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

项目摘要 小儿急性肝衰竭（PALF）是一种罕见的，破坏性的条件，影响估计250 每年在北美的儿童，造成约15%的死亡，需要肝脏 肝移植（LT）占20- 30%。在大多数情况下，肝脏的特定原因 伤害永远无法确定。最近在这些患者中进行的研究支持了以下理论， 这些患者中的许多人患有与日常免疫反应异常有关的肝损伤， 感染或环境暴露。最近的研究表明，T淋巴细胞是 炎症过程的中心驱动因素。照顾PALF患者的医生正在寻找 这种疗法可以抑制这种T细胞反应，抑制炎症级联反应， 剩下的肝细胞愈合和再生。小儿免疫功能异常的临床体会 与其他疾病状态相关的反应，如全身性幼年特发性关节炎， 获得性再生障碍性贫血已经证明，高剂量皮质类固醇和马抗- 胸腺细胞球蛋白可以抑制免疫应答并逆转进行性组织损伤。 拟议的研究网络的目标是支持免疫抑制剂的治疗试验， 使用高剂量皮质类固醇或马抗胸腺细胞球蛋白来逆转有害的 PALF患儿的炎症免疫反应，以防止疾病进一步进展， 降低该人群的死亡率和LT。我们提出了一个双盲，三臂，随机， 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。我们 将检验这一假设，即接受自体肝移植的患者的生存率将显著高于接受自体肝移植的患者。 与接受安慰剂的患者相比，我们还将确定 PALF患者免疫抑制治疗的安全性，并确定风险之间的平衡 副作用和治疗效果的对比我们的结果不仅包括临床终点， 作为患者生存率、疾病和不良健康事件消退时间， 患者报告了疾病康复期间的结局。试验参与者将提供 血液和肝脏样本将被检查，以更好地了解他们的免疫反应， 尤其是T淋巴细胞的免疫反应。样本将储存在 一个储存库，以支持未来的研究探索这种罕见疾病的新方面。

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.