A Pilot Study of Transcutaneous Auricular Vagus Nerve Stimulation for the Treatment of Idiopathic Nephrotic Syndrome in Children

项目总结/摘要 患有肾病综合征的儿童，特别是那些经常复发（FRNS）或对 类固醇治疗（SRNS）暴露于类固醇和其它免疫抑制剂延长疗程 药物治疗考虑到这些药物的不良副作用和可变疗效， 迫切需要确定新的和安全的疗法来治疗儿童肾病综合征。刺激 迷走神经，可通过经皮耳迷走神经刺激非侵入性激活 （taVNS）通过炎症反射和脾调节免疫系统。taVNS已经成为一种治疗方法 用于治疗慢性免疫介导的疾病。核心假设是， 通过taVNS的炎性反射调节免疫应答，减少复发和蛋白尿， 减少肾病综合征患儿对免疫抑制药物的依赖。总体 目的是进行一项大规模、多中心临床试验，以研究taVNS在 小儿肾病综合征的治疗为了更好地准备这项更大规模的临床试验， 该提案旨在进行试点临床试验，以评估taVNS用于 儿童肾病综合征的治疗并生成初步数据来指导功效计算 未来更大的研究。在这方面，本提案的具体目标是： taVNS治疗儿童肾病综合征的方案实施和耐受性;（目的2） 建立肾病儿童治疗反应结果概念证明和产生效应量 与假手术治疗相比，随机分配至taVNS治疗的综合征;（目的3）研究 taVNS对肾病综合征患儿免疫标志物的影响拟议的试点研究将招募30名儿童 FRNS和10名SRNS儿童，年龄3-17岁，来自两个中心，两个平行，双盲， 随机安慰剂对照试验，比较每日使用5分钟taVNS与假治疗， 周测试临床试验的可行性和耐受性，招募过程，依从性 ，装置 功能、时间和资源利用率，以及 将对安全监测进行检查。使用预先指定的证据- 的概念标准，从这个试点研究收集的初步数据将用于确定是否 随后较大的主要审判应向前推进。此外，本发明还 免疫标记物包括血清和单核细胞- 将测量刺激的细胞因子和抗肾配蛋白抗体以表征 taVNS治疗的免疫调节作用。为此目的，实现这项试点研究的目标将提供 初步数据，将通知设计和加强实施计划的大型临床 审判提供这些对进行大规模试验至关重要的初步数据将解决一个重要的问题， 知识差距，并将铺平道路的创新，非药理学，非侵入性， 保留激素治疗儿童特发性肾病综合征

PROJECT SUMMARY/ABSTRACT Children with nephrotic syndrome, especially those that have frequent relapses (FRNS) or are resistant to steroid therapy (SRNS), are exposed to prolonged courses of steroids and other immunosuppressant medications. Given the adverse side effect profiles and variable efficacy of these medications, there is an urgent need to identify novel and safe therapies to treat nephrotic syndrome in children. Stimulation of the vagus nerve, which can be activated non-invasively by transcutaneous auricular vagus nerve stimulation (taVNS), modulates the immune system by the inflammatory reflex and spleen. taVNS has become a therapy of interest for treating chronic immune-mediated illnesses. The central hypothesis is that activation of the inflammatory reflex via taVNS modulates the immune response, attenuates relapses and proteinuria, and reduces reliance on immunosuppressant medications in children with nephrotic syndrome. The overarching goal is to conduct a large scale, multicenter clinical trial to investigate the efficacy and safety of taVNS in the treatment of nephrotic syndrome in children. To optimally prepare for this larger clinical trial, the objective of this proposal is to conduct pilot clinical trials to evaluate the feasibility and tolerability of taVNS for the treatment of nephrotic syndrome in children and generate preliminary data to guide power calculations for a future larger study. In this context, the specific aims of this proposal are: (Aim 1) To determine the feasibility of protocol implementation and tolerability of taVNS in the treatment of nephrotic syndrome in children; (Aim 2) To establish proof of concept and generate effect sizes for treatment response outcomes in children with nephrotic syndrome randomized to taVNS therapy compared with sham therapy; (Aim 3) To investigate the effects of taVNS on immune markers in children with nephrotic syndrome. The proposed pilot study will enroll 30 children with FRNS and 10 children with SRNS age 3-17 years from two sites in two parallel, double-blinded, randomized placebo-controlled trials comparing five minutes of daily taVNS use with sham therapy for 26 weeks. To test for feasibility and tolerability of the clinical trial, the process of recruitment, adherence , device functionality, time and resource utilization, and safety monitoring will be examined. Using pre-specified proof- of-concept criteria, preliminary data gathered from this pilot study will then be used to determine whether a subsequent larger main trial should move forward. Further, immune markers including serum and monocyte- stimulated cytokines and anti-nephrin antibodies will be measured in order to characterize the immunomodulatory effect of taVNS therapy. To this end, accomplishing the goals of this pilot study will provide preliminary data that will inform the design of and strengthen the implementation of a planned larger clinical trial. Providing these preliminary data that are essential to conduct a large-scale trial will address a significant knowledge gap and will pave the way for evaluation of an innovative, non-pharmacologic, non-invasive, steroid-sparing approach to the treatment of idiopathic nephrotic syndrome in children.