背景:合成丝氨酸蛋白酶抑制剂阻断细胞酶跨膜蛋白酶丝氨酸2(TMPRSS2),防止SARS-CoV-2细胞进入。这一类有两种相关药物,nafamostat(静脉内制剂)和camostat(口服制剂)。
目的:确定nafamostat或camostat抑制TMPRSS2是否与COVID-19成人30天全因死亡率风险降低相关。
方法:科学数据库和临床试验注册平台。
在需要COVID-19治疗的成年人中,nafamostat或camostat与常规治疗或安慰剂的预打印或已发表的随机临床试验(RCT)。
■荟萃分析的主要结局是30天全因死亡率。次要结果包括恢复时间,不良事件(AE)和严重不良事件(SAE)。使用修订的CochraneRoB2工具对个别随机试验进行偏倚风险(RoB)评估。使用逆方差和随机效应在R包meta(v7.0-0)中进行Meta分析。协议注册号INPLASY202320120。
结果:纳入12个随机对照试验。总的来说,可用的患者数量很少(nafamostat=387;camostat=1061),符合主要结局的入选患者数量较少(nafamostat=12;camostat=13),异质性很高。在住院的成年人中,我们没有发现30天全因死亡率的差异(风险比(RR)[95%置信区间(CI):0.58[0.19,1.80],p=0.34;I2=0%;n=6)和恢复时间(平均差[95%CI]:0.08天[-0.74,0.89],p=0.86;n=2)nafamostat与常规治疗之间;以及30天全因死亡率(RR[95%CI]:0.99[0.31,3.18],p=0.99;n=2)在camostat与安慰剂之间。
结论:RCT证据无法确定nafamostat或camostat治疗成人COVID-19是否能降低死亡率和安全性。有很高的偏见风险,小样本量,RCT之间的高度异质性。
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.
METHODS: Scientific databases and clinical trial registry platforms.
UNASSIGNED: Preprints or published randomized clinical trials (RCTs) of nafamostat or camostat vs. usual care or placebo in adults requiring treatment for COVID-19.
UNASSIGNED: 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.
CONCLUSIONS: 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.