Table 1 Recent clinical studies that target hyperinflammation in sepsis*
From: Targeting the host response in sepsis: current approaches and future evidence
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) |