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

项目摘要/摘要 患有肾病综合征的儿童，特别是那些经常复发(FRN)或对 类固醇治疗(SRN)，暴露于长疗程的类固醇和其他免疫抑制剂 药物。考虑到这些药物的副作用和不同的疗效，有 迫切需要找到治疗儿童肾病综合征的新的安全疗法。对人的刺激 迷走神经，经皮刺激耳廓迷走神经可无创激活 (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 对治疗慢性免疫介导性疾病很有意义。中心假说是激活 通过taVNS的炎症反射调节免疫反应，减轻复发和蛋白尿，并 减少肾病综合征儿童对免疫抑制药物的依赖。最重要的是 目标是进行大规模、多中心的临床试验，以调查taVNS在患者中的疗效和安全性。 儿童肾病综合征的治疗。为了更好地为这项更大规模的临床试验做准备， 这项建议是进行试点临床试验，以评估TAVNS治疗慢性阻塞性肺疾病的可行性和耐受性 治疗儿童肾病综合征并产生初步数据，以指导功率计算 未来更大规模的研究。在这方面，这项提案的具体目标是：(目标1)确定#年的可行性 TaVNS治疗儿童肾病综合征的方案实施和耐受性；(目标2) 为肾病儿童的治疗反应结果建立概念验证和产生效果大小 将症状随机分为TAVNS治疗组和假手术组；(目的3)观察TVNS治疗组和对照组的治疗效果 肾病综合征患儿免疫标志物的变化。拟议的试点研究将招收30名儿童 FRN和10名年龄在3-17岁的SRN儿童来自两个平行的双盲站点， 随机安慰剂对照试验，比较26例每日使用5分钟taVNS与假治疗的疗效 几周。测试临床试验的可行性和耐受性，招募、依从性的过程 、设备 功能、时间和资源利用率，以及 将对安全监控进行检查。使用预先指定的证明- 概念标准，然后将使用从这项试点研究中收集的初步数据来确定 随后的更大规模的主要试验应该会向前推进。此外， 包括血清和单核细胞在内的免疫标志物- 刺激的细胞因子和抗neparin抗体将被测量，以表征 Tavns治疗的免疫调节作用。为此，完成这项试点研究的目标将提供 初步数据将为设计和加强计划中的更大规模临床的实施提供信息 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重要的 并将为评估一种创新的、非药理学的、非侵入性的、 儿童特发性肾病综合征的非激素治疗。

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.