Senolytics To slOw Progression of Sepsis (STOP-Sepsis) trial

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Senescent cells (SnCs) represent an alternative cellular fate resistant to apoptosis that accompanies and characterizes the aging process. Many of these cells, including immunosenescent cells, manifest a highly pro-inflammatory senescence-associated secretory phenotype that may contribute to a vicious cycle of inflammation following an initial stimulus, such as an acute infection, ultimately leading to organ failure and sepsis. Sepsis represents the leading cause of in-hospital and intensive care unit mortality, and older patients suffer disproportionately poor outcomes, both initially and longer term. Novel senolytic drugs such as fisetin, a flavonoid natural product, effectively reduce senescent cells, inflammation, and organ failure in preclinical models of sepsis. However, dosing, drug target engagement, and biological and clinical efficacy remain unknown in human patients. The overarching goal of this project is to advance the science surrounding the therapeutic potential of senolytics in sepsis. To achieve this goal, we will conduct a multi-center adaptive, dose-finding, placebo-controlled, blinded, randomized control trial with three aims. The first aim is to determine the optimally effective dose of fisetin to reduce SnCs in older admitted patients with an acute infection. We will enroll older patients with acute infection not yet requiring mechanical ventilation or vasopressors and randomize to one of several doses of fisetin or placebo using clinically relevant, bolus dosing and test the short (7 day) and medium term (28 day) effect on peripherally measured SnCs. The second aim will test the effect of treatment on peripherally measured inflammation, with a particular focus on pathways affected by SnCs and relevant to sepsis. Finally, the trial will measure the effect on organ failure at 1 week using validated measures and using a Bayesian paradigm to determine the predictive probability of success of a definitive Phase 3 trial. The anticipated impact of this research is high. This project will promote understanding of the relationship of SnCs to sepsis pathophysiology, determine if fisetin effectively modulates these inflammatory pathways in aging individuals, and establish whether further research investment in a definitive trial is warranted.