A Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis induced AKI (LiMiT AKI)

二甲双胍治疗脓毒症引起的 AKI (LiMiT AKI) 的安全性和可行性的随机临床试验

• 批准号: 10656829
• 负责人: Hernando Gomez Danies
• 金额: $ 31.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-19 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656829
• 关键词: 5' -AMP-activated protein kinase; Accounting; Acute Renal Failure with Renal Papillary Necrosis; Address; Adherence; Adult; Affect; Agreement; Biological; Biological Markers; Blood Platelets; Cardiac; Cellular Metabolic Process; Cessation of life; Clinical Trials Design; Consensus; Consent; Control Groups; Data; Development; Diagnosis; Dose; Drops; Drug Kinetics; Effectiveness; Enteral; Exposure to; Feasibility Studies; Feedback; Functional disorder; Funding; Future; Goals; Heterogeneity; Hospitalization; Human; Hypoglycemia; Immune; Immune response; Infection; Injury to Kidney; Intensive Care Units; International; Intervention; Kidney; Knowledge; Life; Meta-Analysis; Metabolic acidosis; Metformin; Mitochondria; Mitochondrial Electron Transport Complex I; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Oral; Organ; Outcome; Pathway interactions; Patient Admission; Patients; Persons; Pharmaceutical Preparations; Physicians; Placebo Control; Placebos; Predisposition; Protocols documentation; Randomized; Recommendation; Recovery; Regimen; Reporting; Respiration; Retrospective Studies; Risk Factors; Safety; Sepsis; Septic Shock; Serious Adverse Event; Stress; TIMP2 gene; Traumatic Brain Injury; Western Blotting; arm; design; diabetic patient; efficacy evaluation; efficacy trial; energy balance; extracellular; follow-up; gastrointestinal; improved; mitochondrial dysfunction; mitochondrial metabolism; mortality; mortality risk; non-diabetic; organ injury; patient screening; pharmacologic; prevent; protective effect; randomized, clinical trials; recruit; safety and feasibility; safety assessment; septic; therapeutic candidate; treatment arm; treatment strategy; urinary

ABSTRACT Acute kidney injury (AKI) is an independent risk factor for death that affects 10-15% of hospitalized patients and more than 50% of patients admitted to the intensive care unit. The most frequent cause of AKI is sepsis, which affects 48 million people worldwide every year. Importantly, the 6-8-fold increase in the risk of death that AKI carries in sepsis may be reversible because patients with sepsis who recover from AKI have similar 1- and 3-year mortality as those without AKI. These data agree with evidence showing that the development of AKI carries far-reaching consequences like remote organ dysfunction and an increased susceptibility to infection. These data suggest that AKI may be in the causal pathway to death from sepsis and that efforts to reverse AKI may improve the survival in patients with sepsis. However, there are no specific therapies to reverse or prevent the development of AKI during sepsis. We have recently demonstrated that AMP-activated protein kinase (AMPK), a ubiquitous master regulator of cell metabolism and energy balance, is critical to protect the kidney from injury and enhance survival during experimental sepsis. We and others have shown that pharmacologic activation of AMPK protects from AKI and improves survival, while inhibition increases kidney injury and death. Interestingly, metformin, the recommended first-line agent for the treatment of type 2 diabetes mellitus is a known AMPK activator. Based on this, we have demonstrated that treatment with metformin decreases mortal- ity during experimental sepsis. Multiple observational human studies also support this idea. Two recent meta- analyses concluded that exposure to metformin was associated with a decreased risk of mortality. We con- ducted the largest propensity-score matched retrospective study to date and demonstrated that metformin is associated with a decrease in the odds of moderate-severe AKI and death at 90-days, as well as with an in- creased odds of recovery from AKI. Despite this evidence, several gaps in knowledge remain. First, it is un- clear if the protective effect of metformin is due to confounders. Second, it is unknown if the results of available studies are generalizable to non-diabetic patients. Third, despite a track record of over 60 years of use in dia- betic patients, safety has not been established in patients with septic shock. This proposal aims to conduct a randomized, placebo-controlled, feasibility study to establish the safety and feasibility of the use of oral metfor- min to prevent the development of sepsis-induced AKI, and to inform a future full-scale efficacy trial. Our over- arching hypothesis is that, in treatment of patients with sepsis, metformin is safe and effective in reducing sep- sis-induced elevations in AKI biomarkers. We will determine the safety of the use of metformin to treat adult patients with sepsis, and we will determine the pharmacokinetic profile of oral metformin (Aim 1), the feasibility of implementing this therapy (Aim 2), and estimate the heterogeneity of the effect of metformin on markers of kidney injury/stress and on circulating platelet mitochondrial function (Aim 3). This study is the first critical step to inform the design of a future, full-scale efficacy RCT.

抽象的 急性肾脏损伤（AKI）是死亡的独立危险因素，影响10-15％的住院患者 超过50％的患者进入重症监护病房。 AKI的最常见原因是败血症， 每年都会影响全球4800万人。重要的是，死亡风险增加了6-8倍 AKI携带败血症可能是可逆的，因为从AKI中恢复过的败血症患者具有相似的1-和 3年死亡率是没有AKI的人。这些数据与表明AKI发展的证据一致 带来了深远的后果，例如远程器官功能障碍以及对感染的敏感性增加。 这些数据表明，AKI可能处于败血症死亡的因果途径，并扭转AKI的努力 可以改善败血症患者的生存率。但是，没有具体的疗法可以逆转或预防 败血症期间AKI的发展。我们最近证明了AMP激活的蛋白激酶 （AMPK），无处不在的细胞代谢和能量平衡的主调节器，对于保护肾脏至关重要 在实验性败血症过程中受伤并增强生存率。我们和其他人已经表明了药理学 AMPK的激活可保护AKI并提高生存率，而抑制作用会增加肾脏损伤和死亡。 有趣的是，二甲双胍，建议治疗2型糖尿病的一线药物是 已知的AMPK激活剂。基于此，我们已经证明，二甲双胍的治疗可降低致命 实验性败血症期间。多个观察性人类研究也支持这一想法。最近两个元 分析得出的结论是，暴露于二甲双胍与死亡率降低有关。我们con- 迄今为止，导管最大的倾向得分匹配的回顾性研究，并证明二甲双胍是 与中度严重的AKI和90天死亡的几率减少有关，以及 从AKI恢复的几率。尽管有这些证据，但知识的差距仍然存在。首先，这是 清楚地清楚二甲双胍的保护作用是否是由于混杂因素引起的。其次，未知是否可用结果 研究可推广到非糖尿病患者。第三，尽管有60多年的往绩记录 - BETIC患者，在败血性休克患者中尚未确定安全性。该建议旨在进行 随机，安慰剂对照的可行性研究，以确定使用口服Metfor-的安全性和可行性 最小的目的是防止败血症引起的AKI的发展，并为将来的全尺度功效试验提供信息。我们的 拱形假设是，在治疗败血症患者时，二甲双胍可安全有效地减少sep- SIS引起的AKI生物标志物的海拔。我们将确定使用二甲双胍治疗成人的安全性 败血症患者，我们将确定口服二甲双胍的药代动力学特征（AIM 1），可行性 实施这种疗法（AIM 2），并估计二甲双胍对标记的影响的异质性 肾脏损伤/应力和循环血小板线粒体功能（AIM 3）。这项研究是第一个关键步骤 告知设计未来的全尺度功效RCT。