Theophylline Prophylaxis during Hypothermia to Limit Neonatal Nephron Damage

低温期间预防茶碱以限制新生儿肾单位损伤

• 批准号: 10656030
• 负责人: JEFFREY L SEGAR
• 金额: $ 25.85万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656030
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adherence; Adverse effects; Age Years; Aminophylline; Asphyxia Neonatorum; Attenuated; Biological Markers; Birth; Blood flow; Cessation of life; Chronic Kidney Failure; Clinical Data; Clinical Trials; Complex; Complication; Creatinine; Data; Data Analyses; Data Collection; Death Rate; Development; Diagnosis; Disease; Dose; Drug Kinetics; Effectiveness; Enrollment; Ensure; Evaluation; FDA approved; Feasibility Studies; Fluid Balance; Foundations; Functional disorder; Future; Goals; Health; Hospitalization; Hour; Hyperglycemia; Hypertension; Hypoxia; Incidence; Infant; Injury; Injury to Kidney; Intervention; Intervention Studies; Intravenous; Kidney; Life; Literature; Measures; Mechanical ventilation; Methods; Mission; Morbidity - disease rate; Multi-Institutional Clinical Trial; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Nephrons; Neurological outcome; Organ; Outcome; Output; Oxygen; Patients; Pharmacodynamics; Pilot Projects; Placebos; Population; Predisposition; Pregnancy; Prevention; Procedures; Process; Prophylactic treatment; Protocols documentation; Publishing; Regimen; Renal function; Reporting; Research; Risk; Safety; Sampling; Seizures; Serum; Severities; Tachycardia; Telephone; Testing; Theophylline; Therapeutic; Therapeutic Trials; Tubular formation; Urine; clinically relevant; experience; extracellular vesicles; improved; mortality; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; novel; novel marker; novel therapeutics; prevent; primary outcome; randomized trial; recruit; renal hypoxia; response; standard of care; targeted treatment

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is commonly seen in infants diagnosed with hypoxic-ischemic encephalopathy (HIE) and is associated with increased rates of morbidity and mortality. Currently, there are no approved therapies that target the prevention of AKI. Several small trials in infants with HIE suggest that a single dose of theophylline given soon after birth attenuates the development of AKI. However, these studies were not performed in infants being treated with therapeutic hypothermia (the current standard of care for moderate to severe HIE), and only reported short-term outcomes. Therefore, few clinicians use theophylline in the management of these patients. Our long-term goal is to undertake an appropriately powered multicenter clinical trial to test the hypothesis that for infants > 35 weeks gestation treated with therapeutic hypothermia for HIE, intravenous theophylline (or aminophylline) within the first 12 hours after birth will result in a decreased incidence and/or severity of AKI or death (composite primary outcome) and improved long-term (2 year) renal outcomes. Before the conduct of a large trial, the feasibility of implementing the intervention and ability to measure relevant clinical outcomes need to be demonstrated. Therefore, we propose a small pilot and feasibility clinical trial to i) evaluate recruitment, protocol adherence, and data collection procedures in a therapeutic trial of theophylline to decrease the incidence of AKI or death compared to placebo in infants with HIE being treated with therapeutic hypothermia; ii) evaluate the utility and applicability of established measures (serum creatinine, urine output, fluid balance) and novel, exploratory approaches (urine biomarkers, large renal tubular extracellular vesicles and renal oxygen saturation) to identify AKI in infants; and iii) determine theophylline pharmacokinetic, pharmacodynamic, safety and preliminary effectiveness profiles of two different theophylline dosing regimens in a therapeutic trial of theophylline to decrease the incidence of AKI or death compared to placebo. Using a mixed methods data analysis strategy to assess the research and intervention process and examine outcomes of the intervention, we will generate the requisite data to inform development and implementation of an appropriately powered study to determine whether theophylline attenuates the risk and severity of AKI in infants with HIE treated with therapeutic hypothermia.

项目概要/摘要 急性肾损伤 (AKI) 常见于诊断为缺氧缺血性脑病 (HIE) 的婴儿 并与发病率和死亡率的增加有关。目前，尚无批准的治疗方法 旨在预防 AKI。对患有 HIE 的婴儿进行的几项小型试验表明，单剂量 出生后不久给予茶碱可减轻 AKI 的发展。然而，这些研究并没有 在接受治疗性低温治疗的婴儿中进行（当前中度至中度护理标准） 严重 HIE），并且仅报告短期结果。因此，很少有临床医生在治疗中使用茶碱。 对这些患者的管理。我们的长期目标是建立一个适当动力的多中心 临床试验检验以下假设：对于妊娠 > 35 周的婴儿，采用治疗性低温治疗 HIE，出生后 12 小时内静脉注射茶碱（或氨茶碱）将导致出生后 AKI 或死亡的发生率和/或严重程度（复合主要结局）以及长期（2 年）肾功能改善 结果。在进行大型试验之前，实施干预措施的可行性和能力 需要证明测量相关的临床结果。因此，我们建议进行一个小型试点 可行性临床试验 i) 评估招募、方案遵守情况和数据收集程序 与安慰剂相比，茶碱降低婴儿 AKI 或死亡发生率的治疗试验 HIE 正在接受低温治疗； ii) 评估既定措施的效用和适用性 （血清肌酐、尿量、液体平衡）和新颖的探索性方法（尿液生物标志物、大肾 肾小管细胞外囊泡和肾氧饱和度）来识别婴儿 AKI；和 iii) 确定 两种不同茶碱的药代动力学、药效学、安全性和初步有效性概况 茶碱治疗试验中的茶碱给药方案可降低 AKI 或死亡的发生率 与安慰剂相比。使用混合方法数据分析策略来评估研究和干预 处理并检查干预结果，我们将生成必要的数据来为发展提供信息 并实施适当的动力研究以确定茶碱是否可以降低风险 接受低温治疗的 HIE 婴儿的 AKI 严重程度。