Pediatric Acute Liver Failure Immune Response Network (PALF IRN): Treatment for Immune Mediated Pathophysiology (TRIUMPH)

小儿急性肝衰竭免疫反应网络 (PALF IRN)：免疫介导的病理生理学治疗 (TRIUMPH)

• 批准号: 10180251
• 负责人: Estella M. Alonso
• 金额: $ 366.44万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180251
• 关键词: Acute Liver Failure; Adrenal Cortex Hormones; Affect; Anti-Inflammatory Agents; Antigen Receptors; Antithymoglobulin; Aplastic Anemia; Biological Markers; Blood; Blood Circulation; Blood specimen; CD8-Positive T-Lymphocytes; Caring; Case Series; Cause of Death; Cells; Child; Childhood; Clinical; Communities; Cytokine Receptors; Data Coordinating Center; Diagnosis; Disease; Disease Progression; Dose; Double-Blind Method; Drug toxicity; Effectiveness; Enrollment; Environmental Exposure; Equilibrium; Equus caballus; Etiology; Evaluation; Event; Functional disorder; Future; Goals; Health; Hepatic; Hepatocyte; Immune; Immune response; Immunophenotyping; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Intravenous; Knowledge; Life; Liver; Liver diseases; Mediating; Methylprednisolone; Minor; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Network Infrastructure; North America; Organ failure; Outcome; Participant; Pathogenesis; Patient Outcomes Assessments; Patients; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Population; Population Analysis; Process; Prognosis; Prognostic Marker; Public Health; Randomized; Randomized Controlled Trials; Rare Diseases; Rehabilitation therapy; Research; Resolution; Resources; Risk; Role; Safety; Sampling; Severities; Signal Transduction; Specimen; Steroids; Supportive care; Survival Rate; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissues; Translating; Treatment outcome; Virus; Work; adaptive immune response; arm; biobank; design; effective therapy; efficacy testing; experience; functional status; healing; immune activation; immune function; immunoregulation; improved; liver biopsy; liver injury; liver transplantation; mortality; patient subsets; peripheral blood; prevent; primary outcome; programs; randomized placebo controlled trial; rare condition; repository; research study; response; secondary outcome; side effect; systemic juvenile idiopathic arthritis; theories; 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 a hyperinflammatory 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 hyperinflammatory 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 Pediatric Acute Liver Failure Immune Response Network (PALF IRN) 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 the TReatment for ImmUne Mediated PathopHysiology (TRIUMPH) trial, 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 at 21 days post randomization will be significantly higher in patients receiving immunosuppressive therapy as compared to patients that receive supportive care alone. 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，每年影响大约 250 名儿童 年在北美造成约 15% 的死亡，并且需要移植肝 (LT) 在大多数情况下，肝损伤的具体原因从未确定。 在这些患者中进行的研究支持这样的理论，即许多患者患有与以下疾病相关的肝损伤： 研究表明，对日常感染或环境暴露的过度炎症免疫反应。 最近，护理 PALF 的医生发现 T 淋巴细胞是炎症过程的主要驱动因素。 患者正在寻找能够平息这种 T 细胞反应、抑制炎症级联反应并允许 患者剩余肝细胞异常愈合和再生的临床经验。 与其他疾病状态相关的过度炎症免疫反应，例如全身性青少年特发性 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。 儿科急性肝衰竭免疫反应网络 (PALF IRN) 将支持一项治疗试验 使用大剂量皮质类固醇或马抗胸腺细胞球蛋白的免疫抑制治疗可逆转有害的 PALF 儿童的炎症免疫反应，以进一步预防疾病进展并减少 我们建议针对该人群进行免疫介导的病理生理学治疗。 (TRIUMPH) 试验，一项高剂量甲基强的松龙的双盲、三组、随机、安慰剂对照试验 或马抗胸腺细胞球蛋白，我们将检验 21 天后天然肝脏存活的假设。 与接受免疫抑制治疗的患者相比，随机化程度明显更高 我们还将确定仅接受支持治疗的患者的免疫抑制治疗的安全性。 PALF 患者并确定副作用风险和治疗益处之间的平衡。 不仅包括临床终点，例如患者生存、疾病消退时间和不良健康状况 事件，还包括试验参与者在疾病康复期间报告的结果的测量。 将提供血液和肝脏样本，进行检查以更好地了解他们的免疫反应， 特别是循环系统和肝脏中的 T 淋巴细胞样本将被储存在储存库中。 支持未来研究探索这种罕见疾病的新方面。