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

衰老细胞（SnCs）代表了伴随衰老过程并以其为特征的抗凋亡的另一种细胞命运。许多这些细胞，包括免疫衰老细胞，表现出高度促炎衰老相关的分泌表型，这可能有助于炎症在初始刺激后的恶性循环，如急性感染，最终导致器官衰竭和败血症。脓毒症是院内和重症监护病房死亡的主要原因，老年患者的早期和长期预后都不佳。新型的抗衰老药物，如非瑟酮，一种类黄酮的天然产物，在败血症的临床前模型中有效地减少衰老细胞，炎症和器官衰竭。然而，在人类患者中，剂量、药物靶向性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败血症中衰老治疗潜力的科学研究。为了实现这一目标，我们将开展一项多中心自适应、剂量发现、安慰剂对照、盲法、随机对照试验，有三个目标。第一个目的是确定非瑟酮的最佳有效剂量，以减少老年住院急性感染患者的SnCs。我们将招募尚未需要机械通气或血管加压药物的急性感染的老年患者，并使用临床相关的大剂量非赛特酮或安慰剂随机分配几种剂量之一，并测试短期（7天）和中期（28天）对外周测量SnCs的影响。第二个目标将测试治疗对外周炎症的影响，特别关注SnCs影响的途径和与败血症相关的途径。最后，该试验将在1周内使用有效的测量方法测量对器官衰竭的影响，并使用贝叶斯范式来确定最终3期试验成功的预测概率。这项研究的预期影响是很高的。该项目将促进对SnCs与脓毒症病理生理关系的理解，确定非塞汀是否有效调节衰老个体的这些炎症途径，并确定是否需要进一步的研究投资进行明确的试验。

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.