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

Senolytics 减缓脓毒症进展 (STOP-Sepsis) 试验

基本信息

批准号：
10663888
负责人：
Michael A. Puskarich
金额：
$ 49.96万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663888
关键词：
Acute Affect Aging Animals Anti-Inflammatory Agents Antibiotics Apoptosis Biological Biological Markers Blinded Bolus Infusion CD3 Antigens CDKN2A gene Cardiovascular system Cell Aging Cells Cessation of life Characteristics Chronic Clinical Clinical Trials Data Dose Drug Targeting Enrollment Exhibits Fire - disasters Flavonoids Functional disorder Genes Geroscience Goals Health Care Costs Hospital Mortality Hospitalization Hospitals Human Immune Immune response In Vitro Individual Infection Inflammation Inflammatory Intensive Care Units Interruption Intervention Investments Kidney Lung Lymphocyte MAP Kinase Gene Measures Mechanical ventilation Mediating Mediator Messenger RNA Molecular Multiple Organ Failure NF-kappa B National Institute on Aging Natural Products Oral Organ Organ failure Outcome Pathway interactions Patient Admission Patients Pattern Peripheral Pharmaceutical Preparations Phase II Clinical Trials Phenotype Placebo Control Placebos Plasma Pre-Clinical Model Predisposition Probability Process Prognosis Randomized Randomized, Controlled Trials Regimen Research Resistance Rodent Role Running Sampling Science Sepsis Severities Stimulus Syndrome Testing Therapeutic Vasoconstrictor Agents acute infection adverse outcome clinical application clinical efficacy clinically relevant cytokine cytokine release syndrome endothelial dysfunction fisetin hospital care human tissue inflammatory modulation kidney dysfunction mortality mortality risk multidisciplinary novel older patient participant enrollment pathogen phase II trial phase III trial pre-clinical prevent respiratory response senescence side effect success systemic inflammatory response treatment effect

项目摘要

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.

衰老细胞 (SnC) 代表了一种抵抗细胞凋亡的替代细胞命运，它伴随并表征了衰老过程。许多这些细胞，包括免疫衰老细胞，表现出高度促炎性衰老相关的分泌表型，可能在初始刺激（例如急性感染）后导致炎症的恶性循环，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，老年患者无论是最初还是长期，都遭受着不成比例的不良结果。新型抗衰老药物，如非瑟酮（一种类黄酮天然产物），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、药物靶标参与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有关 senolytics 对脓毒症治疗潜力的科学进展。为了实现这一目标，我们将进行一项具有三个目标的多中心适应性、剂量探索、安慰剂对照、盲法、随机对照试验。第一个目标是确定非瑟酮的最佳有效剂量，以减少老年急性感染患者的 SnCs。我们将招募尚未需要机械通气或血管加压药的老年急性感染患者，并使用临床相关的推注剂量随机服用几种剂量的非瑟酮或安慰剂之一，并测试对外周的短期（7 天）和中期（28 天）影响测量的 SnC。第二个目标将测试治疗对外周测量的炎症的影响，特别关注受 SnC 影响和与脓毒症相关的途径。最后，该试验将使用经过验证的措施测量 1 周时对器官衰竭的影响，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途径，并确定是否有必要在最终试验中进行进一步的研究投资。