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

项目摘要 小儿急性肝衰竭（PALF）是一种罕见的，毁灭性的条件，影响估计250名儿童，每 在北美，每年约有15%的人死亡， 增加20- 30%。在大多数情况下，肝损伤的具体原因从未确定。最近 在这些患者中进行的研究支持了这样的理论，即这些患者中的许多人患有与以下疾病相关的肝损伤： 对日常感染或环境暴露的高度炎症免疫反应。研究 最近的研究表明，T淋巴细胞是炎症过程的中心驱动因素。医生照顾PALF 患者正在寻找能够抑制这种T细胞反应，抑制炎症级联反应， 病人剩余的肝细胞来愈合和再生儿童异常妊娠的临床经验 与其他疾病状态相关的炎症性免疫反应，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。的目标 儿科急性肝衰竭免疫反应网络（PALF IRN）将支持以下治疗试验： 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， PALF患儿的炎症免疫反应，以防止疾病进一步进展， 死亡率和LT。我们提出了免疫介导的病理生理学治疗方法 （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。我们将检验移植后21天自体肝存活率的假设， 接受免疫抑制治疗的患者的随机化率显著高于接受免疫抑制治疗的患者， 仅接受支持性治疗的患者。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获益之间的平衡。我们的成果将 包括临床终点，例如患者存活率、疾病消退时间和不良健康状况 事件，而且还测量患者在疾病康复期间报告的结果。试验参与者 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， 尤其是T淋巴细胞的免疫反应。样本将储存在储存库中， 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 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.