Pediatric Acute Liver Failure (PALF) TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)

小儿急性肝衰竭 (PALF) 免疫介导病理生理学治疗 (TRIUMPH)

• 批准号: 9678070
• 负责人: Estella M. Alonso
• 金额: $ 38.42万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9678070
• 关键词: Acetaminophen; Acute; Acute Liver Failure; Adrenal Cortex Hormones; Adverse effects; Affect; Anti-inflammatory; Antigen Receptors; Antithymoglobulin; Aplastic Anemia; Biological Markers; Blood; Blood Circulation; Blood specimen; CD8-Positive T-Lymphocytes; Caring; Case Study; Cause of Death; Cells; Child; Childhood; Chronic Childhood Arthritis; Clinical; Cytokine Receptors; Data; Data Quality; Diagnosis; Disease; Disease Progression; Dose; Double-Blind Method; Effectiveness; Enrollment; Ensure; Environmental Exposure; Equilibrium; Equus caballus; Etiology; Evaluation; Event; Failure; Foundations; Functional disorder; Future; Goals; Grant; Health; Hepatic; Hepatocyte; Immune; Immune response; Immunophenotyping; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Institutional Review Boards; Intravenous; Knowledge; Life; Liver; Liver diseases; Manuals; Measures; Mediating; Methylprednisolone; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Network Infrastructure; North America; Online Systems; Organ failure; Outcome; Participant; Pathogenesis; Patient Outcomes Assessments; Patients; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Placebos; Population; Population Analysis; Process; Prognostic Marker; Protocols documentation; Public Health; Randomized; Randomized Controlled Trials; Rare Diseases; Rehabilitation therapy; Research; Research Personnel; Resolution; Resources; Risk; Role; Safety; Sampling; Severities; Signal Transduction; Site; Steroids; Survival Rate; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Treatment Failure; Treatment outcome; Virus; Work; adaptive immune response; arm; biobank; effective therapy; efficacy testing; experience; follow-up; functional status; healing; immune activation; immune function; immunoregulation; improved; liver biopsy; liver injury; liver transplantation; mortality; operation; outcome forecast; peripheral blood; prevent; primary outcome; programs; randomized placebo controlled trial; rare condition; recruit; repository; research study; response; secondary outcome; theories; tool; treatment center; treatment trial

PROJECT SUMMARY Pediatric Acute Liver Failure (PALF) is a rare, devastating condition that affects an estimated 250 children per year in North America, causing death in approximately 15% and the need for liver transplantation (LT) in an additional 20-30%. In the majority of cases, a specific cause of the liver injury is never determined. Recent research conducted in these patients supports the theory that many of these patients have liver injury related to an abnormal immune response to everyday infections or environmental exposures. Studies have recently implicated T lymphocytes as the central drivers of the inflammatory process. Physicians caring for PALF patients are searching for therapies that quiet this T cell response, dampen the inflammatory cascade and allow the patient’s remaining liver cells to heal and regenerate. Clinical experience in children with abnormal immune responses associated with other disease states such as Systemic Juvenile Idiopathic Arthritis and Acquired Aplastic Anemia has demonstrated that both high dose corticosteroids and equine anti- thymocyte globulin can suppress immune responses and reverse progressive tissue damage. The goal of the proposed research network is to support a treatment trial of immunosuppressive therapy using high dose corticosteroids or equine anti-thymocyte globulin to reverse harmful inflammatory immune responses in children with PALF to prevent further disease progression and reduce mortality and LT in this population. We propose a double-blind, three arm, randomized, placebo controlled trial of high dose methylprednisolone or equine anti-thymocyte globulin. We will test the hypothesis that survival with native liver will be significantly higher in patients receiving immunosuppressive therapy as compared to patients that receive placebo. We will also determine the safety of immunosuppressive therapy in PALF patients and define the balance between risk of side-effects and treatment benefit. Our outcomes will include not only clinical end-points such as patient survival, time to resolution of disease and adverse health events, but also measures of patient reported outcomes during rehabilitation from the illness. Trial participants will provide blood and liver samples that will be examined to better understand their immune responses, especially that of T lymphocytes, in both the circulation and in the liver. Samples will be stored in a repository to support future studies exploring new aspects of this rare disease.

项目概要 小儿急性肝衰竭 (PALF) 是一种罕见的破坏性病症，估计影响 250 名儿童 北美每年导致约 15% 的儿童死亡，并且需要肝脏 在大多数情况下，肝移植（LT）会增加 20-30%。 最近对这些患者进行的研究支持了这样的理论： 其中许多患者患有与日常免疫反应异常相关的肝损伤。 最近的研究表明 T 淋巴细胞是导致感染或环境暴露的原因。 治疗 PALF 患者的医生正在寻找炎症过程的核心驱动因素。 平息这种 T 细胞反应、抑制炎症级联反应并允许患者 免疫异常儿童的剩余肝细胞愈合和再生的临床经验。 与其他疾病状态相关的反应，例如系统性幼年特发性关节炎和 获得性再生障碍性贫血已证明，高剂量皮质类固醇和马抗 胸腺细胞球蛋白可以抑制免疫反应并逆转进行性组织损伤。 拟议研究网络的目标是支持免疫抑制治疗试验 使用大剂量皮质类固醇或马抗胸腺细胞球蛋白的疗法可逆转有害的 PALF 儿童的炎症免疫反应，以进一步预防疾病进展和 我们提出了一种双盲、三组、随机的方法，以降低该人群的死亡率和 LT。 高剂量甲基强的松龙或马抗胸腺细胞球蛋白的安慰剂对照试验。 将检验以下假设：接受天然肝脏治疗的患者的生存率将显着提高 我们还将确定与接受安慰剂的患者相比的免疫抑制治疗。 PALF 患者免疫抑制治疗的安全性并定义风险之间的平衡 我们的结果不仅包括临床终点，例如副作用和治疗益处。 包括患者的生存率、疾病解决时间和不良健康事件，还包括 试验将提供患者报告的疾病康复结果。 将检查血液和肝脏样本以更好地了解他们的免疫反应， 尤其是循环系统和肝脏中的 T 淋巴细胞样本将被储存在其中。 一个支持未来研究探索这种罕见疾病新方面的存储库。