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

Authors:

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

Details:

Clinical Microbiology and Infection, Volume 30, Issue 6, 2024-06-30

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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; I 2 = 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.