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.

项目摘要 小儿急性肝衰竭（PALF）是一种罕见的毁灭性疾病，影响约250名儿童 在北美的一年，造成约15％的死亡，并且需要肝移植（LT） 额外的20-30％。在大多数情况下，永远无法确定肝损伤的特定原因。最近的 这些患者进行的研究支持了许多患者肝损伤与 对每天感染或环境暴露的高炎性免疫反应。研究有 最近，实施了T淋巴细胞作为炎症过程的核心驱动因素。照顾Palf的医师 患者正在寻找使T细胞反应安静的疗法，该死的炎症级联反应并允许 患者剩余的肝细胞可以治愈和再生。异常儿童的临床经验 与其他疾病状态相关的高炎性免疫反应，例如全身少年特发性 关节炎并获得性性贫血表明，高剂量皮质类固醇和马抗 胸腺细胞球蛋白可以抑制免疫血液和反向进行性组织损伤。目标的目标 小儿急性肝衰竭免疫反应网络（PALF IRN）是为了支持一项治疗试验 使用高剂量皮质类固醇或马抗胸腺细胞球蛋白的免疫抑制疗法以逆转有害 PALF儿童的炎症免疫反应，以防止进一步的疾病进展并减少 该人群的死亡率和LT。我们提出了免疫介导的病理生理学的治疗 （胜利）试验，双盲，三个臂，随机的，安慰剂对照试验的高剂量甲基丙酮酮 或马抗胸腺细胞球蛋白。我们将测试以下假设，即在21天后21天与天然肝脏生存 接受免疫抑制疗法的患者的随机化将明显更高 仅接受支持护理的患者。我们还将确定免疫抑制治疗的安全性 PALF患者并定义副作用风险和治疗益处之间的平衡。我们的成果会 不仅包括临床终点，例如患者生存，疾病解决时间和不良健康 事件，但还测量患者报告的疾病康复期间的结果。审判参与者 将提供血液和肝样本，以更好地了解其免疫反应， 尤其是在循环和肝脏中的T淋巴细胞。样本将存储在存储库中 支持未来的研究探索这种罕见疾病的新方面。