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）代表抗凋亡的替代细胞命运，伴随并表征了衰老过程。这些细胞中的许多（包括免疫感细胞）表现出高度促炎性衰老相关的分泌表型，可能会导致初始刺激后的炎症循环，例如急性感染，最终导致器官衰竭和脓毒症。败血症代表了院内和重症监护病房死亡率的主要原因，而老年患者最初和长期的效果却不成比例。新型的鼻溶液药物，例如Fisetin，一种类黄酮天然产物，有效地减少了脓毒症临床前模型中的衰老细胞，炎症和器官衰竭。但是，人类患者的剂量，药物靶标参与以及生物学和临床功效仍然未知。该项目的总体目标是促进败血症中塞溶术的治疗潜力的科学。为了实现这一目标，我们将进行多中心自适应，剂量调查，安慰剂对照，盲目的随机对照试验，并具有三个目标。第一个目的是确定最佳有效剂量的Fisetin降低急性感染的老年患者的SNC。我们将使用临床上相关的，大通给（7天和中期（28天）和测试对外围测量的SNC的临床相关，短期（7天）和中等剂量，并将急性感染的老年患者纳入不需要机械通气或加压剂的急性感染患者，并随机地与几种剂量的fisetin或安慰剂之一。第二个目的将测试治疗对外围测量炎症的影响，特别关注受SNC影响并与败血症相关的途径。最后，该试验将使用经过验证的措施和使用贝叶斯范式来确定确定确定性3期试验成功的预测概率，从而测量1周在1周内对器官故障的影响。这项研究的预期影响很高。该项目将促进对SNC与败血症病理生理学的关系的理解，确定Fisetin是否有效地调节了衰老个体的这些炎症途径，并确定是否有必要进一步研究在确定的试验中进行进一步的研究投资。