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

衰老细胞（SnCs）代表了另一种细胞命运，对伴随和表征衰老过程的细胞凋亡具有抗性。其中许多细胞，包括免疫衰老细胞，表现出高度促炎衰老相关的分泌表型，这可能导致初始刺激（例如急性感染）后炎症的恶性循环，最终导致器官衰竭和败血症。脓毒症是住院和重症监护室死亡的主要原因，老年患者在最初和长期内的预后都不成比例地差。新型衰老清除药物如非瑟酮（一种黄酮类天然产物）可有效减少脓毒症临床前模型中的衰老细胞、炎症和器官衰竭。然而，人类患者的剂量、药物靶点接合以及生物学和临床疗效仍然未知。该项目的总体目标是推进围绕脓毒症中senolytics治疗潜力的科学。为了实现这一目标，我们将进行一项多中心适应性、剂量探索、安慰剂对照、盲态、随机对照试验，有三个目的。第一个目的是确定非瑟酮的最佳有效剂量，以减少患有急性感染的老年住院患者的SnCs。我们将招募患有急性感染但不需要机械通气或血管加压药的老年患者，并使用临床相关的推注剂量随机分配至几种剂量的非瑟酮或安慰剂中的一种，并测试对外周测量的SnC的短期（7天）和中期（28天）影响。第二个目标将测试治疗对外周测量炎症的影响，特别关注受SnC影响并与脓毒症相关的途径。最后，试验将使用经验证的指标和贝叶斯范式测量1周时对器官衰竭的影响，以确定确定性III期试验成功的预测概率。这项研究的预期影响很大。该项目将促进对SnCs与脓毒症病理生理学关系的理解，确定非瑟酮是否能有效调节衰老个体的这些炎症通路，并确定是否需要在确定性试验中进行进一步的研究投资。

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.