TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of randomized clinical trials of nafamostat and camostat mesylate

María Patricia Hernández-Mitre; Susan C Morpeth; Balasubramanian Venkatesh; Thomas E Hills; Joshua Davis; Robert K Mahar; Grace McPhee; Mark Jones; James Totterdell; Steven Y C Tong; Jason A Roberts

doi:10.1016/j.cmi.2024.01.029

TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of randomized clinical trials of nafamostat and camostat mesylate

Clin Microbiol Infect. 2024 Feb 6:S1198-743X(24)00055-7. doi: 10.1016/j.cmi.2024.01.029. Online ahead of print.

Authors

Affiliations

¹ UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia.
² Departments of Microbiology and Infectious Diseases, Middlemore Hospital, Te Whatu Ora Counties Manukau, New Zealand; Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
³ Intensive Care, Princess Alexandra Hospital, The University of Queensland, Brisbane, Queensland, Australia; Intensive Care, Wesley Hospital, Brisbane, Queensland, Australia; The George Institute for Global Health, UNSW Sydney, New South Wales, Australia.
⁴ Departments of Immunology and Infectious Diseases, Auckland District Health Board, Auckland, New Zealand; Medical Research Institute of New Zealand, Wellington, New Zealand.
⁵ Infection Research Program, Hunter Medical Research Institute, Univerity of Newcastle, Newcastle, New South Wales, Australia.
⁶ Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia.
⁷ Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁸ Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁹ Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Victorian Infectious Diseases Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
¹⁰ UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia; Departments of Intensive Care Medicine and Pharmacy, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France; Herston Infectious Diseases Institute (HeIDI), Metro North Health, Herston, Queensland, Australia. Electronic address: j.roberts@uq.edu.au.

PMID: 38331253
DOI: 10.1016/j.cmi.2024.01.029

Abstract

Background: Synthetic serine protease inhibitors block the cellular enzyme transmembrane protease serine 2, thus preventing SARS-CoV-2 cell entry. There are two relevant drugs in this class, namely, nafamostat (intravenous formulation) and camostat (oral formulation).

Objective: To determine whether transmembrane protease serine 2 inhibition with nafamostat or camostat is associated with a reduced risk of 30-day all-cause mortality in adults with COVID-19.

Data sources: Scientific databases and clinical trial registry platforms.

Study eligibility criteria, interventions, and participants: Preprints or published randomized clinical trials (RCTs) of nafamostat or camostat vs. usual care or placebo in adults requiring treatment for COVID-19.

Methods of data synthesis and risk-of-bias assessment: The primary outcome of the meta-analysis was 30-day all-cause mortality. Secondary outcomes included time to recovery, adverse events, and serious adverse events. Risk of bias (RoB) was assessed using the revised Cochrane RoB 2 tool for individually randomized trials. Meta-analysis was conducted in the R package meta (v7.0-0) using inverse variance and random effects. Protocol registration number was INPLASY202320120.

Results: Twelve RCTs were included. Overall, the number of available patients was small (nafamostat = 387; camostat = 1061), the number of enrolled patients meeting the primary outcome was low (nafamostat = 12; camostat = 13), and heterogeneity was high. In hospitalized adults, we did not identify differences in 30-day all-cause mortality (risk ratio [95% CI]: 0.58 [0.19, 1.80], p 0.34; I² = 0%; n = 6) and time to recovery (mean difference [95% CI]: 0.08 days [-0.74, 0.89], p 0.86; n = 2) between nafamostat vs. usual care; and for 30-day all-cause mortality (risk ratio [95% CI]: 0.99 [0.31, 3.18], p 0.99; n = 2) between camostat vs. placebo.

Conclusion: The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults with COVID-19. There were high RoB, small sample size, and high heterogeneity between RCTs.

Keywords: COVID-19; Camostat; Clinical trials; Nafamostat; SARS-CoV-2.

Publication types

Review