and Balasubramanian Venkatesh and Totterdell, \{James A.\} and McPhee, \{Grace M.\} and Mahar, \{Robert K.\} and Mark Jones and Methma Bandara and Barina, \{Lauren A.\} and Basnet, \{Bhupendra K.\} and Bowen, \{Asha C.\} and Burke, \{Andrew J.\} and Belinda Cochrane and Denholm, \{Justin T.\} and Ashesh Dhungana and Dore, \{Gregory J.\} and Ravindra Dotel and Eamon Duffy and Jack Dummer and Hong Foo and Gilbey, \{Timothy L.\} and Hammond, \{Naomi E.\} and Hudson, \{Bernard J.\} and Vivekanand Jha and Jevaji, \{Purnima R.\} and Oommen John and Rajesh Joshi and Gagandeep Kang and Baldeep Kaur and Seungtaek Kim and Das, \{Santa Kumar\} and Lau, \{Jillian S.Y.\} and Roberta Littleford and Marsh, \{Julie A.\} and Marschner, \{Ian C.\} and Gail Matthews and Maze, \{Michael J.\} and McArthur, \{Colin J.\} and McFadyen, \{James D.\} and McMahon, \{James H.\} and McQuilten, \{Zoe K.\} and James Molton and Mora, \{Jocelyn M.\} and Vijaybabu Mudaliar and Vi Nguyen and O{\textquoteright}Sullivan, \{Matthew V.N.\} and Suman Pant and Park, \{Jaha E.\} and Paterson, \{David L.\} and Price, \{David J.\} and Nigel Raymond and Rees, \{Megan A.\} and Robinson, \{James O.\} and Rogers, \{Benjamin A.\} and Wang-Shick Ryu and Joe Sasadeusz and Omar Shum and Snelling, \{Thomas L.\} and Christine Sommerville and Nanette Trask and Lewin, \{Sharon R.\} and Hills, \{Thomas E.\} and Davis, \{Joshua S.\} and Roberts, \{Jason A.\} and Tong, \{Steven Y.C.\}",

note = "Copyright {\textcopyright} 2023 Massachusetts Medical Society.",

year = "2023",

month = oct,

day = "24",

doi = "10.1056/evidoa2300132",

language = "English",

volume = "2",

journal = "NEJM Evidence",

issn = "2766-5526",

publisher = "Massachusetts Medical Society",

number = "11",

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TY - JOUR

T1 - A Randomized Trial of Nafamostat for Covid-19

AU - Morpeth, Susan C.

AU - Venkatesh, Balasubramanian

AU - Totterdell, James A.

AU - McPhee, Grace M.

AU - Mahar, Robert K.

AU - Jones, Mark

AU - Bandara, Methma

AU - Barina, Lauren A.

AU - Basnet, Bhupendra K.

AU - Bowen, Asha C.

AU - Burke, Andrew J.

AU - Cochrane, Belinda

AU - Denholm, Justin T.

AU - Dhungana, Ashesh

AU - Dore, Gregory J.

AU - Dotel, Ravindra

AU - Duffy, Eamon

AU - Dummer, Jack

AU - Foo, Hong

AU - Gilbey, Timothy L.

AU - Hammond, Naomi E.

AU - Hudson, Bernard J.

AU - Jha, Vivekanand

AU - Jevaji, Purnima R.

AU - John, Oommen

AU - Joshi, Rajesh

AU - Kang, Gagandeep

AU - Kaur, Baldeep

AU - Kim, Seungtaek

AU - Das, Santa Kumar

AU - Lau, Jillian S.Y.

AU - Littleford, Roberta

AU - Marsh, Julie A.

AU - Marschner, Ian C.

AU - Matthews, Gail

AU - Maze, Michael J.

AU - McArthur, Colin J.

AU - McFadyen, James D.

AU - McMahon, James H.

AU - McQuilten, Zoe K.

AU - Molton, James

AU - Mora, Jocelyn M.

AU - Mudaliar, Vijaybabu

AU - Nguyen, Vi

AU - O’Sullivan, Matthew V.N.

AU - Pant, Suman

AU - Park, Jaha E.

AU - Paterson, David L.

AU - Price, David J.

AU - Raymond, Nigel

AU - Rees, Megan A.

AU - Robinson, James O.

AU - Rogers, Benjamin A.

AU - Ryu, Wang-Shick

AU - Sasadeusz, Joe

AU - Shum, Omar

AU - Snelling, Thomas L.

AU - Sommerville, Christine

AU - Trask, Nanette

AU - Lewin, Sharon R.

AU - Hills, Thomas E.

AU - Davis, Joshua S.

AU - Roberts, Jason A.

AU - Tong, Steven Y.C.

PY - 2023/10/24

Y1 - 2023/10/24

N2 - Background: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. Methods: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. Results: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. Conclusions: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat.

AB - Background: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. Methods: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. Results: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. Conclusions: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat.

U2 - 10.1056/evidoa2300132

DO - 10.1056/evidoa2300132

M3 - Article

SN - 2766-5526

VL - 2

JO - NEJM Evidence

JF - NEJM Evidence

IS - 11

ER -

A Randomized Trial of Nafamostat for Covid-19

Abstract

Bibliographical note

Funding

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