Table 1.

Recent clinical studies that target hyperinflammation in sepsis*

Anti-inflammatory agent	Mechanism of action	Study population	Primary outcome	Results	Author, year of publication or NCT number
Vitamin C	Inhibition of Nf-kb activation and HMGB1 release, enhancement of chemotaxis and phagocytosis	n = 872, proven or suspected infection (ICU stay < 24 h) and vasopressor therapy	Composite of death or persistent organ dysfunction on day 28	Higher risk of death or persistent organ dysfunction on day 28	Lamontagne et al. 2022 [42]
		n = 167, sepsis and ARDS (< 24 h)	Modified SOFA score at 96 h, CRP and thrombomodulin levels at 168 h	No significant difference in primary endpoints	Fowler et al. 2019 [40]
Hydrocortisone, vitamin C, thiamine	Pleiotropic immunomodulatory effects (e.g., inhibition of NF-kB, AP-1, endothelial and neutrophil activation)	n = 216, early septic shock (< 24 h)	Time alive and free of vasopressors on day 7	No significant difference in primary endpoints	Fujii et al. 2020 [41]
Clarithromycin	Wide-ranging immunomodulatory effects (e.g., inhibition of TLR expression and signaling, inhibition of pro-inflammatory cytokine, chemokine and DAMPs release)	n = 110, sepsis, ARDS and multiple-organ dysfunction	28-day mortality	No significant difference, lower incidence of sepsis recurrence, significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis	Karakike et al. 2022 [51]
Vilobelimab	Novel monoclonal anti-C5a antibody	n = 72, sepsis or septic shock	pharmacodynamics, pharmacokinetics, safety	Dose-dependent neutralization of C5a, higher ICU- and ventilator-free days	Bauer et al. 2021 [31]
Thrombomodulin (ART-123)	Binding of thrombin, activation of protein C, inhibition of DAMPs associated inflammation and organ injury	n = 800, sepsis-associated coagulopathy	28-day mortality	No significant difference	Vincent et al. 2019 [58]
Adrecizumab (HAM8101)	Non-neutralizing adrenomedullin antibody	n = 301, septic shock	Safety (90-day mortality, adverse events), tolerability	No significant difference in 90-day mortality and adverse events, well tolerated	Laterre et al. 2021 [63]
Cytokine adsorption	Adsorption of PAMPs, DAMPs and cytokines	n = 2611, septic shock, cardiac arrest, cardiopulmonary bypass surgery, severe illness	Longest reported mortality	No significant difference	Becker et al. 2023 [67]
Coupled plasma filtration and adsorption	Adsorption of pro-inflammatory and anti-inflammatory mediators	n = 96, septic shock	Adsorption of IL-6, vasopressor requirements, 30-day mortality	No difference in IL-6 and vasopressor requirements, increased mortality hazard ratio	Wendel Garcia et al. 2021 [65]
		n = 115, septic shock	Mortality at hospital discharge	Significantly higher mortality, trial stopped for futility	Garbero et al. 2021 [66]
Therapeutic plasma exchange (TPE)	Elimination of pro-inflammatory and replacement of protective molecules	n = 40, early septic shock (< 24 h)	Early hemodynamic improvement	Significant hemodynamic improvement over first 24 h, higher baseline lactate levels were predictive for more efficient hemodynamic improvement; significant reduction of procalcitonin (PCT), soluble receptor of tyrosine kinase with immunoglobulin-like and EGF-like domains (sTie-2), von Willebrand factor antigen (vWF:Ag); significant repletion of antithrombin-III, ADAMTS13, protein C	Stahl et al. 2022 [68] David et al. 2021 [70]
		n = 20, early septic shock (< 24 h)	Levels of endothelial glycocalyx degradation products (heparan sulfate (HS), heparinase (Hpa)-1 and -2)	HS levels significantly reduced, significantly normalized Hpa-2/Hpa-1 ratio, attenuation of eGC damage ex vivo with serum from TPE group	Stahl et al. 2021 [72]
		n = 80, septic shock and evidence of multiple-organ failure	28-day mortality	Significantly reduced 28-day mortality	Keith et al. 2020 [69]
		n = 274, early septic shock (< 24 h)	28-day mortality	Not yet recruiting	NCT05726825 (EXCHANGE-2)
		n = 80, early septic shock (< 24 h)	Feasibility of a large, multicenter trial of TPE in patients with septic shock	Not yet recruiting	NCT05093075 (PLEXSIS)

*A summary of clinical studies over last past 5 years